CN117964643A

CN117964643A - Pyrrole [2,3-b ] pyridine derivative and preparation method and application thereof

Info

Publication number: CN117964643A
Application number: CN202410383858.4A
Authority: CN
Inventors: 邢莉; 朱炜; 刘海涛; 吴凡
Original assignee: Suzhou Langrui Biopharmaceutical Co ltd
Current assignee: Suzhou Langrui Biopharmaceutical Co ltd
Priority date: 2024-04-01
Filing date: 2024-04-01
Publication date: 2024-05-03
Anticipated expiration: 2044-04-01

Abstract

The application discloses a pyrrole [2,3-b ] pyridine derivative represented by a formula (I) or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, a preparation method thereof and application of the pyrrole [2,3-b ] pyridine derivative serving as a RET kinase inhibitor, and a pharmaceutical composition containing the derivative. Experiments have shown that the compounds according to the application are better able to inhibit the activity of RET and its mutants compared to the prior art drugs.

Description

Pyrrole [2,3-b ] pyridine derivative and preparation method and application thereof

Technical Field

The application belongs to the field of medicines, and in particular relates to application of a pyrrole [2,3-b ] pyridine derivative or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or an isomer mixture thereof, or pharmaceutically acceptable salt or prodrug thereof, or a metabolite thereof, a preparation method thereof and an application of the derivative serving as a RET kinase inhibitor, and a pharmaceutical composition containing the derivative.

Background

With the deep research of RET gene mutation, RET is becoming a target point for accurate treatment of various tumors. At present, small molecule inhibitors targeting RET are mainly divided into: non-specific multi-target inhibitors and specific RET inhibitors.

RET-related multi-target kinase inhibitors are successively developed and approved for marketing, such as Vandetanib (Vandetanib), cabatinib (Carbozantinib) and sunitinib (Sunitinib), but the targeting of the whole RET gene fusion mutation is not strong and the effectiveness is poor; subsequently, tenib drugs such as lenvatinib (Lenvatinib), ai Leti, argatrafinib (Agerafenib), motsemib (Motesanib), dortetinib (Dovitinib), plaitinib (Ponatinib) and the like have also been used to treat patients with RET gene fusion mutant NSCLC; besides RET activity, most of the RET nonspecific multi-target inhibitors inhibit platelet-derived growth factor receptor (platelet-derived growth factor receptors, PDGFR) and vascular endothelial growth factor receptor (vascular endothelial growth factor receptor, VEGFR) simultaneously, so that toxic and side effects are caused in clinical treatment, the response rate of the RET nonspecific multi-target inhibitors is generally less than 50%, and side effects such as hypertension are caused by simultaneously inhibiting VEGFR, most of the RET nonspecific multi-target inhibitors cannot penetrate through the blood brain barrier, and the RET nonspecific multi-target inhibitors have low applicability to patients with advanced brain metastasis of cancers and further limit the use of the patients.

The two new drugs of high-activity high-selectivity RET inhibitor Seapatinib (Selpercatinib, LOXO-292) and common Lei Xiti Ni (Pralsetinib, BLU-667) belong to first-generation selective RET small molecule inhibitors, have higher selectivity specificity than other multi-target inhibitors, have a certain inhibition effect on VEGFR-2, have tolerance, and clinically observe that with increasing dosage, the central nervous system symptoms related to cancer are relieved to a certain extent, and partial relief is realized on the basis of brain metastasis. LOXO-292 and BLU-667 have good therapeutic effects on RET and lower off-target toxicity.

Resistance develops with these two first generation RET inhibitors. Compared with EGFR, ALK and other targets, RET is not provided with a drug aiming at drug-resistant mutation.

It has been reported that RET kinase signal transduction plays an important role in various human cancers, and in which RET's gatekeeper residue RET V804 and solvent front residue G810 mutation in kinase ATP binding site are the main causes of lowering of ATP binding site by Seapatinib (Selpercatinib) and Pr Lei Xiti Ni (Pralsetinib), resulting in the occurrence of drug resistance, leading to the occurrence and progress of cancer, there is an urgent need to develop inhibitors effective for RET mutation, particularly solvent front mutation. The application aims to overcome the drug resistance mutation and develop a next generation RET inhibitor.

Disclosure of Invention

According to one aspect of the present invention, it is an object of the present invention to provide a pyrrolo [2,3-b ] pyridine derivative represented by formula (I) or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof:

Formula (I)

Wherein:

R ₁ is selected from hydrogen, cyano, halogen, carboxyl, -C (=o) NR ₁₃R₁₄, halogen substituted or unsubstituted C ₁-C₃ alkyl, halogen substituted or unsubstituted C ₁-C₃ alkoxy, wherein R ₁₃ and R ₁₄ are each independently selected from hydrogen, C ₁-C₃ alkyl;

R ₂ is selected from hydrogen, C ₁-C₃ alkyl substituted or unsubstituted amino, halogen substituted or unsubstituted C ₁-C₃ alkyl, halogen substituted or unsubstituted C ₁-C₃ alkoxy;

R ₃ is selected from hydrogen, halogen, hydroxy, substituted or unsubstituted saturated or unsaturated C ₁-C₄ alkyl, substituted or unsubstituted saturated or unsaturated C ₁-C₄ alkyl alcohol, substituted or unsubstituted saturated or unsaturated C ₁-C₄ alkoxy, substituted or unsubstituted-C ₁-C₄ alkylamido, substituted or unsubstituted saturated or unsaturated C ₁-C₄ alkylamine; wherein substituted means optionally containing 1 to 3 groups selected from deuterium, hydroxy, halogen, C ₁-C₃ alkyl;

or (b)

R ₃ isWherein ring D is selected from saturated or unsaturated C ₃-C₆ cycloalkyl, saturated or unsaturated 4 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C ₆-C₁₀ aryl, or 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein ring D optionally contains n3 substituents R ₉,

Wherein R ₉ is selected from the group consisting of substituted or unsubstituted-C ₁-C₆ alkyl, substituted or unsubstituted-C ₁-C₆ alkoxy, substituted or unsubstituted-C ₁-C₆ alkyl alcohol, substituted or unsubstituted-C ₁-C₆ alkylamine, substituted or unsubstituted-C ₁-C₆ alkylcyano, substituted or unsubstituted C ₃-C₆ cycloalkyl, substituted or unsubstituted 4 to 10 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, substituted means optionally containing 1 to 4C ₁-C₃ alkyl, acetyl, 3 to 6 membered alkylene oxide groups selected from deuterium, halogen substitution;

R ₄ is selected from hydrogen, halogen substituted or unsubstituted C ₁-C₃ alkoxy, halogen substituted or unsubstituted C ₁-C₃ alkyl;

Ring a is selected from phenyl, 5 to 6 membered heteroaryl containing 1 or 3 heteroatoms selected from N, O and S;

Ring B is selected from a substituted or unsubstituted C ₃-C₁₀ cycloalkyl, a substituted or unsubstituted 4-to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N and O, a substituted or unsubstituted 4-8 membered monocyclic heterocycle containing 1 to 3 heteroatoms selected from N and O, a substituted or unsubstituted 7-12 membered spirocyclic heterocycle containing 1 to 3 heteroatoms selected from N and O, a substituted or unsubstituted 7-12 membered bicyclic heterocycle containing 1 to 3 heteroatoms selected from N and O, a substituted or unsubstituted 7-12 membered bridged bicyclic heterocycle containing 1 to 3 heteroatoms selected from N and O, wherein substituted means optionally containing 1 to 2 substituents R ₅, wherein R ₅ is selected from hydrogen, halogen, amino, hydroxy C ₁-C₃ alkyl, cyano C ₁-C₃ alkyl, C ₁-C₃ alkyl, each R ₅ being the same or different from each other when containing a plurality of R ₅;

L is selected from the group consisting of-C ₁-C₄ alkylene-, -NR ₇-(C₁-C₄ alkylene), Wherein R ₇ and R ₈ are each independently selected from hydrogen, C ₁-C₃ alkyl;

Ring C is selected from substituted or unsubstituted C ₆-C₁₀ aryl, substituted or unsubstituted 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms N, O or S, substituted or unsubstituted 6 to 12 membered benzoheterocycloalkyl containing 1 to 3 heteroatoms N, O or S, wherein substituted means optionally containing 1 or 3 substituents R ₆, wherein R ₆ is selected from hydrogen, halogen, hydroxy, (R ₁₀)_n4 substituted or unsubstituted C ₁-C₃ alkyl, (R ₁₀)_n4 substituted or unsubstituted C ₁-C₃ alkoxy, C ₃-C₆ cycloalkyl, said R ₁₀ being selected from deuterium, halogen, when containing a plurality of R ₆, each R ₆ is the same or different from each other;

n1 is an integer selected from 0,1 or 2;

n2 is an integer selected from 0,1, 2 or 3;

n3 is an integer selected from 0,1 or 2;

n4 is an integer selected from 0,1, 2 or 3.

Preferably, R ₃ isWherein ring D is selected from saturated or unsaturated C ₃-C₆ cycloalkyl, saturated or unsaturated 4 to 6 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O and S, or 5 to 6 membered heteroaryl containing 1 to 2 heteroatoms selected from N, O and S, wherein ring D optionally contains n3 substituents R ₉,

Wherein R ₉ is selected from the group consisting of substituted or unsubstituted-C ₁-C₄ alkyl, substituted or unsubstituted-C ₁-C₃ alkoxy, substituted or unsubstituted-C ₁-C₃ alkyl alcohol, substituted or unsubstituted-C ₁-C₄ alkylamine, substituted or unsubstituted-C ₁-C₃ alkylcyano, substituted or unsubstituted C ₃-C₆ cycloalkyl, substituted or unsubstituted 4 to 10 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O and S, substituted means optionally containing 1 to 4 heteroatoms selected from deuterium, halogen, C ₁-C₃ alkyl, acetyl, 3 to 6 membered alkylene oxide.

More preferably, R ₃ is selected from the following structures:

or (b)

More preferably, R ₃ isA structure selected from the following structures:

。

preferably, R ₉ is selected from the following structures:

。

More preferably, R ₃ is A structure selected from the following structures:

。

preferably, R ₉ is selected from the following structures:

。

Preferably, ring a is selected from: 。

more preferably, ring a is selected from: 。

preferably, ring B is selected from the following groups, substituted or unsubstituted:

。

Wherein substituted means optionally containing 1 to 2 substituents R ₅, wherein R ₅ is selected from

。

Preferably, L is selected from:。

Preferably, ring C is selected from the following groups, substituted or unsubstituted:

；

Wherein substituted means optionally containing 1 or 3 substituents R ₆, wherein R ₆ is selected from hydrogen, halogen, hydroxy, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, methoxy, deuterated methoxy, trifluoromethoxy, cyclopropyl.

More preferably, ring C is selected from the following groups, substituted or unsubstituted:

。

wherein substituted means optionally containing 1 or 3 substituents R ₆, wherein R ₆ is selected from hydrogen, halogen, hydroxy, methyl, methoxy, deuterated methoxy, trifluoromethoxy, cyclopropyl.

More preferably, the pyrrolo [2,3-b ] pyridine derivative represented by formula (I) according to the present invention is represented by the following formula (II):

Formula (II)

Wherein each substituent is as defined above.

The pyrrole [2,3-b ] pyridine derivative or the isotopically-labeled compound thereof, or the optical isomer, the geometric isomer, the tautomer or the isomer mixture thereof, or the pharmaceutically acceptable salt thereof, or the prodrug thereof, or the metabolite thereof, according to the present invention is selected from the following compounds:

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According to a second aspect of the present invention, it is another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of the pyrrolo [2,3-b ] pyridine derivative represented by formula (I) or formula (II) or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, according to the present invention, and a pharmaceutically acceptable carrier.

According to a third aspect of the present invention, it is a further object of the present invention to provide the use of a pyrrolo [2,3-b ] pyridine derivative represented by formula (I) or formula (II) or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, according to the present invention, for the preparation of a medicament for the treatment or prevention of a disease or disorder mediated by RET or a RET mutant in a subject in need thereof.

Wherein the disease or condition mediated by RET or RET mutants is selected from one or more of cancer, metabolic disease, inflammation, pain, developmental disease.

Preferably, the disease or condition mediated by RET or RET mutants is selected from one or more of thyroid cancer, non-small cell lung cancer, pleural mesothelioma, colon cancer, pancreatic cancer, lung adenocarcinoma, breast cancer, ovarian cancer, type II multiple endocrine tumor, colorectal cancer, chronic granulocytic leukemia, salivary gland cancer, cervical cancer, prostate cancer, diabetes, irritable bowel syndrome related pain, neuropathic pain, congenital megacolon.

According to a fourth aspect of the present invention, it is another object of the present invention to provide a kit comprising the pyrrolo [2,3-b ] pyridine derivative represented by formula (I) or formula (II) according to the present invention or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the pharmaceutical composition according to the present invention, together with a container and instructions for use.

According to a fifth aspect of the present invention, it is another object of the present invention to provide a method for treating a disease or condition mediated by RET or a RET mutant, which comprises administering to a subject in need thereof an effective amount of the pyrrole [2,3-b ] pyridine derivative represented by formula (I) or formula (II) or the isotopically labeled compound thereof, or an optical isomer, a geometrical isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the pharmaceutical composition according to the present invention.

Detailed Description

Hereinafter, the present invention will be described in detail. Before the description, it is to be understood that the terms used in this specification and the appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present invention on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. Accordingly, the description set forth herein is merely a preferred example for the purpose of illustration and is not intended to limit the scope of the invention, so that it should be understood that other equivalents or modifications may be made thereto without departing from the spirit and scope of the invention.

In this document, the terms "comprising," "including," "having," "containing," or any other similar term are all open ended terms that are intended to cover a non-exclusive inclusion. For example, a composition or article comprising a plurality of elements is not limited to only those elements listed herein, but may include other elements not explicitly listed but typically inherent to such composition or article. In addition, unless explicitly stated to the contrary, the term "or" refers to an inclusive "or" and not to an exclusive "or". For example, any one of the following conditions satisfies the condition "a or B": a is true (or present) and B is false (or absent), a is false (or absent) and B is true (or present), a and B are both true (or present). Furthermore, the terms "comprising," "including," "having," "containing," and their derivatives, as used herein, are intended to be open ended terms that have been specifically disclosed, and encompass both the closed and semi-closed terms, consisting of …, and consisting essentially of ….

All features or conditions defined herein in terms of numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, the description of a numerical range or percentage range should be considered to cover and specifically disclose all possible sub-ranges and individual values within the range, particularly integer values. For example, a range description of "1 to 8" should be taken as having specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly sub-ranges defined by all integer values, and should be taken as having specifically disclosed individual values such as 1,2, 3, 4, 5, 6, 7, 8, etc. within the range. The foregoing explanation applies to all matters of the invention throughout its entirety unless indicated otherwise, whether or not the scope is broad.

If an amount or other numerical value or parameter is expressed as a range, preferred range, or a series of upper and lower limits, then it is understood that any range, whether or not separately disclosed, from any pair of the upper or preferred value for that range and the lower or preferred value for that range is specifically disclosed herein. Furthermore, where a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range.

In this context, numerical values should be understood to have the accuracy of the numerical significance of the numerical values provided that the objectives of the present invention are achieved. For example, the number 40.0 is understood to cover a range from 39.50 to 40.49.

In this document, where Markush group (Markush group) or option-type language is used to describe features or examples of the present invention, those skilled in the art will appreciate that a sub-group of all elements within a Markush group or option list or any individual element may also be used to describe the present invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it is also meant that the claim of X as X1 and/or X2 have been fully described. Furthermore, where markush groups or option expressions are used to describe features or examples of the present invention, those skilled in the art will appreciate that any combination of sub-groups or individual elements of all elements within a markush group or option list may also be used to describe the present invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3" and Y is described as "selected from the group consisting of Y1, Y2, and Y3," then the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

Definition of the definition

"Alkyl" refers to a group having a straight or branched chain saturated hydrocarbon group of 1 to 6 carbon atoms ("C _1–6 alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C _1-5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C _1-4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C _1-3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C _1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C ₁ alkyl"). Examples of C _1–6 alkyl groups include methyl (C ₁), ethyl (C ₂), propyl (C ₃) (e.g., n-propyl, isopropyl), butyl (C ₄) (e.g., n-butyl, t-butyl, sec-butyl, isobutyl), pentyl (C ₅) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, t-pentyl) and hexyl (C ₆) (e.g., n-hexyl). Unless otherwise indicated, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl is unsubstituted C _1-8 alkyl (e.g., unsubstituted C ₁ alkyl, such as-CH ₃). In certain embodiments, the alkyl is a substituted C _1-8 alkyl (e.g., a substituted C ₁ alkyl, such as-CF ₃).

"Alkoxy" means a monovalent-O-alkyl group in which the alkyl moiety has the indicated number of carbon atoms. Alkoxy groups in this disclosure typically contain 1 to 6 carbon atoms ("C ₁-C₆ alkoxy") or 1 to 4 carbon atoms ("C ₁-C₄ alkoxy"). For example, C ₁-C₄ alkoxy includes methoxy, ethoxy, isopropoxy, tert-butyloxy, and the like. Unless otherwise indicated, each instance of an alkoxy group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkoxy") or substituted (a "substituted alkoxy") with one or more substituents. In certain embodiments, the alkoxy group is an unsubstituted C ₁-C₆ alkoxy group. In certain embodiments, the alkoxy is a substituted C1 to C6 alkoxy.

"Cycloalkyl" refers to a group of a non-aromatic cyclic hydrocarbon group in a non-aromatic ring system having 3 to 6 ring carbon atoms ("C _3-6 cycloalkyl") and zero heteroatoms. In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C _3-6 cycloalkyl"). Exemplary C _3-6 cycloalkyl groups include, but are not limited to, cyclopropyl (C ₃), cyclopropenyl (C ₃), cyclobutyl (C ₄), cyclobutenyl (C ₄), cyclopentyl (C ₅), cyclopentenyl (C ₅), cyclohexyl (C ₆), cyclohexenyl (C ₆), cyclohexadienyl (C ₆), and the like. Each instance of cycloalkyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents, unless otherwise specified. In certain embodiments, the cycloalkyl is unsubstituted C _3-6 cycloalkyl; in certain embodiments, the cycloalkyl is a substituted C _3-6 cycloalkyl.

"Heterocycloalkyl" refers to a group of a 4 to 14 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("4-14 membered heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as the valence permits. The heterocyclic group may be a single ring ("monocyclic heterocyclic group") or a fused, bridged or spiro ring system, for example a bicyclic ring system ("bicyclic heterocyclic group"), and may be saturated or may be partially unsaturated. "heterocyclic group" also includes ring systems in which a heterocycle as defined above is fused to one or more cycloalkyl groups (where the point of attachment is on the cycloalkyl group or heterocycle), or ring systems in which a heterocycle as defined above is fused to one or more aryl or heteroaryl groups (where the point of attachment is on the heterocycle), and in such cases the number of ring members continues to refer to the number of ring members in the heterocyclic system. Each instance of a heterocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocycloalkyl") or substituted by one or more substituents ("substituted heterocycloalkyl"), unless otherwise specified. In certain embodiments, the heterocycloalkyl is an unsubstituted 4-14 membered heterocycloalkyl. In certain embodiments, heterocycloalkyl substituted 4-14 membered heterocycloalkyl.

"Aryl" or "aromatic ring group" refers to a group ("C _6-14 aryl") of a single or multiple ring (e.g., bi-or tri-cyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. In some embodiments, aryl groups have 6 ring carbon atoms ("C ₆ aryl"; e.g., phenyl). In some embodiments, aryl has 10 ring carbon atoms ("C ₁₀ aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, aryl groups have 14 ring carbon atoms ("C ₁₄ aryl"; e.g., anthracenyl). "aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more cycloalkyl or heterocyclic groups, where the point of attachment is on the aromatic ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Each instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents, unless otherwise indicated. In certain embodiments, the aryl is an unsubstituted C _6-14 aryl. In certain embodiments, the aryl is a substituted C _6-14 aryl.

"Heteroaryl" is a 5-14 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise indicated, each instance of heteroaryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted by one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl is a substituted 5-14 membered heteroaryl. Heteroaryl groups may be monocyclic ("monocyclic heteroaryl groups") or fused, bridged or spiro ring systems, for example bicyclic systems ("bicyclic heteroaryl groups"). "heteroaryl group" also includes ring systems in which a heterocycle as defined above is fused to one or more cycloalkyl groups (where the point of attachment is on the cycloalkyl group or heterocycle), or ring systems in which a heterocycle as defined above is fused to one or more aryl or heteroaryl groups (where the point of attachment is on the heterocycle), and in this case the number of ring members continues to refer to the number of ring members in the heterocycle system.

"Halogen" or "halo" means fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) or iodine (iodine, -I).

"Substituted" or "optionally substituted" means that an atom in the group, such as a hydrogen atom, is substituted. In certain embodiments, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are substituted (e.g., "substituted" alkyl, "substituted" cycloalkyl, "substituted" heterocycloalkyl, "substituted" aryl, or "substituted" heteroaryl). Generally, the term "substituted", whether preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., carbon or nitrogen atom) is substituted with an allowable substituent, e.g., a substituent that upon substitution forms a stable compound, e.g., a compound that does not spontaneously undergo conversion (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise indicated, a "substituted" group has substituents at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any substituents described herein which result in the formation of stable compounds. The present disclosure contemplates any and all of these combinations to obtain stable compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein that satisfies the valences of the heteroatoms and results in the formation of a stable moiety. In certain embodiments, the substituent is a carbon atom substituent. In certain embodiments, the substituent is a nitrogen atom substituent. In certain embodiments, the substituent is an oxygen atom substituent. In certain embodiments, the substituent is a sulfur atom substituent.

"Unsaturated" or "partially unsaturated" refers to a group that contains at least one double or triple bond. "partially unsaturated" ring systems are also intended to encompass rings having multiple sites of unsaturation, but are not intended to include aromatic groups (e.g., aryl or heteroaryl). Likewise, "saturated" refers to groups that do not contain double or triple bonds, i.e., all contain single bonds.

The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts (i.e., pharmaceutically acceptable salts) may be obtained by contacting neutral forms of such compounds with sufficient amounts of an acid in pure solution or in a suitable inert solvent, examples include inorganic acid salts and organic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; the organic acids include acids such as benzoic acid, 2-hydroxyethanesulfonic acid, sulfamic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid, propionic acid, oxalic acid, sulfanilic acid, p-toluenesulfonic acid, polygalacturonic acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methanesulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, citric acid, malic acid, glucoheptonic acid, gluconic acid, isethionic acid, lactic acid, lactobionic acid, dodecylsulfonic acid, pamoic acid, salicylic acid, suberic acid, folinic acid, edetic acid, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, stearic acid, and the like; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts. The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

As used herein, the modifier term "about" refers to a change in value that may occur, for example, by routine testing and processing; unintentional errors in passing such tests and processing; differences in source or purity by the manufacture of the components used in the present invention; etc. As used herein, a "about" a particular value also includes the particular value, for example, about 10% includes 10%. Whether or not modified by the term "about", the claims include equivalents to the listed amounts. In one embodiment, the term "about" means within 20% of the reported numerical value.

As used herein, the term "treating" refers to eliminating, alleviating or ameliorating a disease or disorder and/or symptoms associated therewith. Although not excluded, treating a disease or condition does not require complete elimination of the disease, condition, or symptom associated therewith. As used herein, the term "treatment" or the like may include "prophylactic treatment" referring to reducing the likelihood of recurrence of a disease or disorder or a previously controlled disease or disorder in a subject that is free of, or at risk of, suffering from, or susceptible to recurrence of the disease or disorder. The term "treatment" and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For the purposes of the present oral dosage form, an "effective amount" of one active agent in a composition refers to that amount which is required to achieve the desired effect when used in combination with another active agent in the composition. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

The compound represented by formula (I) or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutical composition comprising the compound provided by the present invention may be in various forms such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols and the like, and may be present in a suitable solid or liquid carrier or diluent and in a suitable sterilizing device for injection or instillation.

The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. For example, the unit dose of the formulation comprises 0.05 to 2000mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably the unit dose of the formulation comprises 0.1 to 1000mg of the compound of formula (I).

The compounds and pharmaceutical compositions of the present invention represented by formula (I) may be used clinically in mammals, including humans and animals, by oral, nasal, dermal, pulmonary, or gastrointestinal routes of administration. Most preferably orally. The most preferred daily dosage is 0.01-200 mg/kg body weight, administered at one time, or 0.01-100 mg/kg body weight in divided doses. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment. Typically starting from a small dose, the dose is gradually increased until the most suitable dose is found.

In the present invention, the term "effective amount" may refer to an effective amount of dosage and period of time required to achieve the desired effect. This effective amount may vary depending on factors such as the type of disease or the condition of the disease at the time of treatment, the constitution of the particular target organ to be administered, the individual size of the patient, or the severity of the disease or symptoms. One of ordinary skill in the art will be able to determine empirically the effective amount of a particular compound without undue experimentation.

Typical formulations are prepared by mixing a compound of formula (I) according to the invention with a carrier, diluent or excipient. Suitable carriers, diluents or excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

The particular carrier, diluent or excipient used will depend upon the manner and purpose of use of the compounds of the present invention. The solvent is generally selected based on the solvent that one of ordinary skill in the art would consider to be safe and effective for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG 300), and the like. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorants, flavoring agents or other known additives to make or use the drug in an acceptable form.

When the compound of formula (I) according to the present invention is used in combination with at least one other drug, the two or more drugs may be used separately or in combination, preferably in the form of a pharmaceutical composition. The compounds or pharmaceutical compositions of the invention of formula (I) may be administered to a subject separately or together in any known form of oral, intravenous, rectal, vaginal, transdermal, other topical or systemic administration.

These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorants, flavoring agents or other known additives to make the pharmaceutical composition acceptable for manufacture or use.

The medicament of the invention is preferably administered orally. Solid dosage forms for oral administration may include capsules, tablets, powders or granular formulations. In solid dosage forms, the compounds or pharmaceutical compositions of the invention are admixed with at least one inert excipient, diluent or carrier. Suitable excipients, diluents or carriers include substances such as sodium citrate or dicalcium phosphate, or starches, lactose, sucrose, mannitol, silicic acid and the like; binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia, and the like; humectants such as glycerin and the like; disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates, sodium carbonate, and the like; solution retarders such as paraffin and the like; absorption promoters such as quaternary ammonium compounds and the like; adsorbents such as kaolin, bentonite, and the like; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and the like. In the case of capsules and tablets, the dosage form may also include buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using lactose as well as high molecular weight polyethylene glycols and the like as excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compounds of the present invention or pharmaceutical compositions thereof, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizing agents and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide; oils (e.g., cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.); glycerol; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitan; or a mixture of several of these, etc.

In addition to these inert diluents, the compositions can also include excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening, flavoring and perfuming agents.

As for the suspension, in addition to the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition containing the same of the present invention, a carrier such as a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, or a mixture of several of these substances, or the like, may be further contained.

The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising the same of the present invention can be administered in other topically administrable forms, including ointments, powders, sprays and inhalants. The medicament may be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent or carrier, and with any preservative, buffer or propellant required. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be included within the scope of the present invention.

In addition, kits (e.g., pharmaceutical packaging) are also encompassed by the present disclosure. Kits are provided that can include a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampoule, bottle, syringe, and/or sub-packaging or other suitable container). In some embodiments, the provided kits may optionally further comprise a second container comprising a pharmaceutically acceptable excipient for diluting or suspending the pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical compositions or compounds described herein disposed in the first container and the second container are combined to form one unit dosage form.

