CN118103369A

CN118103369A - Pyridolactam derivatives, preparation method and application thereof

Info

Publication number: CN118103369A
Application number: CN202280058388.3A
Authority: CN
Inventors: 邱海波; 沈栋国; 陈阿欢; 聂开宇; 赵伟峰; 毛文涛; 陈友喜; 张衡; 叶成; 钱文建; 陈磊
Original assignee: Zhejiang Hisun Pharmaceutical Co Ltd; Shanghai Aryl Pharmtech Co Ltd
Current assignee: Zhejiang Hisun Pharmaceutical Co Ltd; Shanghai Aryl Pharmtech Co Ltd
Priority date: 2021-09-03
Filing date: 2022-09-02
Publication date: 2024-05-28
Also published as: WO2023030478A1

Abstract

The invention relates to a pyridolactam derivative, a preparation method thereof and application of a pharmaceutical composition containing the derivative in medicine. In particular, the present invention relates to substituted pyridolactam derivatives of general formula (I), wherein the substituents in general formula (I) are as defined in the specification, to processes for their preparation and to their pharmaceutically acceptable salts, and to their use as therapeutic agents, in particular as HPK1 inhibitors.

Description

Pyridolactam derivatives, preparation method and application thereof

The present application claims priority to chinese patent application 202111031560.X, entitled "pyridolactam derivatives, their preparation and pharmaceutical compositions containing the derivatives" filed on 3 months 2021, 9, and chinese patent application 202210140847.4, entitled "pyridolactam derivatives, their preparation and pharmaceutical compositions containing the derivatives" filed on 16 months 2022, 2, the contents of which are incorporated herein by reference in their entirety.

Technical Field

The present invention relates to pyridolactam derivatives, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents, in particular as HPK1 inhibitors.

Background

Hematopoietic progenitor kinase (HPK 1, also known as MAP4K 1) is a mammalian Ste 20-like serine/threonine kinase, which is the expression product of the gene MAP4K1, mainly in hematopoietic stem cells, belongs to mitogen activated protein kinase kinase family (MAP 4K), it has now been found that this family also includes 5 other members MAP4K2, MAP4K3, MAP4K4, MAP4K5, MAP4K6.HPK1 is a protein of 97kDa in relative molecular weight, and is largely divided into 3 regions, the N-terminal Ste 20-like kinase region, the C-terminal kinase region and the middle 4 proline-rich regions (P1, P2, P3 and P4), which normally interact with the adaptor proteins containing SH2/SH3 regions, activating the transduction of a range of signal pathways.

When HPK1 is activated by a variety of upstream signaling factors, including epidermal growth factor, prostaglandin E2, tumor growth factor, erythropoietin, T cell receptors, B cell receptors, etc., a series of biological cascades are triggered. HPK1 can also interact with the adaptor protein SLP-76 family, CARD11, GRB2 family, CRK family and the like in the downstream signaling pathway to activate the JNK/SAPK signaling pathway of hematopoietic stem cells, thereby back-regulating the T cell pathway. Therefore, HPK1 is involved in regulating cell proliferation and apoptosis, and plays an important role in immunosuppression.

HPK1 acts as a kinase regulating immunosuppression and is a reverse regulator of T cell receptor, when T cell receptor is activated, HPK1 in cytoplasm recruits to the vicinity of cell membrane, activated HPK1 phosphorylates linker protein SLP76, activated SLP76 acts as docking site for T cell regulatory inhibitor protein 14-3-3, multiple proteins combine to form SLP76 complex, SLP76 complex induces ubiquitination degradation, finally leading to instability of T cell receptor signaling complex, thereby down regulating T cell signaling pathway and T cell proliferation.

T cells participate in an important process of anti-tumor immunity, and the antigen receptor of the T cells is used for recognizing specific antibodies on tumor cells to directly kill the tumor cells; or indirectly kill tumor cells by activating macrophages and secreting other lymphokines. Therefore, inhibition of HPK1 can proliferate T cells and activate T cell signaling pathways, further enhancing tumor killing and inhibiting tumor growth. Because of the important role of HPK1 in immunomodulation, HPK1 can be used as a research tool for the treatment of inflammatory responses, autoimmune diseases (e.g., systemic lupus erythematosus, psoriasis) and malignancies (e.g., acute myelogenous leukemia, bladder epithelial cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, blastoma, retinoblastoma, sarcoma, prostate cancer, cholangiocarcinoma, esophageal cancer, gastric cancer, liver cancer, glioblastoma, cervical cancer, ovarian cancer, head and neck cancer, and multiple myeloma).

Only two compounds currently enter the clinic for inhibitors of the HPK1 target, namely CFI-402411 (stage two) of TREADWELL and BGB-15025 (stage one) of Baiji Shenzhou. Even so, there remains a need for safer and more effective HPK1 inhibitors that reduce the risk during treatment and reduce patient pain.

Disclosure of Invention

In view of the above technical problems, the present invention provides a pyridolactam derivative represented by the general formula (I):

Wherein:

R ¹ and R ² are the same or different and are each independently selected from a hydrogen atom, alkyl, halogen, nitro, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸ or-S (O) _rR ⁶; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸、-CH ₂NHC(O)OR ⁶、-CH ₂NR ⁷R ⁸, or-S (O) _rR ⁶;

R ^A is selected from hydrogen, halogen, hydroxy, cyano, alkyl or alkoxy; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; r ^A is preferably a hydrogen atom;

R ³ is selected from a hydrogen atom, halogen, alkyl or alkoxy; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; r ³ is preferably a hydrogen atom;

R ⁴ is selected from the following groups:

(i) A 6-14 membered fused ring, a 5-6 membered aryl group, or a 7-11 membered heterocyclyl group, wherein said 6-14 membered fused ring, 5-6 membered aryl group, or 7-11 membered heterocyclyl group is optionally further substituted with one or more R ^a;

R ^a, which are identical or different, are independently selected from a hydrogen atom, alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸、-CH ₂NHC(O)OR ⁶、-CH ₂NR ⁷R ⁸ or-S (O) rR ⁶; wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸、-CH ₂NHC(O)OR ⁶、-CH ₂NR ⁷R ⁸ or-S (O) rR ⁶;

(ii) A 4-6 membered heterocyclyl or a 5-10 membered heteroaryl, wherein said 4-6 membered heterocyclyl or 5-10 membered heteroaryl is substituted with one or more R ^b;

R ^b, which are identical or different, are independently selected from a hydrogen atom, an alkyl group, -S (O) _rR ⁶, -L-aryl group, -L-heterocyclyl group, -L-cycloalkyl group, -L-fused ring or-L-heteroaryl group; wherein said aryl, heterocyclyl, fused ring, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, hydroxyalkyl, benzyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸、-CH ₂NHC(O)OR ⁶、-CH ₂NR ⁷R ⁸, or-S (O) _rR ⁶, wherein said cycloalkyl is further substituted with one or more substituents selected from the group consisting of alkyl, halo, oxo, or haloalkyl;

Provided that at least one R ^b is selected from the group consisting of-S (O) _rR ⁶, -L-aryl, -L-heterocyclyl, -L-cycloalkyl, -L-fused ring, or-L-heteroaryl;

Each L is independently selected from a bond, -C ₁-C ₆ alkylene, or-C ₁-C ₆ alkyleneoxy; wherein said alkylene or alkyleneoxy group is optionally further substituted with one or more substituents selected from alkyl, halogen or hydroxy; preferably, L is selected from the group consisting of a bond, -CH ₂ -, or-CH ₂ O-;

Or two R ^b together with the same carbon atom to which they are attached form a-C (O) -;

(iii) -NR ^cR ^d、-C(O)NHCH ₂R ^g OR-OR ^f, wherein R ^c、R ^d、R ^f、R ^g, equal OR different, are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a fused ring, -C (O) R ⁶、-C(O)OR ⁶ OR-S (O) _rR ⁶, wherein said alkyl group, cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group OR a fused ring is optionally further substituted with one OR more substituents selected from alkyl group, hydroxyalkyl group, halogen, nitro group, cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group 、＝O、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸、-CH ₂NHC(O)OR ⁶、-CH ₂NR ⁷R ⁸、P(O)R ⁷R ⁸ OR-S (O) _rR ⁶;

R ⁵ is selected from the group consisting of hydrogen, hydroxy, halogen, cyano, alkyl, or alkoxy, wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, alkyl, or alkoxy;

Or R ⁴ and R ⁵ together with the atoms to which they are attached form a heterocyclyl, heteroaryl, or fused ring; the heterocyclyl, heteroaryl, or fused ring is optionally further substituted with one or more R ^e;

R ^e is substituted with a substituent selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸、-CH ₂NHC(O)OR ⁶、-CH ₂NR ⁷R ⁸, or-S (O) rR ⁶; wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸、-CH ₂NHC(O)OR ⁶、-CH ₂NR ⁷R ⁸ or-S (O) rR ⁶;

R ⁶ is selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-C(O)R ⁹、-C(O)OR ⁹、-OC(O)R ⁹、-NR ¹⁰R ¹¹、-C(O)NR ¹⁰R ¹¹、-SO ₂NR ¹⁰R ¹¹, or-NR ¹⁰C(O)R ¹¹;

R ⁷ and R ⁸ are each independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-C(O)R ⁹、-C(O)OR ⁹、-OC(O)R ⁹、-NR ¹⁰R ¹¹、-C(O)NR ¹⁰R ¹¹、-SO ₂NR ¹⁰R ¹¹, or-NR ¹⁰C(O)R ¹¹;

Or R ⁷ and R ⁸ together with the atoms to which they are attached form a 4-8 membered heterocyclyl wherein the 4-8 membered heterocyclyl contains one or more N, O or S (O) _r groups and said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-C(O)R ⁹、-C(O)OR ⁹、-OC(O)R ⁹、-NR ¹⁰R ¹¹、-C(O)NR ¹⁰R ¹¹、-SO ₂NR ¹⁰R ¹¹ or-NR ¹⁰C(O)R ¹¹;

R ⁹、R ¹⁰ and R ¹¹ are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl group, heteroaryl group, carboxyl group, or carboxylate group;

r is selected from 0, 1 or 2.

According to a preferred embodiment of the present invention there is provided a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of formula (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

Wherein:

Ring A is selected from 6-14 membered fused ring, 5-6 membered aryl or 7-11 membered heterocyclyl;

ring B is selected from 4-6 membered heterocyclyl or 5-10 membered heteroaryl;

ring C is selected from heterocyclyl, heteroaryl or fused ring;

m is selected from 0,1,2 or 3;

n is selected from 1,2 or 3;

p is selected from 0,1,2 or 3.

The definitions of R ¹、R ²、R ^a、R ^b and R ^e are as described in the general formula (I).

According to a preferred embodiment of the present invention there is provided a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of formula (V), (VI) or (VII) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

Wherein R ¹、R ²、R ^c、R ^d、R ^f and R ^g are as defined in formula (I).

According to a preferred embodiment of the present invention, there is provided a compound of formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of formula (II-1), (II-2), (II-3) or (II-4) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

Wherein:

ring D is selected from 3-8 membered heterocyclyl or 6-11 membered fused ring;

Ring E is selected from a 5-8 membered aryl, a 5-8 membered heteroaryl or a 6-9 membered fused ring;

Ring F is selected from 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;

q is selected from 0,1,2 or 3;

The definitions of R ¹、R ² and R ^a are as described in formula (II).

According to a preferred embodiment of the present invention, there is provided a compound of formula (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is a compound of formula (III-1) or (III-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:

Wherein R ¹、R ² and R ^b are as defined in formula (III).

According to a preferred embodiment of the present invention there is provided a compound of formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring a is selected from:

In some embodiments of the invention, the compound of formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is a compound of formula (II-1) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. According to a preferred embodiment of the present invention, there is provided a compound of the formula (II-1) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein

Selected from:

Preferably, R ⁴ in formula (I) or R ⁴ in formula (II-1) Selected from the group consisting ofAnd wherein neither R ^a on at least one carbon atom is hydrogen. More preferably, R ⁴ in formula (I) or R ⁴ in formula (II-1)Selected from:

According to a preferred embodiment of the present invention there is provided a compound of formula (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring C is selected from:

According to a preferred embodiment of the present invention, there is provided a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (II-1), (II-2), (II-3), (II-4), (III-1) or (III-2) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from heterocyclyl, heteroaryl, or-NR ⁷R ⁸; wherein said heterocyclyl or heteroaryl is optionally further substituted with one or more alkyl groups; and/or

R ⁷ and R ⁸ are each independently selected from a hydrogen atom, an alkyl group, preferably methyl, or a cycloalkyl group, preferably cyclopropyl or cyclopentyl, wherein the alkyl group is optionally further substituted by a cycloalkyl group.

R ¹ is selected from

R ² is selected from alkyl, heteroaryl, heterocyclyl or-C (O) NR ⁷R ⁸; wherein said alkyl, heteroaryl or heterocyclyl is optionally further substituted with one or more alkyl or-NR ⁷R ⁸;

preferably, R ² is selected from-CH ₂NR ⁷R ⁸; and/or

R ⁷ and R ⁸ are each independently selected from a hydrogen atom, an alkyl group, preferably a methyl group, or a cycloalkyl group, preferably a cyclopropyl group or a cyclopentyl group.

r ² is selected from

In some preferred embodiments of the invention, R ⁴ is defined for formula (I), wherein for (ii) 4-6 membered heterocyclyl or 5-10 membered heteroaryl, said 4-6 membered heterocyclyl or 5-10 membered heteroaryl is substituted with one or more R ^b, and said R ^b is selected from-L-aryl, -L-heterocyclyl, -L-cycloalkyl, -L-heteroaryl and-L-fused ring; wherein each L is independently selected from a bond, -C ₁-C ₆ alkylene, or-C ₁-C ₆ alkyleneoxy.

In some preferred embodiments of the invention, R ¹ is selected from heterocyclyl, heteroaryl, or-NR ⁷R ⁸; in some preferred embodiments of the invention, R ¹ is selected from-NR ⁷R ⁸. Preferably, R ⁷ and R ⁸ are each independently selected from alkyl and cycloalkyl; more preferably, R ⁷ and R ⁸ are each independently selected from methyl, isopropyl and cyclopropyl.

In some preferred embodiments of the invention, R ₁ is selected from And R ² is selected from

Typical compounds of the present invention include, but are not limited to:

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

Note that: if there is a difference between the drawn structure and the name given to the structure, the drawn structure will be given greater weight.

Still further, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (II-1), (II-2), (II-3), (II-4), (III-1) or (III-2) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The invention provides an application of a compound shown in general formulas (I), (II), (III), (IV), (V), (VI), (VII), (II-1), (II-2), (II-3), (II-4), (III-1) or (III-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing an HPK1 inhibitor.

The invention also provides the use of a compound of general formula (I), (II), (III), (IV), (V), (VI), (VII), (II-1), (II-2), (II-3), (II-4), (III-1) or (III-2), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease mediated by HPK1, wherein the disease mediated by HPK1 is preferably an inflammatory, autoimmune or neoplastic disease, wherein the autoimmune disease is preferably systemic lupus erythematosus or psoriasis; wherein the tumor is preferably a hematological malignancy and a solid malignancy; more preferred are acute myelogenous leukemia, bladder epithelial cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, blastoma, retinoblastoma, sarcoma, prostate cancer, cholangiocarcinoma, esophageal cancer, gastric cancer, liver cancer, glioma, cervical cancer, ovarian cancer, head and neck cancer, and multiple myeloma.

The invention further provides an application of the compound shown in the general formula (I), (II), (III), (IV), (V), (VI), (VII), (II-1), (II-2), (II-3), (II-4), (III-1) or (III-2) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicines for treating inflammation, autoimmune diseases or tumor diseases, wherein the autoimmune diseases are preferably systemic lupus erythematosus or psoriasis; wherein the tumor is preferably a hematological malignancy and a solid malignancy; more preferred are acute myelogenous leukemia, bladder epithelial cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, blastoma, retinoblastoma, sarcoma, prostate cancer, cholangiocarcinoma, esophageal cancer, gastric cancer, liver cancer, glioma, cervical cancer, ovarian cancer, head and neck cancer, and multiple myeloma.

The pharmaceutical formulations of the present invention may be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocular, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intradermal, intraperitoneal, subcutaneous, subcuticular or by inhalation. Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable carriers suitable for the manufacture of tablets.

The formulations of the present invention are suitably presented in unit-dose form and may be prepared by any method well known in the pharmaceutical arts. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form can vary depending upon the subject being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form generally refers to the amount of compound that is capable of producing a therapeutic effect.

Dosage forms for topical or transdermal administration of the compounds of the present invention may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be admixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants which may be required.

When the compounds of the invention are administered to humans and animals in the form of a medicament, the compounds may be provided alone or in the form of a pharmaceutical composition containing the active ingredient in combination with a pharmaceutically acceptable carrier, for example 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient.

Examples of pharmaceutically acceptable carriers include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) Polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; (21) Cyclodextrin, e.g., a targeting ligand attached to the nanoparticle, e.g., accurinsTM; and (22) other non-toxic compatible substances used in pharmaceutical formulations, such as polymer-based compositions.

Examples of pharmaceutically acceptable antioxidants include, but are not limited to: (1) Water-soluble antioxidants such as ascorbic acid, cysteamine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) Oil-soluble antioxidants such as ascorbyl palmitate, butylated Hydroxyanisole (BHA), butylated Hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelators such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like. Solid dosage forms (e.g., capsules, dragees, powders, granules and the like) may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) Fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) Binders, such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and/or acacia; (3) humectants, such as glycerin; (4) Disintegrants, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) an absorption accelerator, such as a quaternary ammonium compound; (7) Humectants, such as cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) a colorant. Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizing agents and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (especially cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the active compounds, may also contain suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

In addition to the active compounds, ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

In addition to the active compounds, the powders and sprays can also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. The spray may contain other conventional propellants such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons such as butane and propane.

Detailed description of the invention

Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:

"bond" means that the indicated substituent is absent and that the two end portions of the substituent are directly linked to form a bond.

"Alkyl" when used as a group or part of a group is meant to include C ₁-C ₂₀ straight or branched chain aliphatic hydrocarbon groups. Preferably a C ₁-C ₁₀ alkyl group, more preferably a C ₁-C ₆ alkyl group or a C ₁-C ₄ alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.

"Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Preferred alkenyl groups are C ₂-C ₆ alkenyl groups; representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. Alkenyl groups may be optionally substituted or unsubstituted.

"Alkynyl" refers to an aliphatic hydrocarbon group containing one carbon-carbon triple bond, which may be straight or branched. Preferred are C ₂-C ₁₀ alkynyl groups, more preferably C ₂-C ₆ alkynyl groups, most preferably C ₂-C ₄ alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl groups may be substituted or unsubstituted.

"Alkylene" is a divalent alkyl group. Preferably a C ₁-C ₁₀ alkylene group, more preferably a C ₁-C ₆ alkylene group, particularly preferably a C ₁-C ₄ alkylene group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, -C (CH ₃) ₂ -, n-propylene, etc., alkylene groups may be substituted or unsubstituted.

"Cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocycles. Preferably C ₃-C ₁₂ cycloalkyl, more preferably C ₃-C ₈ cycloalkyl, most preferably C ₃-C ₆ cycloalkyl. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred. Cycloalkyl groups may be optionally substituted or unsubstituted.

"Spirocycloalkyl" refers to a 5-to 18-membered polycyclic group having two or more cyclic structures with single rings sharing one carbon atom (called spiro atom) with each other, which contains 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably a spirocycloalkyl group of 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro group, a double spiro group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, preferably single spiro group and double spirocycloalkyl group, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.

"Fused ring alkyl" refers to a5 to 18 membered, all-carbon polycyclic group containing two or more cyclic structures and sharing a pair of carbon atoms with each other, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably a6 to 12 membered, more preferably a7 to 10 membered fused ring alkyl. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of "fused ring alkyl" include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, decalinyl, or tetradecahydrophenanthryl.

"Bridged cycloalkyl" means a 5 to 18 membered, all-carbon polycyclic group containing two or more cyclic structures and sharing two carbon atoms not directly attached to each other, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably a 6 to 12 membered, more preferably a 7 to 10 membered bridged cycloalkyl. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1 s,4 s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1 s,5 s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1 r,5 r) -bicyclo [3.3.2] decyl.

"Heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably herein and refer to a non-aromatic heterocyclic group in which one or more of the ring-forming atoms is selected from nitrogen, oxygen or a heteroatom of S (O) _t (wherein t is selected from 0, 1 or 2), including monocyclic, polycyclic, fused, bridged and spiro heterocyclic groups. Preferably having a5 to 7 membered single ring or a 7 to 10 membered double or triple ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulphur.

Examples of "monocyclic heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, piperazinyl, hexahydropyrimidinyl,

The monocyclic heterocyclic group may be substituted or unsubstituted.

"Spiroheterocyclyl" refers to a 5-to 18-membered polycyclic group containing two or more cyclic structures and having one atom in common with each other between the monocyclic rings, which may contain 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen or a heteroatom of S (O) _t (wherein t is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered spiroheterocyclyl. The spirocycloalkyl group is classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multiple spiro heterocyclic group according to the number of common spiro atoms between rings, and preferably a single spiro heterocyclic group and a double spiro heterocyclic group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5] decyl, 2-oxa-7-azaspiro [4.4] nonyl, 7-oxaspiro [3.5] nonyl, 5-oxaspiro [2.4] heptyl,

The spiroheterocyclyl groups may be substituted or unsubstituted.

"Fused heterocyclyl" refers to a polycyclic group containing two or more cyclic structures and sharing a pair of atoms with each other, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, wherein one or more of the ring atoms is selected from nitrogen, oxygen, or a heteroatom of S (O) _t (wherein t is selected from 0,1, or 2), and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered, fused heterocyclyl. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered, 5-membered/6-membered or 5-membered/7-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrrolo [3,4-c ] pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0] hexyl, octahydrobenzo [ b ] [1,4] dioxin (dioxine), a pharmaceutical composition,

The fused heterocyclic group may be substituted or unsubstituted.

"Bridged heterocyclyl" refers to a 5-to 14-membered or 5-to 18-membered polycyclic group containing two or more cyclic structures and sharing two atoms not directly linked to each other, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, wherein one or more of the ring atoms is selected from nitrogen, oxygen, or a heteroatom of S (O) _t (wherein n is selected from 0,1, or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered bridged heterocyclyl. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo [2.2.1] heptyl, 2-azabicyclo [2.2.2] octyl, 8-oxa-3-aza-bicyclo [3.2.1] octyl, and 2-azabicyclo [3.3.2] decyl.

The bridged heterocyclic group may be substituted or unsubstituted.

"Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably aryl is C ₆-C ₁₀ aryl, more preferably aryl is phenyl and naphthyl, most preferably naphthyl. Aryl groups may be substituted or unsubstituted.

"Heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 8-to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoxazolyl, and the like,

Heteroaryl groups may be substituted or unsubstituted.

"Fused ring" refers to a polycyclic group wherein two or more cyclic structures share a pair of atoms with each other, wherein one or more rings may contain one or more double bonds, but at least one ring does not have a fully conjugated pi-electron aromatic system, while at least one ring has a fully conjugated pi-electron aromatic system, wherein 0, 1 or more ring atoms are selected from nitrogen, oxygen, or heteroatoms of S (O) _t (wherein t is selected from 0, 1, or 2), and the remaining ring atoms are carbon. When the fused ring is a tricyclic or more fused ring, two of the rings optionally share one or more atoms with each other, and at least two of the rings share a pair of electrons with each other. The fused ring preferably includes a double-or triple-ring fused ring, wherein the double-ring fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group, and the triple-ring fused ring is preferably a fused ring of an aryl or heteroaryl group and a double-ring spiro heterocyclic group or a double-ring bridged heterocyclic group. The "fused ring" is preferably 6 to 14 membered, more preferably 8 to 12 membered. Examples of "fused rings" include, but are not limited to:

the fused ring may be substituted or unsubstituted.

"Alkoxy" refers to a group of (alkyl-O-). Wherein alkyl is as defined herein. Alkoxy groups of C ₁-C ₆ or C ₁-C ₄ are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.

"Hydroxy" refers to an-OH group.

"Halogen" refers to fluorine, chlorine, bromine and iodine.

"Amino" refers to-NH ₂.

"Cyano" refers to-CN.

"Nitro" means-NO ₂.

"Benzyl" means-CH ₂ -phenyl.

"Carboxy" means-C (O) OH.

"Carboxylate" refers to-C (O) O-alkyl or-C (O) O-cycloalkyl, wherein alkyl, cycloalkyl are as defined above.

"DMSO" refers to dimethyl sulfoxide.

"BOC" refers to t-butoxycarbonyl.

"TFA" refers to trifluoroacetic acid.

"Ts" refers to p-toluenesulfonyl.

"Tf" refers to p-trifluoromethylbenzenesulfonyl.

"X-PHOS Pd G2" refers to chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II).

"RuPhos Pd G3" means sulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II).

The term "leaving group (leaving group)", or leaving group, is used in the terms nucleophilic substitution reaction and elimination reaction as an atom or functional group that breaks away from a larger molecule in a chemical reaction. In nucleophilic substitution reactions, the reactant that is attacked by a nucleophile is referred to as a substrate (substrate), and the atom or group of atoms that breaks away from a pair of electrons in the substrate molecule is referred to as a leaving group. Groups that accept electrons easily and bear a strong negative charge are good leaving groups. The smaller the pKa of the leaving group conjugate acid, the easier the leaving group will be to disengage from the other molecule. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to be bound to other atoms, and the tendency to exist in anionic (or charge neutral leaving group) form is enhanced. Common leaving groups include, but are not limited to, halogen, methanesulfonyl, -OTs, -OTf, or-OH.

"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"Substituted" or "substituted" as used herein, unless otherwise indicated, means that the group may be substituted with one or more groups selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate 、＝O、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸、-CH ₂NHC(O)OR ⁶、-CH ₂NR ⁷R ⁸ or a substituent of-S (O) rR ⁶;

r is selected from 0,1 or 2;

The compounds of the invention may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (atropisomer) and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

Unless otherwise indicated, the structures described herein also include all stereoisomers (e.g., diastereomers, enantiomers and atropisomers and geometric (conformational) isomeric forms of such structures, e.g., the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.

"Pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain the original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds represented by the general formula (I) may be metal salts, amine salts with suitable acids.

"Pharmaceutical composition" means a mixture comprising one or more compounds described herein or a physiologically acceptable salt or stereoisomer or tautomer or prodrug thereof, and other chemical components, as well as other components, such as a physiologically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

Synthesis method of compound of the invention

In order to achieve the purpose of the invention, the invention adopts the following technical scheme:

the present invention provides a process for the preparation of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which process comprises:

carrying out Ullmann coupling reaction on the compound of the general formula (IA) and the compound of the general formula (IB) under the action of a copper catalyst and an alkaline reagent, and optionally further removing a protecting group to obtain the compound of the general formula (I);

Wherein:

x is halogen, preferably bromine;

The definitions of R ¹～R ⁵ and R ^A are as described in the general formula (I).

Detailed Description

The invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.

Examples

The preparation of representative compounds represented by formula (I) and related structural identification data are presented in the examples. It must be noted that the following examples are given by way of illustration and not by way of limitation. ¹ The H NMR spectrum was determined with a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. ¹ H NMR representation method: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.

The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.

In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and, unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, all of which are used without further purification and, unless otherwise indicated, commercially available manufacturers include, but are not limited to, ALDRICH CHEMICAL Company, ABCR GmbH & co.kg, acros Organics, praise chemical technology co.ltd, and beauty chemical technology co.ltd.

CD ₃ OD: deuterated methanol.

CDCl ₃: deuterated chloroform.

DMSO-d ₆: deuterated dimethyl sulfoxide.

The argon atmosphere means that the reaction flask is connected to an argon balloon of about 1L volume.

The examples are not particularly described, and the solution in the reaction is an aqueous solution.

Purifying the compound by silica gel column chromatography and reverse phase column chromatography, wherein the eluent system is selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: methylene chloride and methanol systems; c: ethyl acetate and methanol systems; d: ammonium bicarbonate aqueous solution and a methanol system; e: aqueous trifluoroacetic acid and methanol systems; f: dichloromethane and ethyl acetate systems; g: aqueous trifluoroacetic acid and acetonitrile system; the volume ratio of the solvent is different according to the polarity of the compound, and can be adjusted by adding a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine.

Example 1

6-(isopropyl(methyl)amino)-2-(6-(4-isopropyl-5-(methylthio)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -2- (6- (4-isopropyl-5- (methylsulfanyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

6-bromopicolinohydrazide

6-Bromopyridine formylhydrazine

Methyl 6-bromopyridine carboxylate 1a (2.5 g,11.57 mmol) was dissolved in methanol (30 mL), and hydrazine hydrate (1.45 g,23.14mmol, 80%) was added and stirred at 25℃for 5 hours. The reaction was then largely freed of solvent by spinning, slurried with ethyl acetate (30 mL), filtered, and the filter cake was collected and dried to give 6-bromopyridine formylhydrazine 1b (2.2 g,10.18 mmol) in 88.00% yield.

MS m/z(ESI):215.9[M+1] ⁺

Second step

2-(6-bromopicolinoyl)-N-isopropylhydrazine-1-carbothioamide

2- (6-Bromopyridine formyl) -N-isopropylhydrazine-1-carbosulfanamide

6-Bromopyridine formylhydrazine 1b (0.8 g,3.70 mmol) was dissolved in ethanol (15 mL), isopropyl isothiocyanate (749.28 mg,7.41 mmol) was added, and the mixture was heated to 80℃and stirred for 2 hours. The reaction mixture was washed with ethanol (10 mL), and the cake was dried to give 2- (6-bromopyridine formyl) -N-isopropylhydrazine-1-carbosulfanamide 1c (0.9 g,2.84 mmol) in 76.62% yield.

MS m/z(ESI):316.9[M+1] ⁺

Third step

5-(6-bromopyridin-2-yl)-4-isopropyl-2,4-dihydro-3H-1,2,4-triazole-3-thione

5- (6-Bromopyridin-2-yl) -4-isopropyl-2, 4-dihydro-3H-1, 2, 4-triazole-3-thione

2- (6-Bromopyridine formyl) -N-isopropylhydrazine-1-carbosulfanamide 1c (0.85 g,2.68 mmol) was dissolved in water (12 mL), sodium hydroxide (321.54 mg,8.04 mmol) was added, and the mixture was heated to 100℃for 18 hours. The reaction solution was cooled to room temperature, pH was adjusted to 6 to 7 with 2N diluted hydrochloric acid, filtered, washed with water (10 mL), and the cake was collected and dried to give 5- (6-bromopyridin-2-yl) -4-isopropyl-2, 4-dihydro-3H-1, 2, 4-triazole-3-thione 1d (0.55 g,1.84 mmol) in a yield of 68.60%.