In certain embodiments, the kits described herein further comprise instructions contained in the kit for using the compounds or pharmaceutical compositions. The kits described herein may also include information required by regulatory authorities, such as the food and drug administration. In certain embodiments, the information included in the kit is prescription information. In certain embodiments, the kits and instructions provide for treating a RET or RET mutation-mediated disease and/or preventing a RET or RET mutation-mediated disease in a subject in need thereof. The kits described herein may comprise one or more additional pharmaceutical agents as separate compositions.

The invention is described in further detail below in connection with specific examples, but the invention is not limited to the following examples, which are intended to better illustrate certain embodiments of the invention and are not to be construed as limiting the scope of the invention in any way. The conditions not specified in the examples are conventional conditions. Unless otherwise specified, reagents and equipment used in the following examples are commercially available products.

The compound represented by the formula (I) according to the present invention may be synthesized by various methods familiar to those skilled in the art of organic synthesis. Some exemplary synthetic methods of the compounds represented by formula (I) are given in the following specific examples, which are well known in the art of synthetic chemistry. It is apparent that, referring to the exemplary schemes in the present invention, one skilled in the art can easily design synthetic routes of other compounds represented by formula (I) by appropriately adjusting reactants, reaction conditions, and protecting groups.

The invention is further illustrated by the following examples; but these examples do not limit the scope of the invention. All reactants used in each example were obtained commercially unless otherwise stated; the instruments and equipment used in the synthesis experiments and the product analysis and detection are all conventional instruments and equipment commonly used in organic synthesis.

In the following examples, the structure of exemplary compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using BrukerAVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d ₆), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃) as the measurement solvents and Tetramethylsilane (TMS) as the internal standard.

The LC-MS was measured using Agilent 1200 Infinity series mass spectrometer. HPLC determination uses agilent 1200DAD high pressure liquid chromatograph. The thin layer chromatography silica gel plate is prepared from tobacco stage yellow sea HSGF254 or Qingdao GF254 silica gel plate. Column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier. In addition, without specific description, all reactions of the invention are carried out under continuous magnetic stirring in dry nitrogen or argon atmosphere, the solvent is dry solvent, and the reaction temperature is in degrees celsius.

Further, abbreviations used in the examples have the following meanings: HATU:2- (7-azobenzotriazole) -N, N' -tetramethylurea hexafluorophosphate; naOH: sodium hydroxide; BOC: t-butoxycarbonyl; EA: ethyl acetate; PE: petroleum ether; meOH: methanol; etOH: ethanol; DPCI: n, N' -diisopropylcarbodiimide; DIEA: n, N-diisopropylethylamine; DMSO: dimethyl sulfoxide; TEA: triethylamine; DMAP: 4-dimethylaminopyridine; DMF: n, N-dimethylformamide; NMP: n-methylpyrrolidone; THF: tetrahydrofuran; DCM: dichloromethane; TFA: trifluoroacetic acid; TLC: thin layer chromatography; structure: structural formula.

Example 1:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-1)

Step A: 1-methyl-4-trimethylsilylethynyl-1H-pyrazole (3)

4-Iodo-1-methylpyrazole (compound 1, 100 g, 0.48 mol) was placed in DMF (1L), ethynyl trimethylsilane (compound 2, 70.83 g, 721.15 mol), cuprous iodide (4.58 g, 721.15 mmol), bis triphenylphosphine palladium dichloride (16.87 g, 24.04 mmol), stirred at 100 ℃ for 12 hours under nitrogen protection, then the reaction solution was concentrated, diluted with water (1L), extracted with ethyl acetate (1L X2), the organic phases were combined, the organic phases were washed with saturated brine (1L), dried over anhydrous sodium sulfate, concentrated and separated by column chromatography (petroleum ether/ethyl acetate=10/1-5/1) to give compound 3 (brown oil, 76 g, 88%).

LCMS (m/z): 179 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ = 7.59 - 7.55 (m, 1H), 7.49 (s, 1H), 3.87 (s, 3H), 0.25 - 0.20 (m, 9H).

And (B) step (B): 1-methyl-4-ethynyl-1H-pyrazole (4)

1-Methyl-4-trimethylsilylethynyl-1H-pyrazole (compound 3, 57 g, 0.32 mol) was taken up in dichloromethane (500 mL) and methanol (50 mL), potassium carbonate (88.36 g, 0.64 mol) was added, stirred at 25 ℃ for 12 hours, then filtered, the filtered solid was washed with dichloromethane (500 mL X2), the organic phases were combined and the column chromatography (petroleum ether/ethyl acetate=15/1-10/1) after concentration was separated to give compound 4 (brown oil, 22 g, 62%).

LCMS (m/z): 107 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ = 7.38 (s, 1H), 7.30 (s, 1H), 3.67 (s, 3H), 2.78 (s, 1H).

Step C: 4-chloro-5-iodopyridin-2-amine (6)

4-Chloropyridin-2-amine (compound 5, 100 g, 777.85 mmol) was placed in DMF (1.5L), N-iodosuccinimide (192.5 g, 855.64 mmol) was added, stirred at 25 ℃ for 12 hours, then diluted with water (1L) and extracted with ethyl acetate (1L X2), the organic phases were combined, washed with saturated brine (1L), dried over anhydrous sodium sulfate, concentrated and then column chromatographed (petroleum ether/ethyl acetate=15/1-10/1) to give compound 6 (white solid, 155 g, 78%).

¹H NMR (400 MHz, DMSO-d6) δ = 8.21 (s, 1H), 6.70 (s, 1H), 6.42 (s, 2H).

Step D: 4-chloro-5-cyanopyridin-2-amine (7)

4-Chloro-5-iodopyridin-2-amine (compound 6, 70 g, 0.27 mol) was placed in NMP (600 mL), zinc cyanide (16.15 g, 0.14 mol), tetrakis triphenylphosphine palladium (31.79 g, 27.51 mmol), 100 ℃ stirred under nitrogen for 5 hours, then diluted with ethyl acetate (1500 mL), continued room temperature stirring for 5 minutes, filtered, the filtrate washed with saturated brine (1L), dried over anhydrous sodium sulfate, concentrated and column chromatography (petroleum ether/ethyl acetate=1/1) separated to give compound 7 (yellow solid, 33.6 g, 81%).

¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (s, 1H), 7.38 (br s, 2H), 6.62 (s, 1H).

Step E: 3-iodo-4-chloro-5-cyanopyridin-2-amine (8)

4-Chloro-5-cyanopyridin-2-amine (compound 7, 70 g, 0.27 mol) was placed in dichloroethane (600 mL), silver trifluoroacetate (60.41 g, 0.27 mol), iodine (69.41 g, 273.49 mmol) was added sequentially, stirred at 80 ℃ under nitrogen for 18 hours, then diluted with water (1000 mL), extracted with dichloromethane (1000 mL X2), the organic phases combined and washed with saturated brine (1L), dried over anhydrous sodium sulfate, concentrated and isolated as compound 8 (yellow solid, 25.6 g, 47%) by column chromatography (petroleum ether/ethyl acetate=10/1-2/1).

¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (s, 1H), 7.67 - 7.49 (m, 2H).

Step F:3- (5-bromopyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (11)

3, 6-Diazabicyclo [3.1.1] heptane-6-carbonate (compound 9, 30g, 0.15 mol) was placed in DMSO (500 mL), 5-bromo-2-fluoropyridine (compound 10, 31.78 g, 0.18 mol), potassium carbonate (8.104 g, 0.75 mol) were added, stirred at 90 ℃ for 12 hours, then poured into water (1L), extracted with ethyl acetate (1L X3) and filtered, the organic phases combined, washed with saturated brine (1L), dried over anhydrous sodium sulfate, and concentrated to give compound 11 (white solid, 30g, 47%) by column chromatography (dichloromethane/methanol=10/1).

LCMS (m/z): 354 [M+H]⁺.

Step G:3- (5-bromopyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane (12)

Tert-butyl 3- (5-bromopyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbonate (compound 11, 7.06 g, 0.02 mol) was placed in dichloromethane (100 mL), trifluoroacetic acid (100 mL) was added, stirred at 25 ℃ for 3 hours, and then concentrated followed by column chromatography (dichloromethane/methanol=10/1) to give compound 12 (brown oil, 4.5 g, 89%).

LCMS (m/z): 254 [M+H]⁺.

Step H:2- ((3- (5-bromopyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -4-fluorophenol (14)

3- (5-Bromopyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane (compound 12, 2g, 0.79 mmol) was placed in methanol (40 mL), 5-fluoro-2-hydroxybenzaldehyde (compound 13,2.21 g, 15.8 mmol), zinc chloride (3.9 mL, 1M, 3.95 mmol), sodium cyanoborohydride (1.99 g, 31.6 mmol), triethylamine (1.6 g, 15.8 mmol), stirred at 70 ℃ for 16 hours, then poured into saturated ammonium chloride solution (80 mL) for filtration, extracted with ethyl acetate (40 mL X4), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated followed by column chromatography (petroleum ether/ethyl acetate=10/1) to give compound 14 (brown oily, 2.8 g, 94%).

LCMS (m/z): 378 [M+H]⁺.

¹HNMR (400 MHz, CDCl₃) δ 8.25 (d,J= 2 Hz, 1H), 7.62 (dd,J= 9.2 Hz, 2.4 Hz, 1H), 6.88-6.75 (m, 3H), 6.66 (dd,J= 8.4 Hz, 2.8 Hz, 1H), 6.46 (d,J= 8.8 Hz, 1H), 3.83 (d,J= 6 Hz, 1H), 3.73-3.70 (m, 4H), 3.53 (d,J= 12 Hz, 2H), 2.70-2.66 (m, 1H), 1.66 (d,J= 8.8 Hz, 2H).

Step I: (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) boronic acid (15)

2- ((3- (5-Bromopyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -4-fluorophenol (compound 14, 1.2 g, 3.2 mmol) was placed in 1, 4-dioxane (15 mL), bis-pinacolato borate (1.22 g, 4.8 mmol), 1' -bistriphenylphosphine ferrocene palladium dichloride (0.47 g, 0.6 mmol), potassium acetate (0.94 g, 9.6 mmol), stirred at 100 ℃ under nitrogen for 16 hours, then poured into water (30 mL), extracted three times with ethyl acetate (30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography (petroleum ether/ethyl acetate=1/1) after concentration gave compound 15 (yellow oil, 400 mg, 28%).

LCMS (m/z): 344 [M+H]⁺.

Step J: n- (4-chloro-5-cyano-3-iodopyridin-2-yl) -4-methylbenzenesulfonamide (16)

3-Iodo-4-chloro-5-cyanopyridin-2-amine (compound 8, 5.56 g, 0.02 mol) was placed in tetrahydrofuran (100 mL), sodium hydride (800 mg, 0.02 mol), p-toluenesulfonyl chloride (7.6 g, 0.02 mol), stirred at 25 ℃ for 2 hours, then poured into ice water (100 mL), extracted with ethyl acetate (100 mL X3), the organic phases combined, dried over anhydrous sodium sulfate, and concentrated to give compound 16 (brown oily, 3.8 g, 43%) by column chromatography (petroleum ether/ethyl acetate=4/1).

LCMS (m/z): 434 [M+H]⁺.

Step K: 4-chloro-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (17)

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N- (4-chloro-5-cyano-3-iodopyridin-2-yl) -4-methylbenzenesulfonamide (compound 16, 2.16 g,5 mmol) was placed in tetrahydrofuran (80 mL), 1-methyl-4-ethynyl-1H-pyrazole (compound 4, 10.6 g, 10 mmol), bis triphenylphosphine palladium chloride (374.5 mg, 0.5 mmol), cuprous iodide (95.5 mg, 0.5 mmol), diisopropylethylamine (1.29 g, 10 mol), stirred at 30 ℃ under nitrogen for 16 hours, then poured into water (80 mL), extracted with ethyl acetate (80 mL X3), the organic phases combined, dried over anhydrous sodium sulfate, and separated by column chromatography (petroleum ether/ethyl acetate=1/1) after concentration to give compound 17 (yellow solid, 616.5 mg, 30%).

LCMS (m/z): 412 [M+H]⁺.

Step L:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (18)

4-Chloro-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (compound 17, 200mg, 0.49 mmol) was placed in 1, 4-dioxane (10 mL) and water (5 mL), 6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) boronic acid (compound 15, 151 mg, 0.72 mmol), palladium tetraphenylphosphine (59.95 mg, 0.05 mmol), potassium carbonate (135.24 mg, 0.98 mmol) was added to the solution, stirred at 100 ℃ for 16 hours, then filtered, and the filtrate after filtration was concentrated, column chromatography (dichloromethane/methanol=20/1) was separated to give compound 18 (brown oil, mg, 42%).

LCMS (m/z): 675 [M+H]⁺.

Step M:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-1)

4- (6- (6- (5-Fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (compound 18, 30 mg, 0.04 mmol) was placed in tetrahydrofuran (2 mL), potassium tert-butoxide (9.96 mg, 0.09 mmol) was added, stirred at 50 ℃ for 2 hours, then poured into water (10 mL), extracted with ethyl acetate (20 mL X2), the organic phases were combined, dried over anhydrous sodium sulfate, and chromatographed after concentration to give compound I-1 (white solid, 3 mg, 12%).

LCMS (m/z): 521 [M+H]⁺.

¹HNMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 10.27 (s, 1H), 8.56 (s, 1H), 8.55 (d,J= 2.4 Hz, 1H), 8.28 (s, 1H), 8.06 (s, 1H), 7.97 (dd,J= 8.8 Hz,J= 2.4 Hz, 1H), 7.10 (dd,J= 9.6 Hz,J= 3.2 Hz, 1H), 6.92-6.86 (m, 2H), 6.78 (d,J= 1.2 Hz, 1H) 6.74-6.71 (m, 1H), 3.89 (s, 3H), 3.79-3.75 (m, 4H), 3.65 (s, 4H), 2.63-2.61 (m, 1H), 1.65 (d,J= 8.4 Hz, 1H).

Example 2:4- (6- (6- (2-fluoro-6-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-2)

Step A:3- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-4-yl) -pyridin-2-yl) -3, 6-diazabicyclo [3, 1] heptane-6-carboxylic acid tert-butyl ester (20)

3- (5-Bromopyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbonate (compound 11, 500 mg, 1.41 mmol) was placed in 1, 4-dioxane (10 mL), bis-pinacolato borate (464.64 mg, 1.83 mmol), 1 '-bis-triphenylphosphine ferrocene palladium dichloride (205.97 mg, 0.28 mmol), potassium acetate (414.40 mg, 4.22 mmol), stirred for 3 hours at 100 ℃ under nitrogen protection, then 4-chloro-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (249.96 mg, 1.41 mmol), 1' -bis (di-tert-butylphosphine) ferrocene palladium dichloride (183.47 mg, 0.28) mmol), cesium carbonate (917.18 mg, 2.82 mmol), water (2. mL) was again added, stirred for 100 ℃ under nitrogen protection, and then dried over water (20 mL) and dried over water (20 mL) to obtain a saturated brine (20%) and saturated brine solution, which was dried.

LCMS (m/z): 417 [M+H]⁺.

And (B) step (B): 4- (6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (21)

Compound 21 (yellow oil, 150 mg, 45%) was synthesized by the method of referring to compound 12 in step G of example 1, starting from compound 20.

LCMS (m/z): 317 [M+H]⁺.

Step C:4- (6- (6- (2-fluoro-6-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (9)

Compound I-2 (white solid, 2.63 mg, 3%) was synthesized by the method of referring to compound 14 in step H of example 1, starting from compound 21 and 6-hydroxy-2-fluorobenzaldehyde.

LCMS (m/z): 441 [M+H]⁺.

¹HNMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 11.29 (s, 1H), 8.65 (s, 1H), 8.54 (d,J= 2.0 Hz, 1H), 7.96 (d,J= 2.5 Hz, 1H), 7.72 (d,J= 3.0 Hz, 1H ), 7.10 (d,J= 3 Hz, 1H), 6.91-6.86 (m, 1H), 6.61-6.57 (m, 3H), 3.87 (d,J= 11.2 Hz, 2H), 3.76-3.65 (m, 6H), 2.51 (s, 1H), 1.65 (d,J= 8.4 Hz, 1H).

Example 3:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-3)

Compound I-3 (white solid, 23 mg, 16%) was synthesized by the method of referring to compound 14 in step H of example 1 starting from compound 21 and 2-hydroxy-5-fluorobenzaldehyde.

LCMS (m/z): 441 [M+H]⁺.

¹H NMR (500 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.32 (s, 1H), 8.65 (s, 1H), 8.54 (d,J= 2.0 Hz, 1H), 7.96 (d,J= 9.0 Hz,J= 2.5 Hz, 1H), 7.72 (d,J= 3.0 Hz, 1H ), 7.10 (dd,J= 9.5 Hz,J= 3.0 Hz, 1H), 6.91-6.86 (m, 2H), 6.74-6.71 (m, 1H), 6.60 (d,J= 2.0 Hz, 1H), 3.78-3.65 (m, 8H), 2.62 (s, 1H), 1.65 (d,J= 8.5 Hz, 1H).

Example 4:4- (6- (6- (6-methoxy-pyridin-3-yl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-4)

Compound I-4 (white solid, 10 mg, 14%) was synthesized by the method of referring to compound 14 in step H of example 1 starting from compound 21 and 6-methoxypyridine-3-carbaldehyde.

LCMS (m/z): 438 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1H), 8.57 (d,J= 2.0 Hz, 1H), 8.13 (d,J= 2.0 Hz, 1H), 8.05 (dd,J= 8.8 Hz, J = 2.4 Hz , 1H), 7.76 (dd,J= 8.4 Hz,J= 2.4 Hz , 1H), 7.60 (d,J= 3.6 Hz, 1H), 6.99 (d,J= 9.2 Hz, 1H), 6.81 (d,J= 8.8 Hz, 1H), 6.66 (d,J= 3.6 Hz, 1H), 3.98-3.86 (m, 7H), 3.75-3.71 (m, 4H), 2.77 (s, 1H), 1.76 (d,J= 8.8 Hz, 1H).

Example 5:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3-hydroxy-3-methylbut-1-yn-1-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-5)

Step A: 4-chloro-1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (22)

Compound 22 (yellow solid, 1.8 g, 86.9%) was synthesized by the method of referring to compound 16 in step J of example 1 starting from compound 19.

LCMS (m/z): 332 [M+H]⁺.

And (B) step (B): 4-chloro-2-iodo-1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] bipyridine-5-carbonitrile (23)

4-Chloro-1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (compound 22, 600 mg, 1.80: 1.80 mmol) was placed in tetrahydrofuran (25 mL), lithium diisopropylamide (2.7 mL, 1N, 1.35: 1.35 mmol) was added at-78 ℃, iodine (686.43 mg, 2.70: 2.70 mmol) was added after stirring for 2 hours at-78 ℃, stirred for 1 hour at-78 ℃, then warmed to room temperature, quenched with saturated ammonium chloride solution (40 mL), extracted with ethyl acetate (30 mL X3), the organic phases combined, and column chromatography (petroleum ether/ethyl acetate=4/1) after concentration was separated to give compound 23 (yellow solid, 600 mg, 65%).

LCMS (m/z): 458[M+H]⁺.

Step C: 4-chloro-2- (3-hydroxy-3-methylbut-1-yn-1-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (24)

Compound 24 (brown solid, 900 mg, 22.38%) was synthesized by the method of referring to compound 3 in step a of example 1 starting from compound 23 and 2-methyl-3-ethynyl-2-ol.

LCMS (m/z): 414[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3-hydroxy-3-methylbut-1-yn-1-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (25)

Compound 25 (yellow solid, 33.6 mg, 82%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 24 and compound 15.

LCMS (m/z): 677[M+H]⁺.

Step E:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3-hydroxy-3-methylbut-1-yn-1-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-5)

Compound I-5 (brown solid, 1 mg, 5.40%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 25.

LCMS (m/z): 523 [M+H]⁺.

¹HNMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.87 (s, 1H), 8.54 (d,J= 2.4 Hz, 1H), 7.98 (dd,J= 8.8 Hz, 2.4 Hz, 1H), 7.10 (dd,J= 9.6 Hz, 3.2 Hz, 1H), 6.91-6.86 (m, 2H), 6.76 (s, 1H), 6.74-6.71 (m, 1H), 5.65 (s, 1H), 3.78-3.73 (m, 5H), 3.64 (s, 3H), 2.64-2.59 (m, 1H), 1.64 (d,J= 8.8 Hz, 1H), 1.50 (s, 6H).

Example 6:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3-hydroxy-3-methylbutyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-6)

Step A:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3-hydroxy-3-methylbutyl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (26)

4- (6- (6- (5-Fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3-hydroxy-3-methylbut-1-yn-1-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (compound 25, 40 mg, 0.06 mmol) was placed in tetrahydrofuran (6 mL), palladium on carbon (40 mg, 0.06 mmol) was added, stirred at 25 ℃ under hydrogen pressure for 6 hours, then filtered, and the filtrate concentrated to give compound 26 (brown solid, 40 mg, 99%).

LCMS (m/z): 681[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3-hydroxy-3-methylbutyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-6)

Compound I-6 (brown oil, 3 mg, 9.21%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 26.

LCMS (m/z): 527 [M+H]⁺.

¹HNMR (400 MHz, DMSO-d6) δ 8.59 (dd,J= 20.4 Hz, 2.0 Hz, 1H), 8.51 (d,J= 6.8 Hz, 1H), 8.10-8.03 (m, 1H), 7.23-7.07 (m, 3H), 6.99-6.91 (m, 1H), 6.33 (d,J= 14.8 Hz, 1H), 4.72-4.85 (m, 2H), 4.46 (d,J= 13.6 Hz, 1H), 4.29-4.21 (m, 3H), 4.06 (d,J= 13.2 Hz, 1H), 3.63-3.54 (m, 1H), 3.10-3.08 (m, 1H), 2.95-2.90 (m, 2H), 2.19 (t,J= 9.6 Hz, 1H), 1.94-1.89 (m, 2H), 1.29 (s, 6H).

Example 7:4- (6- (6- (2-fluoro-6-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-7)

Step A:2- ((3- (5-bromopyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -3-fluorophenol (27)

Compound 27 (brown oil, 300 mg, 36.28%) was synthesized by the method of referring to compound 14 in step H of example 1 starting from compound 12 and 2-fluoro-6-hydroxybenzaldehyde.

LCMS (m/z): 378 [M+H]⁺.

And (B) step (B): (6- (6- (2-fluoro-6-hydroxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) boronic acid (15)

Compound 28 (brown oil, 80 mg, 89%) was synthesized by the method of referring to compound 15 in step I of example 1 starting from compound 27.

LCMS (m/z): 344 [M+H]⁺.

Step C:4- (6- (6- (2-fluoro-6-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (29)

Compound 29 (white solid, 16 mg, 16.75%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 28 and compound 17.

LCMS (m/z): 675 [M+H]⁺.

Step D:4- (6- (6- (2-fluoro-6-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-7)

Compound I-7 (white solid, 2.03 mg, 17.87%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 29.

LCMS (m/z): 521 [M+H]⁺.

¹HNMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.56 (s, 2H), 8.28 (s, 1H), 8.06 (s, 1H), 7.98 (d,J= 8.80 Hz, 1H), 7.11-7.10 (m, 1H), 6.92 (d,J= 8.80 Hz, 1H), 6.78 (s, 1H), 6.62-6.57 (m, 2H), 4.04 (s, 2H), 3.89 (s, 4H), 3.76 (d,J= 10 Hz, 3H), 3.67 (s, 2H), 2.58 (s, 1H), 1.65 (d,J= 8.4 Hz, 1H).

Example 8:4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-8)

Step A:3- (5-bromopyridin-2-yl) -6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane (30)

Compound 30 (brown oil, 200 mg, 27%) was synthesized by the method of referring to compound 14 in step H of example 1 starting from compound 21 and 6-methoxypyridine-3-carbaldehyde.

LCMS (m/z): 375 [M+H]⁺.

And (B) step (B): (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) boronic acid (31)

Compound 31 (brown oil, 50 mg, 56%) was synthesized by the method of referring to compound 15 in step I of example 1 starting from compound 30.

LCMS (m/z): 341 [M+H]⁺.

Step C:4- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (32)

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Compound 32 (white solid, 40 mg, 44.2%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 31 and compound 17.

LCMS (m/z): 672 [M+H]⁺.

Step D:4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-8)

Compound I-8 (white solid, 12 mg, 36.9%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 32.

LCMS (m/z): 518 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.56 (d,J= 2.3 Hz, 1H), 8.50 (s, 1H), 8.13-8.07 (m, 2H), 8.04 (dd,J= 8.8 Hz, 2.4 Hz, 1H), 7.95 (s, 1H), 7.73 (dd,J= 8.4 Hz, 2.4 Hz, 1H), 6.97 (d,J= 8.8 Hz, 1H), 6.79 (d,J= 8.4 Hz, 1H), 6.73 (s, 1H), 4.00-3.85 (m, 8H), 3.81 (d,J= 6.0 Hz, 2H), 3.74-3.63 (m, 4H), 2.72 (s, 1H), 1.72 (d,J= 8.8 Hz, 1H).

Example 9:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-9)

Step A:1- (2-fluoroethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole (34)

4- (4, 5-Tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole (Compound 33, 500 mg, 2.58 mmol) was placed in DMF (10 mL), sodium hydride (68 mg, 2.83 mmol) was added at 0deg.C, stirred for 2 hours at 0deg.C, then 1-fluoro-2-iodoethane (897 mg, 5.15 mmol), stirred for 4 hours at 25deg.C, diluted with diethyl ether (20 mL), washed with water (10 mL) and saturated sodium chloride solution (10 mL), respectively, dried over anhydrous sodium sulfate, and concentrated to give Compound 34 (yellow oil, 420 mg, 36%).

LCMS (m/z): 458[M+H]⁺.

And (B) step (B): 4-chloro-2- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (35)

4-Chloro-2-iodo-1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (compound 23, 200 mg, 0.44 mmol) was taken up in 1, 4-dioxane (5 mL) and water (1 mL), 1- (2-fluoroethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole (compound 34, 128 mg, 0.17 mmol), 1' -bistriphenylphosphine ferrocene palladium dichloride (88.36 g, 0.64 mol), cesium carbonate (284 mg, 0.87 mmol), stirred at 30 ℃ for 16 hours, and then separated by column chromatography (petroleum ether/ethyl acetate=1/2) after concentration to give compound 35 (yellow solid, 90 mg, 41.8%).

LCMS (m/z): 444[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (36)

Compound 36 (yellow solid, 60 mg, 60%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 35 and compound 15.

LCMS (m/z): 707 [M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-fluoroethyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-9)

Compound I-9 (white solid, 2.53 mg, 10.9%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 36.

LCMS (m/z): 553 [M+H]⁺.

¹HNMR (400 MHz, CDCl₃) δ 10.33 (s, 1H), 8.68 (d,J= 2.4 Hz, 1H), 8.55 (s, 1H), 8.14 (s, 1H), 7.87 (s, 2H), 6.72-6.81 (m, 5H), 4.76-4.89 (m, 2H), 4.47-4.55 (m, 2H), 3.72-3.90 (m, 8H), 2.75 (s, 1H), 1.72 (s, 1H).

Example 10:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3, 6-dihydro-2H-pyran-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-10)

Step A: 4-chloro-2- (3, 6-dihydro-2H-pyran-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (37)

Compound 37 (white solid, 50 mg, 35.37%) was synthesized by the method of referring to compound 35 in step B of example 9 starting from compound 23 and compound 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane.

LCMS (m/z): 414[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3, 6-dihydro-2H-pyran-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (38)

Compound 38 (yellow oil, 20 mg, 18.34%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 37 and compound 15.

LCMS (m/z): 677 [M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3, 6-dihydro-2H-pyran-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-10)

Compound I-10 (brown white solid, 1.84 mg, 11.53%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 38.