MS m/z(ESI):298.9[M+1] ⁺

Fourth step

2-bromo-6-(4-isopropyl-5-(methylthio)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4-isopropyl-5- (methylthio) -4H-1,2, 4-triazol-3-yl) pyridine

5- (6-Bromopyridin-2-yl) -4-isopropyl-2, 4-dihydro-3H-1, 2, 4-triazole-3-thione 1d (0.5 g,1.67 mmol) was dissolved in a mixed solvent of water (10 mL) and ethanol (4 mL), followed by addition of sodium hydroxide (133.68 mg,3.34 mmol) and methyl iodide (1.19 g,8.36 mmol), and stirring was carried out at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: C system) to give 2-bromo-6- (4-isopropyl-5- (methylthio) -4H-1,2, 4-triazol-3-yl) pyridine 1e (0.32 g,1.02 mmol) in 61.13% yield.

MS m/z(ESI):312.9[M+1] ⁺

Fifth step

tert-butyl

((6-chloro-2-(6-(4-isopropyl-5-(methylthio)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6-Chloro-2- (6- (4-isopropyl-5- (methylsulfanyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6-chloro-1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 1f (0.2 g, 641.51. Mu. Mol, prepared according to published patent WO2020100027A 1) and 2-bromo-6- (4-isopropyl-5- (methylthio) -4H-1,2, 4-triazol-3-yl) pyridine 1e (301.40 mg, 962.27. Mu. Mol) were dissolved in1, 4-dioxane (6 mL), and cuprous iodide (61.09 mg, 320.76. Mu. Mol), N-dimethylethylenediamine (56.55 mg, 641.51. Mu. Mol) and potassium carbonate (265.98 mg,1.92 mmol) were added in this order, and the mixture was reacted at 100℃for 4 hours under argon protection. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) and reversed-phase column chromatography (eluent: D system) successively to give 1g (80 mg, 147.04. Mu. Mol) of tert-butyl ((6-chloro-2- (6- (4-isopropyl-5- (methylthio) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate in a yield of 22.92%.

MS m/z(ESI):543.9[M+1] ⁺

Sixth step

tert-butyl

((6-(isopropyl(methyl)amino)-2-(6-(4-isopropyl-5-(methylthio)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -2- (6- (4-isopropyl-5- (methylsulfanyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

1G (70 mg, 128.66. Mu. Mol) of tert-butyl ((6-chloro-2- (6- (4-isopropyl-5- (methylthio) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate (70 mg, 128.66. Mu. Mol) was dissolved in1, 4-dioxane (5 mL), ruPhos Pd G (32.32 mg, 38.60. Mu. Mol), N-isopropylmethylamine (376.41 mg,5.15 mmol) and cesium carbonate (125.76 mg, 385.98. Mu. Mol) were added in this order, and the mixture was heated to 70℃under argon atmosphere and reacted for 8 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (4-isopropyl-5- (methylthio) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate (50 mg, 44.77. Mu. Mol) for 1H in 34.80% yield.

MS m/z(ESI):581.0[M+1] ⁺

Seventh step

Tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (4-isopropyl-5- (methylsulfanyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate (45 mg,77.49 μmol) was dissolved in dichloromethane (4 mL), and a1, 4-dioxane solution of hydrochloric acid (4 m,774.87 μl) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: E system) to give 6- (isopropyl (methyl) amino) -2- (6- (4-isopropyl-5- (methylthio) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 1 (11.5 mg, 18.36. Mu. Mol) in a yield of 23.69%.

MS m/z(ESI):481.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.88(brs,2H),8.66(dd,J＝8.4,0.8Hz,1H),8.12(dd,J＝8.5,7.6Hz,1H),7.79(dd,J＝7.6,0.8Hz,1H),6.92(s,1H),5.49–5.37(m,1H),5.09(s,2H),5.08–4.98(m,1H),4.32(s,2H),2.93(s,3H),2.76(s,3H),2.73(s,3H),1.59(d,J＝7.0Hz,6H),1.16(d,J＝6.7Hz,6H).

Example 2

6-(isopropyl(methyl)amino)-2-(6-(4-isopropyl-5-((2-oxocyclopentyl)thio)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -2- (6- (4-isopropyl-5- ((2-oxocyclopentyl) thio) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-((5-(6-bromopyridin-2-yl)-4-isopropyl-4H-1,2,4-triazol-3-yl)thio)cyclopentan-1-one

2- ((5- (6-Bromopyridin-2-yl) -4-isopropyl-4H-1, 2, 4-triazol-3-yl) thio) cyclopentan-1-one

5- (6-Bromopyridin-2-yl) -4-isopropyl-2, 4-dihydro-3H-1, 2, 4-triazole-3-thione 1d (500 mg,1.67 mmol) was dissolved in N, N-dimethylformamide (10 mL), cesium carbonate (1.63 g,5.01 mmol) and 2-chlorocyclopentanone (594.41 mg,5.01 mmol) were added, and stirred at room temperature for 2 hours. Water (30 mL) was added, the organic phases were combined, washed with ethyl acetate (30 mL. Times.3), dried over saturated brine (30 mL), filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 2- ((5- (6-bromopyridin-2-yl) -4-isopropyl-4H-1, 2, 4-triazol-3-yl) thio) cyclopentan-1-one 2a (500 mg,1.31 mmol) in 78.47% yield.

MS m/z(ESI):380.8[M+1] ⁺

Second step

tert-butyl

((6-(isopropyl(methyl)amino)-2-(6-(4-isopropyl-5-((2-oxocyclopentyl)thio)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -2- (6- (4-isopropyl-5- ((2-oxocyclopentyl) thio) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (70 mg, 200.90. Mu. Mol, prepared according to published patent WO2020100027A 1) and 2- ((5- (6-bromopyridin-2-yl) -4-isopropyl-4H-1, 2, 4-triazol-3-yl) thio) cyclopentane-1-one 2a (153.20 mg, 401.79. Mu. Mol) were dissolved in 1, 4-dioxane (5 mL), and cuprous iodide (19.13 mg, 100.45. Mu. Mol), N-dimethylethylenediamine (17.71 mg, 200.90. Mu. Mol) and potassium carbonate (83.29 mg, 602.69. Mu. Mol) were added in this order and the mixture was heated to 100℃for reaction for 18 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (4-isopropyl-5- ((2-oxocyclopentyl) thio) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2c (30 mg, 46.24. Mu. Mol), yield 23.02%.

MS m/z(ESI):648.9[M+1] ⁺

Third step

Tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (4-isopropyl-5- ((2-oxocyclopentyl) thio) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2c (30 mg,46.24 μmol) was dissolved in dichloromethane (3 mL), and a1, 4-dioxane solution of hydrochloric acid (4 m,462.38 μl) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (separation column: AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm; mobile phase A:0.05% TFA+H2O; mobile phase B: acetonitrile; flow rate: 20 mL/min) to give 6- (isopropyl (methyl) amino) -2- (6- (4-isopropyl-5- ((2-oxocyclopentyl) thio) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 2 (2.6 mg, 3.79. Mu. Mol), yield 8.20%.

MS m/z(ESI):549.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.77(brs,2H),8.64(d,J＝8.4Hz,1H),8.13(t,J＝8.0Hz,1H),7.78(d,J＝7.5Hz,1H),6.91(s,1H),5.44–5.34(m,1H),5.09(s,2H),5.07–4.97(m,1H),4.39–4.30(m,1H),4.30(s,2H),2.92(s,3H),2.71(s,3H),2.29–2.15(m,2H),2.14–2.00(m,2H),2.00–1.86(m,2H),1.59(d,J＝7.0Hz,6H),1.16(d,J＝6.6Hz,6H).

Example 3

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

tert-butyl

((6-(isopropyl(methyl)amino)-1-oxo-2-(6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -1-oxo-2- (6- (5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (75 mg, 215.25. Mu. Mol, prepared according to published patent WO2020100027A 1) and 3- (6-bromopyridin-2-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine 3a (60 mg, 215.25. Mu. Mol, prepared according to published patent WO2018133865A 1) were dissolved in 1, 4-dioxane (5 mL), and cuprous iodide (32.79 mg, 172.20. Mu. Mol), N-dimethylethylenediamine (37.95 mg, 430.49. Mu. Mol) and potassium carbonate (89.24 mg, 645.74. Mu. Mol) were added in this order and reacted at 100℃for 5 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 3b (110 mg, 201.22. Mu. Mol), yield 93.48%.

MS m/z(ESI):547.0[M+1] ⁺

Second step

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 3b (110 mg, 201.22. Mu. Mol) was dissolved in dichloromethane (4 mL), and a1, 4-dioxane solution of hydrochloric acid (4 m,2.01 mL) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (separation column: AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm; mobile phase A:0.05% TFA+H ₂ O; mobile phase B: acetonitrile; flow rate: 20 mL/min) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 3 (80 mg, 142.71. Mu. Mol), 70.92%.

MS m/z(ESI):447.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.18(brs,2H),8.58(d,J＝8.3Hz,1H),8.09(t,J＝8.0Hz,1H),7.96(d,J＝7.6Hz,1H),6.90(s,1H),5.16(s,2H),5.08–4.97(m,1H),4.56(t,J＝6.0Hz,2H),4.37(t,J＝5.9Hz,2H),3.00(t,J＝6.4Hz,2H),2.92(s,3H),2.73(t,J＝5.3Hz,3H),2.09–2.00(m,2H),1.97–1.86(m,2H),1.16(d,J＝6.6Hz,6H).

Example 4

4-(6-(6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pyridin-2-yl)-6-oxa-4-azaspiro[2.4]heptan-5-one

4- (6- (6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -6-oxa-4-azaspiro [2.4] heptane-5-one

First step

(1-((6-bromopyridin-2-yl)amino)cyclopropyl)methanol

(1- ((6-Bromopyridin-2-yl) amino) cyclopropyl) methanol

2-Bromo-6-fluoropyridine 4a (500 mg,2.84 mmol) and 1-aminocyclopropyl methanol hydrochloride 4b (702.22 mg,5.68 mmol) were dissolved in dimethyl sulfoxide (10 mL), and potassium phosphate (1.81 g,8.52 mmol) was added thereto, and the mixture was heated to 120℃to react for 60 hours. The reaction mixture was added with water (30 mL), extracted with ethyl acetate (30 mL. Times.3), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give (1- ((6-bromopyridin-2-yl) amino) cyclopropyl) methanol 4c (600 mg,2.47 mmol) in 86.87% yield.

MS m/z(ESI):242.9[M+1] ⁺

Second step

4-(6-bromopyridin-2-yl)-6-oxa-4-azaspiro[2.4]heptan-5-one

4- (6-Bromopyridin-2-yl) -6-oxa-4-azaspiro [2.4] heptan-5-one

(1- ((6-Bromopyridin-2-yl) amino) cyclopropyl) methanol 4c (400 mg,1.65 mmol) was dissolved in tetrahydrofuran (40 mL), cooled to 0 ℃, N-diisopropylethylamine (850.63 mg,6.58 mmol) and N, N' -carbonyldiimidazole (667.00 mg,4.11 mmol) were added, stirred at room temperature for 2 hours, cooled to 0 ℃, tetrahydrofuran (120 mL) was added to the reaction solution, and then sodium hydride (128.41 mg,4.94 mmol) was added, and stirred at 0 ℃ for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (100 mL), extracted with ethyl acetate (100 mL. Times.3), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 4- (6-bromopyridin-2-yl) -6-oxa-4-azaspiro [2.4] heptan-5-one 4d (150 mg, 557.43. Mu. Mol) in 33.88% yield.

MS m/z(ESI):268.9[M+1] ⁺

Third step

tert-butyl

((6-(isopropyl(methyl)amino)-1-oxo-2-(6-(5-oxo-6-oxa-4-azaspiro[2.4]heptan-4-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -1-oxo-2- (6- (5-oxo-6-oxa-4-azaspiro [2.4] heptan-4-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (70 mg, 200.90. Mu. Mol, prepared according to published patent WO2020100027A 1) was dissolved in1, 4-dioxane (4 mL), 4- (6-bromopyridin-2-yl) -6-oxa-4-azaspiro [2.4] heptan-5-one 4d (81.09 mg, 301.34. Mu. Mol), cuprous iodide (38.26 mg, 200.90. Mu. Mol), N-dimethylethylenediamine (35.42 mg, 401.79. Mu. Mol) and potassium carbonate (83.29 mg, 602.69. Mu. Mol) were added and the mixture was heated to 100℃to react for 6 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (5-oxo-6-oxa-4-azaspiro [2.4] heptan-4-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 4e (85 mg, 158.40. Mu. Mol), yield 78.85%.

MS m/z(ESI):536.7[M+1] ⁺

Fourth step

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (5-oxo-6-oxa-4-azaspiro [2.4] heptan-4-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 4e (85 mg,158.40 μmol) was dissolved in dichloromethane (2.42 mL), and a1, 4-dioxane solution of hydrochloric acid (4 m,1.58 mL) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: E system) to give 4- (6- (6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -6-oxa-4-azaspiro [2.4] heptane-5-one 4 (85 mg, 149.84. Mu. Mol), yield 94.60%.

MS m/z(ESI):437.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.06(brs,2H),8.31(d,J＝8.2Hz,1H),7.96(t,J＝8.1Hz,1H),7.49(d,J＝8.0Hz,1H),6.87(s,1H),5.10–4.97(m,1H),4.96(s,2H),4.46(s,2H),4.36(s,2H),2.92(s,3H),2.74(s,3H),1.85(t,J＝3.5Hz,2H),1.16(d,J＝6.6Hz,6H),0.88–0.82(m,2H).

Example 5

6-(isopropyl(methyl)amino)-2-(6-(5-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

6-methoxy-2-methyl-2,3,4,5-tetrahydropyridine

6-Methoxy-2-methyl-2, 3,4, 5-tetrahydropyridine

6-Methylpiperidin-2-one 5a (1 g,8.84 mmol) was dissolved in dichloromethane (15 mL), and trimethyloxonium tetrafluoroboric acid (2.61 g,17.67 mmol) was added thereto and stirred at room temperature for 48 hours. To the reaction solution was added saturated aqueous sodium hydrogencarbonate (20 mL), stirred for 10 minutes, extracted with methylene chloride (20 mL. Times.3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 6-methoxy-2-methyl-2, 3,4, 5-tetrahydropyridine 5b (500 mg,3.93 mmol) in 44.49% yield.

MS m/z(ESI):128.1[M+1] ⁺

Second step

3-(6-bromopyridin-2-yl)-5-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine

3- (6-Bromopyridin-2-yl) -5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine

6-Bromopyridine formylhydrazine 1b (400 mg,1.85 mmol) was dissolved in dimethyl sulfoxide (8 mL), 6-methoxy-2-methyl-2, 3,4, 5-tetrahydropyridine 5b (470.97 mg,3.70 mmol) was added, and the mixture was reacted at 95℃for 18 hours. The reaction mixture was added with water (24 mL), extracted with ethyl acetate (20 mL. Times.3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 3- (6-bromopyridin-2-yl) -5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine 5C (400 mg,1.36 mmol), yield 73.69%.

MS m/z(ESI):293.0[M+1] ⁺

Third step

tert-butyl

((6-(isopropyl(methyl)amino)-2-(6-(5-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl-1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (75 mg, 215.25. Mu. Mol, prepared according to published patent WO2020100027A 1) and 3- (6-bromopyridin-2-yl) -5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine 5c (113.58 mg, 387.44. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (32.79 mg, 172.20. Mu. Mol), N-dimethylethylenediamine (37.95 mg, 430.49. Mu. Mol) and potassium carbonate (89.24 mg, 645.74. Mu. Mol) were added and reacted at 100℃for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl-1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 5d (115 mg, 205.10. Mu. Mol), yield 95.29%. MS m/z (ESI) 561.0[ M+1] ⁺

Fourth step

Tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl-1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 5d (115 mg, 205.10. Mu. Mol) was dissolved in dichloromethane (4 mL), a1, 4-dioxane solution of hydrochloric acid (4M, 2.05 mL) was added, stirred at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse phase column chromatography (eluent: E system) to give 6- (isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) -4- ((methyl) -2, 3-dihydro-pyrrolo [1, 3-c ] pyridin-2-yl) -4-pyrido-1, 3-7-yl ] pyrido-2-5, 5-7 mg, 8-tetrahydro [1, 3-pyrido-c ] pyrido [1, 3-5-c ] pyrido-5.5 mg (57 mg), yield (100.162 mg).

MS m/z(ESI):461.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.17(brs,2H),8.59(d,J＝8.3Hz,1H),8.10(t,J＝8.0Hz,1H),7.99(d,J＝7.6Hz,1H),6.91(s,1H),5.48–5.39(m,1H),5.23(d,J＝16.8Hz,1H),5.06(d,J＝17.5Hz,1H),5.08–4.97(m,1H),4.35(t,J＝6.0Hz,2H),3.08–3.03(m,1H),2.93(s,3H),2.91–2.82(m,1H),2.74(t,J＝5.3Hz,3H),2.18–1.86(m,4H),1.39(d,J＝6.5Hz,3H),1.16(d,J＝6.6Hz,6H).

Example 6 and example 7

(S)-6-(isopropyl(methyl)amino)-2-(6-(5-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(S) -6- (isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 6

(R)-6-(isopropyl(methyl)amino)-2-(6-(5-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(R) -6- (isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 7

6- (Isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 5 (100 mg, 217.11. Mu. Mol) was chiral resolved by SFC (column number: CHIRALPAK IG, 250X 30mm I.D., 10. Mu.m; mobile phase: A for CO2 and B for Ethanol (0.1% NH ₃H ₂ O); column pressure: 100bar; flow rate: 80mL/min; detection wavelength: 220nm; column temperature: 38 ℃ C.) to give single configuration compounds (shorter retention time) and single configuration compounds (longer retention time).

Single configuration compounds (shorter retention time):

41mg; the retention time was 2.994 minutes and the chiral purity was 100% ee.

MS m/z(ESI):461.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.57(d,J＝7.9Hz,1H),8.12–7.92(m,3H),6.75(s,1H),5.52(t,J＝6.2Hz,1H),5.24(d,J＝17.3Hz,1H),5.12(d,J＝17.4Hz,1H),5.01–4.88(m,1H),3.87(s,2H),3.07–3.02(m,1H),2.87(s,3H),2.87–2.79(m,1H),2.40(s,3H),2.18–1.85(m,4H),1.42(d,J＝6.5Hz,3H),1.14(d,J＝6.7Hz,6H).

Single configuration compounds (longer retention time):

42mg; the retention time was 4.517 minutes and the chiral purity was 100% ee.

MS m/z(ESI):461.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.57(dd,J＝7.9,1.4Hz,1H),8.11–7.93(m,3H),6.75(s,1H),5.58–5.47(m,1H),5.25(d,J＝17.4Hz,1H),5.13(d,J＝17.3Hz,1H),5.01–4.89(m,1H),3.84(d,J＝3.9Hz,2H),3.07–3.02(m,1H),2.86(s,3H),2.85–2.80(m,1H),2.38(s,3H),2.19–1.84(m,4H),1.43(d,J＝6.5Hz,3H),1.14(d,J＝6.6Hz,6H).

Example 8

6-(isopropyl(methyl)amino)-2-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -2- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

tert-butyl

((6-(isopropyl(methyl)amino)-2-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -2- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (65 mg, 186.55. Mu. Mol, prepared according to published patent WO2020100027A 1) and 3- (6-bromopyridin-2-yl) -5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 8a (104.14 mg, 373.09. Mu. Mol, prepared according to published patent WO2018151830A 1) were dissolved in 1, 4-dioxane (5 mL), cuprous iodide (28.42 mg, 149.24. Mu. Mol), N, N-dimethylethylenediamine (32.89 mg, 373.09. Mu. Mol), potassium carbonate (77.35 mg, 559.64. Mu. Mol) were added and the mixture was warmed to 100℃for reaction for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 8b (90 mg, 164.64. Mu. Mol), in 88.25% yield.

MS m/z(ESI):547.0[M+1] ⁺

Second step

Tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 8b (90 mg,164.64 μmol) was dissolved in dichloromethane (4 mL), and a1, 4-dioxane solution of hydrochloric acid (4 m,1.65 mL) was added and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: E system) to give 6- (isopropyl (methyl) amino) -2- (6- (5-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 8 (75 mg, 128.07. Mu. Mol), in a yield of 77.79%.

MS m/z(ESI):447.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.10(brs,2H),8.58(d,J＝8.3Hz,1H),8.08(t,J＝8.0Hz,1H),7.99(d,J＝7.6Hz,1H),6.91(s,1H),5.25(d,J＝16.9Hz,1H),5.15(t,J＝6.7Hz,0H),5.07–4.99(m,1H),5.03(d,J＝16.9Hz,1H),4.36(tq,J＝15.4,7.9,6.0Hz,2H),3.16–2.96(m,2H),2.93(s,3H),2.75(t,J＝5.3Hz,3H),2.43–2.30(m,2H),1.51(d,J＝6.4Hz,3H),1.17(d,J＝6.6Hz,6H).

Example 9

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(4-phenyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-phenyl-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (300 mg,1.11mmol, prepared according to WO2020100027A 1) was dissolved in acetonitrile (6 mL) at room temperature, aniline (515.26 mg,5.53 mmol) and glacial acetic acid (647.01. Mu.L, 11.07 mmol) were added, the mixture was warmed to reflux, reacted for 10 hours, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: F system) to give 2-bromo-6- (4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridine 9b (170 mg, 564.52. Mu. Mol) as a product in 51.02% yield.

MS m/z(ESI):301.0[M+1] ⁺

Second step

tert-butyl

((6-(isopropyl(methyl)amino)-1-oxo-2-(6-(4-phenyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(6- (Isopropyl (methyl) amino) -1-oxo-2- (6- (4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

2-Bromo-6- (4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridine 9b (89.88 mg, 298.47. Mu. Mol) and ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 2b (80 mg, 229.60. Mu. Mol, prepared according to published patent WO2020100027A 1) were dissolved in 1, 4-dioxane (2.5 mL), and tris (dibenzylideneacetone) dipalladium (21.02 mg, 22.96. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (26.57 mg, 45.92. Mu. Mol) and potassium phosphate (146.21 mg, 688.79. Mu. Mol) were added in this order, and the mixture was warmed to 70℃for 16 hours under argon protection. After the reaction solution was concentrated under reduced pressure, methylene chloride (20 mL) was added for dilution, filtration, washing of methylene chloride (3X 5 mL), and concentration of the filtrate under reduced pressure was collected, and the obtained residue was purified by silica gel column chromatography (eluent: F system) to give tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 9c (140 mg, 223.22. Mu. Mol) in 97.22% yield.

MS m/z(ESI):569.4[M+1] ⁺

Third step

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 9c (130 mg,228.60 μmol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (1.31 mL,17.15 mmol) was added, and stirred for 5 hours after slowly warming to room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H ₂ O; mobile phase B: CH ₃ CN) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 9 (100 mg, 170.07. Mu. Mol), yield 74.39%.

MS m/z(ESI):469.2[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.15(brs,2H),8.92(s,1H),8.49(d,J＝8.2Hz,1H),8.08(t,J＝8.0Hz,1H),8.01(d,J＝7.5Hz,1H),7.71–7.59(m,3H),7.57–7.47(m,2H),6.81(s,1H),4.99(q,J＝6.6Hz,1H),4.12(t,J＝5.8Hz,2H),3.85(s,2H),2.89(s,3H),2.83(t,J＝5.3Hz,3H),1.14(d,J＝6.6Hz,6H).

Example 10

2-(6-(5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (5, 6-Dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

tert-butyl

((2-(6-(5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (5, 6-Dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (49.44 mg, 142.29. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazine 10a (80 mg, 284.59. Mu. Mol, prepared according to WO2019034096A 1) were dissolved in 1, 4-dioxane (6 mL), cuprous iodide (13.55 mg, 71.15. Mu. Mol), potassium carbonate (59.00 mg, 426.88. Mu. Mol) and N, N-dimethylethylenediamine (6.27 mg, 71.15. Mu. Mol) were added, the reaction was stirred at 80℃and the reaction was monitored for 1 hour, and after completion of the reaction, the reaction was concentrated under reduced pressure to give a residue which was eluted by silica gel chromatography (A: 6- (2, 4-methyl) to give 1, 6-dihydro-1-pyrrolo [3,4-c ] pyridin-4-yl ] methyl [1, 6-yl ] carbonyl ] amino [1, 4-6-methyl ] 6-methyl ] amino ] 2, 6-methyl ] pyrido [ 6-methyl ] 1, 6-7-methyl ] pyrido [ 6-methyl ] butanoic acid, 426.88. Mu. Mol.

MS m/z(ESI):549.3[M+1] ⁺

Second step

Tert-butyl ((2- (6- (5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 10b (78 mg, 142.17. Mu. Mol) was dissolved in dichloromethane (10 mL), cooled to 0 ℃, trifluoroacetic acid (33. Mu.L, 426.51. Mu. Mol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H ₂ O; mobile phase B: CH ₃ CN) to give 2- (6- (5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 10 (42 mg, 70.42. Mu. Mol), yield 49.53%.

MS m/z(ESI):449.2[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.79(brs,1H),8.59(d,J＝8.3Hz,1H),8.10(t,J＝8.0Hz,1H),7.99(d,J＝7.6Hz,1H),6.90(s,1H),5.14(s,2H),5.09–4.98(m,1H),5.03(s,2H),4.63(t,J＝5.3Hz,2H),4.37(s,2H),4.10(t,J＝5.3Hz,2H),2.92(s,3H),2.73(s,3H),1.16(d,J＝6.6Hz,6H).

Example 11

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(5,6,7,8-tetrahydro-5,8-methano[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (5, 6,7, 8-tetrahydro-5, 8-methanol [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-azabicyclo[2.2.1]heptan-3-one

2-Azabicyclo [2.2.1] heptane-3-one

2-Azabicyclo [2.2.1] hept-5-en-3-one 11a (2 g,18.33 mmol) was dissolved in methanol (20 mL), 10% palladium on carbon (2.23 g,18.33 mmol) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction solution was filtered through celite, washed with methanol (10 mL), and the filtrate was concentrated under reduced pressure to give 2-azabicyclo [2.2.1] heptane-3-one 11b (1.9 g,17.10 mmol), yield 93.28%, which was used directly in the next reaction.

MS m/z(ESI):112.1[M+1] ⁺

Second step

2-azabicyclo[2.2.1]heptane-3-thione

2-Azabicyclo [2.2.1] heptane-3-thione

2-Azabicyclo [2.2.1] heptan-3-one 11b (1.6 g,14.40 mmol) was dissolved in dichloromethane (20 mL), and L.sub.1 (6.99 g,17.28 mmol) was added thereto and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 2-azabicyclo [2.2.1] heptane-3-thione 11c (1.2 g,9.43 mmol) in 65.53% yield.

MS m/z(ESI):128.1[M+1] ⁺

Third step

3-(methylthio)-2-azabicyclo[2.2.1]hept-2-ene

3- (Methylthio) -2-azabicyclo [2.2.1] hept-2-ene

2-Azabicyclo [2.2.1] heptane-3-thione 11c (1 g,7.86 mmol) was dissolved in dichloromethane (10 mL), trimethyloxonium tetrafluoroboric acid (2.33 g,15.72 mmol) was added and stirred at room temperature for 18 hours, and LCMS monitored for reaction completion. The reaction was quenched by addition of saturated sodium bicarbonate solution (10 mL) at 0deg.C, extracted with dichloromethane (10 mL. Times.3), washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3- (methylthio) -2-azabicyclo [2.2.1] hept-2-ene 11d (0.9 g,6.37 mmol), in a yield of 81.06% for direct use in the next reaction.

MS m/z(ESI):142.1[M+1] ⁺

Fourth step

3-(6-bromopyridin-2-yl)-5,6,7,8-tetrahydro-5,8-methano[1,2,4]triazolo[4,3-a]pyridine

3- (6-Bromopyridin-2-yl) -5,6,7, 8-tetrahydro-5, 8-methanol [1,2,4] triazolo [4,3-a ] pyridine

3- (Methylthio) -2-azabicyclo [2.2.1] hept-2-ene 11d (700 mg,4.96 mmol) was dissolved in isoamyl alcohol (10 mL), 6-bromopyridine formylhydrazine 1b (1.07 g,4.96 mmol) and glacial acetic acid (0.2 mL) were added and the reaction was heated to 125℃for 18 hours and LCMS monitored for completion. The reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by preparative liquid chromatograph (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H ₂ O; mobile phase B: CH ₃ CN) to give 3- (6-bromopyridin-2-yl) -5,6,7, 8-tetrahydro-5, 8-methanol [1,2,4] triazolo [4,3-a ] pyridine 11e (50 mg, 171.74. Mu. Mol), yield 3.46%.

MS m/z(ESI):290.9[M+1] ⁺

Fifth step

tert-butyl

((6-(isopropyl(methyl)amino)-1-oxo-2-(6-(5,6,7,8-tetrahydro-5,8-methano[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -1-oxo-2- (6- (5, 6,7, 8-tetrahydro-5, 8-methanol [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (35 mg, 100.45. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5,6,7, 8-tetrahydro-5, 8-methanol [1,2,4] triazolo [4,3-a ] pyridine 11e (46.70 mg, 107.48. Mu. Mol) were dissolved in1, 4-dioxane (4 mL), and cuprous iodide (38.26 mg, 200.90. Mu. Mol), N-dimethylethylenediamine (35.42 mg, 401.79. Mu. Mol) and potassium carbonate (55.53 mg, 401.79. Mu. Mol) were added and reacted under argon atmosphere at 100℃for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (5, 6,7, 8-tetrahydro-5, 8-methanol [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 11f (45 mg, 80.55. Mu. Mol), yield 80.19%.

MS m/z(ESI):559.0[M+1] ⁺

Seventh step

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (5, 6,7, 8-tetrahydro-5, 8-methanol [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 11f (45 mg,80.55 μmol) was dissolved in dichloromethane (4 mL), and a1, 4-dioxane solution of hydrogen chloride (4 m,805.48 μl) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (5, 6,7, 8-tetrahydro-5, 8-methanol [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 11 (39.4 mg, 67.37. Mu. Mol), in a yield of 83.64%.

MS m/z(ESI):459.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.14(brs,2H),8.57(d,J＝8.3Hz,1H),8.08(t,J＝8.0Hz,1H),7.91(d,J＝7.6Hz,1H),6.91(s,1H),5.62(s,1H),5.28(d,J＝16.8Hz,1H),5.13(d,J＝16.9Hz,1H),5.08–4.98(m,1H),4.48–4.28(m,2H),3.73(s,1H),2.93(s,3H),2.75(t,J＝5.3Hz,3H),2.42–2.30(m,2H),2.27–2.11(m,2H),2.07–1.93(m,2H),1.17(d,J＝6.6Hz,6H).

Example 12

6-(isopropyl(methyl)amino)-2-(6-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -2- (6- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

6-methoxy-5-methyl-2,3,4,5-tetrahydropyridine

6-Methoxy-5-methyl-2, 3,4, 5-tetrahydropyridine

3-Methylpiperidin-2-one 12a (300 mg,2.65 mmol) was dissolved in dichloromethane (10 mL), trimethyloxonium tetrafluoroboric acid (1.96 g,13.26 mmol) was added and stirred at room temperature for 18 hours, and LCMS monitored for completion of the reaction. The reaction was quenched by the addition of saturated sodium bicarbonate solution (10 mL) at 0deg.C, extracted with dichloromethane (10 mL. Times.3), washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and mixed with glacial acetic acid (0.5 mL) and concentrated under reduced pressure to give 6-methoxy-5-methyl-2, 3,4, 5-tetrahydropyridine 12b (250 mg,1.97 mmol) in 74.14% yield, which was used directly in the next reaction.

MS m/z(ESI):128.1[M+1] ⁺

Second step

3-(6-bromopyridin-2-yl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine

3- (6-Bromopyridin-2-yl) -8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine

6-Bromopyridine formylhydrazine 1b (200 mg, 925.78. Mu. Mol) and 6-methoxy-5-methyl-2, 3,4, 5-tetrahydropyridine 12b (249.62 mg,1.96 mmol) were dissolved in acetonitrile (5 mL), glacial acetic acid (0.53 mL,9.26 mmol) was added, and the mixture was heated to 80℃for reaction for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 3- (6-bromopyridin-2-yl) -8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine 12C (210 mg, 716.33. Mu. Mol) in a yield of 77.38%.

MS m/z(ESI):292.9[M+1] ⁺

Third step

tert-butyl

((6-(isopropyl(methyl)amino)-2-(6-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -2- (6- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 3- (6-bromopyridin-2-yl) -8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine 12c (84.14 mg, 286.99. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (27.33 mg, 143.50. Mu. Mol), N, N-dimethylethylenediamine (25.30 mg, 286.99. Mu. Mol) and potassium carbonate (59.50 mg, 430.49. Mu. Mol) were added and reacted under argon atmosphere at 100℃for 6 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 12d (72 mg, 128.41. Mu. Mol), yield 89.49%.

MS m/z(ESI):561.0[M+1] ⁺

Fourth step

Tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 12d (72 mg,128.41 μmol) was dissolved in dichloromethane (4 mL), and a1, 4-dioxane solution of hydrogen chloride (4 m,1.28 mL) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -2- (6- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 12 (60 mg, 100.18. Mu. Mol), in a yield of 78.01%.

MS m/z(ESI):461.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.04(brd,2H),8.59(d,J＝8.4Hz,1H),8.10(t,J＝8.0Hz,1H),7.96(d,J＝7.6Hz,1H),6.90(s,1H),5.13(s,2H),5.09–4.97(m,1H),4.75–4.61(m,1H),4.46–4.31(m,3H),3.22–3.04(m,1H),2.92(d,J＝2.2Hz,3H),2.74(t,J＝5.3Hz,3H),2.23–1.79(m,4H),1.43(d,J＝6.9Hz,3H),1.16(dd,J＝6.7,1.9Hz,6H).

Example 13

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (5- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

6-(trifluoromethyl)piperidine-2-thione

6- (Trifluoromethyl) piperidine-2-thione

6- (Trifluoromethyl) piperidin-2-one 13a (100 mg, 598.34. Mu. Mol) was dissolved in dichloromethane (5 mL) and L.sub.Hemsl (290.41 mg, 718.01. Mu. Mol) was added and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 6- (trifluoromethyl) piperidine-2-thione 13b (75 mg, 409.40. Mu. Mol) in a yield of 68.42%.

MS m/z(ESI):184.0[M+1] ⁺

Second step

6-(methylthio)-2-(trifluoromethyl)-2,3,4,5-tetrahydropyridine

6- (Methylthio) -2- (trifluoromethyl) -2,3,4, 5-tetrahydropyridine

6- (Trifluoromethyl) piperidine-2-thione 13b (70 mg, 382.11. Mu. Mol) was dissolved in dichloromethane (2 mL), trimethyloxonium tetrafluoroboric acid (113.04 mg, 764.22. Mu. Mol) was added and stirred at room temperature for 20 hours, and LCMS monitored for reaction completion. The reaction was quenched by the addition of saturated sodium bicarbonate solution (5 mL) at 0deg.C, extracted with dichloromethane (5 mL. Times.3), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and mixed with glacial acetic acid (0.02 mL) and concentrated under reduced pressure to give 6- (methylthio) -2- (trifluoromethyl) -2,3,4, 5-tetrahydropyridine 13c (75 mg, 380.28. Mu. Mol) in 99.52% yield, which was used directly in the next reaction.

MS m/z(ESI):198.0[M+1] ⁺

Third step

3-(6-bromopyridin-2-yl)-5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine

3- (6-Bromopyridin-2-yl) -5- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine

6-Bromopyridine formylhydrazine 1b (82.15 mg, 380.28. Mu. Mol) and 6- (methylthio) -2- (trifluoromethyl) -2,3,4, 5-tetrahydropyridine 13c (75 mg, 380.28. Mu. Mol) were dissolved in acetonitrile (4 mL), glacial acetic acid (0.03 mL,5.24 mmol) was added and heated to 80℃to react for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 3- (6-bromopyridin-2-yl) -5- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine 13d (0.1 g, 288.07. Mu. Mol) in a yield of 75.75%.

MS m/z(ESI):347.0[M+1] ⁺

Fourth step

tert-butyl

((6-(isopropyl(methyl)amino)-1-oxo-2-(6-(5-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -1-oxo-2- (6- (5- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine 13d (49.81 mg, 143.50. Mu. Mol) were dissolved in 1, 4-dioxane (5 mL), tris (dibenzylidene-BASE acetone) dipalladium (39.42 mg, 43.05. Mu. Mol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (24.91 mg, 43.05. Mu. Mol) and potassium phosphate (60.92 mg, 286.99. Mu. Mol) were added in this order, and the reaction was monitored by S reaction at 80℃for 1 hour. After completion of the reaction, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (5- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 13e (62 mg, 100.87. Mu. Mol) in a yield of 70.29%.

MS m/z(ESI):615.0[M+1] ⁺

Fifth step

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (5- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 13e (62 mg, 100.87. Mu. Mol) was dissolved in dichloromethane (10 mL), cooled to 0 ℃, trifluoroacetic acid (23. Mu.l, 302.61. Mu. Mol) was added, and after slow warming to room temperature, stirring was performed for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H ₂ O; mobile phase B: CH ₃ CN) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (5- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 13 (50 mg, 77.64. Mu. Mol), yield 76.97%.

MS m/z(ESI):515.2[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.00(brs,1H),8.53(d,J＝8.3Hz,1H),8.12(t,J＝8.0Hz,1H),7.94(d,J＝7.5Hz,1H),6.91(s,1H),6.40–6.28(m,1H),5.24(d,J＝16.7Hz,1H),5.8–4.97(m,1H),5.00(d,J＝16.6Hz,1H),4.30(d,J＝1.9Hz,2H),3.22–2.96(m,2H),2.92(s,3H),2.72(s,3H),2.46–2.34(m,2H),2.06–1.90(m,2H),1.16(d,J＝6.7Hz,6H).

Example 14

2-(6-(5-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (5-Ethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

6-ethylpiperidin-2-one

6-Ethylpiperidin-2-one

Glutarimide 14a (3 g,26.52 mmol) was dissolved in tetrahydrofuran (20 mL), and after cooling to 0deg.C, ethyl magnesium bromide (26.52 mL,3M diethyl ether solution, 79.57 mmol) was added dropwise, and the mixture was stirred at room temperature for 12 hours, followed by sodium cyanoborohydride (1.83 g,29.17 mmol) and glacial acetic acid (10 mL), and the reaction was continued at room temperature with stirring, and LCMS monitoring the reaction completion. Cooled to 0 ℃, saturated sodium bicarbonate solution (20 mL) was added, extracted with ethyl acetate (30 ml×3), washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: a system) to give 6-ethylpiperidin-2-one 14b (3.37 g,26.50 mmol), yield 100.00%.

MS m/z(ESI):128.1[M+1] ⁺

Second step

2-ethyl-6-methoxy-2,3,4,5-tetrahydropyridine

2-Ethyl-6-methoxy-2, 3,4, 5-tetrahydropyridine

6-Ethyl-2-piperidone 14b (100 mg, 786.26. Mu. Mol) was dissolved in methylene chloride (8 mL), trimethyloxonium tetrafluoroboric acid (348.89 mg,2.36 mmol) was added, and stirred at room temperature for 40 hours, and LCMS monitored the completion of the reaction. The reaction was quenched by the addition of saturated sodium bicarbonate solution (20 mL) at 0deg.C, extracted with dichloromethane (10 mL. Times.3), washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and mixed with glacial acetic acid (0.02 mL) and concentrated under reduced pressure to give 2-ethyl-6-methoxy-2, 3,4, 5-tetrahydropyridine 14c (100 mg, 708.16. Mu. Mol) in a yield of 90.07% which was used directly in the next reaction.

MS m/z(ESI):142.1[M+1] ⁺

Third step

3-(6-bromopyridin-2-yl)-5-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine

3- (6-Bromopyridin-2-yl) -5-ethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine

6-Bromopyridine formylhydrazine 1b (120 mg, 555.47. Mu. Mol) and 2-ethyl-6-methoxy-2, 3,4, 5-tetrahydropyridine 14c (78.44 mg, 555.47. Mu. Mol) were dissolved in acetonitrile (10 mL), glacial acetic acid (0.03 mL,5.24 mmol) was added, and the mixture was heated to 80℃for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 3- (6-bromopyridin-2-yl) -5-ethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine 14d (140 mg, 455.75. Mu. Mol) in a yield of 82.05%.

MS m/z(ESI):307.0[M+1] ⁺

Fourth step

tert-butyl

((2-(6-(5-ethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (5-Ethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5-ethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine 14d (44.08 mg, 143.50. Mu. Mol) were dissolved in 1, 4-dioxane (2 mL), tris- (dibenzene-BASE acetone) dipalladium (39.42 mg, 43.05. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (24.91 mg, 43.05. Mu. Mol) and potassium phosphate (60.92 mg, 286.99. Mu. Mol) were added in this order and the reaction was heated to 80℃for 3 hours, followed by S monitoring the completion of the reaction. Suction filtration and concentration of the filtrate under reduced pressure gave a residue which was purified by silica gel column chromatography (eluent: A system) to give tert-butyl ((2- (6- (5-ethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 14e (62 mg, 100.87. Mu. Mol) in a yield of 70.29%.

MS m/z(ESI):575.0[M+1] ⁺

Fifth step

Tert-butyl ((2- (6- (5-ethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 14e (30 mg, 52.20. Mu. Mol) was dissolved in dichloromethane (6 mL), cooled to 0 ℃, trifluoroacetic acid (12. Mu.l, 156.60. Mu. Mol) was added, and after slow warming to room temperature, stirring was carried out for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H ₂ O; mobile phase B: CH ₃ CN) to give 2- (6- (5-ethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 14 (16 mg, 26.08. Mu. Mol) in 49.97% yield.

MS m/z(ESI):475.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.58(d,J＝8.4Hz,1H),8.09(t,J＝8.0Hz,1H),7.95(d,J＝7.5Hz,1H),6.89(s,1H),5.23–5.15(m,1H),5.20(d,J＝16.8Hz,1H),5.05–4.95(m,1H),5.00(d,J＝16.7Hz,1H),4.36–4.21(m,2H),3.03(s,1H),2.92(s,3H),2.90–2.84(m,1H),2.69(s,3H),2.14–1.71(m,5H),1.65–1.50(m,1H),1.16(d,J＝6.7Hz,6H),0.86(t,J＝7.4Hz,3H).

Examples 15 and 16

(S)-6-(isopropyl(methyl)amino)-2-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]t riazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(S) -6- (isopropyl (methyl) amino) -2- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 15

(S)-2-(6-(5-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(S) -2- (6- (5- (hydroxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 16

First step

(S)-5-methoxy-2-(methoxymethyl)-3,4-dihydro-2H-pyrrole

(S) -5-methoxy-2- (methoxymethyl) -3, 4-dihydro-2H-pyrrole 15b

(S)-(5-methoxy-3,4-dihydro-2H-pyrrol-2-yl)methanol

(S) - (5-methoxy-3, 4-dihydro-2H-pyrrol-2-yl) methanol 16b

Trimethyloxonium tetrafluoroboric acid (770.83 mg,5.21 mmol) was dissolved in dichloromethane (15 mL), after cooling to 0deg.C, L-pyroglutamine 15a (500 mg,4.34 mmol) was added in portions, slowly warmed to room temperature, stirred overnight, and LCMS monitored for completion. Cooled to 0deg.C, quenched with saturated potassium bicarbonate solution (40 mL), extracted with ethyl acetate (50 mL. Times.3), the combined organic phases were washed with water (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a mixture of (S) -5-methoxy-2- (methoxymethyl) -3, 4-dihydro-2H-pyrrole 15b and (S) - (5-methoxy-3, 4-dihydro-2H-pyrrol-2-yl) methanol 16b (283 mg) which was used directly in the next reaction without purification.

15b MS m/z(ESI):144.1[M+1] ⁺

16b MS m/z(ESI):130.1[M+1] ⁺

Second step

(S) -3- (6-bromopyridin-2-yl) -5- (methoxymethyl) -6,7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazo le (S) -3- (6-bromopyridin-2-yl) -5- (methoxymethyl) -6,7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 15c

(S) - (3- (6-bromopyridin-2-yl) -6,7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-5-yl) methanol 16c

The above reaction mixture (146.6 mg) was dissolved in acetonitrile (10 mL), 6-bromopyridine formylhydrazine 1b (120 mg, 555.47. Mu. Mol) was added, glacial acetic acid (3. Mu.L, 55.55. Mu. Mol) was added dropwise, and the mixture was heated to 80℃and reacted for 10 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give a mixture (180 mg) of (S) -3- (6-bromopyridin-2-yl) -5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 15c and (S) - (3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-5-yl) methanol 16 c.

15c MS m/z(ESI):309.0[M+1] ⁺

16c MS m/z(ESI):295.0[M+1] ⁺

Third step

tert-butyl

(S)-((6-(isopropyl(methyl)amino)-2-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(S) - ((6- (isopropyl (methyl) amino) -2- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 15dtert-butyl

(S)-((2-(6-(5-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(S) - ((2- (6- (5- (hydroxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 16d

A mixture of ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 2b (50 mg, 143.50. Mu. Mol), (S) -3- (6-bromopyridin-2-yl) -5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 15c and (S) - (3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-5-yl) methanol 16c (130 mg) was dissolved in 1, 4-dioxane (2 mL), and cuprous iodide (81.99 mg, 430.49. Mu. Mol), N, N-dimethylethylenediamine (37.95 mg, 430.49. Mu. Mol) and potassium carbonate (99.16 mg, 49. Mu. Mol) were added and reacted under argon atmosphere at 70℃for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: F system) to give tert-butyl (S) - ((6- (isopropyl (methyl) amino) -2- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 15d (28 mg, 48.55. Mu. Mol), yield 33.84%; (S) - ((2- (6- (5- (hydroxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 16d (45 mg, 79.98. Mu. Mol) was produced in a yield of 55.73%.

15d MS m/z(ESI):577.3[M+1] ⁺

16d MS m/z(ESI):563.3[M+1] ⁺

Fourth step

(S)-6-(isopropyl(methyl)amino)-2-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(S) -6- (isopropyl (methyl) amino) -2- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(S) - ((6- (isopropyl (methyl) amino) -2- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 15d (30 mg, 52.20. Mu. Mol) was dissolved in dichloromethane (2 mL), cooled to 0 ℃, trifluoroacetic acid (517.86. Mu.L, 6.76 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give (S) -6- (isopropyl (methyl) amino) -2- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 15 (5 mg, 7.94. Mu. Mol) in 17.60% yield.

MS m/z(ESI):477.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.58(d,J＝8.4,0.9Hz,1H),8.08(t,J＝8.0Hz,1H),7.99(d,J＝7.6,0.9Hz,1H),6.85(s,1H),5.76(s,2H),5.22(d,J＝16.9Hz,1H),5.19–5.13(m,1H),5.04–4.96(m,1H),5.00(d,J＝16.8Hz,1H),4.20–4.05(m,2H),3.85–3.78(m,1H),3.78–3.72(m,1H),3.33(s,3H),3.21(s,3H),3.04–2.93(m,2H),2.91(s,3H),2.64–2.56(m,2H),1.16(d,J＝6.6Hz,6H).

Fifth step

(S) -2- (6- (5- (hydroxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(S) - ((2- (6- (5- (hydroxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 16d (40 mg, 71.09. Mu. Mol) was dissolved in dichloromethane (3 mL), cooled to 0 ℃, trifluoroacetic acid (816.56. Mu.L, 10.66 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give (S) -2- (6- (5- (hydroxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 16 (45 mg, 66.42. Mu. Mol), in a yield of 93.43%.

MS m/z(ESI):463.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.35(brs,2H),8.55(d,J＝8.2Hz,1H),8.06(t,J＝8.0Hz,1H),7.97(d,J＝7.6Hz,1H),6.86(s,1H),5.22(d,J＝16.9Hz,1H),5.11–4.97(m,2H),5.01(d,J＝16.9Hz,1H),4.39–4.29(m,2H),3.95–3.89(m,1H),3.77(dd,J＝11.1,5.6Hz,1H),3.06–2.83(m,3H),2.90(s,3H),2.78–2.68(m,1H),2.72(s,3H),2.50(t,J＝2.0Hz,4H),1.14(d,J＝6.6Hz,6H).

Example 17

6-(isopropyl(methyl)amino)-2-(6-(5-methyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-chloro-N-(1-hydroxypropan-2-yl)acetamide

2-Chloro-N- (1-hydroxy-prop-2-yl) acetamide

DL-aminopropanol 17a (2 g,26.63mmol,2.12 mL) was dissolved in tetrahydrofuran (10 mL), N-diisopropylethylamine (3.44 g,26.63mmol,4.64 mL) was added, cooled to 0℃and chloroacetyl chloride 17b (3.61 g,31.95mmol,2.54 mL) was added dropwise, stirred at room temperature for 2 hours, saturated ammonium chloride solution (15 mL) was added after completion of the reaction, ethyl acetate (15 mL. Times.3) was extracted, the organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-chloro-N- (1-hydroxypropyl-2-yl) acetamide 17c (4 g,26.39 mmol), in 99.09% yield, which was used directly in the next reaction.

MS m/z(ESI):152.0[M+1] ⁺

Second step

5-methylmorpholin-3-one

5-Methylmorpholine-3-one

2-Chloro-N- (1-hydroxy-propan-2-yl) acetamide 17c (4 g,26.39 mmol) was dissolved in tetrahydrofuran (6 mL), cooled to 0deg.C, sodium hydride (1.37 g,52.77 mmol) was added, and the reaction was stirred at room temperature slowly for 2 hours. Ethyl acetate (15 mL) was added for dilution, the mixture was cooled to 0℃and quenched with water (5 mL), the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give 5-methylmorpholine-3-one 17d (2 g,17.37 mmol) in a yield of 65.83%.

MS m/z(ESI):116.1[M+1] ⁺

Third step

5-methoxy-3-methyl-3,6-dihydro-2H-1,4-oxazine

5-Methoxy-3-methyl-3, 6-dihydro-2H-1, 4-oxazine

5-Methylmorpholine-3-one 17d (200 mg,1.74 mmol) was dissolved in dichloromethane (2 mL), trimethyloxonium tetrafluoroboric acid (770.83 mg,5.21 mmol) was added and stirred at room temperature for 18 hours and LCMS monitored for reaction completion. The reaction was quenched by the addition of saturated sodium bicarbonate solution (10 mL) at 0deg.C, extracted with dichloromethane (10 mL. Times.3), washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and mixed with glacial acetic acid (0.03 mL) and concentrated under reduced pressure to give 5-methoxy-3-methyl-3, 6-dihydro-2H-1, 4-oxazine 17e (220 mg,1.70 mmol) in 98.05% yield, which was used directly in the next reaction.

MS m/z(ESI):130.1[M+1] ⁺

Fourth step

3-(6-bromopyridin-2-yl)-5-methyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazine

3- (6-Bromopyridin-2-yl) -5-methyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazine

6-Bromopyridine formylhydrazine 1b (367.99 mg,1.70 mmol) and 5-methoxy-3-methyl-3, 6-dihydro-2H-1, 4-oxazine 17e (0.22 g,1.70 mmol) were dissolved in acetonitrile (8 mL), glacial acetic acid (0.03 mL,5.24 mmol) was added and the mixture was heated to 80℃for reaction for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 3- (6-bromopyridin-2-yl) -5-methyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-C ] [1,4] oxazine 17f (140 mg, 455.75. Mu. Mol) in a yield of 39.78%.

MS m/z(ESI):294.9[M+1] ⁺

Fifth step

tert-butyl

((6-(isopropyl(methyl)amino)-2-(6-(5-methyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5-methyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazine 17f (50.82 mg, 172.20. Mu. Mol) were dissolved in 1, 4-dioxane (2 mL), and tris- (dibenzene-BASE acetone) dipalladium (39.42 mg, 43.05. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (41.52 mg, 71.75. Mu. Mol) and potassium phosphate (60.92 mg, 286.99. Mu. Mol) were added in this order, and the reaction was monitored to be complete by heating to 80℃for 3 hours. Suction filtration and concentration of the filtrate under reduced pressure gave a residue which was purified by silica gel column chromatography (eluent: A system) to give 17g (80 mg, 142.18. Mu. Mol) of tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate in 99.08% yield.

MS m/z(ESI):563.3[M+1] ⁺

Sixth step

17G (80 mg, 142.18. Mu. Mol) of tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate (10 g) were dissolved in dichloromethane (10 mL), cooled to 0℃and trifluoroacetic acid (64.85 mg, 568.73. Mu. Mol) was added thereto, followed by stirring for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H ₂ O; mobile phase B: CH ₃ CN) to give 6- (isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 17 (16 mg, 26.08. Mu. Mol) in 77.38% yield.

MS m/z(ESI):463.1[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.97(brs,2H),8.61(dd,J＝8.2,0.9Hz,1H),8.16–8.02(m,2H),6.92(s,1H),5.30(t,J＝7.7Hz,1H),5.23(d,J＝16.8Hz,1H),5.15(d,J＝15.4Hz,1H),5.09–4.98(m,1H),5.03(d,J＝16.7Hz,1H),4.92(d,J＝15.3Hz,1H),4.36(s,2H),4.02(s,2H),2.93(s,3H),2.76(s,3H),1.52(d,J＝6.4Hz,3H),1.17(d,J＝6.6Hz,6H).

Example 18

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6, 7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

7-methoxy-3,4,5,6-tetrahydro-2H-azepine

7-Methoxy-3, 4,5, 6-tetrahydro-2H-azepine

Caprolactam 18a (200 mg,1.77 mmol) was dissolved in dichloromethane (8 mL), trimethyloxonium tetrafluoroboric acid (1.57 g,10.6 mmol) was added and stirred at room temperature for 48 hours and LCMS monitored for reaction completion. The reaction was quenched by the addition of saturated sodium bicarbonate solution (10 mL) at 0deg.C, extracted with dichloromethane (10 mL. Times.3), washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and mixed with glacial acetic acid (0.5 mL) and concentrated under reduced pressure to give 7-methoxy-3, 4,5, 6-tetrahydro-2H-azepine 18b (220 mg, 864.89. Mu. Mol) in 48.93% yield, which was used directly in the next reaction.

MS m/z(ESI):128.1[M+1] ⁺

Second step

3-(6-bromopyridin-2-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine

3- (6-Bromopyridin-2-yl) -6,7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepine

6-Bromopyridine formylhydrazine 1b (100 mg, 462.89. Mu. Mol) and 7-methoxy-3, 4,5, 6-tetrahydro-2H-azepine 18b (176.62 mg, 694.33. Mu. Mol) were dissolved in acetonitrile (5 mL), glacial acetic acid (2.78 mg, 46.29. Mu. Mol) was added, and the mixture was heated to 80℃for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give 3- (6-bromopyridin-2-yl) -6,7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepine 18c (28 mg, 95.51. Mu. Mol) in 20.63% yield.

MS m/z(ESI):293.0[M+1] ⁺

Third step

tert-butyl

((6-(isopropyl(methyl)amino)-1-oxo-2-(6-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -1-oxo-2- (6, 7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (25 mg, 71.75. Mu. Mol) and 3- (6-bromopyridin-2-yl) -6,7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepine 18c (23.14 mg, 78.92. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (40.99 mg, 215.25. Mu. Mol), N, N-dimethylethylenediamine (18.97 mg, 215.25. Mu. Mol) and potassium carbonate (49.58 mg, 358.74. Mu. Mol) were added and reacted under argon atmosphere at 70℃for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6, 7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 18d (39 mg, 65.91. Mu. Mol) in 91.86% yield.

MS m/z(ESI):561.3[M+1] ⁺

Fourth step

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6, 7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 18d (34.00 mg, 60.64. Mu. Mol) was dissolved in dichloromethane (3.5 mL), cooled to 0 ℃, and trifluoroacetic acid (1.04 g,9.10mmol, 696.52. Mu.L) was added and stirred for 1 hour after slowly warming to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6, 7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 18 (34.3 mg, 53.48. Mu. Mol), in 88.20% yield.

MS m/z(ESI):461.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.14(brs,2H),8.58(d,J＝8.4Hz,1H),8.08(t,J＝8.0Hz,1H),7.83(d,J＝7.6Hz,1H),6.88(s,1H),5.09(s,2H),5.07–4.97(m,1H),4.65(s,2H),4.33(s,2H),3.07–2.97(m,2H),2.91(s,3H),2.73(s,3H),1.88(s,4H),1.68(s,2H),1.15(d,J＝6.7Hz,6H).

Example 19

6-(isopropyl(methyl)amino)-2-(6-(6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -2- (6- (6-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

6-methoxy-3-methyl-2,3,4,5-tetrahydropyridine

6-Methoxy-3-methyl-2, 3,4, 5-tetrahydropyridine

5-Methyl-2-piperidone 19a (200 mg,1.77 mmol) was dissolved in dichloromethane (5 mL), trimethyloxonium tetrafluoroboric acid (1.57 g,10.60 mmol) was added, stirred at room temperature for 72 hours, LCMS monitored the completion of the reaction, quenched by the addition of saturated sodium bicarbonate solution (10 mL) at 0deg.C, extracted with dichloromethane (10 mL. Times.3), washed with water (10 mL) and dried over anhydrous sodium sulfate, filtered, and uniformly mixed with glacial acetic acid (0.5 mL) and concentrated under reduced pressure to give 6-methoxy-3-methyl-2, 3,4, 5-tetrahydropyridine 19b (260 mg,1.43 mmol) in 80.96% yield, which was directly used in the next reaction.

MS m/z(ESI):128.1[M+1] ⁺

Second step

3-(6-bromopyridin-2-yl)-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine

3- (6-Bromopyridin-2-yl) -6-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine

6-Bromopyridine formylhydrazine 1b (100 mg, 462.89. Mu. Mol) and 6-methoxy-3-methyl-2, 3,4, 5-tetrahydropyridine 19b (211.94 mg, 833.20. Mu. Mol) were dissolved in acetonitrile (5 mL), glacial acetic acid (2.78 mg, 46.29. Mu. Mol) was added, and the mixture was heated to 80℃for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give 3- (6-bromopyridin-2-yl) -6-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine 19c (28 mg, 95.51. Mu. Mol) in 88.43% yield.

MS m/z(ESI):293.0[M+1] ⁺

Third step

tert-butyl

((6-(isopropyl(methyl)amino)-2-(6-(6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -2- (6- (6-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 3- (6-bromopyridin-2-yl) -6-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine 19c (46.27 mg, 157.85. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (81.99 mg, 430.49. Mu. Mol), N, N-dimethylethylenediamine (37.95 mg, 430.49. Mu. Mol) and potassium carbonate (99.16 mg, 717.49. Mu. Mol) were added and reacted under argon atmosphere at 70℃for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (6-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 19d (115 mg, 123.06. Mu. Mol), yield 85.76%.

MS m/z(ESI):561.3[M+1] ⁺

Fourth step

Tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (6-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 19d (105 mg, 112.36. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, and trifluoroacetic acid (1.54 g,13.48mmol,1.03 mL) was added and stirred for 1 hour after slow warming to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -2- (6- (6-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 19 (27.2 mg, 43.67. Mu. Mol), in a yield of 38.86%.

MS m/z(ESI):461.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.05(brs,2H),8.57(d,J＝8.2Hz,1H),8.09(t,J＝8.0Hz,1H),7.98(d,J＝7.6Hz,1H),6.91(s,1H),5.16(s,2H),5.10–4.97(m,1H),4.83(dd,J＝13.3,5.2Hz,1H),4.37–4.27(m,2H),4.03–3.91(m,1H),3.15–3.05(m,1H),2.97–2.86(m,1H),2.93(s,3H),2.72(t,J＝5.2Hz,3H),2.21–2.07(m,1H),2.06–1.95(m,1H),1.59(tt,J＝11.9,6.1Hz,1H),1.20(d,J＝6.6Hz,3H),1.17(d,J＝6.6Hz,6H).

Example 20

(R)-2-(6-(5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(R) -2- (6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

(R)-2-(fluoromethyl)-5-methoxy-3,4-dihydro-2H-pyrrole

(R) -2- (fluoromethyl) -5-methoxy-3, 4-dihydro-2H-pyrrole

(R) -5- (fluoromethyl) pyrrolidin-2-one 20a (330.00 mg,2.82mmol, prepared according to published patent WO2021220185A 1) was dissolved in dichloromethane (6 mL), trimethyloxonium tetrafluoroboric acid (2.08 g,14.09 mmol) was added and stirred at room temperature for 18 hours, LCMS was monitored to complete the reaction, saturated sodium bicarbonate solution (10 mL) was added at 0℃to quench the reaction, dichloromethane (10 mL. Times.3) was extracted, water washed (10 mL) and dried over anhydrous sodium sulfate, filtered, glacial acetic acid (0.5 mL) was added and mixed well and concentrated under reduced pressure to give (R) -2- (fluoromethyl) -5-methoxy-3, 4-dihydro-2H-pyrrole 20b (300 mg,2.29 mmol), yield 81.19% was used directly in the next reaction.