LCMS (m/z): 523 [M+H]⁺.

¹HNMR (400 MHz, CD₃OD) 8.54 (s, 2H), 8.03 (d,J= 6.4 Hz, 1H), 7.05-7.00 (m, 2H), 6.97-6.95 (m, 4H), 6.56 (s, 1H), 6.50-6.45 (m, 1H), 4.55-4.50 (m, 4H), 4.36-4.33 (m, 1H), 3.91-3.59 (m, 7H), 2.55 (s, 2H), 1.28-1.19 (m, 2H).

Example 11:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-11)

Step A: 4-chloro-2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (39)

Compound 39 was synthesized (yellow solid, 120 mg, 25.75%) by the method of referring to compound 35 in step B of example 9 starting from compound 23 and compound 2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane.

LCMS (m/z): 427[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (40)

Compound 40 (yellow solid, 90 mg, 30.4%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 39 and compound 15.

LCMS (m/z): 690 [M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-11)

Compound I-11 (white solid, 11 mg, 28.9%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 40.

LCMS (m/z): 536 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.53 (d,J= 2.0 Hz, 2H), 8.01 (dd,J= 8.8 Hz, 2.4 Hz, 1H), 6.98 -6.88 (m, 2H), 6.87-6.80 (m, 1H), 6.72 (dd,J= 8.8 Hz, 4.8 Hz, 1H), 6.57 (s, 1H), 6.46 (s, 1H), 4.61 (s, 1H), 3.88 (m, 4H), 3.80 (s, 2H), 3.70 (d,J= 11.6 Hz, 2H), 3.23 (s, 2H), 2.75 (m, 2H), 2.65 (s, 2H), 2.43 (s, 3H), 1.75 (d,J= 9.2 Hz, 1H).

Example 12:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (difluoromethyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-12)

Step A: 4-chloro-2- (1- (difluoromethyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (41)

Compound 41 (white solid, 50 mg, 27.25%) was synthesized by the method of referring to compound 35 in step B of example 9 starting from compound 23 and compound 1- (difluoromethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 448[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (difluoromethyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (42)

Compound 42 (white solid, 15mg, 30%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 41 and compound 15.

LCMS (m/z): 711 [M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (difluoromethyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-12)

Compound I-12 (white solid, 1.86 mg, 8.37%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 42.

LCMS (m/z): 557 [M+H]⁺.

¹HNMR (400 MHz, CD₃OD) 8.58-8.55 (m, 3H), 8.49 (s, 1H), 8.04 (d,J= 8.8 Hz, 1H), 7.56 (s, 1H), 6.98-6.72 (m, 5H), 4.60 (s, 2H), 3.96-3.93 (m, 3H), 3.77-3.75 (m, 3H), 2.75(s, 1H), 1.75 (s, 1H).

Example 13:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2-cyclopropyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-13)

Step A: 4-chloro-2-cyclopropyl-1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (43)

Compound 43 (white solid, 80 mg, 55.78%) was synthesized by the method of referring to compound 35 in step B of example 9 starting from compound 23 and compound 2-cyclopropyl-4, 5-tetramethyl-1, 3, 2-dioxaborane.

LCMS (m/z): 372[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2-cyclopropyl-1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (44)

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Compound 44 (white solid, 30 mg, 17.84%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 43 and compound 15.

LCMS (m/z): 635 [M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2-cyclopropyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-13)

Compound I-13 (white solid, 0.7 mg, 3.49%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 44.

LCMS (m/z): 481 [M+H]⁺.

¹HNMR (400 MHz, DMSO-d6) 12.22 (s, 1H), 8.52-8.48 (m, 2H), 8.32 (s, 1H), 7.91 (d,J= 8.8 Hz, 1H), 7.25-7.20 (m, 1H), 7.00-6.90 (m, 2H), 6.25 (s, 1H), 3.77-7.75 (m, 3H), 3.64 (s, 2H), 2.50-2.49 (m, 3H), 2.07 (s, 2H), 1.63 (s, 1H), 1.05-0.89 (m, 4H).

Example 14:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-14)

Step A: 4-chloro-2- (1-methyl-1H-pyrazol-5-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (45)

Compound 45 (white solid, 100mg, 29.63%) was synthesized by the method of referring to compound 35 in step B of example 9 starting from compound 23 and compound 1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 412[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-5-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (46)

Compound 46 (white solid, 15 mg, 32%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 45 and compound 15.

LCMS (m/z): 675 [M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-5-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-14)

Compound I-14 (white solid, 2.1 mg, 5.23%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 46.

LCMS (m/z): 521 [M+H]⁺.

¹HNMR (400 MHz, DMSO-d6) 8.70 (s, 1H), 8.61 (d,J= 2. 4 Hz, 1H), 8.03 (d,J= 9.2 Hz, 1H), 7.54 (s, 1H), 7.15-7.10 (m, 1H), 7.00-6.85 (m, 4H), 6.73-6.70 (m, 1H), 4.06 (s, 3H), 3.59-3.34 (m, 8H), 2.50 (s, 1H), 1.64 (d,J= 8.8 Hz, 1H).

Example 15:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-15)

Step A: 4-chloro-2- (1-methyl-1H-pyrazol-3-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (47)

Compound 47 (white solid, 110 mg, 61%) was synthesized by the method of referring to compound 35 in step B of example 9 starting from compound 23 and compound 1-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 412[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-3-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (48)

Compound 48 (white solid, 60 mg, 47%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 47 and compound 15.

LCMS (m/z): 675 [M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-15)

Compound I-15 (white solid, 1.85 mg, 9.73%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 48.

LCMS (m/z): 521 [M+H]⁺.

¹HNMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 8.60 (s, 1H), 8.56 (d,J= 2 Hz, 1H), 7.99 (dd,J= 8.8 Hz, 2.4 Hz, 1H), 7.81 (d,J= 2 Hz, 1H), 7.10 (dd,J= 9.6 Hz, 3.2 Hz, 1H), 6.93-6.86 (m, 4H), 6.74-6.71 (m, 1H), 4.04 (s, 3H), 3.78-3.75 (m, 4H), 3.65-3.59 (m, 4H), 2.63-2.61 (m, 1H), 1.65 (d,J= 8.4 Hz, 1H).

Example 16:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-cyclopropyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-16)

Step A: 4-chloro-2- (1-cyclopropyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (49)

Compound 49 (white solid, 150 mg, 41.80%) was synthesized by the method of referring to compound 35 in step B of example 9 starting from compound 24 and compound 1-cyclopropyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 438[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-cyclopropyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (50)

Compound 50 (white solid, 30 mg, 25.86%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 49 and compound 15.

LCMS (m/z): 701 [M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-cyclopropyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-16)

Compound I-16 (white solid, 2 mg, 7.61%) was synthesized by the method of referring to compound I-1 in step M of example I-1, starting from compound 50.

LCMS (m/z): 547 [M+H]⁺.

¹HNMR (400 MHz, CD₃OD) 8.56-8.50 (m, 2H), 8.19 (s, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 6.97-6.74 (m, 5H), 4.60-4.50 (m, 3H), 4.00-3.92 (m, 3H), 3.84-3.80 (m, 1H), 3.80-3.72 (m, 2H), 2.80-2.76 (m, 1H), 1.70-1.60 (m, 1H), 1.13-1.08 (m, 4H).

Example 17:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-hydroxyethyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-17)

Step A: 4-chloro-2- (1-hydroxyethyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (51)

Compound 51 (white solid, 100 mg, 34.53%) was synthesized by the method of reference example I-9 step B, compound 35, starting from compound 23 and compound 1-hydroxyethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 442[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-hydroxyethyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (52)

Compound 52 (yellow solid, 105 mg, 64.8%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 51 and compound 15.

LCMS (m/z): 705 [M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-hydroxyethyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-17)

Compound I-17 (white solid, 3.4 mg, 4.12%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 52.

LCMS (m/z): 551 [M+H]⁺.

¹HNMR (400 MHz, DMSO-d6) 12.64 (s, 1H), 10.26 (s, 1H), 8.56-8.54 (m, 2H), 8.34 (s, 1H), 8.09 (s, 1H), 7.97 (dd,J= 8.8 Hz, 2.4 Hz, 1H), 7.10 (dd,J= 9.6 Hz, 3.2 Hz, 1H), 6.92-6.85 (m, 2H), 6.80 (s, 1H), 6.74-6.71(m, 1H), 4.97 (t,J= 5.2 Hz, 1H), 4.18 (t,J= 5.2 Hz, 2H), 3.79-3.75 (m, 6H), 3.65 (s, 4H), 2.64-2.59 (m, 1H), 1.65(d,J= 8.8 Hz, 1H).

Example 18:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1, 3-dimethyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-18)

Step A: 4-chloro-2- (1, 3-dimethyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (53)

Compound 53 was synthesized (yellow solid, 160 mg, 27.5%) by the method of reference example I-9 step B, compound 35, starting from compound 23 and compound 1, 3-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 426[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1, 3-dimethyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (54)

Compound 54 (yellow solid, 130 mg, 28.82%) was synthesized by the method of referring to compound 18 in step L of example I-1 starting from compound 53 and compound 15.

LCMS (m/z): 689 [M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1, 3-dimethyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-18)

Compound I-18 (white soil, 1.92 mg, 1.89%) was synthesized by the method described in example 1, step M, with compound 54 as the starting material, with reference to compound I-1.

LCMS (m/z): 535 [M+H]⁺.

¹HNMR (400 MHz, CD₃OD) 8.57 (s, 1H), 8.52 (s, 1H), 8.05 (d,J= 6.4 Hz, 1H), 7.97 (s, 1H), 6.98-6.74 (m, 4H), 6.58 (s, 1H), 3.93-3.76 (m, 11H), 2.8 (s, 1H), 2.42 (s, 3H), 1.77 (s, 1H).

Example 19:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-19)

Step A: 4-chloro-2- (1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (55)

Compound 55 (yellow solid, 250 mg, 23.79%) was synthesized by the method of referring to compound 35 in step B of example 9 starting from compound 23 and compound 1-methyl-3-trifluoromethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 480[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (56)

Compound 56 (yellow solid, 100 mg, 26.70%) was synthesized by the method of reference to compound 18 in step L of example I-1 starting from compound 55 and compound 15.

LCMS (m/z): 743 [M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-19)

Compound I-19 (white solid, 1.92 mg, 2.79%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 56.

LCMS (m/z): 589 [M+H]⁺.

¹HNMR (400 MHz, CD₃OD) 8.58 (s, 1H), 8.55 (d,J= 2.4 Hz, 1H), 8.15 (s, 1H), 8.02 (d,J= 2.4 Hz, 1H), 6.99-6.71 (m, 5H), 4.02-3.78 (m, 11H), 2.79 (s, 1H), 1.82 (s, 1H).

Example 20:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-fluoroethyl) -1H-pyrazol-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-20)

Step A: 4-chloro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] bipyridine-5-carbonitrile (57)

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Compound 57 (yellow solid, 2.1 g, 60%) was synthesized according to the method of synthesizing compound 34 in step a of example 9, starting from compound 19 and compound SemCl.

LCMS (m/z): 308 [M+H]⁺.

And (B) step (B): 4-chloro-2-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] bipyridine-5-carbonitrile (58)

Compound 58 (white solid, 600 mg, 71%) was synthesized by the method of referring to compound 23 in step B of example 5, starting from compound 57 and elemental iodine.

LCMS (m/z): 434[M+H]⁺.

Step C: 4-chloro-2- (1H-pyrazol-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (60)

4-Chloro-2-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (compound 58, 672.17 mg, 1.55 mmol) was placed in 1, 4-dioxane (5 mL) and water (1 mL), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole (compound 59, 300 mg, 1.55 mmol), 1' -bistriphenylphosphine ferrocene palladium dichloride (226.26 mg, 0.31 mmol), cesium carbonate (1007.5 mg, 3.09 mmol), stirred at 100 ℃ for 2 hours, then poured into water (5 mL), ethyl acetate (10 mL) extracted three times, the organic phases combined, and column chromatography (dichloromethane/methanol=20/1) separated to give compound 60 (yellow solid, mg, 65.7%).

LCMS (m/z): 374[M+H]⁺.

Step D: 4-chloro-2- (1- (2-fluoroethyl) -1H-pyrazol-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (61)

Compound 61 (yellow solid, 100 mg, 89.07%) was synthesized by the method of referring to compound 34 in step a of example 9 starting from compound 60 and compound 1-fluoro-2-iodoethane.

LCMS (m/z): 420[M+H]⁺.

Step E: (6- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) boronic acid (62)

Compound 62 (brown solid, 3.5 g, 55.32%) was synthesized by the method of referring to compound 15 in step I of example 1 starting from compound 11.

LCMS (m/z): 320 [M+H]⁺.

Step F:4- (6- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-fluoroethyl) -1H-pyrazol-3-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (63)

Compound 63 (yellow solid, 130 mg, 41.4%) was synthesized by the method of referring to compound 18 in step L of example 1 starting from compound 61 and compound 62.

LCMS (m/z): 659 [M+H]⁺.

Step G:4- (6- (3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-fluoroethyl) -1H-pyrazol-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (64)

Compound 64 (yellow solid, 25 mg, 73%) was synthesized by the method of referring to compound 12 in step G of example 1, starting from compound 63.

LCMS (m/z): 429 [M+H]⁺.

Step H:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-fluoroethyl) -1H-pyrazol-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-20)

Compound I-20 (white solid, 1.93 mg, 3.31%) was synthesized by the method of referring to compound 14 in step H of example 1, starting from compound 64 and compound 13.

LCMS (m/z): 553 [M+H]⁺.

¹HNMR (400 MHz, DMSO-d6) 12.82 (s, 1H), 10.30 (s, 1H), 8.62 (s, 1H), 8.57 (d,J= 2.4 Hz, 1H), 8.00 (dd,J= 8.8 Hz, 2.4 Hz, 1H), 7.90 (d,J= 2.4 Hz, 1H), 7.11 (dd,J= 9.6 Hz, 3.2 Hz, 1H), 6.94-6.85 (m, 4H), 6.74-6.71 (m, 1H), 4.89 (t,J= 4.8 Hz, 1H), 4.77 (t,J= 4.4 Hz, 1H), 4.55 (t,J= 4.4 Hz, 1H), 4.48 (t,J= 4.4 Hz, 1H), 3.79-3.65 (m, 8H), 2.61 (s, 1H), 1.65(d,J= 8.4 Hz, 1H).

Example 21:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methylacrid-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-21)

Step A: 4-chloro-2- (1-tert-butoxycarbonylacrid-3-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (66)

Compound 66 (yellow solid, 80 mg, 25.35.5%) was synthesized by the method of referring to compound 17 in step K of example 1, starting from compound 16 and compound 65.

LCMS (m/z): 487 [M+H]⁺.

And (B) step (B): 4-chloro-2- (acridin-3-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (67)

Compound 67 (yellow solid, 56 mg, 88.9%) was synthesized by the method of referring to compound 12 in step G of example 1, starting from compound 66.

LCMS (m/z): 387 [M+H]⁺.

Step C: 4-chloro-2- (1-methylacridin-3-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] naphthyridine-5-carbonitrile (68)

4-Chloro-2- (acridin-3-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (compound 67, 50mg, 0.13 mmol) was placed in methanol (5 mL), formaldehyde (38.7 mg, 0.38 mmol), sodium cyanoborohydride (16.2 mg, 0.26 mmol), acetic acid (0.77 mg, 0.01 mmol), stirred at 25 ℃ for 2 hours, then poured into water (5 mL), extracted three times with ethyl acetate (10 mL), the organic phases combined, and separated by column chromatography (petroleum ether/ethyl acetate=5/1) after concentration to give a yellow solid compound 68 (45 mg, 86.8%).

LCMS (m/z): 401 [M+H]⁺.

Step D:4- (6- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methylacrid-3-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (69)

Compound 69 (yellow solid, 25 mg, 31.6%) was synthesized by the method of referring to compound 18 in step L of example 1 starting from compound 68 and compound 62.

LCMS (m/z): 640 [M+H]⁺.

Step E:4- (6- (3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methylacrid-3-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (70)

Compound 70 (yellow solid, 35 mg, 100%) was synthesized by the method of referring to compound 12 in step G of example 1, starting from compound 69.

LCMS (m/z): 540 [M+H]⁺.

Step F:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methylacrid-3-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (71)

Compound 71 (yellow solid, 21 mg, 48.9%) was synthesized by the method of referring to compound 14 in step H of example 1 starting from compound 70 and compound 5-fluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 664 [M+H]⁺.

Step G:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methylacrid-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-21)

Compound I-21 (white solid, 1.6 mg, 10%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 71.

LCMS (m/z): 510 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 2H), 8.48-8.39 (m, 1H), 8.04 (d,J= 9.2 Hz, 1H), 6.97 (d,J= 9.2 Hz, 2H), 6.93-6.88 (m, 1H), 6.78-6.75 (m, 1H), 6.66 (s, 1H), 4.61 (s, 2H), 4.27 (s, 2H), 4.21-4.19 (m, 1H), 3.99 (m, 6H), 3.90-3.81 (m, 2H), 2.79 (s, 3H), 2.40-2.29 (m, 1H), 1.88-1.81 (m, 1H).

Example 22:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3-methylisoxazol-5-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-22)

Step A: 4-chloro-2- (3-hydroxy-3-methylbut-1-yn-1-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (72)

Compound 72 (yellow solid, 500 mg, 69%) was synthesized by the method of referring to compound 3 in step a of example 1 starting from compound 58 and compound 2-methyl-3-ethynyl-2-ol.

LCMS (m/z): 390[M+H]⁺.

And (B) step (B): 4- (6- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3-hydroxy-3-methylbut-1-yn-1-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (73)

Compound 73 (yellow solid, 60 mg, 33.8%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 72 and compound 62.

LCMS (m/z): 629[M+H]⁺.

Step C:4- (6- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2-ethynyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (74)

4- (6- (6- (Tert-butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3-hydroxy-3-methylbut-1-yn-1-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (compound 73, 300 mg, 0.47 mmol) was placed in toluene (5 mL), potassium hydroxide (53.36 mg, 0.95 mmol) was added, stirred at 50 ℃ under nitrogen for 1 hour, then poured into water (5 mL), ethyl acetate (10 mL) was extracted three times, the organic phases were combined and column chromatography (dichloromethane/methanol=20/1) was separated to give yellow solid compound 74 (180 mg, 67%).

LCMS (m/z): 571[M+H]⁺.

Step D:4- (6- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3-methylisoxazol-5-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (75)

4- (6- (6- (Tert-butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2-ethynyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (180 mg, 0.31 mmol) was placed in tetrahydrofuran (5 mL), N-hydroxyacetimida-chlor (58.78 mg, 0.63 mmol), triethylamine (95.41 mg, 0.94 mmol) was added, stirred under nitrogen for 16 hours at 25 ℃ and then poured into water (5 mL), extracted three times with ethyl acetate (10 mL), the organic phases were combined and column chromatography (dichloromethane/methanol=20/1) was performed after concentration to give compound 75 (90 mg, 45%) as a yellow solid.

LCMS (m/z): 628[M+H]⁺.

Step E:4- (6- (3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3-methylisoxazol-5-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (76)

Compound 76 (yellow solid, 50 mg, 90%) was synthesized by the method of referring to compound 12 in step G of example 1, starting from compound 75.

LCMS (m/z): 398[M+H]⁺.

Step F:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3-methylisoxazol-5-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-22)

Compound I-22 (white solid, 5.2 mg, 6.12%) was synthesized by the method of referring to compound 14 in step H of example 1 starting from compound 76 and compound 5-fluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 522 [M+H]⁺.

¹HNMR (400 MHz, CD₃OD) δ 13.29 (s, 1H), 8.75 (s, 1H), 8.59 (s, 1H), 8.01-8.00 (m, 1H), 7.15-7.12 (m, 2H), 7.00-6.95 (m, 1H), 6.95-6.91 (m, 2H), 3.77-3.63 (m, 8H), 2.50-2.43 (m, 1H), 2.32 (s, 3H), 1.66-1.64 (m, 1H).

Example 23:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (2-fluoroethyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-23)

Step A: 4-chloro-2- (2-hydroxyethyl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (77)

Compound 77 (yellow solid, 480 mg, 53%) was synthesized by the method of referring to compound 17 in step K of example 1 starting from compound 16 and compound 3-butyn-1-ol.

LCMS (m/z): 376 [M+H]⁺.

And (B) step (B): 4-chloro-2- (fluoroethyl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (78)

4-Chloro-2- (2-hydroxyethyl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (compound 77, 400 mg, 1.06 mmol) was placed in dichloromethane (20 mL), diethylaminosulfur trifluoride (256.65 mg, 1.59 mmol) was added, stirred at 25 ℃ for 12 hours, then directly concentrated and then separated by column chromatography (petroleum ether/ethyl acetate=4/1) to give compound 78 (brown oil, 200 mg, 50%).

LCMS (m/z): 378 [M+H]⁺.

Step C:4- (6- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (fluoroethyl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (79)

Compound 79 (yellow solid, 150mg, 46%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 78 and compound 62.

LCMS (m/z): 617 [M+H]⁺.

Step D:4- (6- (3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (fluoroethyl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (80)

Compound 80 (yellow solid, 120 mg, 90%) was synthesized according to the procedure of example 1, step G, compound 12, starting from compound 79.

LCMS (m/z): 517 [M+H]⁺.

Step E:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (fluoroethyl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (81)

Compound 81 (yellow solid, 50 mg, 80%) was synthesized by the method of referring to compound 14 in step H of example 1 starting from compound 80 and compound 5-fluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 641 [M+H]⁺.

Step F:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (fluoroethyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-23)

4- (6- (6- (5-Fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methylacrid-3-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] naphthyridine-5-carbonitrile (compound 71, 40 mg, 0.06 mmol) was placed in dichloromethane (4 mL) and methanol (2 mL), magnesium (7.48 mg, 0.31 mmol) was added, stirred at 35℃for 3 hours, then filtered and then isolated directly by preparative chromatography to give compound I-23 (brown oil, 2.2 mg, 7.22%).

LCMS (m/z): 487 [M+H]⁺.

¹HNMR (400 MHz, CD₃OD) δ 8.54-8.51 (m, 2H), 8.02 (dd,J= 8.8 Hz, 2.4 Hz, 1H), 6.96-6.90 (m, 2H), 6.84-6.81 (m, 1H), 6.73-6.70 (m, 1H), 6.47 (s, 1H), 4.79-4.63 (m, 3H), 3.92-3.87 (m, 4H), 3.74-3.72 (m, 2H), 3.48-3.47 (m, 1H), 3.25-3.12 (m, 3H), 1.76-1.74 (m, 1H).

Example 24:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (hydroxyethyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-24)

Step A:4- (6- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (hydroxyethyl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (82)

Compound 82 (yellow solid, 0.2 g, 41%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 77 and compound 62.

LCMS (m/z): 615 [M+H]⁺.

And (B) step (B): 4- (6- (3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (hydroxyethyl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (83)

Compound 83 (yellow solid, 0.1G, 60%) was synthesized by the method of referring to compound 12 in step G of example 1, starting from compound 82.

LCMS (m/z): 515 [M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (hydroxyethyl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (84)

84 (White solid, 50 mg, 80%) was synthesized by the method of referring to compound 14 in step H of example 1 starting from compound 83 and compound 5-fluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 639 [M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (fluoroethyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-24)

Compound I-24 (brown oil 3.8 mg, 13%) was synthesized by the method of referring to compound I-23 in step F of example 13, starting from compound 84.

LCMS (m/z): 485 [M+H]⁺.

¹HNMR (400 MHz, CD₃OD) δ 8.55 (d,J= 2.0 Hz, 1H), 8.49 (s, 1H), 8.40-8.30 (m, 1H), 8.02 (dd,J= 8.8 Hz, 2.4 Hz, 1H), 7.10-7.03 (m, 1H), 6.97-6.95 (m, 2H), 6.90-6.80 (m, 1H), 6.40 (s, 1H), 4.27-3.95 (m, 7H), 3.92-3.87 (m, 3H), 3.03 (t,J= 13.2Hz, 1H), 2.90-2.83 (m, 1H), 2.00-1.97(m, 1H).

Example 25:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (methylaminocarbonyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-25)

Step A: 4-chloro-2-methoxycarbonyl-1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (85)

4-Chloro-1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (compound 22, 2.50 g, 7.51 mmol) was placed in tetrahydrofuran (50 mL), lithium diisopropylamide (11.27 mL, 1M, 11.27 mmol) was added at-78 ℃, stirred at-78 ℃ for 2 hours, then methyl chloroformate (1.06 g, 11.27 mmol) was added, stirred at 25 ℃ for 2 hours, then poured into saturated ammonium chloride solution (40 mL), extracted three times with ethyl acetate (20 mL), the organic phases were combined, and column chromatography (petroleum ether/ethyl acetate=10/1) was concentrated to give compound 85 (yellow solid, 860 mg, 29%).

LCMS (m/z): 390[M+H]⁺.

And (B) step (B): 4- (6- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (methoxycarbonyl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (86)

Compound 86 (yellow solid 860 mg, 76%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 85 and compound 62.

LCMS (m/z): 629 [M+H]⁺.

Step C:4- (6- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (methylaminocarbonyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (87)

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4- (6- (6- (Tert-butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (methoxycarbonyl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (compound 86, 300 mg, 0.48 mmol) was placed in DMF (10 mL), methylamine (492.46 mg, 4.76 mmol) was added, stirred at 80 ℃ for 16 hours, then poured into water (10 mL), extracted three times with ethyl acetate (20: 20 mL), the organic phases were combined and after concentration column chromatography (dichloromethane/methanol=20/1) separated to give compound 87 (yellow solid, 120: 120 mg, 53%).

LCMS (m/z): 474 [M+H]⁺.

Step D:4- (6- (3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (methylaminocarbonyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (88)

Compound 88 (50 mg, 54%) was synthesized according to the procedure of example 1, step G, using compound 87 as starting material, compound 12.

LCMS (m/z): 374 [M+H]⁺.

Step E:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (methylaminocarbonyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-25)

Compound I-25 (white solid, 10 mg, 15%) was synthesized by the method of referring to compound 14 in step H of example 1, starting from compound 88 and compound 5-fluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 498 [M+H]⁺.

¹HNMR (400 MHz, CD₃OD) 8.68 (s, 1H), 8.60 (d,J= 2.4 Hz, 1H), 8.06 (d,J= 8.8 Hz, 1H), 7.22 (s, 1H), 6.99-6.90 (m, 2H), 6.90-6.80 (m, 1H), 6.80-6.77 (m, 1H), 4.60-4.55(m, 1H), 4.00-3.83 (m, 8H), 2.93 (s, 3H), 1.86 (m, 1H).

Example 26:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1, 1-difluoro-2-hydroxyethyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-26)

Step A: 4-chloro-2-ethoxyoxalyl-1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (89)

4-Chloro-1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (compound 22, 600 mg, 1.80: 1.80 mmol) was placed in tetrahydrofuran (50 mL), lithium diisopropylamide (2.7 mL, 1M, 2.70: 2.70 mmol) was added at-78 ℃, stirred at-78 ℃ for 2 hours, then diethyl oxalate (316.19 mg, 2.16: 2.16 mmol) was added, then poured into saturated ammonium chloride solution (40 mL), extracted three times with ethyl acetate (20: 20 mL), the organic phases were combined, and column chromatography (petroleum ether/ethyl acetate=10/1) after concentration gave compound 89 (brown solid, 130: 130 mg, 15%).

LCMS (m/z): 432[M+H]⁺.