MS m/z(ESI):132.1[M+1] ⁺

Second step

(R) -3- (6-bromopyridin-2-yl) -5- (fluoromethyl) -6,7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazo le (R) -3- (6-bromopyridin-2-yl) -5- (fluoromethyl) -6,7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole

6-Bromopyridine formylhydrazine 1b (300 mg,1.39 mmol) and (R) -2- (fluoromethyl) -5-methoxy-3, 4-dihydro-2H-pyrrole 20b (300.00 mg,2.29 mmol) were dissolved in acetonitrile (6 mL), glacial acetic acid (2.39 mL,41.66 mmol) was added and heated to 80℃for 18H. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give (R) -3- (6-bromopyridin-2-yl) -5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazole 20C (220 mg, 740.43. Mu. Mol), in a yield of 53.32%.

MS m/z(ESI):296.9[M+1] ⁺

Third step

tert-butyl

(R)-((2-(6-(5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(R) - ((2- (6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (45 mg, 129.15. Mu. Mol) and (R) -3- (6-bromopyridin-2-yl) -5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 20c (76.75 mg, 258.30. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (24.60 mg, 129.15. Mu. Mol), N, N-dimethylethylenediamine (22.77 mg, 258.30. Mu. Mol) and potassium carbonate (53.55 mg, 387.44. Mu. Mol) were added and heated to 100℃under argon atmosphere for reaction for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl (R) - ((2- (6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 20d (40 mg, 70.84. Mu. Mol), yield 54.85%.

MS m/z(ESI):565.0[M+1] ⁺

Fourth step

(R) - ((2- (6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 20d (40 mg, 70.84. Mu. Mol) was dissolved in dichloromethane (4 mL), and a1, 4-dioxane solution of hydrogen chloride (4M, 708.40. Mu.L) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give (R) -2- (6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 20 (28 mg, 47.77. Mu. Mol), yield 67.43%.

MS m/z(ESI):465.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.28(brs,2H),8.58(d,J＝8.2Hz,1H),8.08(t,J＝8.0Hz,1H),8.01(d,J＝7.6Hz,1H),6.88(s,1H),5.35(dd,J＝29.1,8.3Hz,1H),5.22(d,J＝16.6Hz,1H),5.11–4.87(m,4H),4.34(q,J＝6.9Hz,2H),3.16–2.94(m,4H),2.92(s,3H),2.73(brt,J＝5.5Hz,3H),1.16(d,J＝6.6Hz,6H).

Example 21

(S)-2-(6-(5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(S) -2- (6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

(S)-2-(fluoromethyl)-5-methoxy-3,4-dihydro-2H-pyrrole

(S) -2- (fluoromethyl) -5-methoxy-3, 4-dihydro-2H-pyrrole

(S) -5- (fluoromethyl) pyrrolidin-2-one 21a (200.00 mg,1.71mmol, prepared according to published patent WO2012021712A 1) was dissolved in dichloromethane (4 mL), trimethyloxonium tetrafluoroboric acid (1.26 g,8.54 mmol) was added and stirred at room temperature for 18 hours, LCMS was monitored to complete the reaction, saturated sodium bicarbonate solution (10 mL) was added at 0℃to quench the reaction, dichloromethane (10 mL. Times.3) was extracted, water washed (10 mL) and dried over anhydrous sodium sulfate, filtered, glacial acetic acid (0.5 mL) was added and mixed well and concentrated under reduced pressure to give (S) -2- (fluoromethyl) -5-methoxy-3, 4-dihydro-2H-pyrrole 21b (222 mg,1.69 mmol), yield 99.13% was used directly in the next reaction.

MS m/z(ESI):132.1[M+1] ⁺

Second step

(S) -3- (6-bromopyridin-2-yl) -5- (fluoromethyl) -6,7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazo le (S) -3- (6-bromopyridin-2-yl) -5- (fluoromethyl) -6,7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole

6-Bromopyridine formylhydrazine 1b (100 mg, 462.89. Mu. Mol) and (S) -2- (fluoromethyl) -5-methoxy-3, 4-dihydro-2H-pyrrole 21b (222.59 mg, 509.18. Mu. Mol) were dissolved in acetonitrile (2 mL), glacial acetic acid (2.78 mg, 46.29. Mu. Mol) was added, and the mixture was heated to 80℃for 24 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give (S) -3- (6-bromopyridin-2-yl) -5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazole 21C (154 mg, 414.64. Mu. Mol), in a yield of 89.58%.

MS m/z(ESI):297.0[M+1] ⁺

Third step

tert-butyl

(S)-((2-(6-(5-(fluoromethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(S) - ((2- (6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and (S) -3- (6-bromopyridin-2-yl) -5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 21c (63.96 mg, 215.25. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (81.99 mg, 430.49. Mu. Mol), N, N-dimethylethylenediamine (50.60 mg, 573.99. Mu. Mol) and potassium carbonate (99.16 mg, 717.49. Mu. Mol) were added and heated to 70℃under argon atmosphere for reaction for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl (S) - ((2- (6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 21d (75 mg, 124.11. Mu. Mol), yield 86.49%.

MS m/z(ESI):565.3[M+1] ⁺

Fourth step

(S) - ((2- (6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 21d (68 mg, 120.43. Mu. Mol) was dissolved in dichloromethane (7 mL), cooled to 0deg.C, trifluoroacetic acid (2.06 g,18.06mmol, 1.38 mL) was added, and slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give (S) -2- (6- (5- (fluoromethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 21 (53 mg, 86.26. Mu. Mol) in a yield of 71.63%.

MS m/z(ESI):465.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.98(brs,2H),8.59(d,J＝7.8Hz,1H),8.10(t,J＝8.0Hz,1H),8.02(d,J＝7.1Hz,1H),6.91(s,1H),5.31(dd,J＝28.2,8.4Hz,1H),5.18(d,J＝16.6Hz,1H),5.10–4.98(m,2H),4.95(d,J＝16.4Hz,1H),4.95–4.87(m,1H),4.35(q,J＝6.2Hz,2H),3.15–2.94(m,4H),2.93(s,3H),2.75(t,J＝5.3Hz,3H),1.17(d,J＝6.7Hz,6H).

Example 22

(R)-2-(3-(6-(6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-5-yl)acetonitrile

(R) -2- (3- (6- (6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-5-yl) acetonitrile

First step

(R)-2-(5-methoxy-3,4-dihydro-2H-pyrrol-2-yl)acetonitrile

(R) -2- (5-methoxy-3, 4-dihydro-2H-pyrrol-2-yl) acetonitrile

(R) -2- (5-oxopyrrolidin-2-yl) acetonitrile 22a (500.00 mg,4.03mmol, prepared according to published patent WO2019217890A 1) was dissolved in dichloromethane (10 mL) and trimethyloxonium tetrafluoroboric acid (2.98 g,20.14 mmol) was added and stirred at room temperature for 18 hours and LCMS monitored reaction completion. The reaction was quenched by the addition of saturated sodium bicarbonate solution (10 mL) at 0deg.C, extracted with dichloromethane (10 mL. Times.3), washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and mixed with glacial acetic acid (0.5 mL) and concentrated under reduced pressure to give (R) -2- (5-methoxy-3, 4-dihydro-2H-pyrrol-2-yl) acetonitrile 22b (554 mg,4.02 mmol) in 99.91% yield, which was used directly in the next reaction.

MS m/z(ESI):139.1[M+1] ⁺

Second step

(R)-2-(3-(6-bromopyridin-2-yl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-5-yl)acetonitrile

(R) -2- (3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-5-yl) acetonitrile

6-Bromopyridine formylhydrazine 1b (156.36 mg, 723.76. Mu. Mol) and (R) -2- (5-methoxy-3, 4-dihydro-2H-pyrrol-2-yl) acetonitrile 22b (100.00 mg, 723.76. Mu. Mol) were dissolved in acetonitrile (5 mL), glacial acetic acid (0.2 mL, 11.45. Mu. Mol) was added and the mixture was heated to 80℃to react for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give (R) -2- (3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-5-yl) acetonitrile 22C (120 mg, 394.55. Mu. Mol), yield 54.51%.

MS m/z(ESI):304.0[M+1] ⁺

Third step

tert-butyl

(R)-((2-(6-(5-(cyanomethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(R) - ((2- (6- (5- (cyanomethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (57.28 mg, 164.40. Mu. Mol) and (R) -2- (3- (6-bromopyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-5-yl) acetonitrile 22c (50.00 mg, 164.40. Mu. Mol) were dissolved in 1, 4-dioxane (2 mL), and tris (dibenzylideneacetone) dipalladium (45.16 mg, 49.32. Mu. Mol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (95.12 mg, 164.40. Mu. Mol) and potassium phosphate (104.69 mg, 493.19. Mu. Mol) were added in this order, and the reaction was heated to 80℃for 3 hours, followed by completion of the S monitoring. Suction filtration and concentration of the filtrate under reduced pressure gave a residue which was purified by silica gel column chromatography (eluent: A system) to give tert-butyl (R) - ((2- (6- (5- (cyanomethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 22d (17 mg, 29.74. Mu. Mol) in 18.09% yield.

MS m/z(ESI):572.3[M+1] ⁺

Fourth step

(R) - ((2- (6- (5- (cyanomethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 22d (17 mg, 29.74. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0℃and trifluoroacetic acid (10.17 mg, 89.21. Mu. Mol) was added and stirred for 2 hours after slowly warming to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give (R) -2- (3- (6- (6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-5-yl) acetonitrile 22 (15 mg, 22.05. Mu. Mol), yield 74.14%.

MS m/z(ESI):472.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.62(d,J＝8.2Hz,1H),8.10(t,J＝7.9Hz,1H),8.04(d,J＝7.6Hz,1H),6.89(s,1H),5.40–5.30(m,1H),5.29(d,J＝16.4Hz,1H),5.07(d,J＝16.5Hz,1H),5.06–4.96(m,1H),4.31(q,J＝15.3Hz,2H),3.23–3.08(m,2H),2.96(d,J＝15.1Hz,2H),2.92(s,3H),2.67(s,3H),2.54(s,2H),1.20–1.12(m,6H).

Example 23

6-(isopropyl(methyl)amino)-2-(6-(5-methyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -2- (6- (5-methyl-6, 7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepin-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

7-methoxy-2-methyl-3,4,5,6-tetrahydro-2H-azepine

7-Methoxy-2-methyl-3, 4,5, 6-tetrahydro-2H-azepine

7-Methylcaprolactam 23a (200 mg,1.57 mmol) was dissolved in dichloromethane (6 mL), trimethyloxonium tetrafluoroboric acid (2.33 g,15.73 mmol) was added, stirred at room temperature for 96 hours, LCMS monitored the completion of the reaction, quenched by the addition of saturated sodium bicarbonate solution (10 mL) at 0deg.C, extracted with dichloromethane (10 mL. Times.3), washed with water (10 mL) and dried over anhydrous sodium sulfate, filtered, and mixed with glacial acetic acid (0.5 mL) and concentrated under reduced pressure to give 7-methoxy-2-methyl-3, 4,5, 6-tetrahydro-2H-azepine 23b (182 mg,1.29 mmol) in 81.96% yield, which was used directly in the next reaction.

MS m/z(ESI):142.1[M+1] ⁺

Second step

3-(6-bromopyridin-2-yl)-5-methyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine

3- (6-Bromopyridin-2-yl) -5-methyl-6, 7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepine

6-Bromopyridine formylhydrazine 1b (150 mg, 694.33. Mu. Mol) and 7-methoxy-2-methyl-3, 4,5, 6-tetrahydro-2H-azepine 23b (182.37 mg,1.29 mmol) were dissolved in acetonitrile (6 mL), glacial acetic acid (416.96 mg,6.94mmol, 406.00. Mu.L) was added and heated to 80℃to react for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 3- (6-bromopyridin-2-yl) -5-methyl-6, 7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepine 23C (70 mg, 227.87. Mu. Mol) in 32.82% yield.

MS m/z(ESI):306.9[M+1] ⁺

Third step

tert-butyl

((6-(isopropyl(methyl)amino)-2-(6-(5-methyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -2- (6- (5-methyl-6, 7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5-methyl-6, 7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepine 23c (61.71 mg, 200.90. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (27.33 mg, 143.50. Mu. Mol), N, N-dimethylethylenediamine (25.30 mg, 286.99. Mu. Mol) and potassium carbonate (59.50 mg, 430.49. Mu. Mol) were added and reacted under argon atmosphere at 100℃for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (5-methyl-6, 7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 23d (65 mg, 113.10. Mu. Mol), yield 78.82%.

MS m/z(ESI):574.8[M+1] ⁺

Fourth step

Tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (5-methyl-6, 7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 23d (65 mg,113.10 μmol) was dissolved in dichloromethane (6 mL), and a1, 4-dioxane solution of hydrogen chloride (4 m,1.13 mL) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -2- (6- (5-methyl-6, 7,8, 9-tetrahydro-5H- [1,2,4] triazolo [4,3-a ] azepin-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 23 (48 mg, 80.99. Mu. Mol), yield 71.61%.

MS m/z(ESI):474.9[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.91(s,2H),8.63(d,J＝8.3Hz,1H),8.11(t,J＝7.9Hz,1H),7.85(d,J＝7.6Hz,1H),6.92(s,1H),5.66–5.58(m,1H),5.10(s,2H),5.07–4.97(m,1H),4.36–4.28(m,2H),2.93(s,3H),2.92–2.86(m,1H),2.74(t,J＝5.4Hz,3H),2.69-2.65(m,1H),2.11–1.93(m,4H),1.81(d,J＝52.7Hz,2H),1.61(d,J＝7.0Hz,3H),1.17(d,J＝6.6Hz,6H).

Example 24

(R)-6-(isopropyl(methyl)amino)-2-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(R) -6- (isopropyl (methyl) amino) -2- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

(R)-5-methoxy-2-(methoxymethyl)-3,4-dihydro-2H-pyrrole

(R) -5-methoxy-2- (methoxymethyl) -3, 4-dihydro-2H-pyrrole

Trimethyloxonium tetrafluoroborate (3.21 g,21.71 mmol) was dissolved in dichloromethane (10 mL), cooled to 0deg.C and (R) -5- (hydroxymethyl) pyrrolidin-2-one 24a (500 mg,4.34 mmol) was added in portions, slowly warmed to room temperature, stirred overnight and LCMS monitored for reaction completion. Cooled to 0deg.C, quenched with saturated potassium bicarbonate solution (40 mL), extracted with ethyl acetate (50 mL. Times.3), the combined organic phases were washed with water (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give (R) -5-methoxy-2- (methoxymethyl) -3, 4-dihydro-2H-pyrrole 24b (591 mg,4.13 mmol) in 95.16% yield, which was used directly in the next reaction.

MS m/z(ESI):144.1[M+1] ⁺

Second step

(R)-3-(6-bromopyridin-2-yl)-5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole

(R) -3- (6-bromopyridin-2-yl) -5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole

(R) -5-methoxy-2- (methoxymethyl) -3, 4-dihydro-2H-pyrrole 24b (591 mg,4.13 mmol) was dissolved in acetonitrile (10 mL), 6-bromopyridine formylhydrazine 1b (250 mg,1.16 mmol) was added dropwise, glacial acetic acid (6.95 mg, 115.72. Mu. Mol) was heated to 80℃and the reaction was complete by LCMS monitoring for 64 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give (R) -3- (6-bromopyridin-2-yl) -5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 24c (360 mg, 815.11. Mu. Mol), in a yield of 70.44%.

24c MS m/z(ESI):309.0[M+1] ⁺

Third step

tert-butyl

(R)-((6-(isopropyl(methyl)amino)-2-(6-(5-(methoxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)car bamate

(R) - ((6- (isopropyl (methyl) amino) -2- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (180 mg, 516.59. Mu. Mol) and (R) -3- (6-bromopyridin-2-yl) -5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 24c (273.79 mg, 619.91. Mu. Mol) were dissolved in 1, 4-dioxane (5 mL), and cuprous iodide (295.15 mg,1.55 mmol), N, N-dimethylethylenediamine (182.15 mg,2.07mmol, 225.71. Mu.L) and potassium carbonate (356.99 mg,2.58 mmol) were added and reacted under argon atmosphere at 70℃for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl (R) - ((6- (isopropyl (methyl) amino) -2- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 24d (200 mg, 346.81. Mu. Mol), yield 67.13%.

MS m/z(ESI):577.3[M+1] ⁺

Fourth step

(R) - ((6- (isopropyl (methyl) amino) -2- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 24d (90 mg, 156.06. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, and trifluoroacetic acid (1.33 g,11.70mmol, 896.29. Mu.L) was added and stirred for 1 hour after slowly warming to room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give (R) -6- (isopropyl (methyl) amino) -2- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 24 (75.9 mg, 126.46. Mu. Mol), yield 81.03%.

MS m/z(ESI):477.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.16(brs,2H),8.58(d,J＝8.2Hz,1H),8.08(t,J＝8.0Hz,1H),7.99(d,J＝7.6Hz,1H),6.91(s,1H),5.22(d,J＝16.8Hz,1H),5.17(s,1H),5.09–4.99(m,1H),4.97(d,J＝16.7Hz,1H),4.44–4.20(m,2H),3.84(dd,J＝9.8,2.9Hz,1H),3.70(dd,J＝9.7,5.3Hz,1H),3.22(s,3H),3.04–2.84(m,3H),2.93(s,3H),2.75(t,J＝5.3Hz,3H),2.70–2.60(m,1H),1.17(d,J＝6.6Hz,6H).

Example 25

(R)-2-(6-(5-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(R) -2- (6- (5- (hydroxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(R) - ((6- (isopropyl (methyl) amino) -2- (6- (5- (methoxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 24d (90 mg, 156.06. Mu. Mol) was dissolved in1, 1-dichloroethane (4.5 mL), cooled to 0 ℃, boron tribromide (2.35 g,9.36mmol, 902.24. Mu. L) was added dropwise, and the mixture was stirred for 1 hour after warming to room temperature. After completion of the reaction, the reaction was cooled again to 0 ℃, quenched by dropwise addition of methanol (2 mL), then adjusted to a slightly alkaline pH by dropwise addition of saturated sodium bicarbonate solution, extracted with dichloromethane (10 ml×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by reverse phase column chromatography (eluent: G system) to give (R) -2- (6- (5- (hydroxymethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 25 (30.3 mg,43.91 μmol), yield 28.13%.

MS m/z(ESI):463.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.26(s,2H),8.57(d,J＝8.2Hz,1H),8.07(t,J＝8.0Hz,1H),7.99(d,J＝7.6Hz,1H),6.89(s,1H),5.29(brs,1H),5.24(d,J＝16.9Hz,1H),5.15–4.93(m,2H),5.03(d,J＝16.7Hz,1H),4.33(q,J＝5.6Hz,2H),3.92(dd,J＝11.0,2.7Hz,1H),3.76(dd,J＝11.0,5.8Hz,1H),3.09–2.82(m,3H),2.92(s,3H),2.79–2.64(m,1H),2.72(t,J＝5.2Hz,3H),1.16(d,J＝6.6Hz,6H).

Example 26

2-(6-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6, 6-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

5-methoxy-3,3-dimethyl-3,4-dihydro-2H-pyrrole

5-Methoxy-3, 3-dimethyl-3, 4-dihydro-2H-pyrrole

4, 4-Dimethylpyrrolidin-2-one 26a (500 mg,4.42 mmol) was dissolved in dichloromethane (10 mL), trimethyloxonium tetrafluoroboric acid (3.27 g,22.09 mmol) was added and stirred at room temperature for 15 hours, and LCMS monitored for reaction completion. The reaction was quenched by addition of saturated sodium bicarbonate solution (15 mL) at 0deg.C, extracted with dichloromethane (15 mL. Times.3), washed with water (15 mL), dried over anhydrous sodium sulfate, filtered, and mixed with glacial acetic acid (0.5 mL) and concentrated under reduced pressure to give 5-methoxy-3, 3-dimethyl-3, 4-dihydro-2H-pyrrole 26b (213 mg,1.67 mmol) in a yield of 37.90% which was used directly in the next reaction.

MS m/z(ESI):128.1[M+1] ⁺

Second step

3-(6-bromopyridin-2-yl)-6,6-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole

3- (6-Bromopyridin-2-yl) -6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole

6-Bromopyridine formylhydrazine 1b (509.58 mg,2.36 mmol) and 5-methoxy-3, 3-dimethyl-3, 4-dihydro-2H-pyrrole 26b (300 mg,2.36 mmol) were dissolved in acetonitrile (15 mL), glacial acetic acid (17.47 mmol,1 mL) was added and heated to 80℃for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 3- (6-bromopyridin-2-yl) -6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazole 26C (104 mg, 354.75. Mu. Mol), in 15.04% yield.

MS m/z(ESI):293.0[M+1] ⁺

Third step

tert-butyl

((2-(6-(6,6-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6, 6-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (59.43 mg, 170.55. Mu. Mol) and 3- (6-bromopyridin-2-yl) -6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 26c (50 mg, 170.55. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (16.24 mg, 85.28. Mu. Mol), N, N-dimethylethylenediamine (7.52 mg, 85.28. Mu. Mol) and potassium carbonate (47.14 mg, 341.11. Mu. Mol) were added and reacted for 16 hours under argon atmosphere at 75 ℃. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 26d (50 mg, 89.18. Mu. Mol), yield 52.29%.

MS m/z(ESI):561.3[M+1] ⁺

Fourth step

Tert-butyl ((2- (6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 26d (60 mg, 107.01. Mu. Mol) was dissolved in dichloromethane (6 mL), cooled to 0 ℃, and trifluoroacetic acid (36.60 mg, 321.03. Mu. Mol) was added and stirred for 1 hour after slowly warming to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6, 6-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 26 (40 mg, 66.09. Mu. Mol), and a yield of 61.76%.

MS m/z(ESI):461.2[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.98(brs,2H),8.59–8.49(m,1H),8.12–8.05(m,1H),7.98–7.91(m,1H),6.92(s,1H),5.18(s,2H),5.09–4.95(m,1H),4.37(t,J＝5.9Hz,1H),4.33–4.25(m,1H),4.28(s,2H),2.93(s,3H),2.83(s,2H),2.74(t,J＝5.4Hz,3H),1.32(s,6H),1.17(d,J＝6.6Hz,6H).

Example 27

2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (5, 5-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

5-methoxy-2,2-dimethyl-3,4-dihydro-2H-pyrrole

5-Methoxy-2, 2-dimethyl-3, 4-dihydro-2H-pyrrole

5, 5-Dimethylpyrrolidin-2-one 27a (300 mg,2.65 mmol) was dissolved in dichloromethane (6 mL), trimethyloxonium tetrafluoroboric acid (1.96 g,13.26 mmol) was added and stirred at room temperature for 48 hours and LCMS monitored for reaction completion. The reaction was quenched by the addition of saturated sodium bicarbonate solution (15 mL) at 0deg.C, extracted with dichloromethane (15 mL. Times.3), washed with water (15 mL), dried over anhydrous sodium sulfate, filtered, and mixed with glacial acetic acid (0.5 mL) and concentrated under reduced pressure to give 5-methoxy-2, 2-dimethyl-3, 4-dihydro-2H-pyrrole 27b (433 mg,1.71 mmol) in a yield of 64.36% for the next reaction.

MS m/z(ESI):128.1[M+1] ⁺

Second step

3-(6-bromopyridin-2-yl)-5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole

3- (6-Bromopyridin-2-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole

6-Bromopyridine formylhydrazine 1b (110.54 mg, 511.66. Mu. Mol) and 5-methoxy-2, 2-dimethyl-3, 4-dihydro-2H-pyrrole 27b (433.83 mg,1.02 mmol) were dissolved in acetonitrile (10 mL), glacial acetic acid (30.73 mg, 511.66. Mu. Mol) was added, and the mixture was heated to 80℃for reaction for 72 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazole 27C (92 mg, 313.82. Mu. Mol), yield 61.33%.

MS m/z(ESI):293.0[M+1] ⁺

Third step

tert-butyl

((2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (5, 5-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 27c (63.10 mg, 215.25. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (81.99 mg, 430.49. Mu. Mol), N, N-dimethylethylenediamine (0.60 mg, 573.99. Mu. Mol) and potassium carbonate (99.16 mg, 717.49. Mu. Mol) were added and reacted under argon atmosphere at 70℃for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 27d (80 mg, 124.20. Mu. Mol), yield 86.56%.

MS m/z(ESI):561.3[M+1] ⁺

Fourth step

Tert-butyl ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 27d (70 mg, 124.85. Mu. Mol) was dissolved in dichloromethane (4 mL), cooled to 0 ℃, trifluoroacetic acid (1.42 g,12.48mmol, 956.01. Mu.L) was added, and stirred for 2 hours after slowly warming to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 27 (66.5 mg, 115.04. Mu. Mol), in 99.40% yield.

MS m/z(ESI):461.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.04(s,2H),8.62(d,J＝8.4Hz,1H),8.09(t,J＝8.0Hz,1H),7.92(d,J＝7.6Hz,1H),6.91(s,1H),5.10(s,2H),5.07–4.95(m,1H),4.32(t,J＝5.9Hz,2H),3.03(t,J＝7.5Hz,2H),2.93(s,3H),2.75(t,J＝5.3Hz,3H),2.61(t,J＝7.5Hz,2H),1.75(s,6H),1.16(d,J＝6.6Hz,6H).

Example 28

2-(6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazol]-3'-yl)pyridin-2-yl)-6-(iso propyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (6 ',7' -Dihydropiro [ cyclopropane-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

5-methoxy-4-azaspiro[2.4]hept-4-ene

5-Methoxy-4-azaspiro [2.4] hept-4-ene

4-Azaspiro [2.4] heptane-5-one 28a (500 mg,4.50mmol, prepared according to published patent WO2020243178A 1) was dissolved in dichloromethane (15 mL), trimethyloxonium tetrafluoroboric acid (2.00 g,13.50 mmol) was added, stirring was carried out at room temperature for 48 hours, LCMS was monitored to complete the reaction, saturated sodium bicarbonate solution (15 mL) was added at 0℃to quench the reaction, dichloromethane (15 mL. Times.3) was extracted, water washed (15 mL) and dried over anhydrous sodium sulfate, filtered, glacial acetic acid (0.2 mL) was added, mixed well and concentrated under reduced pressure to give 5-methoxy-4-azaspiro [2.4] hept-4-ene 28b (0.56 g,4.47 mmol), yield 99.45% was directly used for the next reaction.

MS m/z(ESI):126.1[M+1] ⁺

Second step

3'-(6-bromopyridin-2-yl)-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazole]

3'- (6-Bromopyridin-2-yl) -6',7 '-dihydrospiro [ cyclopropane-1, 5' -pyrrolo [2,1-c ] [1,2,4] triazole ]

6-Bromopyridine formylhydrazine 1b (862.98 mg,3.99 mmol) and 5-methoxy-4-azaspiro [2.4] hept-4-ene 28b (0.5 g,3.99 mmol) were dissolved in acetonitrile (20 mL), glacial acetic acid (0.1 mL,1.75 mmol) was added and heated to 80℃for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 3'- (6-bromopyridin-2-yl) -6',7 '-dihydrospiro [ cyclopropane-1, 5' -pyrrolo [2,1-C ] [1,2,4] triazole ]28C (320 mg,1.10 mmol), yield 27.51%.

MS m/z(ESI):291.0[M+1] ⁺

Third step

tert-butyl

((2-(6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazol]-3'-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (6 ',7' -Dihydropiro [ cyclopropane-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (119.68 mg, 343.47. Mu. Mol) and 3'- (6-bromopyridin-2-yl) -6',7 '-dihydrospiro [ cyclopropane-1, 5' -pyrrolo [2,1-c ] [1,2,4] triazole ]28c (100 mg, 343.47. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), cuprous iodide (32.71 mg, 171.74. Mu. Mol), N, N-dimethylethylenediamine (15.14 mg, 171.74. Mu. Mol) and potassium carbonate (142.41 mg,1.03 mmol) were added and reacted for 2 hours under argon atmosphere at 80 ℃. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6- (6 ',7' -dihydrospiro [ cyclopropane-1, 5 '-pyrrolo [2,1-C ] [1,2,4] triazol ] -3' -yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 28d (20 mg, 35.80. Mu. Mol) in a yield of 10.42%.

MS m/z(ESI):559.0[M+1] ⁺

Fourth step

2-(6-(6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,1-c][1,2,4]triazol]-3'-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

Tert-butyl ((2- (6- (6 ',7' -dihydrospiro [ cyclopropane-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 28d (20 mg, 35.80. Mu. Mol) was dissolved in dichloromethane (3 mL), cooled to 0 ℃, trifluoroacetic acid (8.16 mg, 71.60. Mu. Mol) was added, and stirred for 1 hour after slowly raising the temperature to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (6 ',7' -dihydrospiro [ cyclopropane-1, 5 '-pyrrolo [2,1-c ] [1,2,4] triazol ] -3' -yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 28 (15 mg, 24.35. Mu. Mol), in a yield of 68.02%.

MS m/z(ESI):459.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.63–8.56(m,2H),8.10–8.01(m,1H),7.93(td,J＝7.8,1.8Hz,1H),7.80(d,J＝7.5Hz,1H),6.88(s,1H),5.10(s,2H),5.05–4.96(m,1H),4.25(s,2H), 3.07(dt,J＝17.7,7.8Hz,2H),2.91(s,3H),2.75(dt,J＝12.8,7.7Hz,2H),2.69(s,3H),1.91–1.84(m,2H),1.78–1.71(m,2H),1.15(d,J＝7.1Hz,6H).