And (B) step (B): 2- (4-chloro-5-cyano-1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] bipyridin-2-yl) -2, 2-difluoroacetic acid ethyl ester (89)

4-Chloro-2-ethoxyoxalyl-1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] was taken up in dichloromethane (20 mL), diethylaminosulfur trifluoride (2.98 g, 18.50 mmol) was added at 25 ℃ and stirred for 48 hours at 25 ℃, then diethyl oxalate (88.36 g, 0.64 mol) was added and then poured into saturated sodium bicarbonate solution (40 mL), extracted three times with ethyl acetate (20 mL), the organic phases were combined, and column chromatography (petroleum ether/ethyl acetate=5/1) after concentration gave compound 90 (brown solid, 0.7 g, 42%) was isolated.

LCMS (m/z): 454[M+H]⁺.

Step C:4- (6- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1, 1-difluoro-2-ethoxy-2-oxoethyl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (91)

Compound 91 (brown solid, 200mg, 52%) was synthesized by the method of referring to compound 18 in step L of example 1 starting from compound 90 and compound 62.

LCMS (m/z): 693 [M+H]⁺.

Step D:4- (6- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1, 1-difluoro-2-hydroxyethyl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (92)

4- (6- (6- (Tert-butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1, 1-difluoro-2-ethoxy-2-oxoethyl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (compound 91, 100mg, 0.14 mmol) was placed in methanol (2 mL), sodium borohydride (8.17 mg, 0.22 mmol) was added, stirred at 100 ℃ for 16 hours, then poured into saturated ammonium chloride solution (20 mL), ethyl acetate (20 mL) was extracted three times, the organic phases were combined, and after concentration column chromatography (petroleum ether/ethyl acetate=1/1) separated to give compound 92 (yellow solid, 70 mg, 75%).

LCMS (m/z): 651 [M+H]⁺.

Step E:4- (6- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1, 1-difluoro-2-hydroxyethyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (93)

Compound 93 was synthesized by the method of reference to compound I-1 in step M of example 1 starting from compound 92 (brown solid, 22 g, 62%).

LCMS (m/z): 497 [M+H]⁺.

Step F:4- (6- (3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1, 1-difluoro-2-hydroxyethyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (94)

Compound 94 (yellow solid, 15 mg, 95%) was synthesized by the method of referring to compound 12 in step G of example 1, starting from compound 93.

LCMS (m/z): 397 [M+H]⁺.

Step G:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1, 1-difluoro-2-hydroxyethyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-26)

Compound I-26 (yellow solid, 1.9 mg, 2%) was synthesized by the method of referring to compound 14 in step H of example 1 starting from compound 94 and compound 5-fluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 521 [M+H]⁺.

¹HNMR (400 MHz, CD₃OD) 8.67 (s, 1H), 8.57 (d,J= 2.4 Hz, 1H), 8.00 (d,J= 9.2 Hz, 1H), 7.05-7.00 (m, 2H), 6.89-6.78 (m, 3H), 4.60-4.55 (m, 4H), 4.08-4.00 (m, 6H), 1.85 (s, 1H), 1.28-41.19 (m, 1H).

Example 27:4- (4- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) phenyl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-27)

Step A:3- (4-bromophenyl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (97)

3, 6-Diazabicyclo [3.1.1] heptane-6-carbonate tert-butyl hydrochloride (compound 95, 1000.0 mg, 4.27 mmol) was placed in 1, 4-dioxane (50 mL), p-bromoiodobenzene (compound 96, 1498.3 mg, 5.30 mmol), potassium carbonate (1454.2 mg, 15.13 mmol), dibenzylideneacetone dipalladium (138.6 mg, 0.15 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (262.7 mg, 0.45 mmol), stirred at 80 ℃ for 12 hours, then poured into an aqueous solution (20 mL), extracted three times with ethyl acetate (10 mL), the organic phases were combined, and column chromatography (petroleum ether/ethyl acetate=10/1) was performed after concentration to give the compound (500 mg, 28%) as a yellow oil.

LCMS (m/z): 353 [M+H]⁺.

And (B) step (B): 3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbonic acid tert-butyl ester (98)

Compound 98 (yellow oil, 0.41 g, 36%) was synthesized by the method of referring to compound 15 in step I of example 1, starting from compound 97.

LCMS (m/z): 401 [M+H]⁺.

Step C:4- (4- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) phenyl) -2- (1-methyl-1H-pyrazol-4-yl) -1- (p-toluenesulfonyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (99)

Compound 99 (yellow oil, 110 mg, 13%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 98 and compound 17.

LCMS (m/z): 650 [M+H]⁺.

Step D:4- (4- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) phenyl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (100)

Compound 100 (yellow solid, 40 mg, 75%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 99.

LCMS (m/z): 496 [M+H]⁺.

Step E:4- (4- (3, 6-diazabicyclo [3, 1] heptan-3-yl) phenyl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (101)

Compound 101 (yellow solid, 30 mg, 94%) was synthesized by the method of referring to compound 12 in step G of example 1, starting from compound 100.

LCMS (m/z): 396 [M+H]⁺.

Step F:4- (4- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) phenyl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-27)

Compound I-27 (white solid, 6.0 mg, 15%) was synthesized by the method of referring to compound 14 in step H of example 1 starting from compound 101 and compound 5-fluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 520 [M+H]⁺.

¹HNMR (400 MHz, CD₃OD) 12.57 (s, 1H), 10.23 (s, 1H), 8.52 (s, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.65 (d,J= 8.4 Hz, 1H), 7.08 (dd,J= 9.6 Hz, 3.2 Hz, 1H), 6.99 (d,J= 8.8 Hz, 1H), 6.88-6.86 (m, 1H), 6.74-6.70 (m, 2 H), 3.88 (s, 3H), 3.79 (d,J= 6.0 Hz, 2H), 3.62-3.60 (m, 4H), 3.46-3.42 (m, 2H), 2.62-2.60 (m, 1H), 1.66-1.65(m, 1H).

Example 28: 2-chloro-N- ((3R, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) -6-fluorobenzamide (I-28)

Step A: ((3R, 4S) -1- (5-bromopyridin-2-yl) -3-hydroxypiperidin-4-yl) aminocarbonate (103)

Compound 103 (540 mg, 63%) was synthesized by the method of referring to compound 11 in step F of example 1, starting from compound 102 and compound 10.

LCMS (m/z): 372 [M+H]⁺.

And (B) step (B): ((3R, 4S) -3-hydroxy-1- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) piperidin-4-yl) aminocarbonate (104)

Compound 104 (white solid, 390 mg, 64%) was synthesized by the method of referring to compound 15 in step I of example 1, starting from compound 103.

LCMS (m/z): 420 [M+H]⁺.

Step C: ((3R, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) aminocarbonate (105)

Compound 105 (yellow solid, 65 mg, 41%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 104 and compound 17.

LCMS (m/z): 669 [M+H]⁺.

Step D:4- (6- ((3R, 4S) -4-amino-3-hydroxypiperidin-1-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (106)

Compound 106 (50 mg, 58%) was synthesized by the method of referring to compound 12 in step G of example 1, starting from compound 105.

LCMS (m/z): 569 [M+H]⁺.

Step E: 2-chloro-N- ((3R, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) -6-fluorobenzamide (107)

4- (6- ((3R, 4S) -4-amino-3-hydroxypiperidin-1-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (compound 106, 64 mg, 0.11 mmol), 2-fluoro-6-chlorobenzoic acid (19.60 mg, 0.11 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (42.70 mg, 0.11 mmol) was placed in dichloromethane (5 mL), triethylamine (17.05 mg, 0.17 mmol) was added, stirred at 25℃for 16 hours, then poured into water (10 mL) and extracted three times with ethyl acetate (10 mL), the organic phases were combined, and after concentration, column chromatography gave compound 107 (60 mg, 74%) as a white solid.

LCMS (m/z): 725 [M+H]⁺.

Step F: 2-chloro-N- ((3R, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) -6-fluorobenzamide (I-28)

Compound I-28 (brown oil, 3 mg, 7.55%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 107.

LCMS (m/z): 571 [M+H]⁺.

¹HNMR (400 MHz, CD₃OD) 8.47 (s, 1H), 8.10 (s, 1H), 7.94-7.93 (m, 2H), 7.50-7.45 (m, 1H), 7.40-7.35 (m, 1H), 7.30-7.25 (m, 1H), 7.20-7.10 (m, 1H), 6.70 (s, 1H), 4.87-4.86 (m, 1H), 4.45-4.30 (m, 2H), 4.20-4.10 (m, 1H), 3.95 (s, 3H), 3.50-3.40 (m, 2H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 1H).

Example 29:4- (6- ((3R, 4S) -4- ((2-chloro-6-fluorobenzyl) amino) -3-hydroxypiperidin-1-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-29)

Step A:4- (6- ((3R, 4S) -4- ((2-chloro-6-fluorobenzyl) amino) -3-hydroxypiperidin-1-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (108)

Compound 108 (white solid, 35 mg, 98%) was synthesized by the method of referring to compound 14 in step H of example 1, starting from compound 106 and compound 2-fluoro-6-chlorobenzaldehyde.

LCMS (m/z): 710 [M+H]⁺.

And (B) step (B): 4- (6- ((3R, 4S) -4- ((2-chloro-6-fluorobenzyl) amino) -3-hydroxypiperidin-1-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-29)

Compound I-29 (white solid, 3 mg, 7.41%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 108.

LCMS (m/z): 557 [M+H]⁺.

¹HNMR (400 MHz, CD₃OD) 8.51 (d,J= 19.2 Hz, 1H), 8.38 (s, 1H), 8.00-7.90 (m, 2H), 7.50-7.40 (m, 2H), 7.40-7.35 (m, 1H), 7.15-7.00 (m, 1H), 6.68 (s, 1H), 4.40-4.35 (m, 2H), 4.10-4.00 (m, 3H), 3.95 (s, 3H), 3.50-3.45 (m, 1H), 3.20-3.15 (m, 1H), 3.10-3.05 (m, 1H), 2.00-1.85 (m, 2H).

Example 30:6- (difluoromethyl) -4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-30)

Step A: 4-chloro-5-cyano-1H-pyrrole [2,3-b ] pyridine 7-oxide (109)

4-Chloro-5-cyano-1H-pyrrolo [2,3-b ] pyridine (compound 19, 1g, 5.60 mmol) was placed in ethyl acetate (20 mL), m-chloroperoxybenzoic acid (1.45 g, 8.40 mmol) was added, stirred at 60 ℃ for 16 hours, then poured into water (10 mL), ethyl acetate (10 mL) was extracted three times, the organic phases were combined, and column chromatography (dichloromethane/methanol=20/1) was performed after concentration to obtain compound 109 (0.5 g, 45%) as a white solid.

LCMS (m/z): 194 [M+H]⁺.

And (B) step (B): 4- (6- (6- (t-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -5-cyano-1H-pyrrole [2,3-b ] naphthyridine 7-oxide (63)

4-Chloro-5-cyano-1H-pyrrole [2,3-b ] pyridine 7-oxide (compound 109, 500 mg, 2.58 mmol) was placed in DMSO (20 mL) and water (2 mL), 6- (6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) boronic acid (compound 62, 1039 mg, 2.58 mmol), 1' -bis triphenylphosphine ferrocene palladium dichloride (188.98 mg, 0.26 mmol), potassium carbonate (1071 mg, 7.75 mmol), stirred at 100 ℃ for 8 hours, then poured into water (40 mL), ethyl acetate (40 mL) extracted three times, the organic phases were combined and column chromatography (dichloromethane/methanol=20/1) separated to give compound 110 (100 mg, 10%) as a white solid after concentration.

LCMS (m/z): 433 [M+H]⁺.

Step C:3- (5- (5-cyano-6- (difluoromethyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3, 1] heptane-6-carbonic acid tert-butyl ester (111)

4- (6- (6- (Tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -5-cyano-1H-pyrrolo [2,3-b ] pyridine 7-oxide (compound 110, 60mg, 0.14 mmol) was placed in dichloromethane (2 mL), methyl triflate (60 mg, 0.14 mmol) was added, stirring was carried out at 25℃for 1 hour, triphenylphosphine (108.9 mg, 0.41 mmol), hexamethylphosphoramide (99.21 mg, 0.55 mmol), (bromodifluoromethyl) trimethylsilane (126.49 mg, 0.62 mmol), stirring was carried out at 40℃for 2 hours, then triethylamine (70.02 mg, 0.69 mmol) and water (1 mL) were added, stirring was carried out at 25℃for 16 hours, and then the reaction solution was directly prepared and separated to obtain white solid compound 111 (3 mg, 5%).

LCMS (m/z): 467 [M+H]⁺.

Step D:4- (6- (3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -6- (difluoromethyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (112)

Compound 112 (2G, 91%) was synthesized according to the method of example 1, step G, using compound 111 as a starting material, compound 12.

LCMS (m/z): 367 [M+H]⁺.

Step H:6- (difluoromethyl) -4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-30)

4- (6- (3, 6-Diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -6- (difluoromethyl) -1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (compound 112, 5mg, 0.01 mmol) was placed in DMF (1 mL), 5-fluoro-2-hydroxybenzyl bromide (compound 113,2.79 mg, 0.01 mmol), diisopropylethylamine (5.27 mg, 0.04 mmol) was added, stirred at 25℃for 1 hour, then directly isolated as brown oil compound I-30 (0.21 mg, 3%).

LCMS (m/z): 491 [M+H]⁺.

Example 31: 6-amino-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-31)

Step A: 6-amino-4-chloro-1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (113)

4-Chloro-5-cyano-1H-pyrrolo [2,3-b ] pyridine 7-oxide (compound 109, 300 mg, 1.55 mmol) was placed in chloroform (10 mL), tert-butylamine (736.74 mg, 10.07 mmol) was added, stirred at 30℃for 2 hours, concentrated and then directly chromatographed to give compound 113 (30 mg, 10%) as a white solid.

LCMS (m/z): 193 [M+H]⁺.

And (B) step (B): 6-amino-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-31)

Compound I-31 (white solid, 2.40 mg, 9.11%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 113 and compound 15.

LCMS (m/z): 456 [M+H]⁺.

¹HNMR (400 MHz, DMSO-d6) 8.47 (d,J= 2.4 Hz, 1H), 7.95 (d,J= 8.8 Hz, 1H), 7.13 (s, 1H ), 6.84-6.80 (m, 2H), 6.73-6.70 (m, 1H), 6.70-6.66 (m, 1H), 6.32 (d,J= 3.6 Hz, 1H), 3.79-3.65 (m, 6H), 3.65-3.60 (m, 2H), 2.80-2.70 (m, 1H), 1.75-1.73 (m, 1H).

Example 32:4- (6- (6- (2-fluoro-2-methoxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-32)

Compound I-32 (white solid, 12 mg, 14.43%) was synthesized by the method of referring to compound 14 in step H of example 1, starting from compound 21 and compound 114.

LCMS (m/z): 455 [M+H]⁺.

¹HNMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.65 (s, 1H), 8.54 (d,J= 2.5 Hz, 1H),7.96 (d,J= 7.2 Hz, 1H), 7.72 (d,J= 3.5 Hz, 1H), 7.40-7.37 (m, 1H), 6.91 (d,J= 9 Hz, 1H), 6.77-6.90 (m, 2H), 6.60 (d,J= 3.5 Hz, 1H), 3.80-3.53 (m, 8H), 2.55-2.53 (m, 1H), 1.60 (d,J= 8.5 Hz, 1H).

Example 33:3- (2-Fluoroethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1H-pyrrole [2,3-b ] naphthyridine-5-carbonitrile (I-33)

Step A:3- (5-bromopyridin-2-yl) -6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane (114)

Compound 114 (yellow solid, 4.44 g, 60%) was synthesized by the method of referring to compound 14 in step H of example 1 starting from compound 12 and compound 6-methoxypyridine-3-carbaldehyde.

LCMS (m/z): 375 [M+H]⁺.

And (B) step (B): (6- (6- (6-methoxypyridin-3-yl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) boronic acid (115)

Compound 115 was synthesized (yellow oil, 2.2 g, 55%) using compound 114 as starting material and by the method of example 1, step I, compound 15.

LCMS (m/z): 341 [M+H]⁺.

Step C: 3-bromo-4-chloro-2-methoxy-1-p-toluenesulfonyl-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (113)

4-Chloro-1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (compound 23, 500 mg, 1.5 mmol) was placed in methanol (20 mL), N-bromosuccinimide (401 mg, 2.25 mmol) was added, stirred at 25 ℃ for 16 hours, then poured into water (40 mL), extracted three times with ethyl acetate (40 mL), the organic phases were combined, and column chromatography (petroleum ether/ethyl acetate=3/1) was concentrated to give compound 116 (yellow solid, 380 mg, 57.06%).

LCMS (m/z): 444 [M+H]⁺.

Step D: 3-fluoroethoxy-4-chloro-2-methoxy-1-p-toluenesulfonyl-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (117)

3-Bromo-4-chloro-2-methoxy-1-p-toluenesulfonyl-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (compound 116, 380 mg, 0.86 mmol) was placed in dichloromethane (10 mL), 2-fluoroethanol (274 mg, 4.28 mmol), silver oxide (198 mg, 0.86 mmol), silver triflate (220 mg, 0.86 mmol), stirred at 25 ℃ for 16 hours, then poured into water (20 mL), extracted three times with dichloromethane (20 mL), the organic phases were combined and separated by column chromatography (petroleum ether/ethyl acetate=3/1) after concentration to give compound 117 (white solid, 100 mg, 27.32%).

LCMS (m/z): 426 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1H), 7.92 (d,J= 8.4 Hz, 2H), 7.34-7.27 (m, 2H), 4.69 (s, 1H), 4.66-4.61 (m, 1H), 4.53-4.50 (m, 1H), 4.07 (s, 1H), 4.02-3.90 (m, 2H), 3.61 (s, 3H), 2.42-2.39 (m, 3H).

Step E: 3-fluoroethoxy-4-chloro-1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (118)

3-Fluoroethoxy-4-chloro-2-methoxy-1-p-toluenesulfonyl-2, 3-dihydro-1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (compound 117, 520 mg, 2.50 mmol) was placed in acetonitrile (20 mL), boron trifluoride (480 mg, 7.50 mmol) was added, stirred at 60 ℃ for 16 hours, then poured into water (20 mL), extracted three times with ethyl acetate (20 mL), the organic phases were combined and concentrated and separated to give compound 118 (white solid, 120 mg, 13.1%) by column chromatography (petroleum ether/ethyl acetate=4/1).

LCMS (m/z): 394 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.00 (d,J= 8.4 Hz, 2H), 7.30 (d,J= 8.4 Hz, 3H), 4.92-4.83 (m, 1H), 4.78-4.73 (m, 1H), 4.34-4.23 (m, 2H), 2.40 (s, 3H).

Step F:4- (6- (6- (6-methoxypyridin-3-yl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -3-fluoroethoxy-1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (119)

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Compound 119 (yellow solid, 18 mg, 36.14%) was synthesized by the method of example 1, step L, compound 18, starting from compound 118 and compound 115.

LCMS (m/z): 654 [M+H]⁺.

Step G:3- (2-Fluoroethoxy) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1H-pyrrole [2,3-b ] naphthyridine-5-carbonitrile (I-33)

Compound I-33 (white solid, 6.2 mg, 41.3%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 119.

LCMS (m/z): 500 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 8.43 (d,J= 2.0 Hz, 1H), 8.10 (s, 1H), 7.94 (dd,J= 8.8, 2.4 Hz, 1H), 7.73 (d,J= 8.4 Hz, 1H), 7.16 (s, 1H), 6.88 (d,J= 8.8 Hz, 1H), 6.79 (d,J= 8.4 Hz, 1H), 4.64-4.57 (m, 2H), 4.55-4.50 (m, 1H), 4.11-4.09 (m, 1H), 4.02-4.03 (m, 1H), 3.93 (s, 1H), 3.88 (s, 3H), 3.81 (d,J= 5.2 Hz, 2H), 3.68-3.64 (m, 4H), 2.71-2.70 (m, 1H), 1.73 (d,J= 8.8 Hz, 1H).

Example 34:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-isopropyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-34)

Step A: 4-chloro-2- (1-isopropyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (120)

Compound 120 was synthesized by the method described in step B of example 9, starting from compound 23 and 1-isopropyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 440[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-isopropyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (121)

Compound 121 was synthesized by the method described in step C of example 9, using compound 15 and compound 120 as starting materials.

LCMS (m/z): 703[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-isopropyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-34)

Compound I-34 was synthesized by the method described in example 9, step D, with compound 121 as the starting material, and with reference to compound I-9.

LCMS (m/z): 549 [M+H]⁺.

Example 35:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-35)

Step A: 4-chloro-2- (1- (2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (122)

Compound 122 was synthesized by the method of referring to compound 35 in step B of example 9, starting from compound 23 and 1- (2, 2-trifluoroethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 480[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (123)

Compound 123 was synthesized by the method described in example 9, step C, using compound 15 and compound 122 as starting materials, and referring to compound 36.

LCMS (m/z): 743[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-35)

Compound I-35 was synthesized by the method described in example 9, step D, with compound 123 as the starting material, and with reference to compound I-9.

LCMS (m/z): 589 [M+H]⁺.

Example 36:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-cyanomethyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-36)

Step A: 4-chloro-2- (1- (1-cyanomethyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (124)

Compound 124 was synthesized by the method of referring to compound 35 in step B of example 9, starting from compound 23 and 1- (2-cyanomethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 437[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (1-cyanomethyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (125)

Compound 125 was synthesized by the method described in example 9, step C, using compound 15 and compound 124 as starting materials, and referring to compound 36.

LCMS (m/z): 700[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (1-cyanomethyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-36)

Compound I-36 was synthesized by the method described in example 9, step D, with compound 125 as the starting material, and with reference to compound I-9.

LCMS (m/z): 546 [M+H]⁺.

Example 37:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (3-hydroxypropyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-37)

Step A: 4-chloro-2- (1- (3-hydroxypropyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (126)

Compound 126 was synthesized by the method described in step B of example 9, starting from compound 23 and 1- (3-hydroxypropyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 456[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (3-hydroxypropyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (127)

Compound 127 was synthesized by the method described in example 9, step C, using compound 15 and compound 126 as starting materials, and referring to compound 36.

LCMS (m/z): 719[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (3-hydroxypropyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-37)

Compound I-37 was synthesized by the method described in example 9, step D, with compound 127 as the starting material, and with reference to compound I-9.

LCMS (m/z): 546 [M+H]⁺.

Example 38:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (3-dimethylaminopropyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-38)

Step A: 4-chloro-2- (1- (3-dimethylaminopropyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (128)

Compound 128 was synthesized by the method of referring to compound 35 in step B of example 9, starting from compound 23 and 1- (3-dimethylaminopropyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 483[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (3-dimethylaminopropyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (129)

Compound 129 was synthesized by the method of referring to compound 36 in step C of example 9, starting from compound 15 and compound 128.

LCMS (m/z): 746[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (3-dimethylaminopropyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-38)

Compound I-38 was synthesized by the method described in example 9, step D, with compound 129 as the starting material.

LCMS (m/z): 592 [M+H]⁺.

Example 39:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-39)

Step A: 4-chloro-2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (130)

Compound 130 was synthesized by the method described in step B of example 9, starting from compound 23 and 1- (piperidin-4-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 481[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (131)

Compound 131 was synthesized by the method described in example 9, step C, using compound 15 and compound 130 as starting materials, and referring to compound 36.

LCMS (m/z): 744[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-39)

Compound I-39 was synthesized by the method described in example 9, step D, with compound 131 as the starting material, and with compound I-9.

LCMS (m/z): 590 [M+H]⁺.

Example 40:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-40)

Step A: 4-chloro-2- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (132)

Compound 132 was synthesized by the method of referring to compound 35 in step B of example 9, starting from compound 23 and 1- (1-methylpiperidin-4-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 495[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (133)

Compound 133 was synthesized by the method described in example 9, step C, using compound 15 and compound 132 as starting materials.

LCMS (m/z): 758[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-40)

Compound I-40 was synthesized by the method described in example 9, step D, with compound 133 as a starting material, and with reference to compound I-9.

LCMS (m/z): 604 [M+H]⁺.

Example 41:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-41)

Step A: 4-chloro-2- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (134)

Compound 134 was synthesized by the method of referring to compound 35 in step B of example 9, starting from compound 23 and 1- (oxetan-3-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 454[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (135)

Compound 135 was synthesized by the method described in example 9, step C, using compound 15 and compound 134 as raw materials.

LCMS (m/z): 717[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-41)

Compound I-41 was synthesized by the method described in example 9, step D, with compound 135 as the starting material, and with reference to compound I-9.

LCMS (m/z): 563 [M+H]⁺.

Example 42:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-42)

Step A: 4-chloro-2- (1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (136)

Compound 136 was synthesized by the method of referring to compound 35 in step B of example 9, starting from compound 23 and 1- (oxetan-3-ylmethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 468[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (137)

Compound 137 was synthesized by the method described in step C of example 9, using compound 15 and compound 136 as raw materials.

LCMS (m/z): 731[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (oxetan-3-ylmethyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-42)

Compound I-42 was synthesized by the method described in step D of example 9 with reference to compound I-9, starting from compound 137.

LCMS (m/z): 577 [M+H]⁺.

Example 43:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-43)

Step A: 4-chloro-2- (1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (138)

Compound 138 was synthesized by the method of reference to compound 35 in step B of example 9 starting from compound 23 and 1- ((tetrahydro-2H-pyran-4-yl) methyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 496[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (139)

Compound 139 was synthesized by the method described in step C of example 9, using compound 15 and compound 138 as raw materials.

LCMS (m/z): 759[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-43)

Compound I-43 was synthesized by the method described in example 9, step D, with compound 139 as a starting material, and with reference to compound I-9.

LCMS (m/z): 605 [M+H]⁺.

Example 44:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (1-acetylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-44)

Step A: 4-chloro-2- (1- (1-acetylpiperidin-4-yl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (140)

Compound 140 was synthesized by the method of referring to compound 35 in step B of example 9, starting from compound 23 and 1- (1-acetylpiperidin-4-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole.

LCMS (m/z): 523[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (1-acetylpiperidin-4-yl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (141)

Compound 141 was synthesized by the method described in example 9, step C, using compound 15 and compound 140 as starting materials.

LCMS (m/z): 786[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (1-acetylpiperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-44)

Compound I-44 was synthesized by the method described in example 9, step D, with compound 141 as the starting material, and with reference to compound I-9.

LCMS (m/z): 632 [M+H]⁺.

Example 45:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (3-aminopropyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-45)

Step A: (3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) propyl) aminocarbonate (142)

Compound 142 was synthesized by the method described in step a of example 9, using compound 33 and tert-butyl 3-bromopropylamine carbonate as starting materials.

LCMS (m/z): 352[M+H]⁺.

And (B) step (B): (3- (4- (4-chloro-5-cyano-1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) propyl) aminocarbonate (143)

Compound 143 was synthesized by the method described in example 9, step B, with compound 58 and compound 142 as starting materials, and with compound 35.

LCMS (m/z): 531[M+H]⁺.

Step C: (3- (4- (5-cyano-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) propyl) aminocarbonate (144)

Compound 144 was synthesized by the method described in example 9, step C, using compound 15 and compound 143 as starting materials.

LCMS (m/z): 794[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (3-aminopropyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-45)

Compound I-45 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 144.

LCMS (m/z): 564 [M+H]⁺.

Example 46:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (3-methylaminopropyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-46)

Step A: (3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) propyl) methylamino carbonate (145)

Compound 145 was synthesized by the method of referring to compound 34 in step a of example 9, starting from compound 33 and tert-butyl 3-bromopropylmethylamine carbonate.

LCMS (m/z): 366[M+H]⁺.