Example 29

2-(6-((5R,7R)-5-(fluoromethyl)-7-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- ((5R, 7R) -5- (fluoromethyl) -7-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

1-(tert-butyl)2-methyl(2R,4R)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate

1- (Tert-butyl) 2-methyl (2R, 4R) -4-methyl-5-oxopyrrolidine-1, 2-dicarboxylic acid 29b

1-(tert-butyl)2-methyl(2R,4S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate

1- (Tert-butyl) 2-methyl (2R, 4S) -4-methyl-5-oxopyrrolidine-1, 2-dicarboxylic acid 29c

1- (Tert-butyl) 2-methyl (R) -5-oxopyrrolidine-1, 2-dicarboxylic acid 29a (5.00 g,20.55 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to-78℃under argon, and a solution of lithium bistrimethylsilylamino in tetrahydrofuran (1M, 24.67mL,24.67 mmol) was added, stirred for 30 minutes, methyl iodide (5.84 g,41.11 mmol) was added, and stirring was continued at-78℃for 2 hours. LCMS monitors the reaction, after completion of the reaction, heats to 0deg.C, adds saturated ammonium chloride solution (100 mL), quenches the reaction, extracts with ethyl acetate (100 mL. Times.3), combines the organic phases, washes (100 mL), dries over anhydrous sodium sulfate, filters, concentrates under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: A system) to give 1- (tert-butyl) 2-methyl (2R, 4R) -4-methyl-5-oxopyrrolidine-1, 2-dicarboxylic acid 29b (1.2 g,4.66 mmol), yield 22.69%;1- (tert-butyl) 2-methyl (2R, 4S) -4-methyl-5-oxopyrrolidine-1, 2-dicarboxylic acid 29c (1.3 g,5.05 mmol), yield 24.58%).

29b MS m/z(ESI):158.1[M+H-100] ⁺

29c MS m/z(ESI):158.1[M+H-100] ⁺

Second step

methyl(2R,4R)-4-methyl-5-oxopyrrolidine-2-carboxylate

(2R, 4R) -4-methyl-5-oxopyrrolidine-2-carboxylic acid methyl ester

1- (Tert-butyl) 2-methyl (2R, 4R) -4-methyl-5-oxopyrrolidine-1, 2-dicarboxylic acid 29b (1.3 g,5.05 mmol) was dissolved in dichloromethane (20 mL), and a1, 4-dioxane solution (4M, 1.26 mL) of hydrogen chloride was added and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to give (2R, 4R) -4-methyl-5-oxopyrrolidine-2-carboxylic acid methyl ester 29d (750 mg,4.77 mmol) in 94.44% yield.

MS m/z(ESI):158.1[M+1] ⁺

Third step

(3R,5R)-5-(hydroxymethyl)-3-methylpyrrolidin-2-one

(3R, 5R) -5- (hydroxymethyl) -3-methylpyrrolidin-2-one

(2R, 4R) -4-methyl-5-oxopyrrolidine-2-carboxylic acid methyl ester 29d (700 mg,4.45 mmol) was dissolved in ethanol (8 mL), cooled to 0deg.C, sodium borohydride (674.00 mg,17.82 mmol) was added, slowly warmed to room temperature and stirring was continued for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give (3R, 5R) -5- (hydroxymethyl) -3-methylpyrrolidin-2-one 29e (500 mg,3.87 mmol) in 86.92% yield.

MS m/z(ESI):130.1[M+1] ⁺

Fourth step

((2R,4R)-4-methyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate

((2R, 4R) -4-methyl-5-oxopyrrolidin-2-yl) methyl 4-methylbenzenesulfonate

(3R, 5R) -5- (hydroxymethyl) -3-methylpyrrolidin-2-one 29e (500 mg,3.87 mmol) was dissolved in dichloromethane (10 mL), cooled to 0deg.C, triethylamine (1.18 g,11.61 mmol), 4-dimethylaminopyridine (94.59 mg, 774.25. Mu. Mol), p-toluenesulfonyl chloride (1.11 g,5.81 mmol) was added, slowly warmed to room temperature and stirring continued for 4 hours. After completion of the reaction, methylene chloride (15 mL) was added to dilute the mixture, saturated sodium hydrogencarbonate solution (15 mL) was added to quench the reaction, the mixture was extracted with methylene chloride (15 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give ((2R, 4R) -4-methyl-5-oxopyrrolidin-2-yl) methyl 4-methylbenzenesulfonate 29f (270 mg, 952.91. Mu. Mol) in a yield of 24.61%.

MS m/z(ESI):283.9[M+1] ⁺

Fifth step

(3R,5R)-5-(bromomethyl)-3-methylpyrrolidin-2-one

(3R, 5R) -5- (bromomethyl) -3-methylpyrrolidin-2-one

((2R, 4R) -4-methyl-5-oxopyrrolidin-2-yl) methyl 4-methylbenzenesulfonate 29f (270 mg, 952.91. Mu. Mol) was dissolved in acetone (8 mL), and lithium bromide (413.78 mg,4.76 mmol) was added thereto and heated to 80℃for reaction for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give 29g (150 mg, 781.03. Mu. Mol) of (3R, 5R) -5- (bromomethyl) -3-methylpyrrolidin-2-one in 81.96% yield.

MS m/z(ESI):191.9[M+1] ⁺

Sixth step

(3R,5R)-5-(fluoromethyl)-3-methylpyrrolidin-2-one

(3R, 5R) -5- (fluoromethyl) -3-methylpyrrolidin-2-one

(3R, 5R) -5- (bromomethyl) -3-methylpyrrolidin-2-one 29g (150 mg, 781.03. Mu. Mol) was dissolved in acetonitrile (8 mL), silver fluoride (495.43 mg,3.91 mmol) was added, and the mixture was heated to 30℃and stirred for 48 hours. The reaction solution was filtered and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give (3R, 5R) -5- (fluoromethyl) -3-methylpyrrolidin-2-one 29h (90 mg, 686.25. Mu. Mol) in a yield of 87.86%.

MS m/z(ESI):132.1[M+1] ⁺

Seventh step

(2R,4R)-2-(fluoromethyl)-5-methoxy-4-methyl-3,4-dihydro-2H-pyrrole

(2R, 4R) -2- (fluoromethyl) -5-methoxy-4-methyl-3, 4-dihydro-2H-pyrrole

(3R, 5R) -5- (fluoromethyl) -3-methylpyrrolidin-2-one 29h (90 mg, 686.25. Mu. Mol) was dissolved in dichloromethane (5 mL), trimethyloxonium tetrafluoroboric acid (1.02 g,6.86 mmol) was added and stirred at room temperature for 18 hours and LCMS monitored reaction completion. The reaction was quenched by the addition of saturated sodium bicarbonate solution (15 mL) at 0deg.C, extracted with dichloromethane (15 mL. Times.3), washed with water (15 mL), dried over anhydrous sodium sulfate, filtered, and mixed with glacial acetic acid (0.2 mL) and concentrated under reduced pressure to give (2R, 4R) -2- (fluoromethyl) -5-methoxy-4-methyl-3, 4-dihydro-2H-pyrrole 29i (75 mg, 516.62. Mu. Mol) in a yield of 75.28% for the next reaction.

MS m/z(ESI):146.1[M+1] ⁺

Eighth step

(5R,7R)-3-(6-bromopyridin-2-yl)-5-(fluoromethyl)-7-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole

(5R, 7R) -3- (6-bromopyridin-2-yl) -5- (fluoromethyl) -7-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole

6-Bromopyridine formylhydrazine 1b (111.61 mg, 516.62. Mu. Mol) and (2R, 4R) -2- (fluoromethyl) -5-methoxy-4-methyl-3, 4-dihydro-2H-pyrrole 29i (75 mg, 516.62. Mu. Mol) were dissolved in acetonitrile (6 mL), glacial acetic acid (310.24 mg,5.17 mmol) was added and the mixture was heated to 80℃for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give (5R, 7R) -3- (6-bromopyridin-2-yl) -5- (fluoromethyl) -7-methyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazole 29j (80 mg, 257.11. Mu. Mol), in 49.77% yield.

MS m/z(ESI):311.0[M+1] ⁺

Ninth step

tert-butyl

((2-(6-((5R,7R)-5-(fluoromethyl)-7-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- ((5R, 7R) -5- (fluoromethyl) -7-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (44.79 mg, 128.55. Mu. Mol) and (5R, 7R) -3- (6-bromopyridin-2-yl) -5- (fluoromethyl) -7-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 29j (40 mg, 128.55. Mu. Mol) were dissolved in 1, 4-dioxane (5 mL), and cuprous iodide (24.48 mg, 128.55. Mu. Mol), N, N-dimethylethylenediamine (22.66 mg, 257.11. Mu. Mol) and potassium carbonate (71.07 mg, 514.22. Mu. Mol) were added and reacted under argon atmosphere at 100℃for 12 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6- ((5R, 7R) -5- (fluoromethyl) -7-methyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 29k (34 mg, 58.75. Mu. Mol), yield 45.70%.

MS m/z(ESI):579.0[M+1] ⁺

Tenth step

Tert-butyl ((2- (6- ((5R, 7R) -5- (fluoromethyl) -7-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 29k (34 mg, 58.75. Mu. Mol) was dissolved in dichloromethane (3 mL), and a1, 4-dioxane solution of hydrogen chloride (4M, 440.66. Mu.L) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- ((5R, 7R) -5- (fluoromethyl) -7-methyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 29 (30 mg, 49.17. Mu. Mol), yield 83.68%.

MS m/z(ESI):479.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.98(brs,2H),8.59(dd,J＝8.3,3.4Hz,1H),8.10(t,J＝8.0Hz,1H),8.02(t,J＝7.6Hz,1H),6.91(s,1H),5.28(d,J＝30.6Hz,1H),5.17(dd,J＝16.5,4.9Hz,1H),5.05(p,J＝8.8,7.9Hz,2H),4.94(dd,J＝16.0,4.5Hz,2H),4.34(d,J＝6.7Hz,2H),3.39–3.31(m,2H),2.93(s,3H),2.77–2.72(m,3H),2.70–2.61(m,1H),1.43–1.35(m,3H),1.17(d,J＝6.6Hz,6H).

Example 30

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(4a,5,5a,6-tetrahydrocyclopropa[4,5]pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4 a, 5a, 6-tetrahydrocyclopropa [4,5] pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

3-methoxy-2-azabicyclo[3.1.0]hex-2-ene

3-Methoxy-2-azabicyclo [3.1.0] hex-2-ene

2-Azabicyclo [3.1.0] hexane-3-one 30a (300 mg,3.09mmol, prepared according to published patent WO2018037058A 1) was dissolved in dichloromethane (6 mL), trimethyloxonium tetrafluoroboric acid (4.57 g,30.89 mmol) was added and stirred at room temperature for 18 hours, and LCMS monitored the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution (15 mL) at 0deg.C, extracted with dichloromethane (15 mL. Times.3), washed with water (15 mL), dried over anhydrous sodium sulfate, filtered, and added with glacial acetic acid (0.2 mL) to mix well, and concentrated under reduced pressure to give 3-methoxy-2-azabicyclo [3.1.0] hex-2-ene 30b (250 mg,2.25 mmol) in 72.82% yield, which was used directly in the next reaction.

MS m/z(ESI):112.1[M+1] ⁺

Second step

3-(6-bromopyridin-2-yl)-4a,5,5a,6-tetrahydrocyclopropa[4,5]pyrrolo[2,1-c][1,2,4]triazole

3- (6-Bromopyridin-2-yl) -4a, 5a, 6-tetrahydrocyclopiperidine [4,5] pyrrolo [2,1-c ] [1,2,4] triazole

6-Bromopyridine formylhydrazine 1b (485.95 mg,2.25 mmol) and 3-methoxy-2-azabicyclo [3.1.0] hex-2-ene 30b (250 mg,2.25 mmol) were dissolved in acetonitrile (6 mL), glacial acetic acid (1.35 g,22.49 mmol) was added and heated to 80℃for 18 h. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 3- (6-bromopyridin-2-yl) -4a, 5a, 6-tetrahydrocycloparaffin [4,5] pyrrolo [2,1-C ] [1,2,4] triazole 30C (130 mg, 469.11. Mu. Mol), in 20.86% yield.

MS m/z(ESI):276.9[M+1] ⁺

Third step

tert-butyl

((6-(isopropyl(methyl)amino)-1-oxo-2-(6-(4a,5,5a,6-tetrahydrocyclopropa[4,5]pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -1-oxo-2- (6- (4 a, 5a, 6-tetrahydrocyclopropa [4,5] pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (40 mg, 114.80. Mu. Mol) and 3- (6-bromopyridin-2-yl) -4a, 5a, 6-tetrahydrocyclopropaneo [4,5] pyrrolo [2,1-c ] [1,2,4] triazole 30c (47.72 mg, 172.20. Mu. Mol) were dissolved in1, 4-dioxane (6 mL), and cuprous iodide (21.86 mg, 114.80. Mu. Mol), N, N-dimethylethylenediamine (20.24 mg, 229.60. Mu. Mol) and potassium carbonate (63.46 mg, 459.19. Mu. Mol) were added and heated to 100℃under argon atmosphere to react for 8 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (4 a, 5a, 6-tetrahydrocyclopropaneo [4,5] pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 30d (50 mg, 91.80. Mu. Mol), yield 79.97%.

MS m/z(ESI):545.0[M+1] ⁺

Fourth step

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (4 a, 5a, 6-tetrahydrocyclopropa [4,5] pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 30d (50 mg,91.80 μmol) was dissolved in dichloromethane (4 mL), and a1, 4-dioxane solution of hydrogen chloride (4 m,22.95 μl) was added and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4 a, 5a, 6-tetrahydrocyclopropaneo [4,5] pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 30 (40 mg, 69.55. Mu. Mol), yield 75.76%.

MS m/z(ESI):445.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.00(brs,2H),8.59(d,J＝8.4Hz,1H),8.10(t,J＝8.0Hz,1H),7.92(d,J＝7.6Hz,1H),6.91(s,1H),5.25(d,J＝17.1Hz,1H),5.12(d,J＝17.1Hz,1H),5.08–4.98(m,1H),4.66–4.59(m,1H),4.36(d,J＝5.2Hz,2H),3.25(dd,J＝17.3,6.8Hz,1H),3.05(d,J＝17.4Hz,1H),2.93(s,3H),2.73(t,J＝5.4Hz,3H),2.43–2.35(m,1H),1.39(q,J＝6.3Hz,1H),1.16(d,J＝6.6Hz,6H),0.69(d,J＝6.0Hz,1H).

Example 31

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4- (tetrahydro-2H-pyran-4-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (tetrahydro-2H-pyran-4-yl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridine formyl) -N, N-dimethylformamide 9a (300 mg,1.11 mmol) was dissolved in acetonitrile (6 mL) at room temperature, 4-aminotetrahydropyran 31a (559.64 mg,5.53 mmol) and glacial acetic acid (664.48 mg,11.07 mmol) were added, and the mixture was warmed to reflux and reacted for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give 2-bromo-6- (4- (tetrahydro-2H-pyran-4-yl) -4H-1,2, 4-triazol-3-yl) pyridine 31B (200 mg, 646.91. Mu. Mol) in 58.46% yield.

MS m/z(ESI):308.9[M+1] ⁺

Second step

tert-butyl

((6-(isopropyl(methyl)amino)-1-oxo-2-(6-(4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -1-oxo-2- (6- (4- (tetrahydro-2H-pyran-4-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 2-bromo-6- (4- (tetrahydro-2H-pyran-4-yl) -4H-1,2, 4-triazol-3-yl) pyridine 31b (53.24 mg, 172.20. Mu. Mol) were dissolved in1, 4-dioxane (3 mL), and cuprous iodide (27.33 mg, 143.50. Mu. Mol), N, N-dimethylethylenediamine (25.30 mg, 286.99. Mu. Mol) and potassium carbonate (59.50 mg, 430.49. Mu. Mol) were added and reacted for 18 hours under argon atmosphere at 70 ℃. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (4- (tetrahydro-2H-pyran-4-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 31C (68 mg, 107.73. Mu. Mol) in a yield of 75.07%.

MS m/z(ESI):577.4[M+1] ⁺

Third step

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (4- (tetrahydro-2H-pyran-4-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 31c (60 mg, 104.04. Mu. Mol) was dissolved in dichloromethane (3.6 mL), cooled to 0 ℃, and trifluoroacetic acid (1.78 g,15.61mmol,1.20 mL) was added and stirred after slowly warming to room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4- (tetrahydro-2H-pyran-4-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 31 (60 mg, 94.71. Mu. Mol), yield 91.03%.

MS m/z(ESI):477.4[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.16(brs,2H),9.04(s,1H),8.67(d,J＝8.4Hz,1H),8.13(t,J ＝8.0Hz,1H),7.95(d,J＝7.5Hz,1H),6.91(s,1H),5.40–5.26(m,1H),5.14(s,2H),5.10–4.95(m,1H),4.27(s,2H),4.11–4.00(m,2H),3.67–3.54(m,2H),2.93(s,3H),2.72(s,3H),2.19–1.95(m,4H),1.16(d,J＝6.6Hz,6H).

Example 32

2-(6-((R)-5-((R)-1-fluoroethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- ((R) -5- ((R) -1-fluoroethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

tert-butyl(R)-2-((R)-1-fluoroethyl)pyrrolidine-1-carboxylate

(R) -2- ((R) -1-fluoroethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

(R) -2- ((R) -1-hydroxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester 32a (400 mg,1.86mmol, prepared according to published patent WO2005026152A 1) was dissolved in dichloromethane (10 mL), cooled to 0deg.C, a solution of diethylaminosulfur trifluoride (598.97 mg,3.72 mmol) in dichloromethane (1 mL) was added dropwise and the reaction was stirred at 0deg.C for 3 hours and was complete by LCMS detection. Dichloromethane (10 mL) was added to the reaction mixture, which was then diluted, quenched with water (10 mL), extracted with dichloromethane (10 ml×3), and the organic phases were combined and concentrated under reduced pressure to give tert-butyl (R) -2- ((R) -1-fluoroethyl) pyrrolidine-1-carboxylate 32b (0.4 g,1.84 mmol) in 99.08% yield, which was used directly in the next reaction.

MS m/z(ESI):162.2[M+H-56] ⁺

Second step

tert-butyl(R)-2-((R)-1-fluoroethyl)-5-oxopyrrolidine-1-carboxylate

(R) -2- ((R) -1-fluoroethyl) -5-oxopyrrolidine-1-carboxylic acid tert-butyl ester

(R) -2- ((R) -1-fluoroethyl) pyrrolidine-1-carboxylic acid tert-butyl ester 32b (0.4 g,1.84 mmol) was dissolved in a mixed solvent of ethyl acetate (3 mL) and water (1 mL), sodium periodate (1.97 g,9.20 mmol) was added respectively, ruthenium dioxide hydrate (556.26 mg,3.68 mmol) was stirred at room temperature overnight, and LCMS detection was complete. The reaction solution was filtered off with suction, the filtrate was collected, extracted with ethyl acetate (15 ml×3), the organic phases were combined and concentrated under reduced pressure to give tert-butyl (R) -2- ((R) -1-fluoroethyl) -5-oxopyrrolidine-1-carboxylate 32c (0.35 g,1.51 mmol) in 82.21% yield.

MS m/z(ESI):176.1[M+H-56] ⁺

Third step

(R)-5-((R)-1-fluoroethyl)pyrrolidin-2-one

(R) -5- ((R) -1-fluoroethyl) pyrrolidin-2-one

(R) -2- ((R) -1-fluoroethyl) -5-oxopyrrolidine-1-carboxylic acid tert-butyl ester 32c (150 mg, 648.61. Mu. Mol) was dissolved in methylene chloride (6 mL), and a1, 4-dioxane solution (4M, 200. Mu.L) of hydrogen chloride was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give (R) -5- ((R) -1-fluoroethyl) pyrrolidin-2-one 32d (85 mg, 648.12. Mu. Mol) in 99.92% yield.

MS m/z(ESI):132.2[M+1] ⁺

Fourth step

(R)-2-((R)-1-fluoroethyl)-5-methoxy-3,4-dihydro-2H-pyrrole

(R) -2- ((R) -1-fluoroethyl) -5-methoxy-3, 4-dihydro-2H-pyrrole

(R) -5- ((R) -1-fluoroethyl) pyrrolidin-2-one 32d (85 mg, 648.12. Mu. Mol) was dissolved in dichloromethane (5 mL), trimethyloxonium tetrafluoroboric acid (285.82 mg,1.94 mmol) was added and stirred at room temperature for 24 hours and LCMS monitored for reaction completion. The reaction was quenched by the addition of saturated sodium bicarbonate solution (15 mL) at 0deg.C, extracted with dichloromethane (10 mL. Times.3), the combined organic phases were washed with water (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure after adding glacial acetic acid (0.2 mL) and mixing to give (R) -2- ((R) -1-fluoroethyl) -5-methoxy-3, 4-dihydro-2H-pyrrole 32e (90 mg, 619.94. Mu. Mol) in 95.65% yield, which was used directly in the next reaction.

MS m/z(ESI):146.2[M+1] ⁺

Fifth step

(R)-3-(6-bromopyridin-2-yl)-5-((R)-1-fluoroethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole

(R) -3- (6-bromopyridin-2-yl) -5- ((R) -1-fluoroethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole

6-Bromopyridine formylhydrazine 1b (133.93 mg, 619.94. Mu. Mol) and (R) -2- ((R) -1-fluoroethyl) -5-methoxy-3, 4-dihydro-2H-pyrrole 32e (90 mg, 619.94. Mu. Mol) were dissolved in acetonitrile (6 mL), glacial acetic acid (0.05 mL) was added and heated to 80℃for 20 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give (R) -3- (6-bromopyridin-2-yl) -5- ((R) -1-fluoroethyl) -6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazole 32f (0.15 g, 482.08. Mu. Mol), yield 77.76%.

MS m/z(ESI):311.1[M+1] ⁺

Sixth step

tert-butyl

((2-(6-((R)-5-((R)-1-fluoroethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- ((R) -5- ((R) -1-fluoroethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (111.98 mg, 321.39. Mu. Mol) and (R) -3- (6-bromopyridin-2-yl) -5- ((R) -1-fluoroethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 32f (100 mg, 321.39. Mu. Mol) were dissolved in 1, 4-dioxane (3 mL), tris (dibenzylidene-BASE acetone) dipalladium (147.15 mg, 160.69. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (371.92 mg, 642.77. Mu. Mol) and potassium phosphate (204.66 mg, 964.16. Mu.) were added in this order, and the reaction was heated to 80℃for 2 hours, and S was monitored to be complete. The reaction solution was filtered under suction, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give ((2- (6- ((R) -5- ((R) -1-fluoroethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 32g (83 mg, 143.43. Mu. Mol), yield 44.63%.

MS m/z(ESI):579.4[M+1] ⁺

Seventh step

(2- (6- ((R) -5- ((R) -1-fluoroethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 32g (83 mg, 143.43. Mu. Mol) was dissolved in dichloromethane (10 mL), cooled to 0 ℃, trifluoroacetic acid (49.06 mg, 430.29. Mu. Mol) was added, and after slow warming to room temperature, stirring was carried out for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- ((R) -5- ((R) -1-fluoroethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) -pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 32 (10 mg, 15.90. Mu. Mol), yield 11.09%.

MS m/z(ESI):479.3[M+1] ⁺

Example 33

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(5,5,6-trimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (5, 6-trimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

methyl 3,4-dimethyl-4-nitropentanoate

3, 4-Dimethyl-4-nitropentanoic acid methyl ester

Methyl (E) -but-2-enoate 33a (2 g,19.98 mmol) was dissolved in acetonitrile (10 mL), 2-nitropropane (2.14 g,23.97 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (3.04 g,19.98 mmol) were added and stirred at room temperature for 18 hours and LCMS monitored to be complete. The reaction mixture was quenched with water (50 mL), adjusted to pH 2-3 with 2M hydrochloric acid solution, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give methyl 3, 4-dimethyl-4-nitrovalerate 33b (2.1 g,11.10 mmol), 55.56% yield.

MS m/z(ESI):190[M+1] ⁺

Second step

4,5,5-trimethylpyrrolidin-2-one

4, 5-Trimethylpyrrolidin-2-one

Methyl 3, 4-dimethyl-4-nitrovalerate 33b (400 mg,2.11 mmol) was dissolved in methanol (15 mL), raney nickel (372.22 mg,6.34 mmol) was added and the reaction was stirred at room temperature overnight and LCMS monitored to completion. The reaction solution was filtered under suction, and the filtrate was concentrated under reduced pressure to give 4, 5-trimethylpyrrolidin-2-one 33c (268 mg,2.11 mmol) in 99.67% yield, which was directly used in the next reaction.

MS m/z(ESI):128.2[M+1] ⁺

Third step

5-methoxy-2,2,3-trimethyl-3,4-dihydro-2H-pyrrole

5-Methoxy-2, 3-trimethyl-3, 4-dihydro-2H-pyrrole

4, 5-Trimethylpyrrolidin-2-one 33c (100 mg, 786.26. Mu. Mol) was dissolved in dichloromethane (5 mL), trimethyloxonium tetrafluoroboric acid (346.74 mg,2.36 mmol) was added and stirred at room temperature for 24 hours, and LCMS monitored for reaction completion. The reaction was quenched by adding saturated sodium bicarbonate solution (10 mL) at 0deg.C, extracted with dichloromethane (10 mL. Times.3), the organic phases were combined, washed with water (10 mL) and dried over anhydrous sodium sulfate, filtered, and glacial acetic acid (0.2 mL) was added, mixed well and concentrated under reduced pressure to give 5-methoxy-2, 3-trimethyl-3, 4-dihydro-2H-pyrrole 33d (100 mg, 708.16. Mu. Mol) in a yield of 90.07% for the next reaction directly.

MS m/z(ESI):142.2[M+1] ⁺

Fourth step

3-(6-bromopyridin-2-yl)-5,5,6-trimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole

3- (6-Bromopyridin-2-yl) -5, 6-trimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole

6-Bromopyridine formylhydrazine 1b (152.99 mg, 708.16. Mu. Mol) and 5-methoxy-2, 3-trimethyl-3, 4-dihydro-2H-pyrrole 33d (100 mg, 708.16. Mu. Mol) were dissolved in acetonitrile (5 mL), glacial acetic acid (0.1 mL) was added, and the mixture was heated to 80℃for 20 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 3- (6-bromopyridin-2-yl) -5, 6-trimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazole 33e (0.2 g, 651.07. Mu. Mol) in 91.94% yield.

MS m/z(ESI):307.1[M+1] ⁺

Fifth step

tert-butyl

((6-(isopropyl(methyl)amino)-1-oxo-2-(6-(5,5,6-trimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -1-oxo-2- (6- (5, 6-trimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (113.43 mg, 325.53. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5, 6-trimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 33e (100 mg, 325.53. Mu. Mol) were dissolved in1, 4-dioxane (3 mL), and cuprous iodide (30.93 mg, 162.77. Mu. Mol), N, N-dimethylethylenediamine (14.35 mg, 162.77. Mu. Mol) and potassium carbonate (89.98 mg, 651.07. Mu. Mol) were added and heated to 80℃under argon atmosphere to react for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (5, 6-trimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 33f (102 mg, 177.48. Mu. Mol), yield 54.52%.

MS m/z(ESI):575.4[M+1] ⁺

Sixth step

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (5, 6-trimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 33f (102 mg, 177.48. Mu. Mol) was dissolved in dichloromethane (10 mL), cooled to 0 ℃, and trifluoroacetic acid (60.71 mg, 532.44. Mu. Mol) was added and stirred for 3 hours after slowly warming to room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (5, 6-trimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 33 (10 mg, 16.76. Mu. Mol), yield 9.44%.

MS m/z(ESI):475.4[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.24(brs,2H),8.63(d,J＝8.3Hz,1H),8.13–8.05(m,1H),7.88(d,J＝7.6Hz,1H),6.91(s,1H),5.13(d,J＝6.8Hz,2H),5.09–4.99(m,1H),4.30(s,2H),3.06(dd,J＝15.2,7.2Hz,2H),2.93(s,3H),2.86–2.78(m,1H),2.74(s,3H),1.62(d,J＝17.2Hz,6H),1.17(d,J＝6.4Hz,3H),1.16(d,J＝6.7Hz,6H).

Example 34

2-(6-(4-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (4- (4-Fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (4-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridine formyl) -N, N-dimethylformamide 9a (150 mg, 553.27. Mu. Mol) was dissolved in acetonitrile (3 mL) at room temperature, 4-fluoroaniline 34a (307.40 mg,2.77 mmol) and glacial acetic acid (332.24 mg,5.53 mmol) were added and the mixture was warmed to reflux for 24 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 34b (130 mg, 379.29. Mu. Mol) of 2-bromo-6- (4- (4-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine in 68.55% yield.

MS m/z(ESI):319.1[M+1] ⁺

Second step

tert-butyl

((2-(6-(4-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (4- (4-Fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (100 mg, 286.99. Mu. Mol) and 2-bromo-6- (4- (4-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine 34b (109.91 mg, 344.39. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), tris (dibenzylidene-BASE acetone) dipalladium (26.28 mg, 28.70. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (33.21 mg, 57.40. Mu. Mol) and potassium phosphate (82.76 mg, 860.98. Mu. Mol) were added in this order and heated to 70℃for 18 hours, and LCMS monitored to be complete. The reaction solution was filtered under suction, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: F system) to give tert-butyl ((2- (6- (4- (4-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 34c (160 mg, 268.69. Mu. Mol), yield 93.62%.

MS m/z(ESI):587.3[M+1] ⁺

Third step

Tert-butyl ((2- (6- (4- (4-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 34c (150 mg, 255.69. Mu. Mol) was dissolved in dichloromethane (15 mL), cooled to 0 ℃, trifluoroacetic acid (2.33 g,20.45 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (4- (4-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 34 (10 mg, 16.76. Mu. Mol), in 9.44% yield.

MS m/z(ESI):487.2[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.00(s,2H),8.90(s,1H),8.52(dd,J＝8.2,1.0Hz,1H),8.09(t,J＝7.9Hz,1H),8.03(dd,J＝7.6,1.0Hz,1H),7.68–7.59(m,2H),7.50(t,J＝8.7Hz,2H),6.83(s,1H),5.07–4.94(m,1H),4.13(t,J＝5.8Hz,2H),4.00(s,2H),2.90(s,3H),2.86–2.76(m,3H),1.15(d,J＝6.6Hz,6H).

Example 35

(S)-6-(isopropyl(methyl)amino)-2-(6-(5-methyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(S) -6- (isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

(S)-5-methoxy-3-methyl-3,6-dihydro-2H-1,4-oxazine

(S) -5-methoxy-3-methyl-3, 6-dihydro-2H-1, 4-oxazine

(S) -5-methylmorpholine-3-one 35a (1 g,8.69 mmol) was dissolved in dichloromethane (20 mL), trimethyloxonium tetrafluoroboric acid (3.83 g,26.06 mmol) was added and stirred at room temperature for 5 hours, LCMS was monitored to complete the reaction, the reaction was quenched by adding saturated sodium bicarbonate solution (20 mL) at 0℃and extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with water (20 mL) and dried over anhydrous sodium sulfate, filtered, and glacial acetic acid (0.2 mL) was added and mixed well and concentrated under reduced pressure to give (S) -5-methoxy-3-methyl-3, 6-dihydro-2H-1, 4-oxazine 35b (1 g,7.74 mmol), yield 89.14% and used directly in the next reaction.

MS m/z(ESI):130.1[M+1] ⁺

Second step

(S)-3-(6-bromopyridin-2-yl)-5-methyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazine

(S) -3- (6-bromopyridin-2-yl) -5-methyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazine

6-Bromopyridine formylhydrazine 1b (1.67 g,7.74 mmol) and (S) -5-methoxy-3-methyl-3, 6-dihydro-2H-1, 4-oxazine 35b (1 g,7.74 mmol) were dissolved in acetonitrile (20 mL), glacial acetic acid (1 mL) was added, and the mixture was heated to 80℃for 24 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give (S) -3- (6-bromopyridin-2-yl) -5-methyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-C ] [1,4] oxazine 35C (470 mg,1.59 mmol) in 20.57% yield.

MS m/z(ESI):295.1[M+1] ⁺

Third step

tert-butyl

(S)-((6-(isopropyl(methyl)amino)-2-(6-(5-methyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxaz in-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(S) - ((6- (isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (118.06 mg, 338.83. Mu. Mol) and (S) -3- (6-bromopyridin-2-yl) -5-methyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazine 35c (100 mg, 338.83. Mu. Mol) were dissolved in1, 4-dioxane (3 mL), and cuprous iodide (32.19 mg, 169.41. Mu. Mol), N, N-dimethylethylenediamine (14.93 mg, 169.41. Mu. Mol) and potassium carbonate (93.66 mg, 677.66. Mu. Mol) were added and heated under argon atmosphere to 80℃for reaction for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl (S) - ((6- (isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-C ] [1,4] oxazin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 35d (70 mg, 124.41. Mu. Mol) in a yield of 36.72%.

MS m/z(ESI):563.4[M+1] ⁺

Fourth step

(S) - ((6- (isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 35d (70 mg, 124.41. Mu. Mol) was dissolved in dichloromethane (10 mL), cooled to 0deg.C, trifluoroacetic acid (42.56 mg, 373.23. Mu. Mol) was added, and the mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give (S) -6- (isopropyl (methyl) amino) -2- (6- (5-methyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 35 (55 mg, 93.18. Mu. Mol), yield 74.90%.

MS m/z(ESI):463.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.95(s,2H),8.61(d,J＝8.2Hz,1H),8.12(t,J＝7.9Hz,1H),8.06(d,J＝7.5Hz,1H),6.92(s,1H),5.34–5.26(m,1H),5.23(d,J＝16.7Hz,1H),5.15(d,J＝15.4Hz,1H),5.08–4.97(m,1H),5.03(d,J＝16.7Hz,1H),4.93(d,J＝15.4Hz,1H),4.40–4.27(m,1H),4.36(q,J＝5.5Hz,1H),4.02(t,J＝2.4Hz,2H),2.93(s,3H),2.76(t,J＝5.4Hz,3H),1.52(d,J＝6.4Hz,3H),1.17(d,J＝6.7Hz,6H).

Example 36

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(5,5,7-trimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (5,5,7-trimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

5-methoxy-2,2,4-trimethyl-3,4-dihydro-2H-pyrrole

5-Methoxy-2, 4-trimethyl-3, 4-dihydro-2H-pyrrole

3, 5-Trimethylpyrrolidin-2-one 36a (250 mg,1.97 mmol) was dissolved in dichloromethane (10 mL), trimethyloxonium tetrafluoroboric acid (2.91 g,19.66 mmol) was added and stirred at room temperature for 5 hours, and LCMS monitored for reaction completion. The reaction was quenched by the addition of saturated sodium bicarbonate solution (10 mL) at 0deg.C, extracted with dichloromethane (10 mL. Times.3), the organic phases were combined, washed with water (10 mL) and dried over anhydrous sodium sulfate, filtered, and glacial acetic acid (0.2 mL) was added, mixed well and concentrated under reduced pressure to give 5-methoxy-2, 4-trimethyl-3, 4-dihydro-2H-pyrrole 36b (240 mg,1.70 mmol) in a yield of 86.46% which was used directly in the next reaction.

MS m/z(ESI):142.1[M+1] ⁺

Second step

3-(6-bromopyridin-2-yl)-5,5,7-trimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole

3- (6-Bromopyridin-2-yl) -5,5,7-trimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole

6-Bromopyridine formylhydrazine 1b (220.30 mg,1.02 mmol) and 5-methoxy-2, 4-trimethyl-3, 4-dihydro-2H-pyrrole 36b (240 mg,1.70 mmol) were dissolved in acetonitrile (6 mL), glacial acetic acid (1.02 g,17.00 mmol) was added and heated to 80℃for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 3- (6-bromopyridin-2-yl) -5,5,7-trimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazole 36C (200 mg, 651.07. Mu. Mol), in a yield of 38.31%.

MS m/z(ESI):306.9[M+1] ⁺

Third step

tert-butyl

((6-(isopropyl(methyl)amino)-1-oxo-2-(6-(5,5,7-trimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -1-oxo-2- (6- (5,5,7-trimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (60 mg, 172.20. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5,5,7-trimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 36c (79.35 mg, 258.30. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (32.79 mg, 172.20. Mu. Mol), N, N-dimethylethylenediamine (30.36 mg, 344.39. Mu. Mol) and potassium carbonate (95.19 mg, 688.79. Mu. Mol) were added and reacted for 18 hours under argon atmosphere at 95 ℃. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (5,5,7-trimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 36d (90 mg, 156.60. Mu. Mol), yield 90.94%.

MS m/z(ESI):575.0[M+1] ⁺

Fourth step

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (5,5,7-trimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 36d (90 mg, 156.60. Mu. Mol) was dissolved in dichloromethane (4 mL), and a1, 4-dioxane solution of hydrogen chloride (4M, 1.17 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (5,5,7-trimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 36 (80 mg, 134.51. Mu. Mol), in a yield of 98.97%.

MS m/z(ESI):475.1[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.13(brs,2H),8.62(d,J＝8.4Hz,1H),8.09(t,J＝8.0Hz,1H),7.92(d,J＝7.6Hz,1H),6.91(s,1H),5.10(d,J＝3.0Hz,2H),5.08–4.96(m,1H),4.30(t,J＝6.0Hz,2H),3.55–3.42(m,1H),2.93(s,3H),2.80(dd,J＝12.6,8.0Hz,1H),2.74(t,J＝5.3Hz,3H),2.25(dd,J＝12.6,9.3Hz,1H),1.81(s,3H),1.68(s,3H),1.38(d,J＝6.9Hz,3H),1.16(d,J＝6.6Hz,6H).

Example 37

2-(6-(4-(2-fluorobenzyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (4- (2-Fluorobenzyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(2-fluorobenzyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (2-fluorobenzyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (500 mg,1.84 mmol) was dissolved in acetonitrile (12.5 mL) at room temperature, 2-fluorobenzylamine 37a (923.18 mg,7.38 mmol) and glacial acetic acid (2.5 mL) were added, and the mixture was heated to 95℃and concentrated under reduced pressure after reaction for 18 hours, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 2-bromo-6- (4- (2-fluorobenzyl) -4H-1,2, 4-triazol-3-yl) pyridine 37b (300 mg, 900.47. Mu. Mol) in a yield of 48.83%.

MS m/z(ESI):332.9[M+1] ⁺

Second step

tert-butyl

((2-(6-(4-(2-fluorobenzyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (4- (2-Fluorobenzyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 2-bromo-6- (4- (2-fluorobenzyl) -4H-1,2, 4-triazol-3-yl) pyridine 37b (95.33 mg, 286.99. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (27.33 mg, 143.50. Mu. Mol), N, N-dimethylethylenediamine (25.30 mg, 286.99. Mu. Mol) and potassium carbonate (79.33 mg, 573.99. Mu. Mol) were added and reacted for 18 hours under argon atmosphere at 95 ℃. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6- (4- (2-fluorobenzyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 37C (70 mg, 116.53. Mu. Mol), yield 81.21%.

MS m/z(ESI):601.0[M+1] ⁺

Third step

Tert-butyl ((2- (6- (4- (2-fluorobenzyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 37c (70 mg, 116.53. Mu. Mol) was dissolved in dichloromethane (4 mL), and a1, 4-dioxane solution of hydrogen chloride (4M, 874.00. Mu. L) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (4- (2-fluorobenzyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 37 (65 mg, 101.97. Mu. Mol) in 96.42% yield.

MS m/z(ESI):501.1[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.26(brs,2H),8.81(s,1H),8.58(d,J＝8.4Hz,1H),8.09(t,J＝8.0Hz,1H),7.97(d,J＝7.6Hz,1H),7.42–7.26(m,2H),7.13(t,J＝7.5Hz,1H),6.87(s,1H),6.83(t,J＝7.7Hz,1H),5.97(s,2H),5.11–4.96(m,1H),4.78(s,2H),4.13(s,2H),2.91(s,3H),2.72(s,3H),1.14(d,J＝6.6Hz,6H).

Example 38

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

tert-butyl 3-(6-chloropyridin-2-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate

3- (6-Chloropyridin-2-yl) -5, 6-dihydroimidazo [1,2-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester

(6-Chloropyridin-2-yl) boronic acid 38a (0.8 g,5.08 mmol) and 3-bromo-5, 6-dihydroimidazo [1,2-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester 38b (512.05 mg,1.69mmol, commercially available) were dissolved in1, 4-dioxane (10 mL), potassium carbonate (702.61 mg,5.08 mmol) was added, 1-bis (diphenylphosphine) bis-iron palladium dichloride (123.99 mg, 169.46. Mu. Mol) was heated to 95℃under argon, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: C system) to give 3- (6-chloropyridin-2-yl) -5, 6-dihydroimidazo [1,2-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester 38C (300 mg, 896.06. Mu. Mol) in a yield of 52.88%.

MS m/z(ESI):335.0[M+1] ⁺

Second step

tert-butyl

3-(6-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-(isopropyl(methyl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pyridin-2-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate

3- (6- (4- (((Tert-Butoxycarbonyl) (methyl) amino) methyl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -5, 6-dihydroimidazo [1,2-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 3- (6-chloropyridin-2-yl) -5, 6-dihydroimidazo [1,2-a ] pyrazine-7 (8H) -carboxylate 38c (144.13 mg, 430.49. Mu. Mol) were dissolved in 1, 4-dioxane (5 mL), tris (dibenzylideneacetone) dipalladium (13.14 mg, 14.35. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (16.61 mg, 28.70. Mu. Mol) and potassium phosphate (91.38 mg, 430.49. Mu. Mol) were added in this order, and the reaction was heated to 70℃for 18 hours, and the S was monitored to be complete. The reaction solution was filtered under suction, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: F system) to give tert-butyl 3- (6- (4- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -5, 6-dihydroimidazo [1,2-a ] pyrazine-7 (8H) -carboxylate 38d (30 mg, 46.38. Mu. Mol), yield 32.32%.

MS m/z(ESI):647.0[M+1] ⁺

Third step

3- (6- (4- (((Tert-Butoxycarbonyl) (methyl) amino) methyl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -5, 6-dihydroimidazo [1,2-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester 38d (30 mg, 46.38. Mu. Mol) was dissolved in dichloromethane (4 mL), and a1, 4-dioxane solution of hydrogen chloride (4M, 347.88. Mu. L) was added and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyrazin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 38 (22 mg, 36.62. Mu. Mol), yield 78.95%.

MS m/z(ESI):447.1[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.22(brs,2H),8.38(d,J＝8.3Hz,1H),7.96(t,J＝8.1Hz,1H),7.73(s,1H),7.64(d,J＝7.7Hz,1H),6.90(s,1H),5.16(s,2H),5.11–4.97(m,1H),4.74(s,2H),4.45–4.32(m,4H),3.63(s,2H),2.93(s,3H),2.74(s,3H),2.48–2.43(m,2H),1.16(d,J＝6.6Hz,6H).

Example 39

4-(3-(6-(6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pyridin-2-yl)-4H-1,2,4-triazol-4-yl)benzonitrile

4- (3- (6- (6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -4H-1,2, 4-triazol-4-yl) benzonitrile

First step

4-(3-(6-bromopyridin-2-yl)-4H-1,2,4-triazol-4-yl)benzonitrile

4- (3- (6-Bromopyridin-2-yl) -4H-1,2, 4-triazol-4-yl) benzonitrile

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (1 g,3.69 mmol) was dissolved in acetonitrile (3 mL) at room temperature, and p-aminobenzonitrile 39a (1.74 g,14.75 mmol) and glacial acetic acid (3 mL) were added thereto, and the mixture was warmed to 95℃and reacted for 40 hours, and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 4- (3- (6-bromopyridin-2-yl) -4H-1,2, 4-triazol-4-yl) benzonitrile 39b (300 mg, 919.82. Mu. Mol) in 24.94% yield.

MS m/z(ESI):325.9[M+1] ⁺

Second step

tert-butyl

((2-(6-(4-(4-cyanophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (4- (4-Cyanophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 4- (3- (6-bromopyridin-2-yl) -4H-1,2, 4-triazol-4-yl) benzonitrile 39b (140.41 mg, 430.49. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and tris (dibenzylidene-BASE acetone) dipalladium (13.14 mg, 14.35. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (16.61 mg, 28.70. Mu. Mol) and potassium phosphate (121.84 mg, 573.99. Mu. Mol) were added in this order and heated to 95℃for 6 hours, and S was monitored to be complete. The reaction solution was filtered by suction, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) successively to give tert-butyl ((2- (6- (4- (4-cyanophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 39d (50 mg, 84.22. Mu. Mol) in a yield of 58.69%.

MS m/z(ESI):594.0[M+1] ⁺

Third step

Tert-butyl ((2- (6- (4- (4-cyanophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 39d (50 mg, 84.22. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (288.09 mg,2.53 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 5 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 4- (3- (6- (6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -4H-1,2, 4-triazol-4-yl) benzonitrile 39 (15 mg, 23.59. Mu. Mol), in 28.01% yield.

MS m/z(ESI):494.2[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.00(brs,2H),8.99(s,1H),8.54(d,J＝8.3Hz,1H),8.11(dd,J＝10.9,8.2Hz,3H),8.02(d,J＝7.6Hz,1H),7.79(d,J＝8.3Hz,2H),6.84(s,1H),5.06–4.93(m,1H),4.15(t,J＝6.1Hz,2H),3.94(s,2H),2.90(s,3H),2.86(t,J＝5.3Hz,3H),1.15(d,J＝6.6Hz,6H).

Example 40

2-(6-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-1-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (5, 6-Dihydro-4H-benzo [ f ] [1,2,4] triazolo [4,3-a ] azepin-1-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-methoxy-4,5-dihydro-3H-benzo[b]azepine

2-Methoxy-4, 5-dihydro-3H-benzo [ b ] azepine

1,3,4, 5-Tetrahydro-2H-benzo [ b ] azepin-2-one 40a (300 mg,1.84 mmol) was dissolved in dichloromethane (10 mL), trimethyloxonium tetrafluoroboric acid (2.72 g,18.38 mmol) was added, the reaction was heated to 30deg.C and stirred for 40 hours, and LCMS monitored the reaction was complete. The reaction was quenched by the addition of saturated sodium bicarbonate solution (10 mL) at 0deg.C, extracted with dichloromethane (10 mL. Times.3), the combined organic phases were washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure after adding glacial acetic acid (0.2 mL) and mixing to give 2-methoxy-4, 5-dihydro-3H-benzo [ b ] azepine 40b (200 mg,1.13 mmol) in 61.39% yield, which was used directly in the next reaction.

MS m/z(ESI):194.1[M+H+18] ⁺

Second step

1-(6-bromopyridin-2-yl)-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepine

1- (6-Bromopyridin-2-yl) -5, 6-dihydro-4H-benzo [ f ] [1,2,4] triazolo [4,3-a ] azepine

6-Bromopyridine formylhydrazine 1b (120 mg, 555.47. Mu. Mol) and 2-methoxy-4, 5-dihydro-3H-benzo [ b ] azepine 40b (196.90 mg,1.11 mmol) were dissolved in acetonitrile (5 mL), glacial acetic acid (667.13 mg,11.11 mmol) was added and heated to 80℃for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 1- (6-bromopyridin-2-yl) -5, 6-dihydro-4H-benzo [ f ] [1,2,4] triazolo [4,3-a ] azepine 40C (130 mg, 381.00. Mu. Mol) in a yield of 68.59%.

MS m/z(ESI):341.0[M+1] ⁺

Third step

tert-butyl

((2-(6-(5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepin-1-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (5, 6-Dihydro-4H-benzo [ f ] [1,2,4] triazolo [4,3-a ] azepin-1-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50.38 mg, 144.59. Mu. Mol) and 1- (6-bromopyridin-2-yl) -5, 6-dihydro-4H-benzo [ f ] [1,2,4] triazolo [4,3-a ] azepine 40c (74 mg, 216.88. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (13.77 mg, 72.29. Mu. Mol), N, N-dimethylethylenediamine (12.75 mg, 144.59. Mu. Mol) and potassium carbonate (59.95 mg, 433.76. Mu. Mol) were added and reacted for 18 hours under argon atmosphere at 100 ℃. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6- (5, 6-dihydro-4H-benzo [ f ] [1,2,4] triazolo [4,3-a ] azepin-1-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 40C (80 mg, 131.42. Mu. Mol), yield 90.89%.

MS m/z(ESI):609.4[M+1] ⁺

Fourth step

Tert-butyl ((2- (6- (5, 6-dihydro-4H-benzo [ f ] [1,2,4] triazolo [4,3-a ] azepin-1-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 40c (80 mg, 131.42. Mu. Mol) was dissolved in dichloromethane (4 mL), and a1, 4-dioxane solution of hydrogen chloride (4M, 32.86. Mu.L) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (5, 6-dihydro-4H-benzo [ f ] [1,2,4] triazolo [4,3-a ] azepin-1-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 40 (75 mg, 114.44. Mu. Mol), in a yield of 87.08%.

MS m/z(ESI):509.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.19(brs,2H),8.48(d,J＝8.4Hz,1H),8.09(t,J＝8.0Hz,1H),7.95(d,J＝7.6Hz,1H),7.66(d,J＝7.5Hz,1H),7.53(t,J＝7.5Hz,1H),7.35(t,J＝7.7Hz,1H),7.19(d,J＝7.9Hz,1H),6.81(s,1H),5.07–4.94(m,1H),4.36–3.92(m,2H),4.00(s,2H),2.89(s,3H),2.83–2.74(m,3H),2.48–2.30(m,4H),2.19(s,2H),1.14(d,J＝6.6Hz,6H).

Example 41

6-(isopropyl(methyl)amino)-2-(6-(4-(4-methoxyphenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -2- (6- (4- (4-methoxyphenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(4-methoxyphenyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (4-methoxyphenyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (300 mg,1.11 mmol) was dissolved in acetonitrile (10 mL) at room temperature, p-methoxyaniline 41a (545.09 mg,4.43 mmol) and glacial acetic acid (1 mL) were added, the mixture was warmed to 95℃and reacted for 18 hours, and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 2-bromo-6- (4- (4-methoxyphenyl) -4H-1,2, 4-triazol-3-yl) pyridine 41b (220 mg, 664.32. Mu. Mol) in a yield of 60.04%.

MS m/z(ESI):331.0[M+1] ⁺

Second step

tert-butyl

((6-(isopropyl(methyl)amino)-2-(6-(4-(4-methoxyphenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -2- (6- (4- (4-methoxyphenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (55 mg, 157.85. Mu. Mol) and 2-bromo-6- (4- (4-methoxyphenyl) -4H-1,2, 4-triazol-3-yl) pyridine 41b (78.41 mg, 236.77. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (15.03 mg, 78.92. Mu. Mol), N, N-dimethylethylenediamine (13.91 mg, 157.85. Mu. Mol) and potassium carbonate (65.45 mg, 473.54. Mu. Mol) were added and reacted under argon atmosphere at 100℃for 6 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (4- (4-methoxyphenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 41C (85 mg, 141.98. Mu. Mol), yield 89.95%.

MS m/z(ESI):599.3[M+1] ⁺

Third step

Tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (4- (4-methoxyphenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 41c (85 mg,141.98 μmol) was dissolved in dichloromethane (5 mL), and a1, 4-dioxane solution of hydrogen chloride (4 m,35.49 μl) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -2- (6- (4- (4-methoxyphenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 41 (40 mg, 65.30. Mu. Mol), in 45.99% yield.

MS m/z(ESI):499.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.95(brs,2H),8.85(s,1H),8.51(d,J＝8.4Hz,1H),8.07(t,J＝8.0Hz,1H),7.98(d,J＝7.6Hz,1H),7.46(d,J＝8.6Hz,2H),7.17(d,J＝8.7Hz,2H),6.83(s,1H),5.07–4.94(m,1H),4.13(t,J＝6.1Hz,2H),4.03(s,2H),3.82(s,3H),2.90(s,3H),2.82(t,J＝5.3Hz,3H),1.15(d,J＝6.6Hz,6H).

Example 42

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(4-(p-tolyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4- (p-tolyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(p-tolyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (p-tolyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (120 mg, 442.62. Mu. Mol) was dissolved in acetonitrile (4 mL) at room temperature, p-aminotoluene 42a (94.86 mg, 885.24. Mu. Mol) and glacial acetic acid (142.86. Mu.L) were added, and the mixture was warmed to 120℃and concentrated under reduced pressure after reaction for 4 hours, and the resulting residue was purified by silica gel column chromatography (eluent: C system) to give 2-bromo-6- (4- (p-tolyl) -4H-1,2, 4-triazol-3-yl) pyridine 42b (100 mg, 317.29. Mu. Mol) in 71.69% yield.

MS m/z(ESI):314.9[M+1] ⁺

Second step

tert-butyl

((6-(isopropyl(methyl)amino)-1-oxo-2-(6-(4-(p-tolyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -1-oxo-2- (6- (4- (p-tolyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (110.56 mg, 317.29. Mu. Mol) and 2-bromo-6- (4- (p-tolyl) -4H-1,2, 4-triazol-3-yl) pyridine 42b (100 mg, 317.29. Mu. Mol) were dissolved in1, 4-dioxane (4 mL), and cuprous iodide (30.14 mg, 158.65. Mu. Mol), N, N-dimethylethylenediamine (13.98 mg, 158.65. Mu. Mol) and potassium carbonate (87.71 mg, 634.58. Mu. Mol) were added and reacted under argon atmosphere at 80℃for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (4- (p-tolyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 42C (0.18 g, 308.91. Mu. Mol), yield 97.36%.

MS m/z(ESI):583.4[M+1] ⁺

Third step

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (4- (p-tolyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 42c (0.18 g, 308.91. Mu. Mol) was dissolved in dichloromethane (10 mL), cooled to 0 ℃, trifluoroacetic acid (105.67 mg, 926.73. Mu. Mol) was added, and the mixture was slowly warmed to room temperature and stirred for 5 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4- (p-tolyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 42 (0.137G, 218.71. Mu. Mol), yield 70.80%.

MS m/z(ESI):483.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.20(brs,2H),8.88(s,1H),8.51(d,J＝8.3Hz,1H),8.07(t,J＝8.0Hz,1H),7.91(d,J＝7.6Hz,1H),7.38(q,J＝8.4Hz,4H),6.83(s,1H),5.06–4.94(m,1H),4.11(t,J＝5.7Hz,2H),4.03(s,2H),2.90(s,3H),2.79(t,J＝5.3Hz,3H),2.41(s,3H),1.14(d,J＝6.7Hz,6H).

Example 43

2-(6-(5,5-dimethyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (5, 5-Dimethyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-chloro-N-(1-hydroxy-2-methylpropan-2-yl)acetamide

2-Chloro-N- (1-hydroxy-2-methylpropan-2-yl) acetamide

2-Amino-2-methylpropan-1-ol 43a (1.5 g,16.83 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to 0 ℃, N-diisopropylethylamine (6.52 g,50.48 mmol) was added, chloroacetyl chloride (2.47 g,21.88mmol,1.74 mL) was slowly added dropwise, the reaction was continued under stirring at 0℃for 3 hours, saturated sodium bicarbonate solution (10 mL) was added to quench the reaction, ethyl acetate (20 mL. Times.3) was extracted, water (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 2-chloro-N- (1-hydroxy-2-methylpropan-2-yl) acetamide 43b (2 g,12.08 mmol), yield 71.76% was directly used for the next reaction.

MS m/z(ESI):166.1[M+1] ⁺

Second step

5,5-dimethylmorpholin-3-one

5, 5-Dimethylmorpholine-3-one

2-Chloro-N- (1-hydroxy-2-methylpropan-2-yl) acetamide 43b (1.8 g,10.87 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to 0deg.C, sodium hydride (1.30 g,32.61mmol,60% oil dispersion) was added and the reaction stirred at 0deg.C for 4 hours. Quench with water (10 mL), extract with ethyl acetate (20 mL. Times.3), combine the organic phases, wash with water (10 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to give 5, 5-dimethylmorpholin-3-one 43c (1 g,7.74 mmol) in 71.24% yield, which is used directly in the next reaction.

MS m/z(ESI):130.2[M+1] ⁺

Third step

5-methoxy-3,3-dimethyl-3,6-dihydro-2H-1,4-oxazine

5-Methoxy-3, 3-dimethyl-3, 6-dihydro-2H-1, 4-oxazine

5, 5-Dimethylmorpholine-3-one 43c (300 mg,2.32 mmol) was dissolved in dichloromethane (10 mL), trimethyloxonium tetrafluoroboric acid (3.44 g,23.23 mmol) was added, the reaction was stirred at 25℃for 24 hours, LCMS was monitored to complete the reaction, saturated sodium bicarbonate solution (10 mL) was added at 0℃to quench the reaction, dichloromethane (10 mL. Times.3) was extracted, the organic phases were combined, washed with water (10 mL) and dried over anhydrous sodium sulfate, filtered, glacial acetic acid (0.5 mL) was added to mix well and concentrated under reduced pressure to give 5-methoxy-3, 3-dimethyl-3, 6-dihydro-2H-1, 4-oxazine 43d (266 mg,1.86 mmol), yield 79.98% was used directly in the next reaction.

MS m/z(ESI):144.1[M+1] ⁺

Fourth step

3-(6-bromopyridin-2-yl)-5,5-dimethyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazine

3- (6-Bromopyridin-2-yl) -5, 5-dimethyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazine

6-Bromopyridine formylhydrazine 1b (200 mg, 925.78. Mu. Mol) and 5-methoxy-3, 3-dimethyl-3, 6-dihydro-2H-1, 4-oxazine 43d (265.11 mg,1.85 mmol) were dissolved in acetonitrile (6 mL), glacial acetic acid (555.94 mg,9.26 mmol) was added, and the mixture was heated to 80℃for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-C ] [1,4] oxazine 43e (70 mg, 226.42. Mu. Mol) in 24.46% yield.

MS m/z(ESI):308.9[M+1] ⁺

Fifth step

tert-butyl

((2-(6-(5,5-dimethyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (5, 5-Dimethyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazine 43e (62.11 mg, 200.90. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (13.66 mg, 71.75. Mu. Mol), N, N-dimethylethylenediamine (12.65 mg, 143.50. Mu. Mol) and potassium carbonate (79.33 mg, 573.99. Mu. Mol) were added and heated under argon atmosphere to 100℃for reaction for 10 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6- (5, 5-dimethyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-C ] [1,4] oxazin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 43f (75 mg, 130.05. Mu. Mol) in a yield of 90.63%.

MS m/z(ESI):577.0[M+1] ⁺

Sixth step

Tert-butyl ((2- (6- (5, 5-dimethyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 43f (75 mg, 130.05. Mu. Mol) was dissolved in dichloromethane (5 mL), and a 1, 4-dioxane solution of hydrogen chloride (4M, 975.40. Mu. L) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (5, 5-dimethyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 43 (60 mg, 98.94. Mu. Mol), yield 76.08%.

MS m/z(ESI):477.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.93(brs,2H),8.69(d,J＝8.5Hz,1H),8.13(t,J＝8.0Hz,1H),7.66(d,J＝7.5Hz,1H),6.92(s,1H),5.07(s,2H),5.02(s,2H),4.32(t,J＝6.0Hz,2H),3.73(s,2H),2.93(s,3H),2.71(t,J＝5.3Hz,3H),1.53(s,6H),1.16(d,J＝6.6Hz,6H).

Example 44

2-(6-(4-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (4- (Bicyclo [4.2.0] oct-1, 3, 5-trien-3-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-(4-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-4H-1,2,4-triazol-3-yl)-6-bromopyridine

2- (4- (Bicyclo [4.2.0] oct-1, 3, 5-trien-3-yl) -4H-1,2, 4-triazol-3-yl) -6-bromopyridine

(E) -N' - (6-bromopyridine formyl) -N, N-dimethylformamide 9a (300 mg,1.11 mmol) was dissolved in acetonitrile (8 mL) at room temperature, bicyclo [4.2.0] octa-1 (6), 2, 4-trien-3-amine 44a (94.86 mg, 885.24. Mu. Mol, prepared according to published patent WO 2018057973A 1) and glacial acetic acid (1.5 mL) were added, and the mixture was warmed to 95℃and concentrated under reduced pressure after reaction for 18 hours, and the resulting residue was purified by silica gel column chromatography (eluent: C system) to give 2- (4- (bicyclo [4.2.0] octa-1, 3, 5-trien-3-yl) -4H-1,2, 4-triazol-3-yl) -6-bromopyridine 44b (200 mg, 611.29. Mu. Mol), yield 55.24%.

MS m/z(ESI):327.0[M+1] ⁺

Second step

tert-butyl

((2-(6-(4-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (4- (Bicyclo [4.2.0] oct-1, 3, 5-trien-3-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (55 mg, 157.85. Mu. Mol) and 2- (4- (bicyclo [4.2.0] octa-1, 3, 5-trien-3-yl) -4H-1,2, 4-triazol-3-yl) -6-bromopyridine 44b (103.29 mg, 315.69. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (15.03 mg, 78.92. Mu. Mol), N, N-dimethylethylenediamine (13.91 mg, 157.85. Mu. Mol) and potassium carbonate (87.26 mg, 631.39. Mu. Mol) were added and reacted under argon atmosphere at 100℃for 10 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6- (4- (bicyclo [4.2.0] oct-1, 3, 5-trien-3-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 44C (80 mg, 134.52. Mu. Mol), yield 85.22%.