And (B) step (B): (3- (4- (4-chloro-5-cyano-1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) propyl) methylamino carbonate tert-butyl ester (146)

Compound 146 was synthesized by the method described in example 9, step B, with reference to compound 35, starting from compound 58 and compound 145.

LCMS (m/z): 545[M+H]⁺.

Step C: (3- (4- (5-cyano-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) propyl) aminocarbonate (147)

Compound 147 was synthesized by the method described in step C of example 9, using compound 15 and compound 146 as raw materials.

LCMS (m/z): 808[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (3-methylaminopropyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-46)

Compound I-46 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 147.

LCMS (m/z): 578 [M+H]⁺.

Example 47:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((R) -pyrrolidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-47)

Step A: (R) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (148)

Compound 148 was synthesized by the method of referring to compound 34 in step a of example 9, starting from compound 33 and (S) -3- (methylsulfonyloxy) pyrrolidine-1-carbonate.

LCMS (m/z): 364[M+H]⁺.

And (B) step (B): (R) -3- (4- (4-chloro-5-cyano-1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (149)

Compound 149 was synthesized by the method described in example 9, step B, with reference to compound 35, starting from compound 58 and compound 148.

LCMS (m/z): 543[M+H]⁺.

Step C: (3R) - (3- (4- (5-cyano-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] naphthyridin-2-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carbonate tert-butyl ester (150)

Compound 150 was synthesized by the method described in example 9, step C, using compound 15 and compound 149 as starting materials, and referring to compound 36.

LCMS (m/z): 806[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((R) -pyrrolidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-47)

Compound I-47 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 150.

LCMS (m/z): 576 [M+H]⁺.

Example 48:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((S) -pyrrolidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-48)

Step A: (S) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (151)

Compound 151 was synthesized by the method of referring to compound 34 in step a of example 9, starting from compound 33 and (R) -3- (methylsulfonyloxy) pyrrolidine-1-carbonate.

LCMS (m/z): 364[M+H]⁺.

And (B) step (B): (S) -3- (4- (4-chloro-5-cyano-1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (152)

Compound 152 was synthesized by the method described in example 9, step B, with reference to compound 35, starting from compound 58 and compound 151.

LCMS (m/z): 543[M+H]⁺.

Step C: (3S) - (3- (4- (5-cyano-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] naphthyridin-2-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carbonate tert-butyl ester (153)

Compound 153 was synthesized by the method described in example 9, step C, using compound 15 and compound 152 as raw materials.

LCMS (m/z): 806[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((S) -pyrrolidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-48)

Compound I-48 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 153.

LCMS (m/z): 576 [M+H]⁺.

Example 49:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-49)

Step A:4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (154)

Compound 154 was synthesized by the method of referring to compound 34 in step a of example 9, starting from compound 33 and 4-iodopiperidine-1-carbonate.

LCMS (m/z): 388[M+H]⁺.

And (B) step (B): 4- (4- (4-chloro-5-cyano-1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (155)

Compound 155 was synthesized by the method described in example 9, step B, with reference to compound 35, starting from compound 58 and compound 154.

LCMS (m/z): 557[M+H]⁺.

Step C: 4- (4- (4- (5-cyano-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] naphthyridin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (156)

Compound 156 was synthesized by the method described in example 9, step C, using compound 15 and compound 155 as raw materials.

LCMS (m/z): 820[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-49)

Compound I-49 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 156.

LCMS (m/z): 590 [M+H]⁺.

Example 50:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-50)

Step A:3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) azetidine-1-carbonate tert-butyl ester (157)

Compound 157 was synthesized by the method of referring to compound 34 in step a of example 9, starting from compound 33 and 3-iodoazetidine-1-carbonate.

LCMS (m/z): 360[M+H]⁺.

And (B) step (B): 3- (4- (4-chloro-5-cyano-1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) azetidine-1-carboxylic acid tert-butyl ester (158)

Compound 158 was synthesized by the method described in example 9, step B, with reference to compound 35, starting from compound 58 and compound 157.

LCMS (m/z): 529[M+H]⁺.

Step C: 3- (4- (4- (5-cyano-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] naphthyridin-2-yl) -1H-pyrazol-1-yl) azetidine-1-carbonate tert-butyl ester (159)

Compound 159 was synthesized by the method described in example 9, step C, using compound 15 and compound 158 as starting materials.

LCMS (m/z): 792[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (azetidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-50)

Compound I-50 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 159.

LCMS (m/z): 562 [M+H]⁺.

Example 51:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((R) -piperidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-51)

Step A: (R) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (160)

Compound 160 was synthesized by the method of referring to compound 34 in step a of example 9, starting from compound 33 and tert-butyl (S) -3- (methylsulfonyloxy) piperidine-1-carbonate.

LCMS (m/z): 388[M+H]⁺.

And (B) step (B): (R) -3- (4- (4-chloro-5-cyano-1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (161)

Compound 161 was synthesized by the method described in step B of example 9 with reference to compound 35, starting from compound 58 and compound 160.

LCMS (m/z): 557[M+H]⁺.

Step C: (3R) - (3- (4- (5-cyano-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] naphthyridin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carbonate (162)

Compound 162 was synthesized by the method described in step C of example 9, using compound 15 and compound 161 as raw materials.

LCMS (m/z): 820[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((R) -piperidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-51)

Compound I-51 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 162.

LCMS (m/z): 590 [M+H]⁺.

Example 52:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((S) -piperidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-52)

Step A: (S) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (163)

Compound 163 was synthesized by the method of referring to compound 34 in step a of example 9, starting from compound 33 and tert-butyl (R) -3- (methylsulfonyloxy) piperidine-1-carbonate.

LCMS (m/z): 378[M+H]⁺.

And (B) step (B): (S) -3- (4- (4-chloro-5-cyano-1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (164)

Compound 164 was synthesized by the method described in example 9, step B, with compound 58 and compound 163 as starting materials.

LCMS (m/z): 557[M+H]⁺.

Step C: (3S) - (3- (4- (5-cyano-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] naphthyridin-2-yl) -1H-pyrazol-1-yl) piperidine-1-carbonate (165)

Compound 165 was synthesized by the method described in step C of example 9, using compound 15 and compound 164 as starting materials.

LCMS (m/z): 820[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((S) -piperidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-52)

Compound I-52 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 165.

LCMS (m/z): 576 [M+H]⁺.

Example 53:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((R) -1-acetylpyrrolidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-53)

Step A: (R) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) -1-acetylpyrrolidine (166)

Compound 166 was synthesized by the method of referring to compound 34 in step a of example 9, starting from compound 33 and (S) -3- (methylsulfonyloxy) -1-acetylpyrrolidine.

LCMS (m/z): 306[M+H]⁺.

And (B) step (B): (R) -3- (4- (4-chloro-5-cyano-1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) -1-acetylpyrrolidine (167)

Compound 167 was synthesized by the method described in example 9, step B, with compound 58 and compound 166 as starting materials, and with reference to compound 35.

LCMS (m/z): 485[M+H]⁺.

Step C: (3R) - (3- (4- (5-cyano-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) -1-acetylpyrrolidine (168)

Compound 168 was synthesized by the method described in example 9, step C, using compound 15 and compound 167 as starting materials, and referring to compound 36.

LCMS (m/z): 748[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((R) -1-acetylpyrrolidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-53)

Compound I-53 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 168.

LCMS (m/z): 618 [M+H]⁺.

Example 54:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((S) -1-acetylpyrrolidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-54)

Step A: (S) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) -1-acetylpyrrolidine (169)

Compound 169 was synthesized according to the procedure of step a of example 9, using compound 33 and (R) -3- (methylsulfonyloxy) -1-acetylpyrrolidine as starting materials.

LCMS (m/z): 306[M+H]⁺.

And (B) step (B): (S) -3- (4- (4-chloro-5-cyano-1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) -1-acetylpyrrolidine (170)

Compound 170 was synthesized by the method described in example 9, step B, with reference to compound 35, starting from compound 58 and compound 169.

LCMS (m/z): 485[M+H]⁺.

Step C: (3S) - (3- (4- (5-cyano-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) -1-acetylpyrrolidine (171)

Compound 171 was synthesized by the method described in example 9, step C, using compound 15 and compound 170 as starting materials.

LCMS (m/z): 748[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((S) -1-acetylpyrrolidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-54)

Compound I-54 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 171.

LCMS (m/z): 618 [M+H]⁺.

Example 55:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((R) -1-acetylpiperidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-55)

Step A: (R) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) -1-acetylpiperidine (172)

Compound 172 was synthesized by the method of referring to compound 34 in step a of example 9, starting from compound 33 and (S) -3- (methylsulfonyloxy) -1-acetylpiperidine.

LCMS (m/z): 320[M+H]⁺.

And (B) step (B): (R) -3- (4- (4-chloro-5-cyano-1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] naphthyridin-2-yl) -1H-pyrazol-1-yl) -1-acetylpiperidine (173)

Compound 173 was synthesized by the method described in example 9, step B, with compound 58 and compound 172 as starting materials, and with compound 35.

LCMS (m/z): 499[M+H]⁺.

Step C: (3R) - (3- (4- (5-cyano-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] naphthyridin-2-yl) -1H-pyrazol-1-yl) -1-acetylpiperidine (174)

Compound 174 was synthesized by the method described in example 9, step C, using compound 15 and compound 173 as starting materials, and referring to compound 36.

LCMS (m/z): 762[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((R) -1-acetylpiperidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-55)

Compound I-55 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 174.

LCMS (m/z): 632 [M+H]⁺.

Example 56:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((S) -1-acetylpiperidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-56)

Step A: (S) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) -1-acetylpiperidine (175)

Compound 175 was synthesized by the method of referring to compound 34 in step a of example 9, starting from compound 33 and (R) -3- (methylsulfonyloxy) -1-acetylpiperidine.

LCMS (m/z): 320[M+H]⁺.

And (B) step (B): (S) -3- (4- (4-chloro-5-cyano-1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) -1-acetylpiperidine (176)

Compound 176 was synthesized by the method described in example 9, step B, with compound 58 and compound 175 as starting materials.

LCMS (m/z): 499[M+H]⁺.

Step C: (3S) - (3- (4- (5-cyano-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] naphthyridin-2-yl) -1H-pyrazol-1-yl) -1-acetylpiperidine (177)

Compound 177 was synthesized by the method described in step C of example 9, using compound 15 and compound 176 as starting materials.

LCMS (m/z): 762[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((S) -1-acetylpiperidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-56)

Compound I-56 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 177.

LCMS (m/z): 632 [M+H]⁺.

Example 57:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (4-acetamidobutyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-57)

Step A: n- (4- (4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) butyl) acetamide (178)

Compound 178 was synthesized by the method of referring to compound 34 in step a of example 9, starting from compound 33 and N-4-bromobutyl acetamide.

LCMS (m/z): 308[M+H]⁺.

And (B) step (B): n- (4- (4- (4-chloro-5-cyano-1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) butyl) acetamide (179)

Compound 179 was synthesized by the method described in example 9, step B, with reference to compound 35, starting from compound 58 and compound 178.

LCMS (m/z): 487[M+H]⁺.

Step C: n- (3- (4- (5-cyano-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) butyl) acetamide (180)

Compound 180 was synthesized by the method described in example 9, step C, using compound 15 and compound 179 as starting materials.

LCMS (m/z): 750[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (4-acetamidobutyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-57)

Compound I-57 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 180.

LCMS (m/z): 620 [M+H]⁺.

Example 58:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (4-acetamidopropyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-58)

Step A: N-methyl-N- (4- (4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) propyl) acetamide (181)

Compound 181 was synthesized by the method described in step a of example 9, using compound 33 and N-methyl-N-3-bromopropylacetamide as starting materials.

LCMS (m/z): 308[M+H]⁺.

And (B) step (B): N-methyl-N- (4- (4- (4-chloro-5-cyano-1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) propyl) acetamide (179)

Compound 182 was synthesized by the method described in step B of example 9 with reference to compound 35, starting from compound 58 and compound 181.

LCMS (m/z): 487[M+H]⁺.

Step C: N-methyl-N- (3- (4- (5-cyano-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) propyl) acetamide (183)

Compound 183 was synthesized by the method described in example 9, step C, using compound 15 and compound 182 as starting materials.

LCMS (m/z): 750[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (4-acetamidopropyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-58)

Compound I-58 was synthesized by the method described in example 20, step G, with compound 183 as a starting material, and compound 64.

LCMS (m/z): 620 [M+H]⁺.

Example 59:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (4-acetamidopropyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-59)

Step A: n- (4- (4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) propyl) acetamide (184)

Compound 184 was synthesized by the method described in step a of example 9, using compound 33 and N-4-bromopropyl acetamide as starting materials.

LCMS (m/z): 294[M+H]⁺.

And (B) step (B): n- (4- (4- (4-chloro-5-cyano-1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) propyl) acetamide (185)

Compound 185 was synthesized by the method described in example 9, step B, with reference to compound 35, starting from compound 58 and compound 184.

LCMS (m/z): 473[M+H]⁺.

Step C: n- (3- (4- (5-cyano-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) propyl) acetamide (186)

Compound 186 was synthesized by the method described in example 9, step C, using compound 15 and compound 185 as starting materials.

LCMS (m/z): 736[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (4-acetamidopropyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-59)

Compound I-59 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 186.

LCMS (m/z): 606 [M+H]⁺.

Example 60:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (1-acetylazetidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-60)

Step A:3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) -1-acetylazetidine (187)

Compound 187 was synthesized by the method described in step a of example 9, starting from compound 33 and 3-iodo-1-acetylazetidine.

LCMS (m/z): 292[M+H]⁺.

And (B) step (B): 3- (4- (4-chloro-5-cyano-1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] naphthyridin-2-yl) -1H-pyrazol-1-yl) -1-acetylazetidine (188)

Compound 188 was synthesized by the method described in step B of example 9 with reference to compound 35, starting from compound 58 and compound 187.

LCMS (m/z): 471[M+H]⁺.

Step C: 3- (4- (4- (5-cyano-4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1- ((2- ((trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridin-2-yl) -1H-pyrazol-1-yl) -1-acetylazetidine (189)

Compound 189 was synthesized by the method described in example 9, step C, using compound 15 and compound 188 as starting materials.

LCMS (m/z): 734[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (1-acetylazetidin-3-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-60)

Compound I-60 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 189.

LCMS (m/z): 604 [M+H]⁺.

Example 61:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((R) -2-hydroxypropyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-61)

Step A: (R) -1- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) -2-propanol (190)

Compound 190 was synthesized by the method of referring to compound 34 in step a of example 9, starting from compound 33 and (R) -propylene oxide.

LCMS (m/z): 253[M+H]⁺.

And (B) step (B): 4-chloro-2- (1- ((R) -2-hydroxypropyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (191)

Compound 191 was synthesized by the method described in example 9, step B, with reference to compound 35, starting from compound 23 and compound 190.

LCMS (m/z): 456[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((R) -2-hydroxypropyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (192)

Compound 192 was synthesized by the method described in example 9, step C, using compound 15 and compound 191 as starting materials.

LCMS (m/z): 719[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((R) -2-hydroxypropyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-61)

Compound I-61 was synthesized by the method described in example 9, step D, with compound 192 as the starting material, and compound I-9.

LCMS (m/z): 565 [M+H]⁺.

Example 62:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((S) -2-hydroxypropyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-62)

Step A: (S) -1- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazol-1-yl) -2-propanol (193)

Compound 193 was synthesized by the method described in step a of example 9, using compound 33 and (S) -propylene oxide as starting materials.

LCMS (m/z): 253[M+H]⁺.

And (B) step (B): 4-chloro-2- (1- ((S) -2-hydroxypropyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (194)

Compound 194 was synthesized by the method described in step B of example 9 with reference to compound 35, starting from compound 23 and compound 193.

LCMS (m/z): 456[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((S) -2-hydroxypropyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (195)

Compound 195 was synthesized by the method described in example 9, step C, using compound 15 and compound 194 as starting materials.

LCMS (m/z): 719[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- ((S) -2-hydroxypropyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-62)

Compound I-62 was synthesized by the method described in example 9, step D, with compound 195 as a starting material, and with reference to compound I-9.

LCMS (m/z): 565 [M+H]⁺.

Example 63:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2- (oxetan-3-yl) ethyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-63)

Step A: 1- (2- (oxetan-3-yl) ethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole (196)

Compound 196 was synthesized by the method described in step a of example 9, starting from compound 33 and 3- (2-bromoethyl) oxetane.

LCMS (m/z): 279[M+H]⁺.

And (B) step (B): 4-chloro-2- (1- (2- (oxetan-3-yl) ethyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (197)

Compound 197 was synthesized by the method described in example 9, step B, with reference to compound 35, starting from compound 23 and compound 196.

LCMS (m/z): 482[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2- (oxetan-3-yl) ethyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (198)

Compound 198 was synthesized by the method described in example 9, step C, using compound 15 and compound 197 as starting materials.

LCMS (m/z): 745[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2- (oxetan-3-yl) ethyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-63)

Compound I-63 was synthesized by the method described in example 9, step D, with compound 198 as the starting material.

LCMS (m/z): 591 [M+H]⁺.

Example 64:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-difluoromethoxyethyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-64)

Step A: 1- (2- (oxetan-3-yl) ethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole (199)

Compound 199 was synthesized by the method described in step a of example 9, starting from compound 33 and (2-bromoethyl) difluoromethyl ether.

LCMS (m/z): 289[M+H]⁺.

And (B) step (B): 4-chloro-2- (1- (2-difluoromethoxyethyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (200)

Compound 200 was synthesized by the method described in example 9, step B, with reference to compound 35, starting from compound 23 and compound 199.

LCMS (m/z): 492[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-difluoromethoxyethyl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (201)

Compound 201 was synthesized by the method of referring to compound 36 in step C of example 9, starting from compound 15 and compound 200.

LCMS (m/z): 755[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-difluoromethoxyethyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-64)

Compound I-64 was synthesized by the method described in step D of example 9 with reference to compound I-9, starting from compound 201.

LCMS (m/z): 601 [M+H]⁺.

Example 65:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (difluoromethoxyethyl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-65)

Step A: 1- (2-oxaspiro [3.3] heptan-6-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole (202)

Compound 202 was synthesized by the method of referring to compound 34 in step a of example 9, starting from compound 33 and 2-oxaspiro [3.3] heptane-6-yl methanesulfonate.

LCMS (m/z): 291[M+H]⁺.

And (B) step (B): 4-chloro-2- (1- (2-oxaspiro [3.3] heptane-6-yl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (203)

Compound 203 was synthesized by the method described in example 9, step B, with reference to compound 35, starting from compound 23 and compound 202.

LCMS (m/z): 494[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-oxaspiro [3.3] heptan-6-yl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (204)

Compound 204 was synthesized by the method described in example 9, step C, using compound 15 and compound 203 as starting materials, and referring to compound 36.

LCMS (m/z): 757[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-oxaspiro [3.3] heptan-6-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-65)

Compound I-65 was synthesized by the method described in step D of example 9 with reference to compound I-9, starting from compound 204.

LCMS (m/z): 603 [M+H]⁺.

Example 66:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-acetyl-2-azaspiro [3.3] heptan-6-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-66)

Step A: 1- (2-acetyl-2-azaspiro [3.3] heptane-6-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole (205)

Compound 205 was synthesized by the method of referring to compound 34 in step a of example 9, starting from compound 33 and 2-acetyl-2-azaspiro [3.3] heptane-6-yl methanesulfonate.

LCMS (m/z): 332[M+H]⁺.

And (B) step (B): 4-chloro-2- (1- (2-acetyl-2-azaspiro [3.3] heptane-6-yl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (206)

Compound 206 was synthesized by the method described in example 9, step B, with reference to compound 35, starting from compound 23 and compound 205.

LCMS (m/z): 535[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-acetyl-2-azaspiro [3.3] heptan-6-yl) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (207)

Compound 207 was synthesized by the method described in example 9, step C, using compound 15 and compound 206 as starting materials.

LCMS (m/z): 783[M+H]⁺.

Step D:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-acetyl-2-azaspiro [3.3] heptan-6-yl) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-66)

Compound I-66 was synthesized by the method described in example 9, step D, with compound 207 as the starting material.

LCMS (m/z): 644 [M+H]⁺.

Example 67:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (5-methyl-oxazol-2-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-67)

Step A: 4-chloro-2- (5-methyl-oxazol-2-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (208)

Compound 208 was synthesized by the method described in step B of example 9, referring to compound 35, starting from compound 23 and 5-methyl-2-tributylstannyl oxazole.

LCMS (m/z): 413[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (5-methyl-oxazol-2-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (209)

Compound 209 was synthesized by the method described in example 9, step C, with reference to compound 36, starting from compound 15 and compound 208.

LCMS (m/z): 676[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (5-methyl-oxazol-2-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-67)

Compound I-67 was synthesized by the method described in example 9, step D, with compound 209 as the starting material, and with reference to compound I-9.

LCMS (m/z): 522 [M+H]⁺.

Example 68:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (4-methyl-oxazol-2-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-68)

Step A: 4-chloro-2- (4-methyl-oxazol-2-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (210)

Compound 210 was synthesized by the method described in step B of example 9, starting from compound 23 and 4-methyl-2-tributylstannyl oxazole, with reference to compound 35.

LCMS (m/z): 413[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (4-methyl-oxazol-2-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (211)

Compound 211 was synthesized by the method described in example 9, step C, using compound 15 and compound 210 as starting materials.

LCMS (m/z): 676[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (4-methyl-oxazol-2-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-68)

Compound I-68 was synthesized by the method described in example 9, step D, with compound 211 as the starting material.

LCMS (m/z): 522 [M+H]⁺.

Example 69:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (5-methylthiazol-2-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-69)

Step A: 4-chloro-2- (5-methylthiazol-2-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (212)

Compound 212 was synthesized by the method described in step B of example 9, starting from compound 23 and 5-methyl-2-tributylstannylthiazole, with reference to compound 35.

LCMS (m/z): 429[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (5-methylthiazol-2-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (213)

Compound 213 was synthesized by the method described in example 9, step C, using compound 15 and compound 212 as starting materials.

LCMS (m/z): 692[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (5-methylthiazol-2-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-69)

Compound I-69 was synthesized by the method described in step D of example 9 with reference to compound I-9, starting from compound 213.

LCMS (m/z): 538 [M+H]⁺.

Example 70:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (4-methylthiazol-2-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-70)

Step A: 4-chloro-2- (4-methylthiazol-2-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (214)

Compound 214 was synthesized by the method described in step B of example 9, with reference to compound 35, starting from compound 23 and 4-methyl-2-tributylstannylthiazole.

LCMS (m/z): 429[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (4-methylthiazol-2-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (215)

Compound 215 was synthesized by the method described in example 9, step C, using compound 15 and compound 214 as starting materials.

LCMS (m/z): 692[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (4-methylthiazol-2-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-70)

Compound I-70 was synthesized by the method described in step D of example 9 with reference to compound I-9, starting from compound 215.

LCMS (m/z): 538 [M+H]⁺.

Example 71:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (5-methylisoxazol-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-71)

Step A: 4-chloro-2- (5-methylisoxazol-3-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (216)

Compound 216 was synthesized by the method described in step B of example 9, starting from compound 23 and 5-methyl-3-tributylstannyl isoxazole.

LCMS (m/z): 413[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (5-methylisoxazol-3-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (217)

Compound 217 was synthesized by the method described in example 9, step C, using compound 15 and compound 216 as starting materials.

LCMS (m/z): 676[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (5-methylisoxazol-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-71)

Compound I-71 was synthesized by the method described in example 9, step D, with compound 217 as a starting material, and with reference to compound I-9.

LCMS (m/z): 522 [M+H]⁺.

Example 72:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (5-methyl-1H-pyrazol-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-71)

Step A: 4-chloro-2- (5-methyl-1H-pyrazol-3-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (218)

Compound 218 was synthesized by the method described in step B of example 9, starting from compound 23 and 5-methyl-3-tributylstannyl-1H-pyrazole.

LCMS (m/z): 412[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (5-methyl-1H-pyrazol-3-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (219)

Compound 219 was synthesized by the method described in example 9, step C, using compound 15 and compound 218 as starting materials.

LCMS (m/z): 675[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (5-methyl-1H-pyrazol-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-72)

Compound I-72 was synthesized by the method described in step D of example 9 with reference to compound I-9, starting from compound 219.

LCMS (m/z): 521 [M+H]⁺.

Example 73:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2-morpholin-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-73)

Step A: 2-iodo-4- ((4-methoxybenzyl) oxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (220)

P-methoxybenzyl alcohol (138 mg,1 mmol) was placed in tetrahydrofuran (20 mL), potassium tert-butoxide (112 mg,1 mmol) was added at 25 ℃, stirred at0 ℃ for 2 hours, then 2-iodo-4-chloro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (compound 58, 433 mg,1 mmol), stirred at 25 ℃ for 2 hours, then poured into water (20 mL), extracted three times with ethyl acetate (20 mL), the organic phases combined, and column chromatography (petroleum ether/ethyl acetate=1/1) separated to give compound 220 (348 mg, 65%) as a white solid.

LCMS (m/z): 536[M+H]⁺.

And (B) step (B): 2-morpholin-4- ((4-methoxybenzyl) oxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (221)

2-Iodo-4- ((4-methoxybenzyl) oxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (compound 220, 348 mg, 0.65 mmol) was placed in 1, 4-dioxane (20 mL), morpholine (56.55 mg, 0.65 mol) was added, dichloro [1, 3-bis (2, 6-diisoheptylphenyl) imidazol-2-ylidene ] (3-chloropyridinyl) palladium (II) (40.7 mg, 0.06 mol), cesium carbonate (422.5 mg, 1.3 mol) was stirred at 100 ℃ for 6 hours, then concentrated and then column chromatography (dichloromethane/methanol=10/1) was isolated as yellow oil compound 221 (55 mg, 17%).

LCMS (m/z): 495[M+H]⁺.

Step C: 2-morpholin-4-hydroxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (222)

2-Morpholin-4- ((4-methoxybenzyl) oxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (compound 221, 55 mg, 0.11 mol) was placed in methanol (10 mL), palladium on carbon (10 mg) was added, stirred under hydrogen for 2 hours at 25 ℃, then filtered, and the filtrate after filtration was concentrated to give compound 222 (40 mg, 97%) as a yellow oil.

LCMS (m/z): 375[M+H]⁺.

Step D: 2-morpholin-4-trifluoromethanesulfonyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (223)

2-Morpholin-4-hydroxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (compound 222, 40 mg, 0.11 mol) was placed in tetrahydrofuran (10 mL), diisopropylethylamine (27 mg, 0.22 mol), trifluoromethanesulfonic anhydride (31 mg, 0.11 mol) was added, stirred at 25 ℃ for 2 hours, then poured into water (10 mL), extracted three times with ethyl acetate (10 mL), the organic phases were combined, and column chromatography (dichloromethane/methanol=10/1) was separated to give yellow oil compound 223 (35 mg, 63%).

LCMS (m/z): 507[M+H]⁺.

Step E:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2-morpholin-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (224)

Compound 224 (yellow oil, 20 mg, 43%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 223 and compound 15.

LCMS (m/z): 656 [M+H]⁺.

Step F:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2-morpholin-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-73)

I-73 (white solid, 1.5 mg, 9%) was synthesized by the method of referring to compound 64 in step G of example 20, starting from compound 224.

LCMS (m/z): 526 [M+H]⁺.

Example 74:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3 hydroxy-3-methylazetidin-1-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-74)

Step A:2- (3 hydroxy-3-methylazetidin-1-yl) -4- ((4-methoxybenzyl) oxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (225)

Compound 225 was synthesized by the method described in step B of example 73, starting from compound 220 and compound 3-hydroxy-3-methylazetidine.

LCMS (m/z): 495[M+H]⁺.

And (B) step (B): 2- (3 hydroxy-3-methylazetidin-1-yl) -4-hydroxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (226)

Compound 226 was synthesized by the method described in step C of example 73 with reference to compound 222, starting from compound 225.

LCMS (m/z): 375[M+H]⁺.

Step C:2- (3 hydroxy-3-methylazetidin-1-yl) -4-trifluoromethanesulfonyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (227)

Compound 227 was synthesized by the method described in step D of example 73 with reference to compound 223, starting from compound 226.

LCMS (m/z): 507[M+H]⁺.

Step E:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3 hydroxy-3-methylazetidin-1-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (228)

Compound 228 was synthesized by the method described in step E of example 73, using compound 227 and compound 15 as starting materials.

LCMS (m/z): 656 [M+H]⁺.

Step F:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (3 hydroxy-3-methylazetidin-1-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-74)

Compound I-74 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 228.

LCMS (m/z): 526 [M+H]⁺.

Example 75:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (4-methylpiperazin-1-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-75)

Step A:2- (4-methylpiperazin-1-yl) -4- ((4-methoxybenzyl) oxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (229)

Compound 229 was synthesized by the method of reference to compound 221 in step B of example 73, starting with compound 220 and compound 1-methylpiperazine.

LCMS (m/z): 508[M+H]⁺.

And (B) step (B): 2- (4-methylpiperazin-1-yl) -4-hydroxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (230)

Compound 230 was synthesized by the method described in step C of example 73, using compound 229 as a starting material.

LCMS (m/z): 388[M+H]⁺.

Step C:2- (4-methylpiperazin-1-yl) -4-trifluoromethanesulphonyloxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (231)

Compound 231 was synthesized by the method described in step D of example 73 with reference to compound 223, starting from compound 230.

LCMS (m/z): 520[M+H]⁺.

Step E:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (4-methylpiperazin-1-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (232)

Compound 232 was synthesized by the method described in step E of example 73, using compound 231 and compound 15 as starting materials.

LCMS (m/z): 669 [M+H]⁺.

Step F:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (4-methylpiperazin-1-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-75)

Compound I-75 was synthesized by the method described in example 20, step G, with reference to compound 64, starting from compound 228.

LCMS (m/z): 526 [M+H]⁺.

Example 76:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (2-fluoroethoxy) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-76)

Step A:2- (2-Fluoroethoxy) -4- ((4-methoxybenzyl) oxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (233)

Compound 233 was synthesized by the method described in step B of example 73, using compound 220 and compound 2-fluoroethanol as starting materials.

LCMS (m/z): 472[M+H]⁺.

And (B) step (B): 2- (2-Fluoroethoxy) -4-hydroxy-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (234)

Compound 234 was synthesized by the method described in step C of example 73, using compound 233 as a starting material.

LCMS (m/z): 388[M+H]⁺.

Step C:2- (2-Fluoroethoxy) -4-trifluoromethanesulfonyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (235)

Compound 235 was synthesized by the method described in step D of example 73, using compound 234 as a starting material.

LCMS (m/z): 484[M+H]⁺.

Step E:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (2-fluoroethoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (236)

Compound 236 was synthesized by the method described in step E of example 73, with reference to compound 224, starting from compound 235 and compound 15.

LCMS (m/z): 633 [M+H]⁺.

Step F:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (2-fluoroethoxy) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-76)

Compound 236 was used as a starting material, and compound I-76 was synthesized by the method described with reference to compound 64 in step G of example 20.

LCMS (m/z): 503 [M+H]⁺.

Example 77:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methylpiperazin-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-77)

Step A: 4-chloro-2- (1-methylpiperazin-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (237)

Compound 237 was synthesized by the method described in step B of example 9, using compound 23 and 1-methylpiperazine-4-boronic acid as starting materials.

LCMS (m/z): 429[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methylpiperazin-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (238)

Compound 238 was synthesized by the method described in step C of example 9, starting from compound 15 and compound 237.

LCMS (m/z): 692[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (1-methylpiperazin-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-77)

Compound I-77 was synthesized by the method described in example 9, step D, with compound 238 as the starting material, and with compound I-9.

LCMS (m/z): 538 [M+H]⁺.

Example 78:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (tetrahydropyran-2H-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-78)

Step A: 4-chloro-2- (tetrahydropyran-2H-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] naphthyridine-5-carbonitrile (239)

Compound 239 was synthesized by the method described in step B of example 9, with reference to compound 35, starting from compound 23 and tetrahydropyran-2H-4-boronic acid.

LCMS (m/z): 429[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (tetrahydropyran-2H-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (240)

Compound 240 was synthesized by the method described in example 9, step C, using compound 15 and compound 239 as raw materials, and referring to compound 36.

LCMS (m/z): 679[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (tetrahydropyran-2H-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-78)

Compound I-78 was synthesized by the method described in example 9, step D, with compound 240 as the starting material.

LCMS (m/z): 525 [M+H]⁺.

Example 79:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (methyl-d 3) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-79)

Step A: 4-chloro-2- (1- (methyl-d 3) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (241)

Compound 241 was synthesized by the method of referring to compound 35 in step B of example 9, starting from compound 23 and 1- (methyl-d 3) -1H-pyrazole-4-boronic acid.

LCMS (m/z): 415[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (methyl-d 3) -1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (242)

Compound 242 was synthesized by the method described in example 9, step C, using compound 15 and compound 241 as raw materials.

LCMS (m/z): 678[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (1- (methyl-d 3) -1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-79)

Compound I-79 was synthesized by the method described in example 9, step D, with compound 242 as the starting material.

LCMS (m/z): 524 [M+H]⁺.

Example 80:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (2-methylthiazol-2-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-80)

Step A: 4-chloro-2- (4-methylthiazol-5-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (243)

Compound 243 was synthesized by the method described in step B of example 9, with reference to compound 35, starting from compound 23 and 2-methyl-5-tributylstannylthiazole.

LCMS (m/z): 429[M+H]⁺.

And (B) step (B): 4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (2-methylthiazol-5-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (244)

Compound 244 was synthesized by the method described in example 9, step C, with compound 15 and compound 243 as starting materials, and with compound 36.

LCMS (m/z): 692[M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1- (2-methylthiazol-5-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-80)

Compound I-80 was synthesized by the method described in step D of example 9 with reference to compound I-9, starting from compound 244.

LCMS (m/z): 538 [M+H]⁺.

Example 81:4- (2- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) thiazol-5-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-81)

Step A:3- (5-Bromothiazol-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (245)

Compound 245 was synthesized by the method described in step F of example 1, using compound 9 and compound 2, 5-dibromothiazole as starting materials.

LCMS (m/z): 361 [M+H]⁺.

And (B) step (B): 3- (5- (tributylstannyl) thiazol-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (246)

A solution of compound 245 (1.3 mmol) in anhydrous tetrahydrofuran (10 mL) was cooled to-78℃under nitrogen, tri-n-butyltin chloride (0.708 mL,2.61 mmol) was added dropwise to the above mixed solution and the reaction was continued at-78℃for 2-3 hours, after the completion of the reaction, a saturated aqueous ammonium chloride solution (3 mL), water (20 mL) and ethyl acetate (25 mL) were added in this order to dilute the reaction mixture, the organic layer was separated, and the aqueous layer was back-extracted with ethyl acetate (25 mL X2). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting compound 246 was purified by silica gel column chromatography (60-120 mesh) with 10% ethyl acetate in hexane.

LCMS (m/z): 572 [M+H]⁺.

Step C:4- (2- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) thiazol-5-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1- (p-toluenesulfonyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (247)

Compound 247 was synthesized by the method described in step L of example 1, using compound 246 and compound 17 as starting materials.

LCMS (m/z): 657 [M+H]⁺.

Step D:4- (2- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) thiazol-5-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (248)

Compound 248 was synthesized by the method described in example 1, step M, with reference to compound I-1, starting from compound 247.

LCMS (m/z): 503 [M+H]⁺.

Step E:4- (2- (3, 6-diazabicyclo [3, 1] heptan-3-yl) thiazol-5-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (249)

Compound 249 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 248.

LCMS (m/z): 403 [M+H]⁺.

Step F:4- (2- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) thiazol-5-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-81)

Compound I-81 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 249 and compound 5-fluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 527 [M+H]⁺.

Example 82:4- (2- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrimidin-5-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-82)

Step A:3- (5-bromopyrimidin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (250)

Compound 250 was synthesized by the method described in example 1, step F, with respect to compound 11, starting from compound 9 and compound 2-chloro-5-bromopyrimidine.

LCMS (m/z): 354 [M+H]⁺.

And (B) step (B): 3- (5- (tributylstannyl) pyrimidin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbonic acid tert-butyl ester (251)

Compound 251 was synthesized by the method described in example 81, step B, starting from compound 250.

LCMS (m/z): 567 [M+H]⁺.

Step C:4- (2- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrimidin-5-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1- (p-toluenesulfonyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (252)

Compound 252 was synthesized by the method described in step L of example 1, with reference to compound 18, starting from compound 251 and compound 17.

LCMS (m/z): 652 [M+H]⁺.

Step D:4- (2- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrimidin-5-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (253)

Compound 253 was synthesized by the method described in example 1, step M, with reference to compound I-1, starting from compound 252.

LCMS (m/z): 498 [M+H]⁺.

Step E:4- (2- (3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrimidin-5-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (254)

Compound 254 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 253.

LCMS (m/z): 398 [M+H]⁺.

Step F:4- (2- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrimidin-5-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-82)

Compound I-82 was synthesized by the method described in example 1, step H, with compound 254 and compound 5-fluoro-2-hydroxybenzaldehyde as starting materials, compound 14.

LCMS (m/z): 522 [M+H]⁺.

Example 83:4- (5- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrazin-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-83)

Step A:3- (5-bromopyrazin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (255)

Compound 255 was synthesized by the method described in example 1, step F, with reference to compound 11, starting from compound 2, 5-dibromopyrazine and compound 9.

LCMS (m/z): 354 [M+H]⁺.

And (B) step (B): 3- (5- (tributylstannyl) pyrazin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (256)

Compound 256 was synthesized by the method described in step B of example 81 using compound 255 as a starting material.

LCMS (m/z): 567 [M+H]⁺.

Step C:4- (5- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrazin-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1- (p-toluenesulfonyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (257)

Compound 257 was synthesized by the method described in step L of example 1 with reference to compound 18, starting from compound 256 and compound 17.

LCMS (m/z): 652 [M+H]⁺.

Step D:4- (5- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrazin-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (258)

Compound 258 was synthesized by the method described in example 1, step M, with compound 257 as a starting material, and compound I-1.

LCMS (m/z): 498 [M+H]⁺.

Step E:4- (5- (3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrazin-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (259)

Compound 259 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 258.

LCMS (m/z): 398 [M+H]⁺.

Step F:4- (5- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrazin-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-83)

Compound I-83 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 259 and compound 5-fluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 522 [M+H]⁺.

Example 84:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridazin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-84)

Step A:3- (6-Chloropyridazin-3-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbonic acid tert-butyl ester (260)

Compound 260 was synthesized by the method described in example 1, step F, with reference to compound 11, starting from compound 3, 6-dichloropyridazine and compound 9.

LCMS (m/z): 311 [M+H]⁺.

And (B) step (B): 3- (6- (tributylstannyl) pyridazin-3-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (261)

Compound 261 was synthesized by the method described in example 81, step B, with compound 260 as a starting material.

LCMS (m/z): 567 [M+H]⁺.

Step C:4- (6- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridazin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1- (p-toluenesulfonyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (262)

Compound 262 was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 261 and compound 17.

LCMS (m/z): 652 [M+H]⁺.

Step D:4- (6- (6- (tert-Butoxycarbonyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridazin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (263)

Compound 263 was synthesized by the method described in example 1, step M, with compound I-1 as starting material, compound 262.

LCMS (m/z): 498 [M+H]⁺.

Step E:4- (6- (3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridazin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (264)

Compound 264 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 263.

LCMS (m/z): 398 [M+H]⁺.

Step F:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridazin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-84)

Compound I-84 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 264 and compound 5-fluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 522 [M+H]⁺.

Example 85:4- (6- (4- (5-fluoro-2-hydroxybenzyl) piperazin-1-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-85)

Step A: 4-chloro-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (266)

Compound 266 (white solid, 2.52 g, 65%) was synthesized by the method of referring to compound 35 in step B of example 9, starting from compound 58 and compound 265.

LCMS (m/z): 388[M+H]⁺.

And (B) step (B): 4- (6-Fluoropyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (268)

Compound 268 (2.46 g, 55%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 266 and compound 267.

LCMS (m/z): 449 [M+H]⁺.

Step C: 4- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (270)

Compound 270 (460 mg, 75%) was synthesized by the method of referring to compound 11 in step F of example 1, starting from compound 268 and compound 269.

LCMS (m/z): 615 [M+H]⁺.

Step D:2- (1-methyl-1H-pyrazol-4-yl) -4- (6- (piperazin-1-yl) pyridin-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (271)

Compound 271 (86.4 mg, 45%) was synthesized starting from compound 270 and from compound 12 in step G of example 1.

LCMS (m/z): 385 [M+H]⁺.

Step E:4- (6- (4- (5-fluoro-2-hydroxybenzyl) piperazin-1-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-85)

Compound I-85 (5.5 mg, 10.8%) was synthesized by the method of referring to compound 14 in step H of example 1, starting from compound 271 and compound 13.

LCMS (m/z): 509 [M+H]⁺.

Example 86:4- (6- (4- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-86)

Step A: 6- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-3-carbonate (273)

Compound 273 was synthesized by the method described in step F of example 1, starting from compound 268 and compound 272,3,6-diazabicyclo [3.1.1] heptane-3-tert-butyl carbonate.

LCMS (m/z): 627 [M+H]⁺.

And (B) step (B): 2- (1-methyl-1H-pyrazol-4-yl) -4- (6- (3, 6-diazabicyclo [3.1.1] heptan-6-yl) pyridin-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (274)

Compound 274 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 273.

LCMS (m/z): 397 [M+H]⁺.

Step C:4- (6- (4- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-86)

Compound I-86 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 274 and compound 13.

LCMS (m/z): 521 [M+H]⁺.

Example 87:4- (6- (5- (5-fluoro-2-hydroxybenzyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-87)

Step A:5- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -2, 5-diazabicyclo [2.2.1] heptane-2-carbonate (276)

Compound 276 was synthesized by the method described in step F of example 1, starting from compound 268 and compound 275,2,5-diazabicyclo [2.2.1] heptane-2-tert-butyl carbonate.

LCMS (m/z): 627 [M+H]⁺.

And (B) step (B): 4- (6- (2, 5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (277)

Compound 277 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 276.

LCMS (m/z): 397 [M+H]⁺.

Step C:4- (6- (4- (5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-87)

Compound I-87 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 277 and compound 13.

LCMS (m/z): 521 [M+H]⁺.

Example 88:4- (6- (5- (5-fluoro-2-hydroxybenzyl) -2, 5-diazabicyclo [2.2.2] oct-2-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-88)

Step A:5- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -2, 5-diazabicyclo [2.2.2] octane-2-carbonic acid tert-butyl ester (279)

Compound 279 was synthesized by the method of referring to compound 11 in step F of example 1, starting from compound 268 and compound 278,2,5-diazabicyclo [2.2.2] octane-2-carbonate.

LCMS (m/z): 641 [M+H]⁺.

And (B) step (B): 4- (6- (2, 5-diazabicyclo [2.2.2] oct-2-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (280)

Compound 280 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 279.

LCMS (m/z): 411 [M+H]⁺.

Step C:4- (6- (4- (5-fluoro-2-hydroxybenzyl) -2, 5-diazabicyclo [2.2.2] oct-6-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-88)

Compound I-88 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 280.

LCMS (m/z): 535 [M+H]⁺.

Example 89:4- (6- (8- (5-fluoro-2-hydroxybenzyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-89)

Step A:3- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carbonic acid tert-butyl ester (282)

Compound 282 was synthesized by the method described in step F of example 1, starting from compound 268 and compound 281,3,8-diazabicyclo [3.2.1] octane-8-carbonate.

LCMS (m/z): 641 [M+H]⁺.

And (B) step (B): 4- (6- (3, 8-diazabicyclo [3.2.1] oct-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (283)

Compound 283 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 282.

LCMS (m/z): 411 [M+H]⁺.

Step C:4- (6- (8- (5-fluoro-2-hydroxybenzyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-89)

Compound I-89 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 283 and compound 13.

LCMS (m/z): 535 [M+H]⁺.

Example 90:4- (6- (3- (5-fluoro-2-hydroxybenzyl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-90)

Step A:8- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-3-carbonic acid tert-butyl ester (285)

Compound 285 was synthesized by the method of example 1, step F, using compound 268 and compound 284,3,8-diazabicyclo [3.2.1] octane-8-carbonate as starting materials.

LCMS (m/z): 641 [M+H]⁺.

And (B) step (B): 4- (6- (3, 8-diazabicyclo [3.2.1] oct-8-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (286)

Compound 286 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 285.

LCMS (m/z): 411 [M+H]⁺.

Step C:4- (6- (3- (5-fluoro-2-hydroxybenzyl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-90)

Compound I-90 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 286 and compound 13.

LCMS (m/z): 535 [M+H]⁺.

Example 91:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-91)

Step A:6- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (288)

Compound 288 was synthesized by the method of referring to compound 11 in step F of example 1, starting from compound 268 and compound 287,2,6-diazaspiro [3.3] heptane-2-carbonate.

LCMS (m/z): 627 [M+H]⁺.

And (B) step (B): 4- (6- (2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (289)

Compound 289 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 288.

LCMS (m/z): 397 [M+H]⁺.

Step C:4- (6- (6- (5-fluoro-2-hydroxybenzyl) -2, 6-diazaspiro [3.3] heptan-2-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-91)

Compound I-91 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 289 and compound 13.

LCMS (m/z): 521 [M+H]⁺.

Example 92:4- (6- ((3 aR,6 aS) -5- (5-fluoro-2-hydroxybenzyl) -hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (I-92)

Step A: (3 aR,6 aS) -5- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carbonic acid tert-butyl ester (291)

Compound 291 was synthesized by the method described in step F of example 1, using, as starting materials, compound 286 and compound 290, (3 ar,6 as) -hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carbonate tert-butyl ester.

LCMS (m/z): 641 [M+H]⁺.

And (B) step (B): 4- (6- ((3 aR,6 aS) -hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (292)

Compound 292 was synthesized by the method described in example 1, step G, with compound 291 as a starting material, and with reference to compound 12.

LCMS (m/z): 411 [M+H]⁺.

Step C:4- (6- ((3 aR,6 aS) -5- (5-fluoro-2-hydroxybenzyl) -hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (I-92)

Compound I-92 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 292 and compound 13.

LCMS (m/z): 535 [M+H]⁺.

Example 93:4- (6- ((1R, 5S,6 r) -6- ((5-fluoro-2-hydroxybenzyl) amino) -3-azabicyclo [3.1.0] hexane-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-93)

Step A: (1R, 5S,6 r) -3- (5- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3-azabicyclo [3,1,0] hexan-6-yl) carbamic acid tert-butyl ester (294)

Compound 294 was synthesized by the method of example 1, step F, using compound 268 and compound 293, ((1 r,5s,6 r) -3-azabicyclo [3,1,0] hexane-6-yl) -tert-butyl carbonate as starting materials.

LCMS (m/z): 627 [M+H]⁺.

And (B) step (B): 4- (6- ((1R, 5S,6 r) -6-amino-3-azabicyclo [3,1,0] hexan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (295)

Compound 295 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 294.

LCMS (m/z): 397 [M+H]⁺.

Step C:4- (6- ((1R, 5S,6 r) -6- ((5-fluoro-2-hydroxybenzyl) amino) -3-azabicyclo [3.1.0] hexane-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-93)

Compound I-93 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 295 and compound 13.

LCMS (m/z): 521 [M+H]⁺.

Example 94:4- (6- ((1R, 5S,6 s) -6- ((5-fluoro-2-hydroxybenzyl) amino) -3-azabicyclo [3.1.0] hexane-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-94)

Step A: (1R, 5S,6 s) -3- (5- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3-azabicyclo [3,1,0] hexane-6-yl) carbamic acid tert-butyl ester (297)

Compound 297 was synthesized by the method of compound 11 in step F of example 1, starting from compound 268 and compound 296, ((1 r,5s,6 s) -3-azabicyclo [3,1,0] hexane-6-yl) -tert-butyl carbonate.

LCMS (m/z): 627 [M+H]⁺.

And (B) step (B): 4- (6- ((1R, 5S,6 s) -6-amino-3-azabicyclo [3,1,0] hexan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (298)

Compound 298 was synthesized by the method of referring to compound 12 in step G of example 1, starting from compound 297.

LCMS (m/z): 397 [M+H]⁺.

Step C:4- (6- ((1R, 5S,6 s) -6- ((5-fluoro-2-hydroxybenzyl) amino) -3-azabicyclo [3.1.0] hexane-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-94)

Compound I-94 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 298 and compound 13.

LCMS (m/z): 521 [M+H]⁺.

Example 95:6- ((6-methoxypyridin-3-yl) methyl) -3- (5- (5-methyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3, 1] heptane (I-95)

Compound I-95 (white solid, 1 mg, 4.99%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 31 and compound 299.

LCMS (m/z): 427 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.27 (s, 1H), 8.15 (s, 1H),7.80-7.75 (m, 2H), 7.36 (d,J= 3.2 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.82 (d,J= 8.4 Hz, 1H), 6.30 (d,J= 3.2 Hz, 1H), 5.51 (s, 1H), 3.96-3.83 (m, 5H), 3.72-3.70 (m, 4H), 2.80-2.73 (m, 2H), 2.39 (s, 3H), 1.77 (d,J= 8.8 Hz, 1H), 1.34-1.31 (m, 1H).

Example 96:6- ((6-methoxypyridin-3-yl) methyl) -3- (5- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3, 1] heptane (I-96)

Compound I-96 (white solid, 8.0 mg, 6.8%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 31 and compound 300.

LCMS (m/z): 447 [M+H]⁺.

¹HNMR (400 MHz, CD₃OD) δ 8.40 (d,J= 2.0 Hz, 1H), 8.29 (s, 1H), 6.13 (d,J= 1.6 Hz, 1H), 7.90 (dd,J= 8.8 Hz, 2.0 Hz, 1H), 7.76 (dd,J= 8.4 Hz, 2.4 Hz, 1H), 7.47 (d,J= 3.2 Hz, 1H), 6.94 (d,J= 8.8 Hz, 1H), 6.81 (d,J= 8.4 Hz, 1H), 6.41 (d,J= 3.6 Hz, 1H), 3.96-3.84 (m, 6H), 3.72-3.69 (m, 3H), 2.75 (s, 1H), 1.75 (d, J = 8.8 Hz, 1H), 1.31 (s, 1H).

Example 97:6- ((6-methoxypyridin-3-yl) methyl) -3- (5- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3, 1] heptane (I-97)

Compound I-97 (white solid, 6.2 mg, 3.6%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 31 and compound 301.

LCMS (m/z): 431 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 8.19 (d,J= 3.6 Hz, 1H), 8.12 (d,J= 1.6 Hz, 1H), 8.02 (d,J= 8.8 Hz, 1H), 7.75 (dd,J= 8.4 Hz, 2.0 Hz, 1H), 7.52 (d,J= 3.6 Hz, 1H), 6.95 (d,J= 8.8 Hz, 1H), 6.81 (d,J= 8.4 Hz, 1H), 6.61 (d,J= 3.2 Hz, 1H), 3.96-3.90 (m, 5H), 3.86-3.83 (m, 2H), 3.72-3.68 (m, 4H), 2.76 (s, 1H), 1.74 (d,J= 8.8 Hz, 1H).

Example 98:6- ((6-methoxypyridin-3-yl) methyl) -3- (5- (5-methylaminocarbonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3, 1] heptane (I-98)

Compound I-98 was synthesized by the method described in step L of example 1 with reference to compound 18, starting from compound 31 and compound 302.

LCMS (m/z): 470 [M+H]⁺.

Example 99:6- ((6-methoxypyridin-3-yl) methyl) -3- (5- (5-aminocarbonyl-1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3, 1] heptane (I-99)

Compound I-99 was synthesized by the method described in step L of example 1 with reference to compound 18, starting from compound 31 and compound 303.

LCMS (m/z): 456 [M+H]⁺.

Example 100:6- ((6-methoxypyridin-3-yl) methyl) -3- (5- (5-methoxy-1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3, 1] heptane (I-100)

Compound I-100 was synthesized by the method described in step L of example 1 with reference to compound 18, starting from compound 31 and compound 304.

LCMS (m/z): 443 [M+H]⁺.

Example 101: 2-chloro-N- ((3R, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) -6-fluorobenzamide (I-101)

Step A: (1- (5-bromopyridin-2-yl) -4-methylpiperidin-4-yl) aminocarbonyl tert-butyl ester (306)

Compound 306 (3 g, 87%) was synthesized by the method of referring to compound 11 in step F of example 1, starting from compound 305 and compound 10.

LCMS (m/z): 370 [M+H]⁺.

And (B) step (B): (4-methyl-1- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) piperidin-4-yl) aminocarbonate (307)

Compound 307 (yellow solid, 1.9 g, 84%) was synthesized by the method of referring to compound 15 in step I of example 1 starting from compound 306.

LCMS (m/z): 418 [M+H]⁺.

Step C: (4-methyl-1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) piperidin-4-yl) aminocarbonate (308)

Compound 308 (yellow solid, 1.4 g) was synthesized by the method described with reference to compound 18 in step L of example 1, starting from compound 307 and compound 17.

LCMS (m/z): 667 [M+H]⁺.

Step D:4- (6- ((3R, 4S) -4-amino-3-hydroxypiperidin-1-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (309)

Compound 309 (300 mg, 58%) was synthesized by the method of referring to compound 12 in step G of example 1, starting from compound 308.

LCMS (m/z): 569 [M+H]⁺.

Step E: 2-chloro-N- (4-methyl-1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridin-4-yl) pyridin-2-yl) piperidin-4-yl) -6-fluorobenzamide (310)

Compound 310 (yellow solid, 100 mg, 78%) was synthesized by the method of referring to compound 107 in step E of example 28, starting from compound 309 and compound 2-fluoro-6-chlorobenzoic acid.

LCMS (m/z): 725 [M+H]⁺.

Step F: 2-chloro-N- ((3R, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) -6-fluorobenzamide (I-101)

Compound I-101 (yellow solid, 3 mg, 8%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 310.

LCMS (m/z): 569 [M+H]⁺.

¹HNMR (400 MHz, DMSO-d6) 12.62 (s, 1H), 8.54 (s, 1H), 8.48 (s, 1H), 8.45 (s, 1H), 8.28 (s, 1H), 8.05 (s, 1H), 7.89 (d,J= 8.8 Hz, 1H), 7.45 (t,J= 8.0 Hz, 1H), 7.38-7.35 (m, 1H), 7.29 (t,J= 8.0 Hz, 1H), 7.09 (d,J= 9.6 Hz, 1H), 6.76 (s, 1H), 4.16 (d,J= 13.6 Hz, 2H), 3.89 (s, 3H), 2.67 (s, 1H), 2.35-2.32 (m, 3H), 1.57 (t,J= 11.2 Hz, 2H), 1.45 (s, 3H).

Example 102:4- (6- (6- ((5-fluoro-6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-102)

Step A: 3- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3, 1] heptane-6-carbonic acid tert-butyl ester (311)

Compound 311 (5.2 g) was synthesized by the method described in example 1, step F, with compound 268 and compound 9 as starting materials, and with reference to compound 11.

LCMS (m/z): 627 [M+H]⁺.

And (B) step (B): 2- (1-methyl-1H-pyrazol-4-yl) -4- (6- (3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (312)

Compound 312 (3.2G,) was synthesized starting from compound 311 and from compound 12 in step G of example 1.