MS m/z(ESI):595.0[M+1] ⁺

Third step

Tert-butyl ((2- (6- (4- (bicyclo [4.2.0] oct-1, 3, 5-trien-3-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 44c (80 mg, 134.52. Mu. Mol) was dissolved in dichloromethane (5 mL), and a1, 4-dioxane solution of hydrogen chloride (4M, 1.01 mL) was added and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (4- (bicyclo [4.2.0] oct-1, 3, 5-trien-3-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 44 (30 mg, 49.21. Mu. Mol), in a yield of 36.58%.

MS m/z(ESI):495.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.14(brs,2H),8.86(s,1H),8.52(d,J＝8.4Hz,1H),8.07(t,J＝8.0Hz,1H),7.90(d,J＝7.6Hz,1H),7.42–7.31(m,2H),7.16(s,1H),6.84(s,1H),5.08–4.93(m,1H),4.14(t,J＝5.9Hz,2H),4.10(s,2H),3.26–3.19(m,2H),3.19–3.12(m,2H),2.90(s,3H),2.77(t,J＝5.4Hz,3H),1.15(d,J＝6.6Hz,6H).

Example 45

(S)-6-(isopropyl(methyl)amino)-2-(6-(5-isopropyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(S) -6- (isopropyl (methyl) amino) -2- (6- (5-isopropyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

(S)-3-isopropyl-5-methoxy-3,6-dihydro-2H-1,4-oxazine

(S) -3-isopropyl-5-methoxy-3, 6-dihydro-2H-1, 4-oxazine

(S) -5-Isopropylmorpholin-3-one 45a (300 mg,2.32mmol, prepared according to published patent WO 2016161279A 1) was dissolved in dichloromethane (10 mL), trimethyloxonium tetrafluoroboric acid (2.05 g,13.97 mmol) was added and the reaction was stirred at 25℃for 24 hours and monitored by LCMS for completion. The reaction was quenched by addition of saturated sodium bicarbonate solution (10 mL) at 0deg.C, extracted with dichloromethane (10 mL. Times.3), the organic phases were combined, washed with water (10 mL) and dried over anhydrous sodium sulfate, filtered, and glacial acetic acid (0.5 mL) was added, mixed well and concentrated under reduced pressure to give (S) -3-isopropyl-5-methoxy-3, 6-dihydro-2H-1, 4-oxazine 45b (0.5 g,3.18 mmol) in 91.08% yield, which was used directly in the next reaction.

MS m/z(ESI):158.1[M+1] ⁺

Second step

(S)-3-(6-bromopyridin-2-yl)-5-isopropyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazine

(S) -3- (6-bromopyridin-2-yl) -5-isopropyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazine

6-Bromopyridine formylhydrazine 1b (687.09 mg,3.18 mmol) and (S) -3-isopropyl-5-methoxy-3, 6-dihydro-2H-1, 4-oxazine 45b (0.5 g,3.18 mmol) were dissolved in acetonitrile (10 mL), glacial acetic acid (0.5 mL) was added, and the mixture was heated to 80℃for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give (S) -3- (6-bromopyridin-2-yl) -5-isopropyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-C ] [1,4] oxazine 45C (950 mg,2.94 mmol) in 92.42% yield.

MS m/z(ESI):323.1[M+1] ⁺

Third step

tert-butyl

(S)-((6-(isopropyl(methyl)amino)-2-(6-(5-isopropyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(S) - ((6- (isopropyl (methyl) amino) -2- (6- (5-isopropyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (86.25 mg, 247.53. Mu. Mol) and (S) -3- (6-bromopyridin-2-yl) -5-isopropyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazine 45c (80 mg, 247.53. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (23.52 mg, 123.77. Mu. Mol), N, N-dimethylethylenediamine (10.91 mg, 123.77. Mu. Mol) and potassium carbonate (68.42 mg, 495.07. Mu. Mol) were added and reacted under argon atmosphere at 80℃for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl (S) - ((6- (isopropyl (methyl) amino) -2- (6- (5-isopropyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-C ] [1,4] oxazin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 45d (0.1 g, 169.29. Mu. Mol), yield 68.39%.

MS m/z(ESI):591.4[M+1] ⁺

Fourth step

(S) - ((6- (isopropyl (methyl) amino) -2- (6- (5-isopropyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 45d (0.1 g, 169.29. Mu. Mol) was dissolved in dichloromethane (10 mL), cooled to 0℃and trifluoroacetic acid (57.91 mg, 507.86. Mu. Mol) was added and stirred for 3 hours after slowly warming to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give (S) -6- (isopropyl (methyl) amino) -2- (6- (5-isopropyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 45 (34 mg, 53.33. Mu. Mol), yield 31.50%.

MS m/z(ESI):491.4[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.04(brs,2H),8.59(d,J＝8.2Hz,1H),8.11(t,J＝8.0Hz,1H),8.04(d,J＝7.6Hz,1H),6.92(s,1H),5.23(d,J＝16.6Hz,1H),5.12(d,J＝15.4Hz,1H),5.12–5.08(m,1H),5.07–4.99(m,1H),4.95(d,J＝9.9Hz,1H),4.91(d,J＝8.6Hz,1H),4.43–4.23(m,3H),3.98(dd,J＝12.8,3.6Hz,1H),2.93(s,3H),2.75–2.70(m,3H),2.00(q,J＝7.1,6.6Hz,1H),1.16(d,J＝6.6Hz,6H),0.97(d,J＝6.9Hz,3H),0.69(d,J＝7.0Hz,3H).

Example 46

(S)-2-(6-(5-ethyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(S) -2- (6- (5-ethyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

(S)-3-ethyl-5-methoxy-3,6-dihydro-2H-1,4-oxazine

(S) -3-ethyl-5-methoxy-3, 6-dihydro-2H-1, 4-oxazine

(S) -5-ethylmorpholin-3-one 46a (400 mg,3.10mmol, prepared according to published patent WO 2008019372A 2) was dissolved in dichloromethane (12 mL), trimethyloxonium tetrafluoroboric acid (4.58 g,30.97 mmol) was added, the temperature was raised to 28 ℃, the reaction was stirred for 40 hours, and the completion of the reaction was monitored by LCMS. The reaction was quenched by addition of saturated sodium bicarbonate solution (15 mL) at 0deg.C, extracted with dichloromethane (15 mL. Times.3), the organic phases were combined, washed with water (15 mL) and dried over anhydrous sodium sulfate, filtered, and glacial acetic acid (0.5 mL) was added, mixed well and concentrated under reduced pressure to give (S) -3-ethyl-5-methoxy-3, 6-dihydro-2H-1, 4-oxazine 46b (266 mg,1.86 mmol) in 59.99% yield, which was used directly in the next reaction.

MS m/z(ESI):162.1[M+H+18] ⁺

Second step

(S)-3-(6-bromopyridin-2-yl)-5-ethyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazine

(S) -3- (6-bromopyridin-2-yl) -5-ethyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazine

6-Bromopyridine formylhydrazine 1b (200 mg, 925.78. Mu. Mol) and (S) -3-ethyl-5-methoxy-3, 6-dihydro-2H-1, 4-oxazine 46b (265.11 mg,1.85 mmol) were dissolved in acetonitrile (6 mL), glacial acetic acid (0.2 mL) was added, and the mixture was heated to 80℃for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give (S) -3- (6-bromopyridin-2-yl) -5-ethyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-C ] [1,4] oxazine 46C (66 mg, 213.48. Mu. Mol) in 23.06% yield.

MS m/z(ESI):308.9[M+1] ⁺

Third step

tert-butyl

(S)-((2-(6-(5-ethyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(S) - ((2- (6- (5-ethyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (40 mg, 114.80. Mu. Mol) and (S) -3- (6-bromopyridin-2-yl) -5-ethyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazine 46c (53.24 mg, 172.20. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (10.93 mg, 57.40. Mu. Mol), N, N-dimethylethylenediamine (10.12 mg, 114.80. Mu. Mol) and potassium carbonate (63.46 mg, 459.19. Mu. Mol) were added and heated to 100℃under argon atmosphere for reaction for 10 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl (S) - ((2- (6- (5-ethyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-C ] [1,4] oxazin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 46d (35 mg, 60.69. Mu. Mol), yield 52.87%.

MS m/z(ESI):577.4[M+1] ⁺

Fourth step

(S) - ((2- (6- (5-ethyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 46d (35 mg, 60.69. Mu. Mol) was dissolved in dichloromethane (4 mL), and a 1, 4-dioxane solution of hydrogen chloride (4M, 455.19. Mu.L) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give (S) -2- (6- (5-ethyl-5, 6-dihydro-8H- [1,2,4] triazolo [3,4-c ] [1,4] oxazin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 46 (13 mg, 21.82. Mu. Mol), yield 35.96%.

MS m/z(ESI):477.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.94(brs,2H),8.62(d,J＝8.3Hz,1H),8.12(t,J＝8.0Hz,1H),8.04(d,J＝7.6Hz,1H),6.92(s,1H),5.21(d,J＝16.6Hz,1H),5.14(d,J＝15.4Hz,1H),5.14–5.00(m,2H),4.96(t,J＝15.8Hz,2H),4.44–4.26(m,2H),4.20(d,J＝12.3Hz,1H),3.98(dd,J＝12.4,3.1Hz,1H),2.93(s,3H),2.74(t,J＝5.4Hz,3H),2.03–1.86(m,1H),1.84–1.71(m,1H),1.17(d,J＝6.7Hz,6H),0.93(t,J＝7.4Hz,3H).

Example 47

2-(6-(5,5-dimethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (5, 5-Dimethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

6,6-dimethylpiperidin-2-one

6, 6-Dimethylpiperidin-2-one 47b

3,3-dimethylpiperidin-2-one

3, 3-Dimethylpiperidin-2-one 47c

2, 2-Dimethylcyclopentan-1-one 47a (4.5 g,40.12 mmol) was dissolved in formic acid (45 mL), and hydroxylamine sulfonic acid (6.81 g,60.18mmol,3.09 mL) was added in portions, heated to 100℃and reacted with stirring for 20 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, the residue was diluted with water (100 mL), pH was adjusted to more than 7 with 4M sodium hydroxide solution at 0℃and the aqueous phase was extracted with methylene chloride (150 mL. Times.3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a mixture (4.27 g,33.57 mmol) of 6, 6-dimethylpiperidin-2-one 47b and 3, 3-dimethylpiperidin-2-one 47c in a yield of 83.69% which was directly used in the next reaction.

47b MS m/z(ESI):128.1[M+1] ⁺

47c MS m/z(ESI):128.1[M+1] ⁺

Second step

6-methoxy-2,2-dimethyl-2,3,4,5-tetrahydropyridine

6-Methoxy-2, 2-dimethyl-2, 3,4, 5-tetrahydropyridine 47d

6-methoxy-5,5-dimethyl-2,3,4,5-tetrahydropyridine

6-Methoxy-5, 5-dimethyl-2, 3,4, 5-tetrahydropyridine 47e

The reaction mixture from the previous step (4.60 g,36.19 mmol) was dissolved in dichloromethane (100 mL), cooled to 0deg.C, added in portions with trimethyloxonium tetrafluoroborate (16.06 g,108.58 mmol), stirred for 48 hours after warming to room temperature, LCMS monitored the completion of the reaction, quenched with saturated sodium bicarbonate solution (100 mL) at 0deg.C, extracted with dichloromethane (150 mL. Times.3), the organic phases combined, washed with water (100 mL) and dried over anhydrous sodium sulfate, filtered, added with glacial acetic acid (2 mL) and concentrated under reduced pressure after mixing to give a mixture of 6-methoxy-2, 2-dimethyl-2, 3,4, 5-tetrahydropyridine 47d and 6-methoxy-5, 5-dimethyl-2, 3,4, 5-tetrahydropyridine 47e (5.1 g,18.06 mmol), 99.80% yield, which was used directly in the next step.

47d MS m/z(ESI):142.1[M+1] ⁺

47e MS m/z(ESI):142.1[M+1] ⁺

Third step

3-(6-bromopyridin-2-yl)-5,5-dimethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine

3- (6-Bromopyridin-2-yl) -5, 5-dimethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine 47f

3-(6-bromopyridin-2-yl)-8,8-dimethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine

47G of 3- (6-bromopyridin-2-yl) -8, 8-dimethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine

6-Bromopyridine formylhydrazine 1b (1.5 g,6.94 mmol) and the reaction mixture of the previous step (5.1 g,18.06 mmol) were dissolved in acetonitrile (100 mL), glacial acetic acid (416.95 mg,6.94 mmol) was added and heated to 95℃for 48 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine 47f (720 mg,2.34 mmol), yield 33.76%; 47g (308 mg,1.00 mmol) of 3- (6-bromopyridin-2-yl) -8, 8-dimethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine was obtained in a yield of 14.44%.

47f MS m/z(ESI):307.0[M+1] ⁺

47g MS m/z(ESI):307.0[M+1] ⁺

Fourth step

tert-butyl

((2-(6-(5,5-dimethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (5, 5-Dimethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridine 47f (52.90 mg, 172.20. Mu. Mol) were dissolved in1, 4-dioxane (2.5 mL), and cuprous iodide (27.33 mg, 143.50. Mu. Mol), N, N-dimethylethylenediamine (25.30 mg, 286.99. Mu. Mol) and potassium carbonate (59.50 mg, 430.49. Mu. Mol) were added and heated to 70℃under argon atmosphere for reaction for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6- (5, 5-dimethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 47H (89 mg, 136.55. Mu. Mol) in 95.16% yield.

MS m/z(ESI):575.4[M+1] ⁺

Fifth step

Tert-butyl ((2- (6- (5, 5-dimethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 47H (80 mg,139.20 μmol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (1.59 g,13.92 mmol) was added, and stirred slowly to room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (5, 5-dimethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyridin-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 47 (30 mg, 50.23. Mu. Mol), in a yield of 36.08%.

MS m/z(ESI):475.1[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.01(d,J＝8.8Hz,2H),8.71(d,J＝8.5Hz,1H),8.18–8.09(m,1H),7.56(d,J＝7.4Hz,1H),6.91(s,1H),5.04(s,3H),4.30(t,J＝6.0Hz,2H),3.00(t,J＝6.5Hz,2H),2.92(s,3H),2.70(t,J＝5.4Hz,3H),2.03–1.92(m,2H),1.93–1.83(m,2H),1.50(s,6H),1.16(d,J＝6.6Hz,6H).

Example 48

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

tert-butyl 5-methoxy-3,6-dihydropyrazine-1(2H)-carboxylate

5-Methoxy-3, 6-dihydropyrazine-1 (2H) -carboxylic acid tert-butyl ester

3-Oxopyrazine-1-carboxylic acid tert-butyl ester 48a (500 mg,2.50 mmol) was dissolved in dichloromethane (12 mL), trimethyloxonium tetrafluoroboric acid (2.20 g,14.98 mmol) was added, the reaction was stirred at room temperature for 18 hours, LCMS was monitored to complete the reaction, saturated aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction, dichloromethane (10 mL. Times.3) was extracted, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, and glacial acetic acid (0.5 mL) was added to mix well and concentrated under reduced pressure to give 5-methoxy-3, 6-dihydropyrazine-1 (2H) -carboxylic acid tert-butyl ester 48b (0.5 g,2.33 mmol), yield 93.45% was used directly in the next reaction. MS m/z (ESI): 215.1[ M+1] ⁺

Second step

tert-butyl 3-(6-bromopyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate

3- (6-Bromopyridin-2-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester

6-Bromopyridine formylhydrazine 1b (504.14 mg,2.33 mmol) and 5-methoxy-3, 6-dihydropyrazine-1 (2H) -carboxylic acid tert-butyl ester 48b (0.5 g,2.33 mmol) were dissolved in dimethyl sulfoxide (20 mL), heated to 95℃and reacted for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl 3- (6-bromopyridin-2-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazine-7 (8H) -carboxylate 48C (0.5 g,1.31 mmol) in 56.35% yield.

MS m/z(ESI):380.1[M+1] ⁺

Third step

tert-butyl

3-(6-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-(isopropyl(methyl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate

3- (6- (4- (((Tert-Butoxycarbonyl) (methyl) amino) methyl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (91.64 mg, 262.99. Mu. Mol) and tert-butyl 3- (6-bromopyridin-2-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazine-7 (8H) -carboxylate 48c (100 mg, 262.99. Mu. Mol) were dissolved in1, 4-dioxane (4 mL), and cuprous iodide (24.98 mg, 131.50. Mu. Mol), N, N-dimethylethylenediamine (11.59 mg, 131.50. Mu. Mol) and potassium carbonate (72.70 mg, 525.98. Mu. Mol) were added and reacted for 10 hours under argon atmosphere at 100 ℃. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl 3- (6- (4- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-C ] pyridin-2-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazine-7 (8H) -carboxylate 48d (0.156 g, 240.83. Mu. Mol), yield 91.57%.

MS m/z(ESI):648.5[M+1] ⁺

Fourth step

3- (6- (4- (((Tert-Butoxycarbonyl) (methyl) amino) methyl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester 48d (156 mg, 240.83. Mu. Mol) was dissolved in dichloromethane (10 mL), cooled to 0deg.C, and trifluoroacetic acid (82.38 mg, 722.48. Mu. Mol) was added, followed by stirring for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 48 (45 mg, 74.02. Mu. Mol), yield 30.73%.

MS m/z(ESI):448.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.08(brs,2H),8.60(d,J＝8.3Hz,1H),8.36(brs,1H),8.12(t,J＝8.0Hz,1H),8.01(d,J＝7.6Hz,1H),6.91(s,1H),5.14(s,2H),5.10–4.94(m,1H),4.70(t,J＝5.7Hz,2H),4.45(s,2H),4.38(s,2H),3.50(s,2H),2.93(s,3H),2.75(s,3H),1.16(t,J＝6.6Hz,6H).

Example 49

2-(6-(4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (4- (2-Fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (2-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (150 mg, 553.27. Mu. Mol) was dissolved in acetonitrile (10 mL) at room temperature, 2-fluoroaniline 49a (122.96 mg,1.11 mmol) and glacial acetic acid (0.3 mL) were added, and the mixture was warmed to 90℃and reacted for 16 hours, and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 2-bromo-6- (4- (2-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine 49b (85 mg, 266.35. Mu. Mol) in 48.14% yield.

MS m/z(ESI):319.0[M+1] ⁺

Second step

tert-butyl

((2-(6-(4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (4- (2-Fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (92.81 mg, 266.35. Mu. Mol) and 2-bromo-6- (4- (2-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine 49b (85 mg, 266.35. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (10.12 mg, 53.27. Mu. Mol), N, N-dimethylethylenediamine (4.70 mg, 53.27. Mu. Mol) and potassium carbonate (110.44 mg, 799.04. Mu. Mol) were added and reacted under argon atmosphere at 80℃for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6- (4- (2-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 49C (86 mg, 146.59. Mu. Mol), yield 55.04%.

MS m/z(ESI):587.4[M+1] ⁺

Third step

Tert-butyl ((2- (6- (4- (2-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 49c (45 mg, 76.71. Mu. Mol) was dissolved in dichloromethane (10 mL), cooled to 0 ℃, trifluoroacetic acid (26.24 mg, 230.12. Mu. Mol) was added, and the mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (4- (2-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 49 (45 mg, 69.42. Mu. Mol), in 90.50% yield.

MS m/z(ESI):487.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.07(brs,2H),8.97(s,1H),8.54(dd,J＝7.8,1.5Hz,1H),8.15–8.05(m,2H),7.82–7.70(m,2H),7.63–7.52(m,2H),6.82(s,1H),5.07–4.92(m,1H),4.13(s,2H),3.85(s,2H),2.90(s,3H),2.85(s,3H),1.14(d,J＝6.6Hz,6H).

Example 50

2-(6-(4-(3-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (4- (3-Fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(3-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (3-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (150 mg, 553.27. Mu. Mol) was dissolved in acetonitrile (10 mL) at room temperature, 3-fluoroaniline 50a (92.22 mg, 829.91. Mu. Mol) and glacial acetic acid (0.3 mL) were added, and the mixture was warmed to 90℃and concentrated under reduced pressure after reaction for 16 hours, and the resulting residue was purified by silica gel column chromatography (eluent: C system) to give 2-bromo-6- (4- (3-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine 50b (104 mg, 325.88. Mu. Mol) in a yield of 58.90%.

MS m/z(ESI):319.0[M+1] ⁺

Second step

tert-butyl

((2-(6-(4-(3-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (4- (3-Fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (113.55 mg, 325.88. Mu. Mol) and 2-bromo-6- (4- (3-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine 50b (104 mg, 325.88. Mu. Mol) were dissolved in1, 4-dioxane (3 mL), and cuprous iodide (30.96 mg, 162.94. Mu. Mol), N, N-dimethylethylenediamine (14.36 mg, 162.94. Mu. Mol) and potassium carbonate (225.20 mg,1.63 mmol) were added and reacted under argon atmosphere at 80℃for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6- (4- (3-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 50C (50 mg, 85.23. Mu. Mol), yield 26.15%.

MS m/z(ESI):587.4[M+1] ⁺

Third step

Tert-butyl ((2- (6- (4- (3-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 50c (50 mg, 85.23. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (29.15 mg, 255.69. Mu. Mol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (4- (3-fluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 50 (5 mg, 7.09. Mu. Mol), in 8.32% yield.

MS m/z(ESI):487.3[M+1] ⁺

Example 51

2-(6-(4-(3,3-difluorocyclobutyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (4- (3, 3-Difluorocyclobutyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(3,3-difluorocyclobutyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (3, 3-difluorocyclobutyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (100 mg, 368.85. Mu. Mol, prepared according to WO2020100027A 1) was dissolved in acetonitrile (10 mL) at room temperature, 3-difluorocyclobutane 51a (52.67 mg, 491.80. Mu. Mol) and glacial acetic acid (0.1 mL) were added, and the mixture was warmed to 80℃and reacted for 16 hours, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: C system) to give 2-bromo-6- (4- (3, 3-difluorocyclobutyl) -4H-1,2, 4-triazol-3-yl) pyridine 51b (35 mg, 111.07. Mu. Mol), yield 45.17%.

MS m/z(ESI):315.0[M+1] ⁺

Second step

tert-butyl

((2-(6-(4-(3,3-difluorocyclobutyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (4- (3, 3-Difluorocyclobutyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (38.70 mg, 111.07. Mu. Mol) and 2-bromo-6- (4- (3, 3-difluorocyclobutyl) -4H-1,2, 4-triazol-3-yl) pyridine 51b (35 mg, 111.07. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (10.55 mg, 55.54. Mu. Mol), N, N-dimethylethylenediamine (48.95 mg, 555.35. Mu. Mol) and potassium carbonate (30.70 mg, 222.14. Mu. Mol) were added and reacted for 2 hours under argon atmosphere at 80 ℃. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6- (4- (3, 3-difluorocyclobutyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 51C (50 mg, 85.82. Mu. Mol) in a yield of 77.26%.

MS m/z(ESI):583.4[M+1] ⁺

Third step

Tert-butyl ((2- (6- (4- (3, 3-difluorocyclobutyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 51c (50 mg, 85.82. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (29.35 mg, 257.45. Mu. Mol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (4- (3, 3-difluorocyclobutyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 51 (40 mg, 58.49. Mu. Mol) in a yield of 68.16%.

MS m/z(ESI):483.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.13(s,1H),8.94(brs,2H),8.63(d,J＝8.3Hz,1H),8.13(t,J＝8.0Hz,1H),8.01(d,J＝7.6Hz,1H),6.93(s,1H),5.91–5.78(m,1H),5.14(s,2H),5.09–4.98(m,1H),4.28(t,J＝5.9Hz,2H),3.43–3.18(m,4H),2.93(s,3H),2.72(t,J＝5.3Hz,3H),1.17(d,J＝6.6Hz,6H).

Example 52

4-(2-aminopropan-2-yl)-2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

4- (2-Aminopropane-2-yl) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

4-(2-aminopropan-2-yl)-6-(isopropyl(methyl)amino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

4- (2-Aminopropane-2-yl) -6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

6- (Isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carbonitrile 52a (500 mg,2.17mmol, prepared according to published patent WO 2021220185A 1) was dissolved in tetrahydrofuran (10 mL), a solution of lanthanum (III) bis (lithium chloride) complex in tetrahydrofuran (0.6M, 10.86mL,6.52 mmol) was added dropwise under argon, stirred at room temperature for 30 min, cooled to-78℃and then stirred for 8 hours at-78℃with an ether solution of methyllithium (1.3M, 10.02mL,13.03 mmol), quenched by a saturated ammonium chloride solution (15 mL) and diluted with dichloromethane (30 mL), stirred for 10 min, filtered, the filtrate was extracted with dichloromethane (15 mL. Times 3), washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue obtained was purified by column chromatography on silica gel (eluent: B) purification to give 4- (2-aminopropane-2-yl) -6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 52B (120 mg, 457.40. Mu. Mol), 21.06% yield.

MS m/z(ESI):263.0[M+1] ⁺

Second step

tert-butyl

(2-(6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propan-2-yl)carbamate

(2- (6- (Isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) propan-2-yl) carbamic acid tert-butyl ester

4- (2-Aminopropane-2-yl) -6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-1-one 52b (120 mg, 457.40. Mu. Mol) was dissolved in tetrahydrofuran (10 mL), triethylamine (138.85 mg,1.37 mmol) and di-tert-butyl dicarbonate (149.74 mg, 686.11. Mu. Mol) were added, the reaction mixture was stirred at 25℃for 4 hours, and the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl (2- (6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) propan-2-yl) carbamate 52C (60 mg, 165.53. Mu. Mol), yield 36.19%.

MS m/z(ESI):363.0[M+1] ⁺

Third step

tert-butyl

(2-(2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propan-2-yl)carbamate

(2- (2- (6- (5, 5-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) propan-2-yl) carbamic acid tert-butyl ester

Tert-butyl (2- (6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) propan-2-yl) carbamate 52c (50 mg, 137.94. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 27c (56.62 mg, 193.12. Mu. Mol) were dissolved in1, 4-dioxane (6 mL), and cuprous iodide (13.14 mg, 68.97. Mu. Mol), N, N-dimethylethylenediamine (12.16 mg, 137.94. Mu. Mol) and potassium carbonate (76.26 mg, 551.78. Mu. Mol) were added and reacted under argon atmosphere at 100℃for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl (2- (2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) propan-2-yl) carbamate 52d (50 mg, 87.00. Mu. Mol), yield 63.07%.

MS m/z(ESI):575.0[M+1] ⁺

Fourth step

Tert-butyl (2- (2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) propan-2-yl) carbamate 52d (50 mg, 87.00. Mu. Mol) was dissolved in dichloromethane (5 mL), and a1, 4-dioxane solution of hydrogen chloride (4M, 870.00. Mu.L) was added and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 4- (2-aminopropane-2-yl) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 52 (38 mg, 63.96. Mu. Mol), yield 73.51%.

MS m/z(ESI):475.4[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.64(d,J＝8.3Hz,1H),8.29(brs,3H),8.09(t,J＝8.0Hz,1H),7.98(d,J＝7.5Hz,1H),6.96(s,1H),5.29(s,2H),4.98–4.88(m,1H),3.02(t,J＝7.5Hz,2H),2.95(s,3H),2.61(t,J＝7.6Hz,2H),1.76(s,6H),1.67(s,6H),1.18(d,J＝6.6Hz,6H).

Example 53

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(4-(4-oxocyclohexyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4- (4-oxocyclohexyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

4-(3-(6-bromopyridin-2-yl)-4H-1,2,4-triazol-4-yl)cyclohexan-1-one

4- (3- (6-Bromopyridin-2-yl) -4H-1,2, 4-triazol-4-yl) cyclohexan-1-one

(E) -N' - (6-bromopyridyl-formyl) -N, N-dimethylformamide 9a (119.80 mg, 441.86. Mu. Mol) was dissolved in acetonitrile (10 mL), 4-aminocyclohexane-1-one 53a (50 mg, 441.86. Mu. Mol) and glacial acetic acid (0.1 mL) were added, the mixture was warmed to 85℃and reacted for 16 hours, and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 4- (3- (6-bromopyridin-2-yl) -4H-1,2, 4-triazol-4-yl) cyclohexane-1-one 53b (54 mg, 168.13. Mu. Mol), yield 38.05%.

MS m/z(ESI):321.1[M+1] ⁺

Second step

tert-butyl

((6-(isopropyl(methyl)amino)-1-oxo-2-(6-(4-(4-oxocyclohexyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(6- (Isopropyl (methyl) amino) -1-oxo-2- (6- (4- (4-oxocyclohexyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (86.79 mg, 249.09. Mu. Mol) and 4- (3- (6-bromopyridin-2-yl) -4H-1,2, 4-triazol-4-yl) cyclohexane-1-one 53b (80 mg, 249.09. Mu. Mol) were dissolved in1, 4-dioxane (6 mL), and cuprous iodide (23.66 mg, 124.54. Mu. Mol), N, N-dimethylethylenediamine (21.96 mg, 249.09. Mu. Mol) and potassium carbonate (17.21 mg, 124.54. Mu. Mol) were added and reacted for 2 hours under argon atmosphere at 85 ℃. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (4- (4-oxocyclohexyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 53C (30 mg, 50.96. Mu. Mol), yield 20.46%.

MS m/z(ESI):589.4[M+1] ⁺

Third step

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (4- (4-oxocyclohexyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 53c (30 mg,50.96 μmol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (17.43 mg,152.88 μmol) was added, and the mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4- (4-oxocyclohexyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 53 (5 mg, 7.95. Mu. Mol), in 15.60% yield.

MS m/z(ESI):489.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.00(s,1H),8.69(d,J＝8.3Hz,1H),8.19–8.12(m,1H),7.94(d,J＝7.5Hz,1H),6.92(s,1H),5.32(t,J＝4.7Hz,2H),5.19(s,2H),4.23(s,2H),2.93(s,3H),2.67(s,3H),2.46–2.30(m,4H),2.04–1.94(m,4H),1.16(d,J＝6.6Hz,6H).

Example 54

6-(isopropyl(methyl)amino)-2-(6-(4-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -2- (6- (4- (1-methyl-1H-pyrazol-4-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (1-methyl-1H-pyrazol-4-yl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (200 mg, 737.70. Mu. Mol) was dissolved in acetonitrile (7.5 mL) at room temperature, 1-methyl-1H-pyrazol-4-amine 54a (286.6 mg,2.95 mmol) and glacial acetic acid (1.5 mL) were added, the mixture was warmed to 80℃and reacted for 18 hours, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: C system) to give 2-bromo-6- (4- (1-methyl-1H-pyrazol-4-yl) -4H-1,2, 4-triazol-3-yl) pyridine 54b (80 mg, 262.18. Mu. Mol) in a yield of 35.54%.