LCMS (m/z): 397 [M+H]⁺.

Step C:4- (6- (6- ((5-fluoro-6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-102)

Compound I-102 (30 mg) was synthesized by the method described in step H of example 1 with reference to compound 14, starting from compound 312 and compound 5-fluoro-6-methoxynicotinaldehyde.

LCMS (m/z): 536 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.56 (s, 1H),8.55 (d,J= 2.4 Hz, 1H), 8.28 (s, 1H), 8.06 (s, 1H), 7.98-7.96 (m, 2H),7.67 (dd,J= 11.6, 1.6 Hz, 1H), 6.91 (d,J= 8.8 Hz, 1H), 6.76 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.79-3.76 (m, 2H), 3.72 (d,J= 6.0 Hz, 2H), 3.60-3.50(m, 4H), 2.56-2.54 (m, 1H), 1.60 (d,J= 8.4 Hz, 1H).

Example 103:4- (6- (6- (2-fluoro-4-methoxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-103)

Compound I-103 (30 mg) was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 312 and compound 2-fluoro-4-methoxybenzaldehyde.

LCMS (m/z): 535 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.56 (s, 1H),8.55 (d,J= 2.4 Hz, 1H), 8.28 (s, 1H), 8.06 (s, 1H), 7.97 (dd,J= 8.8, 2.4 Hz, 1H), 7.39 (t,J= 8.4 Hz, 1H), 6.91 (d,J= 8.8 Hz, 1H), 6.78-6.74 (m, 3H), 3.89 (s, 3H), 3.82-3.79 (m, 2H), 3.75 (s, 3H), 3.70 (d,J= 5.6 Hz, 2H), 3.57-3.53 (m, 4H), 2.56-2.53 (m, 1H), 1.60 (d,J= 8.4 Hz, 1H).

Example 104:4- (6- (6- (5-fluoro-2-methoxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-104)

Compound I-104 (30 mg) was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 312 and compound 5-fluoro-2-methoxybenzaldehyde.

LCMS (m/z): 535 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.56 (s, 1H),8.54 (d,J= 2.4 Hz, 1H), 8.28 (s, 1H), 8.06 (s, 1H), 7.96 (dd,J= 8.8, 2.4 Hz, 1H), 7.24 (dd,J= 9.6, 3.2 Hz, 1H), 7.05-7.00 (m, 1H), 6.96-6.89 (m, 2H),6.79 (s, 1H), 3.89 (s, 3H), 3.79-3.73 (m, 7H), 3.61-3.54 (m, 4H), 2.63-2.61 (m, 1H), 1.62 (d,J= 8.4 Hz, 1H).

Example 105:4- (6- (6- ((5-cyclopropyl-1H-pyrazol-3-yl) methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-105)

Compound I-105 (10 mg) was synthesized by the method described in step H of example 1, with reference to compound 14, starting from compound 312 and compound 5-cyclopropyl-1H-pyrazole-3-carbaldehyde.

LCMS (m/z): 517 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 12.15 (s, 1H), 8.56 (s, 1H),8.54 (d,J= 2.0 Hz, 1H), 8.28 (s, 1H), 8.06 (s, 1H), 7.96 (dd,J= 8.8, 2.4 Hz, 1H), 6.89 (d,J= 8.8 Hz, 1H), 6.77 (s, 1H), 5.84 (s, 1H), 3.89 (s, 3H), 3.79-3.75 (m, 2H), 3.67 (d,J= 5.6 Hz, 2H), 3.56-3.47 (m, 4H), 2.50-2.49 (m, 1H), 1.83 (s, 1H),1.57 (d,J= 8.4 Hz, 1H), 0.86-0.85 (m, 2H), 0.63-0.62 (m, 2H).

Example 106:4- (6- (6- (3, 5-difluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-106)

Compound I-106 was synthesized by the method described in step H of example 1, with reference to compound 14, starting from compound 312 and compound 3, 5-difluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 539 [M+H]⁺.

Example 107:4- (6- (6- (3-methyl-5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-107)

Compound I-107 was synthesized by the method of referring to compound 14 in step H of example 1, starting from compound 312 and compound 3-methyl-5-fluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 535 [M+H]⁺.

Example 108:4- (6- (6- (3-methoxy-5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-108)

Compound I-108 was synthesized by the method described in step H of example 1, with reference to compound 14, starting from compound 312 and compound 3-methoxy-5-fluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 551 [M+H]⁺.

Example 109:4- (6- (6- (3-chloro-5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-109)

Compound I-109 was synthesized by the method described in step H of example 1, with reference to compound 14, starting from compound 312 and compound 3-chloro-5-fluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 555[M+H]⁺.

Example 110:4- (6- (6- ((1-H-indol-7-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-110)

Compound I-110 was synthesized by the method described in example 1, step H, with compound 312 and compound 1-H-indole-7-carbaldehyde as starting materials, with reference to compound 14.

LCMS (m/z): 526[M+H]⁺.

Example 111:4- (6- (6- ((5-fluoro-1-H-indol-7-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-111)

Compound I-111 was synthesized by the method of referring to compound 14 in step H of example 1, starting from compound 312 and compound 5-fluoro-1-H-indole-7-carbaldehyde.

LCMS (m/z): 544[M+H]⁺.

Example 112:4- (6- (6- ((1-H-indazol-7-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-112)

Compound I-112 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 312 and compound 1-H-indazole-7-carbaldehyde.

LCMS (m/z): 527[M+H]⁺.

Example 113:4- (6- (6- ((5-fluoro-1-H-indazol-7-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-113)

Compound I-113 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 312 and compound 5-fluoro-1-H-indazole-7-carbaldehyde.

LCMS (m/z): 545[M+H]⁺.

Example 114:4- (6- (6- ((4-methoxy-5-fluoro-1-H-indazol-7-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-114)

Compound I-114 was synthesized by the method described in step H of example 1 with reference to compound 14, starting from compound 312 and compound 4-methoxy-5-fluoro-1-H-indazole-7-carbaldehyde.

LCMS (m/z): 575[M+H]⁺.

Example 115:4- (6- (6- ((5-fluoro-1-H-benzimidazol-7-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-115)

Compound I-115 was synthesized by the method of referring to compound 14 in step H of example 1, starting from compound 312 and compound 5-fluoro-1-H-benzimidazole-7-carbaldehyde.

LCMS (m/z): 545[M+H]⁺.

Example 116:4- (6- (6- ((6-fluoro-1, 2,3, 4-tetrahydroquinolin-8-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-116)

Compound I-116 was synthesized by the method described in step H of example 1, referring to compound 14, starting from compound 312 and compound 6-fluoro-1, 2,3, 4-tetrahydroquinoline-8-carbaldehyde.

LCMS (m/z): 560[M+H]⁺.

Example 117:4- (6- (6- ((5-fluoroindolin-7-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-117)

Compound I-117 was synthesized by the method described in example 1, step H, with compound 312 and compound 5-fluoroindoline-7-carbaldehyde as starting materials, referring to compound 14.

LCMS (m/z): 546 [M+H]⁺.

Example 118:4- (6- (6- ((7-fluoro-3, 4-dihydrobenzo [ b ] [1,4] oxazin-5-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridine-5-carbonitrile (I-118)

Compound I-118 was synthesized by the method described in step H of example 1, referring to compound 14, starting from compound 312 and compound 7-fluoro-3, 4-dihydrobenzo [ b ] [1,4] oxazine-5-carbaldehyde.

LCMS (m/z): 546 [M+H]⁺.

Example 119:4- (6- (6- ((1-H-indol-6-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-119)

Compound I-119 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 312 and compound 1-H-indole-6-carbaldehyde.

LCMS (m/z): 526[M+H]⁺.

Example 120:4- (6- (6- ((1-H-indazol-6-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-120)

Compound I-119 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 312 and compound 1-H-indazole-6-carbaldehyde.

LCMS (m/z): 527[M+H]⁺.

Example 121:4- (6- (6- ((5-fluoro-1-H-indol-6-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-121)

Compound I-121 was synthesized by the method of referring to compound 14 in step H of example 1, starting from compound 312 and compound 5-fluoro-1-H-indole-6-carbaldehyde.

LCMS (m/z): 544[M+H]⁺.

Example 122:4- (6- (6- ((5-fluoro-1-H-indazol-6-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-122)

Compound I-122 was synthesized by the method described in step H of example 1, with reference to compound 14, starting from compound 312 and compound 5-fluoro-1-H-indazole-6-carbaldehyde.

LCMS (m/z): 545[M+H]⁺.

Example 123:4- (6- (6- ((indolin-7-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-123)

Compound I-123 was synthesized by the method of referring to compound 14 in step H of example 1, starting from compound 312 and the compound indoline-7-carbaldehyde.

LCMS (m/z): 528 [M+H]⁺.

Example 124:4- (6- (6- ((1-H-benzoimidazol-7-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-124)

Compound I-124 was synthesized by the method described with reference to compound 14 in step H of example 1, starting from compound 312 and compound 1-H-benzimidazole-7-carbaldehyde.

LCMS (m/z): 527[M+H]⁺.

Example 125:4- (6- (6- ((4-fluoro-1-H-pyrazol-3-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-125)

Compound I-125 was synthesized by the method described in step H of example 1 with reference to compound 14, starting from compound 312 and compound 4-fluoro-1-H-pyrazole-3-carbaldehyde.

LCMS (m/z): 495[M+H]⁺.

Example 126:4- (6- (6- ((5-methyl-1-H-pyrazol-3-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-126)

Compound I-126 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 312 and compound 5-methyl-1-H-pyrazole-3-carbaldehyde.

LCMS (m/z): 491[M+H]⁺.

Example 127:4- (6- (6- ((4, 5-dimethyl-1-H-pyrazol-3-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-127)

Compound I-127 was synthesized by the method described in step H of example 1, with reference to compound 14, starting from compound 312 and compound 4, 5-dimethyl-1-H-pyrazole-3-carbaldehyde.

LCMS (m/z): 505[M+H]⁺.

Example 128:4- (6- (6- ((1-H-indazol-3-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-128)

Compound I-128 was synthesized by the method described in example 1, step H, with compound 312 and compound 1-H-indazole-3-carbaldehyde as starting materials, compound 14.

LCMS (m/z): 527[M+H]⁺.

Example 129:4- (6- (6- ((5-fluoro-1-H-indazol-3-yl) -methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-129)

Compound I-129 was synthesized by the method of referring to compound 14 in step H of example 1, starting from compound 312 and compound 5-fluoro-1-H-indazole-3-carbaldehyde.

LCMS (m/z): 545[M+H]⁺.

Example 130:4- (6- (6- (2-difluoromethyl-5-fluorobenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-130)

Compound I-130 was synthesized by the method described in example 1, step H, with compound 312 and compound 2-difluoromethyl-5-fluorobenzaldehyde as starting materials, compound 14.

LCMS (m/z): 555[M+H]⁺

Example 131:4- (6- (6- ((2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-131)

Compound I-131 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 312 and compound 2-oxo-1, 2-dihydropyridine-3-carbaldehyde.

LCMS (m/z): 504[M+H]⁺

Example 132:4- (6- (6- ((1-methyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-132)

Compound I-132 was synthesized by the method of referring to compound 14 in step H of example 1, starting from compound 312 and compound 1-methyl-2-oxo-1, 2-dihydropyridine-3-carbaldehyde.

LCMS (m/z): 518[M+H]⁺

Example 133:4- (6- (6- ((6-oxo-1, 6-dihydropyridin-2-yl) methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-133)

Compound I-133 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 312 and compound 6-oxo-1, 6-dihydropyridine-2-carbaldehyde.

LCMS (m/z): 504[M+H]⁺

Example 134:4- (5- (6- (6-methoxypyridine-3-methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrazin-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-134)

Compound I-134 was synthesized by the method described in example 1, step H, with compound 259 and compound 6-methoxypyridine-3-carbaldehyde as starting materials, referring to compound 14.

LCMS (m/z): 519 [M+H]⁺

1H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.75 (s, 1H),8.57 (s, 1H), 8.45 (s, 1H), 8.30 (s, 1H), 8.14 (s, 1H),8.07 (s, 1H), 7.72 (dd,J= 8.8 Hz,J= 2.4 Hz, 1H), 6.96 (d,J= 1.6 Hz, 1H), 6.78 (d,J= 8.4 Hz, 1H), 3.90-3.82 (m, 8H), 3.72-3.66 (m, 4H), 3.58 (s, 2H), 2.60-2.54 (m, 1H), 1.64 (d,J= 8.8 Hz, 1H).

Example 135:4- (5- (6- (5-fluoro 6-methoxypyridine-3-methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrazin-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-135)

Compound I-135 was synthesized by the method described in example 1, step H, with compound 259 and compound 5-fluoro-6-methoxypyridine-3-carbaldehyde as starting materials, referring to compound 14.

LCMS (m/z): 537 [M+H]⁺

Example 136:4- (5- (6- (2-fluoro-6-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrazin-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-136)

Compound I-136 was synthesized by the method described in example 1, step H, with respect to compound 14, starting from compound 259 and compound 2-fluoro-6-hydroxybenzaldehyde.

LCMS (m/z): 522[M+H]⁺

Example 137:4- (5- (6- (2-fluoro-4-methoxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrazin-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-137)

Compound I-137 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 259 and compound 2-fluoro-4-methoxybenzaldehyde.

LCMS (m/z): 536[M+H]⁺

Example 138:4- (5- (6- (3, 5-difluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrazin-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-138)

Compound I-138 was synthesized by the method described in step H of example 1, with reference to compound 14, starting from compound 259 and compound 3, 5-difluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 540[M+H]⁺

Example 139:4- (5- (6- (3-chloro-5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrazin-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-139)

Compound I-139 was synthesized by the method described in step H of example 1 with reference to compound 14, starting from compound 259 and compound 3-chloro-5-fluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 556[M+H]⁺

Example 140:4- (5- (6- (3-methyl-5-fluoro-2-hydroxybenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrazin-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-140)

Compound I-140 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 259 and compound 3-methyl-5-fluoro-2-hydroxybenzaldehyde.

LCMS (m/z): 536[M+H]⁺

Example 141:4- (5- (6- (2-6-difluorobenzyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrazin-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-141)

Compound I-141 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 259 and compound 2-6-difluorobenzaldehyde.

LCMS (m/z): 524[M+H]⁺

Example 142:4- (5- (6- (6-methoxy-d 3-pyridin-3-methyl) -3, 6-diazabicyclo [3, 1] heptan-3-yl) pyrazin-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-142)

Compound I-142 was synthesized by the method described in example 1, step H, with compound 259 and compound 6-methoxy-d 3-pyridine-3-carbaldehyde as starting materials, compound 14.

LCMS (m/z): 522 [M+H]⁺

Example 143: n-1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -4-hydroxymethylpiperidin-4-yl) -6-fluorobenzamide (I-143)

Step A: 1- (5-bromopyridin-2-yl) -4- ((tert-butoxycarbonyl) amino) piperidine-4-carboxylic acid methyl ester (314)

Compound 314 (600 mg, 55%) was synthesized by the method of referring to compound 11 in step F of example 1, starting from compound 313 and compound 10.

LCMS (m/z): 414 [M+H]⁺.

And (B) step (B): 1- (5-bromopyridin-2-yl) -4- (hydroxymethyl) piperidin-4-amine carbonic acid tert-butyl ester (315)

Methyl 1- (5-bromopyridin-2-yl) -4- ((t-butoxycarbonyl) amino) piperidine-4-carboxylate (compound 314, 600 mg, 1.45 mmol) was placed in tetrahydrofuran (30 mL), a solution of lithium aluminum in tetrahydrofuran (2.9 mL, 2.9 mmol) was added under ice-bath, stirred at 0 ℃ for 1 hour, then quenched with sodium sulfate decahydrate, filtered, concentrated and separated by column chromatography (dichloromethane/methanol=20/1) to give compound 315 (330 mg, 59%).

LCMS (m/z): 386 [M+H]⁺.

Step C: (4-amino-1- (5-bromopyridin-2-yl) piperidin-4-yl) methanol (316)

Compound 316 (250 mg, 97%) was synthesized by the method of referring to compound 12 in step G of example 1, starting from compound 315.

LCMS (m/z): 286 [M+H]⁺.

Step D: n- (1- (5-bromopyridin-2-yl) -4- (hydroxymethyl) piperidin-4-yl) -2,6-d difluorobenzamide (318)

Compound 318 (yellow solid, 220 mg, 59%) was synthesized according to the procedure of example 1, step H, using compound 316 and compound 317,2,6-difluorobenzoic acid as starting materials, compound 14.

LCMS (m/z): 725 [M+H]⁺

Step E: n- (1- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) -4- (hydroxymethyl) piperidin-4-yl) -2,6-d difluorobenzamide (319)

Compound 319 (yellow oil, 90 mg, 37%) was synthesized by the method of referring to compound 15 in step I of example 1 starting from compound 318.

LCMS (m/z): 474 [M+H]⁺.

Step F: n-1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -4-hydroxymethylpiperidin-4-yl) -2, 6-difluorobenzamide (320)

Compound 320 (yellow solid, 50 mg, 41%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 319 and compound 17.

LCMS (m/z): 723 [M+H]⁺.

Step F: n-1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -4-hydroxymethylpiperidin-4-yl) -6-fluorobenzamide (I-143)

Compound I-143 (white solid, 2.5 mg, 7.10%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 320.

LCMS (m/z): 569 [M+H]⁺.

¹HNMR (400 MHz, CD₃OD) 8.50 (s, 1H), 8.48 (s, 1H), 8.09 (s, 1H), 7.97-7.95 (m, 2H), 7.48-7.44 (m, 1H), 7.00-7.05 (m, 3H), 6.72 (s, 1H), 4.33-4.29 (m, 2H), 3.95 (s, 3H), 3.79 (s, 2H), 3.33-3.30 (m, 2H), 2.40-2.37 (m, 2H), 1.84-1.81 (m, 2H).

Example 144: n-1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -4-cyanomethylpiperidin-4-yl) -6-fluorobenzamide (I-144)

Step A: 1- (5-bromopyridin-2-yl) -4- ((tert-butoxycarbonyl) amino) piperidine-4-carboxylic acid methyl ester (322)

Compound 322 (300 mg, 63%) was synthesized by the method of referring to compound 11 in step F of example 1, starting from compound 321 and compound 10.

LCMS (m/z): 395 [M+H]⁺.

And (B) step (B): (4-amino-1- (5-bromopyridin-2-yl) piperidin-4-yl) acetonitrile (323)

Compound 323 (200 mg, 92%) was synthesized by the method of referring to compound 12 in step G of example 1, starting from compound 322.

LCMS (m/z): 295 [M+H]⁺.

Step C: n- (1- (5-bromopyridin-2-yl) -4- (cyanomethyl) piperidin-4-yl) -2,6-d difluorobenzamide (324)

Compound 324 (white solid, 140 mg, 47%) was synthesized by the method of referring to compound 14 in step H of example 1 starting from compound 323 and compound 317,2,6-difluorobenzoic acid.

LCMS (m/z): 725 [M+H]⁺

Step D: n- (1- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) -4- (cyanomethyl) piperidin-4-yl) -2,6-d difluorobenzamide (325)

Compound 325 (yellow oil, 80 mg, 50%) was synthesized by the method of referring to compound 15 in step I of example 1, starting from compound 324.

LCMS (m/z): 474 [M+H]⁺.

Step E: n-1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -4-cyanomethylpiperidin-4-yl) -2, 6-difluorobenzamide (326)

Compound 326 (yellow solid, 40 mg, 42%) was synthesized by the method of referring to compound 18 in step L of example 1, starting from compound 325 and compound 17.

LCMS (m/z): 732 [M+H]⁺.

Step F: n-1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -4-cyanomethylpiperidin-4-yl) -6-fluorobenzamide (I-144)

Compound I-144 (white solid, 1.5 mg, 4.55%) was synthesized by the method of referring to compound I-1 in step M of example 1, starting from compound 320.

LCMS (m/z): 578 [M+H]⁺.

Example 145: 2-chloro-N- ((3S, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) -6-fluorobenzamide (I-145)

Step A: ((3S, 4S) -1- (5-bromopyridin-2-yl) -3-hydroxypiperidin-4-yl) aminocarbonate tert-butyl ester (328)

Compound 328 was synthesized by the method described in example 1, step F, with reference to compound 11, starting from compound 327 and compound 10.

LCMS (m/z): 372 [M+H]⁺.

And (B) step (B): ((3S, 4S) -3-hydroxy-1- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) piperidin-4-yl) aminocarbonate (329)

Compound 329 was synthesized by the method described in example 1, step I, with reference to compound 15, starting from compound 328.

LCMS (m/z): 420 [M+H]⁺.

Step C: ((3S, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) aminocarbonate (330)

Compound 330 was synthesized by the method described in step L of example 1 with reference to compound 18, starting from compound 329 and compound 17.

LCMS (m/z): 669 [M+H]⁺.

Step D:4- (6- ((3S, 4S) -4-amino-3-hydroxypiperidin-1-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (331)

Compound 331 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 330.

LCMS (m/z): 569 [M+H]⁺.

Step E: 2-chloro-N- ((3S, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) -6-fluorobenzamide (332)

Compound 332 was synthesized by the method described in example 1, step H, with reference to compound 14, starting from compound 331 and compound 2-fluoro-6-chlorobenzoic acid.

LCMS (m/z): 725 [M+H]⁺.

Step F: 2-chloro-N- ((3S, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -3-hydroxypiperidin-4-yl) -6-fluorobenzamide (I-145)

Compound I-145 was synthesized by the method described in example 1, step M, with compound 332 as a starting material.

LCMS (m/z): 571 [M+H]⁺.

Example 146: 2-chloro-N- ((3R, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -3-fluoropiperidin-4-yl) -6-fluorobenzamide (I-146)

Step A: ((3R, 4S) -1- (5-bromopyridin-2-yl) -3-fluoropiperidin-4-yl) aminocarbonate (334)

Compound 334 was synthesized by the method described in example 1, step F, with reference to compound 11, starting from compound 333 and compound 10.

LCMS (m/z): 374 [M+H]⁺.

And (B) step (B): ((3R, 4S) -3-fluoro-1- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) piperidin-4-yl) aminocarbonate (335)

Compound 335 was synthesized by the method described in example 1, step I, with compound 334 as starting material, and with reference to compound 15.

LCMS (m/z): 422 [M+H]⁺.

Step C: ((3R, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3-fluoropiperidin-4-yl) aminocarbonate (336)

Compound 336 was synthesized by the method described in step L of example 1, with reference to compound 18, starting from compound 335 and compound 17.

LCMS (m/z): 671 [M+H]⁺.

Step D:4- (6- ((3R, 4S) -4-amino-3-fluoropiperidin-1-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (337)

Compound 337 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 336.

LCMS (m/z): 571 [M+H]⁺.

Step E: 2-chloro-N- ((3R, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -3-fluoropiperidin-4-yl) -6-fluorobenzamide (338)

Compound 338 was synthesized by the method described in step E of example 28, with reference to compound 107, starting from compound 337 and compound 2-fluoro-6-chlorobenzoic acid.

LCMS (m/z): 727 [M+H]⁺.

Step F: 2-chloro-N- ((3R, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -3-fluoropiperidin-4-yl) -6-fluorobenzamide (I-145)

Compound I-146 was synthesized by the method described in example 1, step M, with reference to compound I-1, starting from compound 338.

LCMS (m/z): 573 [M+H]⁺.

Example 147: 2-chloro-N- ((3R, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -3-cyanopiperidin-4-yl) -6-fluorobenzamide (I-146)

Step A: ((3R, 4S) -1- (5-bromopyridin-2-yl) -3-cyanopiperidin-4-yl) aminocarbonate (340)

Compound 340 was synthesized by the method described in example 1, step F, with reference to compound 11, starting from compound 339 and compound 10.

LCMS (m/z): 381 [M+H]⁺.

And (B) step (B): ((3R, 4S) -3-cyano-1- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) piperidin-4-yl) aminocarbonate (341)

Compound 341 was synthesized by the method described in example 1, step I, with reference to compound 15, starting from compound 340.

LCMS (m/z): 429 [M+H]⁺.

Step C: ((3R, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3-cyanopiperidin-4-yl) aminocarbonate (342)

Compound 342 was synthesized by the method described in step L of example 1 with reference to compound 18, starting from compound 341 and compound 17.

LCMS (m/z): 678 [M+H]⁺.

Step D:4- (6- ((3R, 4S) -4-amino-3-cyanopiperidin-1-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (343)

Compound 343 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 342.

LCMS (m/z): 578 [M+H]⁺.

Step E: 2-chloro-N- ((3R, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -3-cyanopiperidin-4-yl) -6-fluorobenzamide (344)

Compound 344 was synthesized by the method described in step E of example 28, with respect to compound 343 and compound 2-fluoro-6-chlorobenzoic acid as starting materials.

LCMS (m/z): 734 [M+H]⁺.

Step F: 2-chloro-N- ((3R, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -3-cyanopiperidin-4-yl) -6-fluorobenzamide (I-147)

Compound I-147 was synthesized by the method described in example 1, step M, using compound 344 as a starting material.

LCMS (m/z): 580 [M+H]⁺.

Example 148:4- (6- ((1S, 4S, 5S) -4- (cyanomethyl) -3- ((6-methoxypyridin-3-yl) methyl) -2, 6-diazabicyclo [3.2.0] heptan-6-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridine-5-carbonitrile (I-148)

Step A: (1S, 4S, 5S) -6- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridin-4-yl) pyridin-2-yl) -4-cyanomethyl-2, 6-diazabicyclo [3.2.0] heptane-2-carbonic acid tert-butyl ester (346)

Compound 346 was synthesized by the method described in step F of example 1, starting from compound 268 and compound 345, ((1 s,4s,5 s) -4- (cyanomethyl) -2, 6-diazabicyclo [3.2.0] heptane-2-carbonate tert-butyl ester.

LCMS (m/z): 666 [M+H]⁺.

And (B) step (B): 4- (6- ((1S, 4S, 5S) -2- (cyanomethyl) -3, 6-diazabicyclo [3.2.0] heptan-6-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (347)

Compound 347 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 346.

LCMS (m/z): 436 [M+H]⁺.

Step C: 4- (6- ((1S, 4S, 5S) -4- (cyanomethyl) -3- ((6-methoxypyridin-3-yl) methyl) -2, 6-diazabicyclo [3.2.0] heptan-6-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridine-5-carbonitrile (I-148)

Compound I-148 was synthesized by the method described in step H of example 1, with compound 347 and compound 6-methoxypyridine-3-carbaldehyde as starting materials.

LCMS (m/z): 557 [M+H]⁺.

Example 149:4- (6- ((1S, 4R, 5R) -4-methyl-4-amino-2- ((6-methoxypyridin-3-yl) methyl) -2, 6-diazabicyclo [3.2.0] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridine-5-carbonitrile (I-149)

Step A: (1S, 4R, 5R) -6- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridin-4-yl) pyridin-2-yl) -4-t-butoxycarboxamido-4-methyl-2, 6-diazabicyclo [3.2.0] heptane-2-carbonic acid tert-butyl ester (349)

Compound 349 was synthesized by the method of referring to compound 11 in step F of example 1, starting from compound 268 and compound 348, (1 s,4r,5 s) -4- (t-butoxycarboxamido) -4-methyl-2, 6-diazabicyclo [3.2.0] heptane-2-carbonate.

LCMS (m/z): 756 [M+H]⁺.

And (B) step (B): 4- (6- ((1S, 4R, 5R) -4-methyl-4-amino-2, 6-diazabicyclo [3.2.0] heptan-6-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (350)

Compound 350 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 349.

LCMS (m/z): 426 [M+H]⁺.

Step C: 4- (6- ((1S, 4R, 5R) -4-methyl-4-amino-2- ((6-methoxypyridin-3-yl) methyl) -2, 6-diazabicyclo [3.2.0] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridine-5-carbonitrile (I-149)

Compound I-149 was synthesized by the method described in example 1, step H, with compound 350 and compound 6-methoxypyridine-3-carbaldehyde as starting materials, with compound 14.

LCMS (m/z): 547 [M+H]⁺.

Example 150:4- (6- ((1S, 4S, 5R) -4-methyl-4-amino-2- ((6-methoxypyridin-3-yl) methyl) -2, 6-diazabicyclo [3.2.0] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridine-5-carbonitrile (I-150)

Step A: (1S, 4S, 5R) -6- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -4-tert-butoxycarboxamido-4-methyl-2, 6-diazabicyclo [3.2.0] heptane-2-carbonate tert-butyl ester (352)

Compound 352 was synthesized by the method of referring to compound 11 in step F of example 1, starting from compound 268 and compound 348, (1 s,4s,5 r) -4- (tert-butoxycarboxamido) -4-methyl-2, 6-diazabicyclo [3.2.0] heptane-2-carbonate.

LCMS (m/z): 756 [M+H]⁺.

And (B) step (B): 4- (6- ((1S, 4S, 5R) -4-methyl-4-amino-2, 6-diazabicyclo [3.2.0] heptan-6-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (353)

Compound 353 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 352.

LCMS (m/z): 426 [M+H]⁺.

Step C: 4- (6- ((1S, 4S, 5R) -4-methyl-4-amino-2- ((6-methoxypyridin-3-yl) methyl) -2, 6-diazabicyclo [3.2.0] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridine-5-carbonitrile (I-150)

Compound I-150 was synthesized by the method described in example 1, step H, with compound 353 and compound 6-methoxypyridine-3-carbaldehyde as starting materials, compound 14.

LCMS (m/z): 547 [M+H]⁺.

Example 151: 2-chloro-N- ((3R, 4S) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -3-cyanopiperidin-4-yl) -6-fluorobenzamide (I-151)

Step A: ((1R, 3S,5s,7 s) -2- (5-bromopyridin-2-yl) -2-azaadamantan-5-yl) aminocarbonate tert-butyl ester (355)

Compound 355 was synthesized by the method described in example 1, step F, with compound 354 and compound 10 as starting materials, and with reference to compound 11.

LCMS (m/z): 408 [M+H]⁺.

And (B) step (B): ((1R, 3S,5s,7 s) -3-cyano-2- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) -2-azaadamantan-5-yl) aminocarbonate (356)

Compound 356 was synthesized by the method described in example 1, step I, with reference to compound 15, starting from compound 355.

LCMS (m/z): 456 [M+H]⁺.

Step C: ((1R, 3S,5s,7 s) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -2-azaadamantan-5-yl) aminocarbonate tert-butyl ester (357)

Compound 357 was synthesized by the method described in step L of example 1, with reference to compound 18, starting from compound 356 and compound 17.

LCMS (m/z): 705 [M+H]⁺.

Step D:4- (6- ((1R, 3S,5s,7 s) -5-amino-2-azaadamantan-2-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (358)

Compound 358 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 357.

LCMS (m/z): 605 [M+H]⁺.

Step E: 2-chloro-N- ((1R, 3S,5s,7 s) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -2-azaadamantan-5-yl) -6-fluorobenzamide (359)

Compound 359 was synthesized by the method described in step E of example 28, with reference to compound 107, starting from compound 358 and compound 2-fluoro-6-chlorobenzoic acid.

LCMS (m/z): 761 [M+H]⁺.

Step F: 2-chloro-N- ((1R, 3S,5s,7 s) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] naphthyridin-4-yl) pyridin-2-yl) -2-azaadamantan-5-yl) -6-fluorobenzamide (I-151)

Compound I-151 was synthesized by the method described in example 1, step M, with compound 359 as a starting material, with reference to compound I-1.

LCMS (m/z): 607 [M+H]⁺.

Example 152: 2-chloro-N- ((3 aR,5s,6 aS) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -5-methyl octahydrocyclopenta [ C ] pyrrol-5-yl) -6-fluorobenzamide (I-152)

Step A: ((3 aR,5s,6 aS) -2- (5-bromopyridin-2-yl) -5-methyl octahydrocyclopenta [ C ] pyrrol-5-yl) aminocarbonyl tert-butyl ester (361)

Compound 361 was synthesized by the method described in example 1, step F, using compound 360 and compound 10 as raw materials, and referring to compound 11.

LCMS (m/z): 396 [M+H]⁺.

And (B) step (B): ((3 aR,5s,6 aS) -3-cyano-2- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) -5-methyl octahydrocyclopentan [ C ] pyrrol-5-yl) aminocarbonate tert-butyl ester (362)

Compound 362 was synthesized by the method described in example 1, step I, with reference to compound 15, starting from compound 361.

LCMS (m/z): 444 [M+H]⁺.

Step C: ((3 aR,5s,6 aS) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -5-methyl octahydrocyclopenta [ C ] pyrrol-5-yl) aminocarbonate tert-butyl ester (363)

Compound 363 was synthesized by the method described in step L of example 1 with reference to compound 18, starting from compound 362 and compound 17.

LCMS (m/z): 693 [M+H]⁺.

Step D:4- (6- ((3 aR,5s,6 aS) -5-amino-55-methyl octahydrocyclopenta [ C ] pyrrol-2 (1H) -yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine-5-carbonitrile (364)

Compound 364 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 363.

LCMS (m/z): 593 [M+H]⁺.

Step E: 2-chloro-N- ((3 aR,5s,6 aS) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -5-methyl octahydrocyclopenta [ C ] pyrrol-5-yl) -6-fluorobenzamide (365)

Compound 365 was synthesized by the method described in step E of example 28, using compound 364 and compound 2-fluoro-6-chlorobenzoic acid as starting materials.

LCMS (m/z): 749 [M+H]⁺.

Step F: 2-chloro-N- ((3 aR,5s,6 aS) -1- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -5-methyl octahydrocyclopenta [ C ] pyrrol-5-yl) -6-fluorobenzamide (I-152)

Compound I-152 was synthesized by the method described in example 1, step M, using compound 365 as a starting material.

LCMS (m/z): 595 [M+H]⁺.

Example 153:4- (6- ((1S, 5R, 7R) -7- (cyanomethyl) -6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.2.0] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-153)

Step A: (1S, 5R, 7R) -6- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -7-cyanomethyl-3, 6-diazabicyclo [3.2.0] heptane-3-carbonate tert-butyl ester (367)

Compound 367 was synthesized by the method described in step F of example 1, starting from compound 268 and compound 366, ((1 s,5r,7 r) -7- (cyanomethyl) -3, 6-diazabicyclo [3.2.0] heptane-3-carboxylic acid tert-butyl ester.

LCMS (m/z): 666 [M+H]⁺.

And (B) step (B): 4- (6- ((1S, 5R, 7R) -7- (cyanomethyl) -3, 6-diazabicyclo [3.2.0] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (368)

Compound 368 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 367.

LCMS (m/z): 436 [M+H]⁺.

Step C:4- (6- ((1S, 5R, 7R) -7- (cyanomethyl) -6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.2.0] heptan-3-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-153)

Compound I-153 was synthesized by the method of referring to compound 14 in step H of example 1, starting from compound 368 and compound 6-methoxypyridine-3-carbaldehyde.

LCMS (m/z): 557 [M+H]⁺.

Example 154:4- (6- (9- ((6-methoxypyridin-3-yl) methyl) -3-oxo-7, 9-diazabicyclo [3.3.1] nonan-7-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-154)

Step A: 7- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyridin-2-yl) -3-oxo-7, 9-diazabicyclo [3.3.1] nonane-9-carbonic acid tert-butyl ester (370)

Compound 370 was synthesized by the method described in step F of example 1, with reference to compound 11, starting from compound 268 and compound 369,3-oxo-7, 9-diazabicyclo [3.3.1] nonane-9-carbonate.

LCMS (m/z): 659 [M+H]⁺.

And (B) step (B): 4- (6- (3-oxo-7, 9-diazabicyclo [3.3.1] nonan-7-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (371)

LCMS (m/z): 427 [M+H]⁺.

Step C:4- (6- (9- ((6-methoxypyridin-3-yl) methyl) -3-oxo-7, 9-diazabicyclo [3.3.1] nonan-7-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-154)

Compound I-154 was synthesized by the method of referring to compound 14 in step H of example 1, starting from compound 371 and compound 6-methoxypyridine-3-carbaldehyde.

LCMS (m/z): 548 [M+H]⁺.

Example 155:4- (6- ((1S, 5S, 6S) -5-cyano-3- ((6-methoxypyridin-3-yl) methyl) -2, 7-diazabicyclo [4.2.0] oct-7-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-155)

Step A: (1S, 5S, 6S) -7- (5- (5-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridin-4-yl) pyridin-2-yl) -5-cyano-2, 7-diazabicyclo [4.2.0] octane-2-carbonic acid tert-butyl ester (373)

Compound 373 was synthesized by the method described in step F of example 1, starting from compound 268 and tert-butyl ((1S, 5S, 6S) -5-cyano-2, 7-diazabicyclo [4.2.0] octane-7-carbonate) compound 372.

LCMS (m/z): 666 [M+H]⁺.

And (B) step (B): 4- (6- ((1S, 5S, 6S) -5-cyano-2, 7-diazabicyclo [4.2.0] oct-7-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (374)

Compound 374 was synthesized by the method described in example 1, step G, with compound 373 as a starting material, and with reference to compound 12.

LCMS (m/z): 436 [M+H]⁺.

Step C: 4- (6- ((1S, 5S, 6S) -5-cyano-3- ((6-methoxypyridin-3-yl) methyl) -2, 7-diazabicyclo [4.2.0] oct-7-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-155)

Compound I-155 was synthesized by the method described in example 1, step H, with compound 374 and compound 6-methoxypyridine-3-carbaldehyde as starting materials, with compound 14.

LCMS (m/z): 557 [M+H]⁺.

Example 156:4- (6- ((1S, 5S, 6S) -4-cyano-3- ((6-methoxypyridin-3-yl) methyl) -2, 7-diazabicyclo [4.2.0] oct-7-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-156)

Step A: (1S, 5S, 6S) -7- (5- (4-cyano-2- (1-methyl-1H-pyrazol-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridin-4-yl) pyridin-2-yl) -5-cyano-2, 7-diazabicyclo [4.2.0] octane-2-carbonic acid tert-butyl ester (376)

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Compound 376 was synthesized by the method described in step F of example 1, starting from compound 268 and tert-butyl ((1S, 5S, 6S) -4-cyano-2, 7-diazabicyclo [4.2.0] octane-7-carbonate) compound 375.

LCMS (m/z): 666 [M+H]⁺.

And (B) step (B): 4- (6- ((1S, 5S, 6S) -4-cyano-2, 7-diazabicyclo [4.2.0] oct-7-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (377)

Compound 377 was synthesized by the method described in example 1, step G, with reference to compound 12, starting from compound 376.

LCMS (m/z): 436 [M+H]⁺.

Step C: 4- (6- ((1S, 5S, 6S) -4-cyano-3- ((6-methoxypyridin-3-yl) methyl) -2, 7-diazabicyclo [4.2.0] oct-7-yl) pyridin-3-yl) -2- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole [2,3-b ] pyridine-5-carbonitrile (I-156)

Compound I-156 was synthesized by the method described in example 1, step H, with compound 377 and compound 6-methoxypyridine-3-carbaldehyde as starting materials, compound 14.

LCMS (m/z): 557 [M+H]⁺.

Biological evaluation

The following further description explains the disclosure in connection with test examples, which are not meant to limit the scope of the disclosure.

Test example 1: in vitro test of the Activity of Compounds on RET ^WT for the laser

Compound preparation: dissolving the compound in 100% DMSO to prepare 10mM storage solution, freezing at-20 ℃, and preparing 10mM DMSO solution, and performing ultrasonic treatment on the compound for 30min to obtain clear solution;

Kinase reaction process: (1) preparation of 1 Xkinase buffer. (2) preparation of compound concentration gradient: the test compounds were tested at an initial concentration of 0.1. Mu.M, diluted to 100-fold final concentration of 100% DMSO in 384 source plates (source plates) and the compounds were diluted 3-fold accurately with buffer, 10 concentrations. 250nL of 100-fold final concentration of compound was transferred to the target plate (OptiPlate-384F) using a dispenser Echo 550. Positive and negative control wells were added 250nL DMSO. (3) A2.5-fold final concentration of kinase solution was prepared with 1 Xkinase buffer. (4) Adding 10 mu L of kinase solution with 2.5 times of final concentration to each of the compound well and the positive control well; mu.L of 1 Xkinase buffer was added to the negative control wells. (5) Centrifugation at 1000rpm for 30 seconds, the reaction plate was shaken and mixed well and incubated at room temperature for 10 minutes. (6) A5/3-fold final concentration of the mixed solution of ATP and kinase buffer was prepared with 1 Xkinase buffer. (7) The reaction was initiated by adding 15. Mu.L of a 5/3-fold final concentration of the mixed solution of ATP and substrate. (8) The 384-well plate was centrifuged at 1000rpm for 30 seconds, and after shaking and mixing, incubated at room temperature for a corresponding period of time. (9) The kinase reaction was stopped by adding 30. Mu.L of stop detection solution, centrifuging at 1000rpm for 30 seconds, and shaking and mixing. (10) The conversion was read with Caliper EZ Reader (instrument trade name). The test results are shown in table 1 below.

Two common mutations of RET, such as G810S and V804M, are referred to the experimental procedure described above.

Table 1: RET ^WT kinase Activity test results for example Compounds (IC ₅₀: nM)

The experimental results in Table 1 show that the inhibitory activity of the compounds I-4, 3, 32, 2,8, 1 and the like on RET ^WT is obviously better than that of LOXO-292;

Table 2: RET ^G810S kinase Activity test results for example Compounds (IC ₅₀: nM)

The experimental results in Table 2 show that the inhibitory activity of the compounds I-4, 3, 32, 8, 33, 39, 47, 55, 56, 58, 49, 51, 68, 53, 41, 59, 91, 66, 81 and the like on RET ^G810S is obviously better than that of LOXO-292;

Table 3: RET ^V804M kinase Activity test results for example Compounds (IC ₅₀: nM)

The experimental results in Table 3 show that the inhibitory activity of compounds I-4, 3, 8, 96, 52, 7, 30, 45, 57, 62, 74, 83, 87, 92, 97, 69, 41, 54 and the like on RET ^V804M is significantly better than that of LOXO-292;

test example 2: in vitro cytological Activity test of Compounds against Ba/F3-KIF5B-RET ^WT

The experimental method comprises the following steps: cell seeding, (1) rotating the suspension cells and re-suspending in growth medium, then counting with a cell counter; (2) Diluting the cell suspension in the growth medium to a desired density; (3) placing 95 μl of the cell suspension in a 96-well plate; (4) A control was set, a solution of the compound was added to a 96-well plate, and the final concentration of DMSO in each well was set; (5) culturing at 37℃under 5% CO2 for 72 hours; testing, (5) equilibrate the assay plate to room temperature prior to measurement; (6) To each well was added 50 parts CELLTITER GLO (trade name of kit) of reagent; (7) Mixing the contents on an orbital shaker for 2 minutes to induce cell lysis; (8) incubating for 10 minutes at room temperature to stabilize the luminescent signal; (9) record luminescence on Paradigm (Instrument model); data analysis, (10) inhibition (Inh) was calculated relative to vehicle (DMSO) -treated control wells using the following formula: cell growth inhibition = (1-As/Ac) ×100 inhibition was calculated. Wherein As is RLU sample (cell+CTG+test compound) -RLU Min (cell-free culture solution), ac is RLU normal growth cell control (cell+CTG+DMSO) -RLU Min (cell-free culture solution). Inputting the inhibition rate inh% (Y) corresponding to each concentration (X) in EXCEL, calculating the half inhibition concentration IC ₅₀ value of each compound according to a built-in four-parameter fitting formula Y=bottom+ (Top-Bottom)/(1+ (IC ₅₀/X)) HillSlope by using an XLfit plug-in, wherein Bottom refers to a baseline response, top refers to a maximum response, and HillSlope refers to the gradient of a curve; (11) The data was analyzed using GRAPHPAD PRISM 7.0.0 (analytical data software) and a 4 parameter equation was fitted to generate a concentration response curve.

Two common mutations of RET, such as G810S, V804M, G810R, and the complex mutations, were referred to the experimental procedure described above.

Table 4: ba/F3-KIF5B-RET ^WT cell Activity test results for exemplary Compounds (IC ₅₀: nM)

The experimental results in Table 4 show that the inhibition activity of the compounds I-8, 1, 40, 43, 54, 57, 48, 65, 60, 63, 17, 9, 101, 28, 27, 68, 134, 143 and the like on Ba/F3-KIF5B-RET ^WT is obviously better than that of LOXO-292;

Table 5: ba/F3-KIF5B-RET ^G810S cell Activity test results for exemplary Compounds (IC ₅₀: nM)

The experimental results in Table 5 show that the inhibition activity of the compounds I-4, 3, 2, 8, 1, 9, 15, 30, 38, 42, 61, 85, 76, 94, 92, 73, 149, 151 and the like on Ba/F3-KIF5B-RET ^G810S is obviously better than that of LOXO-292;

Table 6: ba/F3-KIF5B-RET ^V804M cell Activity test results for exemplary Compounds (IC ₅₀: nM)

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The experimental results in Table 6 show that the inhibition activity of the compounds I-2, 8, 1, 9, 15, 44, 75, 76, 77, 78, 90, 98, 99, 100, 152, 154 and the like on Ba/F3-KIF5B-RET ^V804M is obviously better than that of LOXO-292;

Table 7: ba/F3-KIF5B-RET ^G810R cell Activity test results for exemplary Compounds (IC ₅₀: nM)

The experimental results in Table 7 show that the inhibition activity of the compound I-1、27、28、29、9、17、12、16、18、19、14、15、20、22、25、11、10、5、6、24、34、35、36、37、62、67、68、69、70、71、72、74、79、41、46、50、64、82、83、84、86、88、89、87、101、102、103、104、105、8、134、107、109、112、125、126、130、106、143、148 and the like on Ba/F3-KIF5B-RET ^G810R is obviously better than that of LOXO-292;

Table 8: complex mutant cell Activity test results (IC ₅₀: nM) for example compounds

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The experimental results in Table 8 show that the inhibitory activity of the compounds I-1, 9, 17, 134, 143, 148 and the like on the complex mutations Ba/F3-KIF5B-RET ^V804M-G810S and Ba/F3-KIF5B-RET ^V804M-G810R is obviously better than that of LOXO-292;

Test example 3: evaluation of in vivo efficacy of Compounds on Ba/F3 KIF5B-RET-G810R cell subcutaneous allograft tumor model

Experiment design: cell culture: the Ba/F3 KIF5B-RET-G810R cell strain is cultured by adopting RPMI1640 culture medium, 10% fetal bovine serum and 1% double antibody, 37 ℃ and 5% CO2, and is subjected to passage treatment for 2-3 times a week. When the saturation of the cells is 80% -90% and the number reaches the requirement, the cells are collected, counted and inoculated. Animals: balb/c nude mice (athymic nude mice), females, 6-8 weeks old, weighing 18-22 grams, were offered by Jiangsu Jiuzhikang Biotechnology Co., ltd or Beijing Vitolith laboratory animal technology Co., ltd. Tumor inoculation: 0.2 ml (1X 106) Ba/F3 KIF5B-RET-G810R cells (matrigel added, volume ratio 1:1) were inoculated subcutaneously on the right back of each mouse and the group administration was started when the tumor average volume reached about 100-120 mm ³ (as close to 100 mm ³ as possible). Animal experiment grouping and dosing regimen: cell lines: ba/F3 KIF5B-RET-G810R, 6 animals in each group, vehicle group, positive control group and administration group; the dosage is 10 mg/kg or 25 mg/kg, the volume parameter is 10 μl/g, the administration route is gastric lavage, and the administration frequency is BID. Animal feeding: after animals arrive, the experiment can be started after 3-7 days of isolated quarantine feeding in the experimental environment. Animals were kept in SPF-class animal houses with independent air supply cages, no more than 5 animals per cage. Grouping animals: subcutaneous tumor states were observed daily after inoculation was completed, animals were weighed before grouping, tumor volumes were measured, and random groupings were made according to data. Tumor volume was measured by vernier calipers, with the formula tv=0.5 a ×b2, where a is the long diameter of the tumor and b is the short diameter of the tumor. The tumor-inhibiting effect of the compound was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) = [ (1- (mean tumor volume at the end of the treatment group administration-mean tumor volume at the beginning of the treatment group administration))/(mean tumor volume at the end of the treatment with solvent control group-mean tumor volume at the beginning of the treatment with solvent control group) ]x100%.

Table 9: example Compounds TGI on Ba/F3 KIF5B-RET-G810R cell subcutaneous allograft tumor model

During the experiment, as the vehicle group died successively on day 14, the TGI of each of the dosing groups after day 14 could not be calculated, but the tumor growth of the LOXO-292 two dose group was continuously increased, while the tumor volume of the compound dosing group was not further developed or remained continuously decreased, as observed from the subsequent tumor measurement of the dosing group, effectively controlling the tumor development.

As can be seen from Table 9, on day 12, compound I-9 (TGI: 54%) was significantly better than compound Loxo-292 (TGI: 15%), compound I-1 (TGI: 92%), I-9 (TGI: 77%) was significantly better than compound Loxo-292 (TGI: 41%) in the 10mg/kg dosing group, compound I-8 (TGI: 88%) was significantly better than compound Loxo-292 (TGI: 52%) and compound I-28 (TGI: 93%) was significantly better than compound Loxo-292 (TGI: 52%) in the 20mg/kg dosing group, and compounds I-1, I-8, I-9 and I-28 could be further dose explored and drug developed.

Test example 4: evaluation of pharmacokinetic Properties of Compounds

Experiment design: compound I-8 biological sample detection in mice, sampling group: compound I-8 mg/kg, sampling time points 0.25h,2h,6h,8h,9h,24h, plasma samples: 1. after all samples are completely melted, the mixture is mixed for 10 to 30 seconds and centrifuged for 0.5 minutes at 4000 rpm and 4 ℃.2. Remove 20.0. Mu.L of plasma sample (blank sample and internal standard blank sample plus 20.0. Mu.L of blank plasma) to 96-well plate, add 200. Mu.L of 50% methanol acetonitrile solution containing internal standard (50 ng/mL) (blank k sample without internal standard, without test compound plus 200. Mu.L of 50% methanol acetonitrile solution). 3. After vortexing the sample for 5 minutes, centrifuging at 4000 rpm ℃for 10 minutes, removing 100. Mu.L, adding to 100. Mu.L of pure water, mixing well, and subjecting to LC-MS/MS analysis. API 4000 LCMS/MS analyzer using ESI source positive ion mode multi-reaction monitoring, the analysis results were as follows:

Table 10: pK parameters of example Compounds

As can be seen from Table 10, compound I-8 has excellent pharmacokinetic properties, a half-life of about 2.5 hours, a clearance of about 7.9 mL/min/kg, a sufficient plasma exposure of 5.2 ten thousand hours ng/mL, and is worthy of further development.

The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.

In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.

Moreover, any combination of the various embodiments of the invention can be made without departing from the spirit of the invention, which should also be considered as disclosed herein.

The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily appreciate variations or alternatives within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims

1. A pyrrolo [2,3-b ] pyridine derivative represented by formula (I) or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer, or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof:

Formula (I)

Wherein:

R ₃ is selected from hydrogen, halogen, hydroxy, substituted or unsubstituted saturated or unsaturated C ₁-C₄ alkyl, substituted or unsubstituted saturated or unsaturated C ₁-C₄ alkyl alcohol, substituted or unsubstituted saturated or unsaturated C ₁-C₄ alkoxy, substituted or unsubstituted-C ₁-C₄ alkylamide group, substituted or unsubstituted saturated or unsaturated C ₁-C₄ alkylamine; wherein substituted means optionally containing 1 to 3 groups selected from deuterium, hydroxy, halogen, C ₁-C₃ alkyl;

or (b)

n1 is an integer selected from 0,1 or 2;

n2 is an integer selected from 0,1, 2 or 3;

n3 is an integer selected from 0,1 or 2;

n4 is an integer selected from 0,1, 2 or 3.

2. The pyrrolo [2,3-b ] pyridine derivative represented by formula (I), or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, according to claim 1,

R ₃ isWherein ring D is selected from saturated or unsaturated C ₃-C₆ cycloalkyl, saturated or unsaturated 4 to 6 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O and S, or 5 to 6 membered heteroaryl containing 1 to 2 heteroatoms selected from N, O and S, wherein ring D optionally contains n3 substituents R ₉,

3. The pyrrolo [2,3-b ] pyridine derivative represented by formula (I), or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, according to claim 1,

R ₃ is selected from the following structures:

or (b)

R ₃ isA structure selected from the following structures:

。

4. The pyrrolo [2,3-b ] pyridine derivative represented by formula (I) or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, according to any one of claim 1 to 3,

R ₉ is selected from the following structures:

。

5. The pyrrolo [2,3-b ] pyridine derivative represented by formula (I), or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, according to claim 1,

Ring a is selected from:。

6. The pyrrolo [2,3-b ] pyridine derivative represented by formula (I), or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, according to claim 1,

Ring B is selected from the following groups, substituted or unsubstituted:

。

7. The pyrrolo [2,3-b ] pyridine derivative represented by formula (I), or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, according to claim 1,

L is selected from:

。

8. the pyrrolo [2,3-b ] pyridine derivative represented by formula (I), or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, according to claim 1,

Ring C is selected from the following groups, substituted or unsubstituted:

；

9. The pyrrolo [2,3-b ] pyridine derivative represented by formula (I) or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, according to claim 1, wherein the pyrrolo [2,3-b ] pyridine derivative represented by formula (I) is represented by the following formula (II):

Formula (II)

Wherein each substituent is as defined in any one of claims 1 to 8.

10. The pyrrolo [2,3-b ] pyridine derivative or isotopically-labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof is selected from the following compounds:

/> />

/> /> 。

11. A pharmaceutical composition comprising a therapeutically effective amount of a pyrrolo [2,3-b ] pyridine derivative represented by formula (I) or formula (II) according to any one of claims 1 to 10, or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.

12. Use of a pyrrolo [2,3-b ] pyridine derivative represented by formula (I) or formula (II) or an isotopically-labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, according to any one of claims 1 to 10, for the preparation of a medicament for the treatment or prevention of a disease or disorder mediated by RET or a RET mutant in a subject in need thereof.

13. The use according to claim 12, wherein the disease or condition mediated by RET or RET mutants is selected from one or more of cancer, metabolic disease, inflammation, pain, developmental disease.

14. The use according to claim 12, wherein the disease or condition mediated by RET or RET mutants is selected from one or more of thyroid cancer, non-small cell lung cancer, pleural mesothelioma, colon cancer, pancreatic cancer, lung adenocarcinoma, breast cancer, ovarian cancer, type II multiple endocrine neoplasia, colorectal cancer, chronic granulocytic leukemia, salivary gland cancer, cervical cancer, prostate cancer, diabetes, irritable bowel syndrome, pain associated with irritable bowel syndrome, neuropathic pain, congenital megacolon.

15. A method of treating a disease or disorder mediated with RET or a RET mutant, the method comprising administering to a subject in need thereof an effective amount of a pyrrolo [2,3-b ] pyridine derivative represented by formula (I) or formula (II) according to any one of claims 1-10, or an isotopically labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or a mixture of isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition according to claim 11.