MS m/z(ESI):305.0[M+1] ⁺

Second step

tert-butyl

((6-(isopropyl(methyl)amino)-2-(6-(4-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -2- (6- (4- (1-methyl-1H-pyrazol-4-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 2-bromo-6- (4- (1-methyl-1H-pyrazol-4-yl) -4H-1,2, 4-triazol-3-yl) pyridine 54b (70.06 mg, 229.60. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (13.66 mg, 71.75. Mu. Mol), N, N-dimethylethylenediamine (12.65 mg, 143.50. Mu. Mol) and potassium carbonate (19.83 mg, 143.50. Mu. Mol) were added and reacted for 5 hours under argon atmosphere at 100 ℃. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (4- (1-methyl-1H-pyrazol-4-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 54C (70 mg, 122.24. Mu. Mol), in a yield of 85.18%.

MS m/z(ESI):573.0[M+1] ⁺

Third step

Tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (4- (1-methyl-1H-pyrazol-4-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 54c (70 mg,122.24 μmol) was dissolved in dichloromethane (5 mL), and a1, 4-dioxane solution of hydrogen chloride (4 m,1.22 mL) was added thereto and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -2- (6- (4- (1-methyl-1H-pyrazol-4-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 54 (50 mg, 83.41. Mu. Mol), yield 68.24%.

MS m/z(ESI):473.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.99(brs,2H),8.80(s,1H),8.55(d,J＝8.4Hz,1H),8.10(d,J＝2.4Hz,1H),8.06(d,J＝8.1Hz,1H),7.95(d,J＝7.6Hz,1H),7.88(s,1H),6.87(s,1H),5.09–4.97(m,1H),4.40–4.29(m,4H),3.90(s,3H),2.92(s,3H),2.84–2.76(m,3H),1.16(d,J＝6.6Hz,6H).

Example 55

2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(2,2-dimethylpyrrolidin-1-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (5, 5-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (2, 2-dimethylpyrrolidin-1-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-chloro-6-(2,2-dimethylpyrrolidin-1-yl)-N,N-dimethylisonicotinamide

2-Chloro-6- (2, 2-dimethylpyrrolidin-1-yl) -N, N-dimethylisonicotinamide

2, 6-Dichloro-N, N-dimethylisonicotinamide 55a (1.5 g,6.85mmol, prepared according to WO 2012035055A 1) was dissolved in dimethyl sulfoxide (10 mL), 2-dimethylpyrrolidine hydrochloride (1.86 g,13.69 mmol) and cesium fluoride (4.16 g,27.39 mmol) were added, and the mixture was stirred at 100℃for 18 hours. After dilution with water (30 mL), ethyl acetate (20 mL. Times.3) was used for extraction, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 2-chloro-6- (2, 2-dimethylpyrrolidin-1-yl) -N, N-dimethylisonicotinamide 55b (1.65 g,3.81 mmol) in 55.59% yield.

MS m/z(ESI):282.0[M+1] ⁺

Second step

2-chloro-6-(2,2-dimethylpyrrolidin-1-yl)-3-formyl-N,N-dimethylisonicotinamide

2-Chloro-6- (2, 2-dimethylpyrrolidin-1-yl) -3-formyl-N, N-dimethylisonicotinamide

N, N-dimethylformamide (1.82 g,24.84 mmol) was dissolved in1, 2-dichloroethane (20 mL), cooled to 0℃and phosphorus oxychloride (3.81 g,24.84 mmol) was slowly added dropwise, and the mixture was stirred for 30 minutes after warming to room temperature. 2-chloro-6- (2, 2-dimethylpyrrolidin-1-yl) -N, N-dimethylisonicotinamide 55b (1 g,3.55 mmol) was dissolved in1, 2-dichloroethane (5 mL), and the reaction mixture was added dropwise thereto, and the temperature was raised to 75℃and the reaction was stirred for 18 hours. Saturated ammonium bicarbonate aqueous solution was added to adjust pH to basicity, dichloromethane (20 mL. Times.3) was used for extraction, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 2-chloro-6- (2, 2-dimethylpyrrolidin-1-yl) -3-formyl-N, N-dimethylisonicotinamide 55c (800 mg,2.58 mmol). The yield was 72.77%.

MS m/z(ESI):310.0[M+1] ⁺

Third step

(E)-3-(((tert-butylsulfinyl)imino)methyl)-2-chloro-6-(2,2-dimethylpyrrolidin-1-yl)-N,N-dimethylisonicotinamide

(E) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-6- (2, 2-dimethylpyrrolidin-1-yl) -N, N-dimethylisonicotinamide

2-Chloro-6- (2, 2-dimethylpyrrolidin-1-yl) -3-formyl-N, N-dimethylisonicotinamide 55c (1.2 g,3.87 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0℃and tert-butylsulfinamide (704.22 mg,5.81 mmol) and ethyl titanate (2.65 g,11.62 mmol) were added, the reaction was warmed to 50℃for 18 hours, cooled to room temperature, ethyl acetate (40 mL) was diluted, saturated sodium bicarbonate solution (40 mL) was added, stirred for 30 minutes, filtered, the filtrate was extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with water (40 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give (E) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-6- (2, 2-dimethylpyrrolidin-1-yl) -N, N-dimethylisonicotinamide 55d (1.39 g, 3.574 mmol), yield 25%.

MS m/z(ESI):413.0[M+1] ⁺

Fourth step

4-chloro-6-(2,2-dimethylpyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

4-Chloro-6- (2, 2-dimethylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(E) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-6- (2, 2-dimethylpyrrolidin-1-yl) -N, N-dimethylisonicotinamide 55d (1.3 g,3.15 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to 0℃and lithium borohydride (137.14 mg,6.30 mmol) was added, the reaction was continued with stirring at 0℃for 1 hour, sodium methoxide (2.55 g,47.22 mmol) was added, stirred slowly until it was stirred at room temperature for 18 hours, water (30 mL) was added to quench the reaction, ethyl acetate (25 mL. Times.3) was extracted, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 4-chloro-6- (2, 2-dimethylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one (700 mg, 35 mmol), yield of 83.68%.

MS m/z(ESI):266.1[M+1] ⁺

Fifth step

tert-butyl

4-chloro-6-(2,2-dimethylpyrrolidin-1-yl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate

4-Chloro-6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxylic acid tert-butyl ester

4-Chloro-6- (2, 2-dimethylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 55e (700 mg,2.63 mmol) was dissolved in tetrahydrofuran (15 mL), 4-dimethylaminopyridine (64.36 mg, 526.83. Mu. Mol), triethylamine (799.65 mg,7.90 mmol) and di-tert-butyl dicarbonate (862.35 mg,3.95 mmol) were sequentially added, the reaction was stirred at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 4-chloro-6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxylic acid tert-butyl ester 55f (460 mg,2.32 mmol) in 88.20% yield.

MS m/z(ESI):366.0[M+1] ⁺

Sixth step

2-(tert-butyl)4-methyl

6- (2, 2-Dimethylpyrrolidin-1-yl) -1-oxo-1,3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2,4-dicarboxylate2- (tert-butyl) 4-methyl-6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-1,3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2, 4-dicarboxylic acid ester

4-Chloro-6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxylic acid tert-butyl ester 55f (850 mg,2.32 mmol) was dissolved in methanol (15 mL), triethylamine (705.29 mg,6.97 mmol) and 1, 1-bis (diphenylphosphine) bis-iron palladium dichloride (169.84 mg, 232.33. Mu. Mol) were added thereto, and the mixture was stirred under carbon monoxide atmosphere at a temperature of 70℃for 8 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 55g (700 mg,1.80 mmol) of 2- (tert-butyl) 4-methyl 6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2, 4-dicarboxylic acid ester in a yield of 77.36%.

MS m/z(ESI):390.0[M+1] ⁺

Seventh step

methyl

6-(2,2-dimethylpyrrolidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

6- (2, 2-Dimethylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carboxylic acid methyl ester

55G (700 mg,1.80 mmol) of 2- (tert-butyl) 4-methyl 6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2, 4-dicarboxylic acid ester was dissolved in methylene chloride (10 mL), a1, 4-dioxane solution (4M, 17.97 mL) of hydrogen chloride was added, stirring was carried out at room temperature for 3 hours, and the reaction mixture was concentrated under reduced pressure to give methyl 6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carboxylate 55H (500 mg,1.73 mmol), in 96.14% yield, which was directly used for the next reaction.

MS m/z(ESI):289.9[M+1] ⁺

Eighth step

6-(2,2-dimethylpyrrolidin-1-yl)-4-(hydroxymethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (2, 2-Dimethylpyrrolidin-1-yl) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

Methyl 6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridine-4-carboxylate (500 mg,1.73 mmol) was dissolved in tetrahydrofuran (6.54 mL), cooled to 0 ℃, a solution of lithium borohydride in tetrahydrofuran (2M, 3.46mL,6.92 mmol) was slowly added dropwise, stirred for 18 hours after warming to room temperature, water (1 mL) was added to quench the reaction, and the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: C system) to give 6- (2, 2-dimethylpyrrolidin-1-yl) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-1-one 55i (350 mg,1.34 mmol) in a yield of 77.50%.

MS m/z(ESI):261.9[M+1] ⁺

Ninth step

(6-(2,2-dimethylpyrrolidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methylmethanesulfonate

(6- (2, 2-Dimethylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate

6- (2, 2-Dimethylpyrrolidin-1-yl) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 55i (330 mg,1.26 mmol) was dissolved in tetrahydrofuran (33 mL), cooled to 0deg.C, triethylamine (511.14 mg,5.05 mmol) and methanesulfonyl chloride (361.64 mg,3.16 mmol) were added, respectively, stirring was continued at 0deg.C for 2 hours, the reaction was quenched with saturated sodium bicarbonate solution (5 mL), extracted with ethyl acetate (25 mL. Times.3), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give (6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate 55j (mg, 1.18 mmol), yield 93.32%) which was used directly in the next step.

MS m/z(ESI):340.0[M+1] ⁺

Tenth step

6-(2,2-dimethylpyrrolidin-1-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (2, 2-Dimethylpyrrolidin-1-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(6- (2, 2-Dimethylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate 55j (400 mg,1.18 mmol) was dissolved in tetrahydrofuran (2.09 mL), a solution of methylamine in ethanol (33%, 23.57mmol, 955.64. Mu.L) was added, and the reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure to give 6- (2, 2-dimethylpyrrolidin-1-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 55k (300 mg,1.09 mmol) in yield 92.78% and was used directly in the next reaction.

MS m/z(ESI):275.0[M+1] ⁺

Eleventh step tert-butyl

((6-(2,2-dimethylpyrrolidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (2, 2-Dimethylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

6- (2, 2-Dimethylpyrrolidin-1-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 55k (300 mg,1.09 mmol) was dissolved in tetrahydrofuran (15 mL), triethylamine (331.94 mg,3.28 mmol) and di-tert-butyl dicarbonate (357.96 mg,1.64 mmol) were added, respectively, and the reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give ((6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 55l (350 mg, 934.64. Mu. Mol) in 85.48% yield.

MS m/z(ESI):375.0[M+1] ⁺

Twelfth step

tert-butyl

((2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(2,2-dimethylpyrrolidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (5, 5-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 55l (50 mg, 133.52. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 27c (58.71 mg, 200.28. Mu. Mol) were dissolved in1, 4-dioxane (6 mL), and cuprous iodide (25.43 mg, 133.52. Mu. Mol), N, N-dimethylethylenediamine (23.54 mg, 267.04. Mu. Mol) and potassium carbonate (55.36 mg, 400.56. Mu. Mol) were added and heated to 100℃under argon atmosphere for reaction for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 55m (68 mg, 115.90. Mu. Mol) in 86.80% yield.

MS m/z(ESI):587.0[M+1] ⁺

Thirteenth step

Tert-butyl ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 55M (68 mg,115.90 μmol) was dissolved in dichloromethane (5 mL), and a 1, 4-dioxane solution of hydrogen chloride (4M, 1.16 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (2, 2-dimethylpyrrolidin-1-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 55 (50 mg, 82.32. Mu. Mol) in 71.03% yield.

MS m/z(ESI):487.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.87(brs,2H),8.61(d,J＝8.4Hz,1H),8.09(t,J＝8.0Hz,1H),7.91(d,J＝7.6Hz,1H),6.76(s,1H),5.12(s,2H),4.28(t,J＝5.8Hz,2H),3.61–3.50(m,2H),3.03(t,J＝7.4Hz,2H),2.76(t,J＝5.2Hz,3H),2.61(t,J＝7.4Hz,2H),1.95(d,J＝3.3Hz,4H),1.74(s,6H),1.53(s,6H).

Example 56

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

Tert-butyl 3- (6-chloropyridin-2-yl) -6,7-dihydropyrazolo [1,5-a ] pyrazine-5 (4H) -carbox-ylate 3- (6-chloropyridin-2-yl) -6,7-dihydropyrazolo [1,5-a ] pyrazine-5 (4H) -carboxylic acid tert-butyl ester

2-Chloro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine 56a (475.58 mg,1.99 mmol) and 3-bromo-6, 7-dihydropyrazolo [1,5-a ] piperazine-5 (4H) -carboxylic acid tert-butyl ester 56b (300 mg, 992.83. Mu. Mol) were dissolved in a mixed solvent of 1, 4-dioxane (7.5 mL) and water (1.5 mL), and bis (4-dimethylaminophenyl-di-tert-butylphosphine) palladium dichloride (70.30 mg, 99.28. Mu. Mol) and cesium carbonate (970.45 mg,2.98 mmol) were added and reacted at a temperature elevated to 140℃under argon atmosphere for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: A system) to give tert-butyl 3- (6-chloropyridin-2-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-5 (4H) -carboxylate 56c (300 mg, 896.06. Mu. Mol) in 90.25% yield.

MS m/z(ESI):335.1[M+1] ⁺

Second step

tert-butyl

3-(6-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-(isopropyl(methyl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pyridin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

3- (6- (4- (((Tert-Butoxycarbonyl) (methyl) amino) methyl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-5 (4H) -carboxylic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 3- (6-chloropyridin-2-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-5 (4H) -carboxylate 56c (96.09 mg, 286.99. Mu. Mol) were dissolved in 1, 4-dioxane (6 mL), tris (dibenzylideneacetone) dipalladium (13.14 mg, 14.35. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (16.61 mg, 28.70. Mu. Mol) and potassium phosphate (91.38 mg, 430.49. Mu. Mol) were added in this order, and the reaction was heated to 110℃for 32 hours, and the S was monitored to be complete. The reaction solution was filtered by suction, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) successively to give tert-butyl 3- (6- (4- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-5 (4H) -carboxylate 56d (50 mg, 77.31. Mu. Mol), yield 53.87%.

MS m/z(ESI):647.0[M+1] ⁺

Third step

3- (6- (4- (((Tert-Butoxycarbonyl) (methyl) amino) methyl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-5 (4H) -carboxylic acid tert-butyl ester 56d (50 mg, 77.31. Mu. Mol) was dissolved in dichloromethane (5 mL), and a1, 4-dioxane solution of hydrogen chloride (4M, 773.06. Mu.L) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 56 (40 mg, 70.26. Mu. Mol), yield 90.88%.

MS m/z(ESI):447.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.75(brs,2H),9.05(brs,2H),8.33(d,J＝8.4Hz,1H),8.28(s,1H),7.94(t,J＝8.0Hz,1H),7.58(d,J＝7.7Hz,1H),6.91(d,J＝3.2Hz,1H),5.30–4.81(m,5H),4.49–4.31(m,4H),3.75(s,2H),2.93(s,3H),2.76(s,3H),1.17(d,J＝6.6Hz,6H).

Example 57

(S)-2-(6-(4-(1-(2-fluorophenyl)ethyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(S) -2- (6- (4- (1- (2-fluorophenyl) ethyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

(S)-2-bromo-6-(4-(1-(2-fluorophenyl)ethyl)-4H-1,2,4-triazol-3-yl)pyridine

(S) -2-bromo-6- (4- (1- (2-fluorophenyl) ethyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (200 mg, 737.70. Mu. Mol) was dissolved in acetonitrile (7.5 mL) at room temperature, and (S) -1- (2-fluorophenyl) ethyl-1-amine 57a (410.7 mg,2.95 mmol) and glacial acetic acid (1.5 mL) were added, and the mixture was warmed to 85℃and concentrated under reduced pressure after reaction for 18 hours, and the resulting residue was purified by silica gel column chromatography (eluent: C system) to give (S) -2-bromo-6- (4- (1- (2-fluorophenyl) ethyl) -4H-1,2, 4-triazol-3-yl) pyridine 57b (200 mg, 576.06. Mu. Mol) in a yield of 78.09%.

MS m/z(ESI):347.0[M+1] ⁺

Second step

tert-butyl

(S)-((2-(6-(4-(1-(2-fluorophenyl)ethyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(S) - ((2- (6- (4- (1- (2-fluorophenyl) ethyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and (S) -2-bromo-6- (4- (1- (2-fluorophenyl) ethyl) -4H-1,2, 4-triazol-3-yl) pyridine 57b (99.64 mg, 286.99. Mu. Mol) were dissolved in1, 4-dioxane (6 mL), and cuprous iodide (27.33 mg, 143.50. Mu. Mol), N, N-dimethylethylenediamine (25.30 mg, 286.99. Mu. Mol) and potassium carbonate (79.33 mg, 573.99. Mu. Mol) were added and reacted for 8 hours under argon atmosphere at 100 ℃. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl (S) - ((2- (6- (4- (1- (2-fluorophenyl) ethyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 57C (60 mg, 97.61. Mu. Mol), in a yield of 68.02%.

MS m/z(ESI):615.0[M+1] ⁺

Third step

(S) - ((2- (6- (4- (1- (2-fluorophenyl) ethyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 57c (60 mg, 97.61. Mu. Mol) was dissolved in dichloromethane (4 mL), and a1, 4-dioxane solution of hydrogen chloride (4M, 976.07. Mu. L) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give (S) -2- (6- (4- (1- (2-fluorophenyl) ethyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 57 (45 mg, 70.96. Mu. Mol) in a yield of 72.70%.

MS m/z(ESI):515.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.98(brs,2H),8.87(s,1H),8.60(d,J＝8.4Hz,1H),8.09(t,J＝8.0Hz,1H),7.84(d,J＝7.5Hz,1H),7.41–7.33(m,1H),7.33–7.27(m,1H),7.26–7.19(m,1H),7.15(dd,J＝11.0,8.2Hz,1H),6.91(s,1H),6.81(q,J＝7.0Hz,1H),5.06–4.99(m,1H),5.05(q,J＝16.8Hz,2H),4.31(d,J＝5.9,3.0Hz,2H),2.93(s,3H),2.74(t,J＝5.3Hz,3H),2.03(d,J＝7.0Hz,3H),1.17(d,J＝6.6Hz,6H).

Example 58

6-(2,2-dimethylpyrrolidin-1-yl)-4-((methylamino)methyl)-2-(6-(4-phenyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (2, 2-Dimethylpyrrolidin-1-yl) -4- ((methylamino) methyl) -2- (6- (4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

tert-butyl

((6-(2,2-dimethylpyrrolidin-1-yl)-1-oxo-2-(6-(4-phenyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (2, 2-Dimethylpyrrolidin-1-yl) -1-oxo-2- (6- (4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 55l (45 mg, 120.17. Mu. Mol) and 2-bromo-6- (4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridine 9b (50.66 mg, 168.24. Mu. Mol) were dissolved in1, 4-dioxane (6 mL), and cuprous iodide (22.89 mg, 120.17. Mu. Mol), N, N-dimethylethylenediamine (21.19 mg, 240.34. Mu. Mol) and potassium carbonate (66.43 mg, 480.67. Mu. Mol) were added and reacted for 8 hours under argon atmosphere at 100 ℃. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-2- (6- (4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 58a (65 mg, 109.30. Mu. Mol), yield 90.95%.

MS m/z(ESI):595.0[M+1] ⁺

Second step

Tert-butyl ((6- (2, 2-dimethylpyrrolidin-1-yl) -1-oxo-2- (6- (4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 58a (65 mg, 109.30. Mu. Mol) was dissolved in dichloromethane (5 mL), and a1, 4-dioxane solution of hydrogen chloride (4M, 1.09 mL) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (2, 2-dimethylpyrrolidin-1-yl) -4- ((methylamino) methyl) -2- (6- (4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 58 (45 mg, 73.94. Mu. Mol) in a yield of 67.65%.

MS m/z(ESI):495.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.92(brs,1H),8.82(s,2H),8.50(d,J＝8.3Hz,1H),8.08(t,J＝8.0Hz,1H),8.00(d,J＝7.6Hz,1H),7.68–7.59(m,3H),7.58–7.48(m,2H),6.67(s,1H),4.10(t,J＝5.7Hz,2H),3.90(s,2H),3.60–3.16(m,2H),2.85(t,J＝5.3Hz,3H),1.92(s,4H),1.50(s,6H).

Example 59

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(4-(1-(trifluoromethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4- (1- (trifluoromethyl) cyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(1-(trifluoromethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (1- (trifluoromethyl) cyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (200 mg, 737.70. Mu. Mol) was dissolved in acetonitrile (4 mL) at room temperature, 1- (trifluoromethyl) cyclopropylamine hydrochloride 59a (276.84 mg,1.71 mmol) and glacial acetic acid (442.99 mg,7.38mmol, 422.30. Mu.L) were added, and the mixture was warmed to 85℃and reacted for 18 hours, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: C system) to give 2-bromo-6- (4- (1- (trifluoromethyl) cyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridine 59b (208 mg, 624.42. Mu. Mol) in a yield of 84.64%.

MS m/z(ESI):333.0[M+1] ⁺

Second step

tert-butyl

((6-(isopropyl(methyl)amino)-1-oxo-2-(6-(4-(1-(trifluoromethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -1-oxo-2- (6- (4- (1- (trifluoromethyl) cyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 2-bromo-6- (4- (1- (trifluoromethyl) cyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridine 59b (95.60 mg, 286.99. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (81.99 mg, 430.49. Mu. Mol), N, N-dimethylethylenediamine (50.60 mg, 573.99. Mu. Mol, 62.70. Mu. L) and potassium carbonate (99.16 mg, 717.49. Mu. Mol) were added and reacted for 18 hours under argon atmosphere at 70 ℃. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (4- (1- (trifluoromethyl) cyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 59C (100 mg, 99.89. Mu. Mol), yield 69.61%.

MS m/z(ESI):601.3[M+1] ⁺

Third step

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (4- (1- (trifluoromethyl) cyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 59c (90 mg, 149.84. Mu. Mol) was dissolved in dichloromethane (4.5 mL), cooled to 0 ℃, trifluoroacetic acid (1.71 g,14.98 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4- (1- (trifluoromethyl) cyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 59 (47 mg, 74.80. Mu. Mol), yield 49.92%.

MS m/z(ESI):501.2[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.04(brs,1H),8.96(s,2H),8.70(d,J＝8.4Hz,1H),8.13(t,J＝8.0Hz,1H),7.92(d,J＝7.5Hz,1H),6.92(s,1H),5.10–4.98(m,1H),5.05(s,2H),4.28(t,J＝5.8Hz,2H),2.93(s,3H),2.74(t,J＝5.3Hz,3H),1.89–1.80(m,2H),1.71(s,2H),1.16(d,J＝6.6Hz,6H).

Example 60

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(4-(o-tolyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4- (o-tolyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(o-tolyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (o-tolyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (200 mg, 737.70. Mu. Mol) was dissolved in acetonitrile (3 mL) at room temperature, o-toluidine 60a (395.23 mg,3.69mmol, 392.10. Mu.L) and glacial acetic acid (442.99 mg,7.38mmol, 422.30. Mu.L) were added, the mixture was warmed to 85℃and reacted for 18 hours, and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 2-bromo-6- (4- (o-tolyl) -4H-1,2, 4-triazol-3-yl) pyridine 60b (360 mg, 571.12. Mu. Mol) in 77.42% yield.

MS m/z(ESI):315.0[M+1] ⁺

Second step

tert-butyl

((6-(isopropyl(methyl)amino)-1-oxo-2-(6-(4-(o-tolyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -1-oxo-2- (6- (4- (o-tolyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 2-bromo-6- (4- (o-tolyl) -4H-1,2, 4-triazol-3-yl) pyridine 60b (90.45 mg, 286.99. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (81.99 mg, 430.49. Mu. Mol), N, N-dimethylethylenediamine (50.60 mg, 573.99. Mu. Mol, 62.70. Mu. L) and potassium carbonate (99.16 mg, 717.49. Mu. Mol) were added and reacted for 5 hours under argon atmosphere at 70 ℃. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (4- (o-tolyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 60C (130 mg, 131.25. Mu. Mol), yield 91.47%.

MS m/z(ESI):583.4[M+1] ⁺

Third step

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (4- (o-tolyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 60c (120 mg,205.94 μmol) was dissolved in dichloromethane (4.5 mL), cooled to 0 ℃, trifluoroacetic acid (2.35 g,20.59 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4- (o-tolyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 60 (45 mg, 71.57. Mu. Mol), yield 34.75%.

MS m/z(ESI):483.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.96(brs,2H),8.83(s,1H),8.51(dd,J＝6.3,3.0Hz,1H),8.11–8.04(m,2H),7.62–7.53(m,2H),7.52–7.42(m,2H),6.82(s,1H),5.06–4.93(m,1H),4.20(s,2H),3.90–3.76(m,2H),2.90(s,3H),2.87(t,J＝5.4Hz,3H),1.99(s,3H),1.15(d,J＝6.6Hz,6H).

Example 61

6-(isopropyl(methyl)amino)-2-(6-(4-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -2- (6- (4- (1-methyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (1-methyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (300 mg,1.11 mmol) was dissolved in acetonitrile (3 mL) at room temperature, 1-methyl-1H-pyrazol-5-amine 61a (322.40 mg,3.32 mmol) and glacial acetic acid (6 mL) were added, the mixture was warmed to 85℃and the tube was sealed for 48 hours, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: C system) to give 2-bromo-6- (4- (1-methyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridine 61b (58 mg, 190.08. Mu. Mol), yield 17.18%.

MS m/z(ESI):305.1[M+1] ⁺

Second step

tert-butyl

((6-(isopropyl(methyl)amino)-2-(6-(4-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -2- (6- (4- (1-methyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (66.23 mg, 190.08. Mu. Mol) and bromo-6- (4- (1-methyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridine 61b (58 mg, 190.08. Mu. Mol) were dissolved in1, 4-dioxane (6 mL), and tris (dibenzylidene-BASE acetone) dipalladium (87.03 mg, 95.04. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (54.99 mg, 95.04. Mu. Mol) and potassium phosphate (121.05 mg, 570.24. Mu. Mol) were added in this order and reacted for 24 hours at 80 ℃. The reaction mixture was filtered under suction, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (4- (1-methyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 61c (30 mg, 52.39. Mu. Mol), yield 27.56%.

MS m/z(ESI):573.3[M+1] ⁺

Third step

Tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (4- (1-methyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 61c (30 mg,52.39 μmol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (17.92 mg,157.16 μmol) was added, and stirred slowly to room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -2- (6- (4- (1-methyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 61 (6 mg, 10.01. Mu. Mol), yield 19.11%.

MS m/z(ESI):473.2[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.99(s,1H),8.58(dd,J＝6.3,3.0Hz,1H),8.15–8.09(m,2H),7.75(d,J＝2.0Hz,1H),6.85(s,1H),6.61(d,J＝2.0Hz,1H),5.32(t,J＝4.9Hz,1H),5.02(brs,2H),4.32(s,2H),4.12(s,2H),3.69(s,3H),2.91(s,3H),2.81(s,3H),1.16(d,J＝6.6Hz,6H).

Example 62

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(4-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4- (pyridin-3-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (pyridin-3-yl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (180 mg, 663.93. Mu. Mol) was dissolved in acetonitrile (10 mL) at room temperature, 3-aminopyridine 62a (249.94 mg,2.66 mmol) and glacial acetic acid (2 mL) were added, and the mixture was warmed to 85℃and reacted under reduced pressure after stirring for 48 hours, and the resulting residue was purified by silica gel column chromatography (eluent: C system) to give 2-bromo-6- (4- (pyridin-3-yl) -4H-1,2, 4-triazol-3-yl) pyridine 62b (50 mg, 165.49. Mu. Mol) in 24.93% yield.

MS m/z(ESI):302.0[M+1] ⁺

Second step

tert-butyl

((6-(isopropyl(methyl)amino)-1-oxo-2-(6-(4-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(6- (Isopropyl (methyl) amino) -1-oxo-2- (6- (4- (pyridin-3-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (57.66 mg, 165.49. Mu. Mol) and 2-bromo-6- (4- (pyridin-3-yl) -4H-1,2, 4-triazol-3-yl) pyridine 62b (50 mg, 165.49. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), tris (dibenzylidene-BASE acetone) dipalladium (30.31 mg, 33.10. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (19.15 mg, 33.10. Mu. Mol) and potassium phosphate (70.26 mg, 330.98. Mu. Mol) were added in this order and reacted at 80℃for 6 hours. The reaction mixture was filtered under suction, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (4- (pyridin-3-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 62c (52 mg, 91.28. Mu. Mol), yield 55.16%.

MS m/z(ESI):570.3[M+1] ⁺

Third step

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2- (6- (4- (pyridin-3-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 62c (52 mg,91.28 μmol) was dissolved in dichloromethane (6 mL), cooled to 0 ℃, trifluoroacetic acid (31.22 mg,273.85 μmol) was added, and stirred slowly to room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4- (pyridin-3-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 62 (44 mg, 71.30. Mu. Mol), yield 78.11%.

MS m/z(ESI):470.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.98(s,1H),8.92(brs,2H),8.88(d,J＝2.5Hz,1H),8.84(dd,J＝4.8,1.4Hz,1H),8.52(dd,J＝8.0,1.2Hz,1H),8.14–8.01(m,3H),7.69(dd,J＝8.1,4.9Hz,1H),6.84(s,1H),5.07–4.95(m,1H),4.20(t,J＝5.9Hz,2H),3.87(s,2H),2.90(s,3H),2.85(t,J＝5.4Hz,3H),1.15(d,J＝6.7Hz,6H).

Example 63

(R)-2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-6-(2-methylpyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(R) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

tert-butyl

((6-chloro-2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6-Chloro-2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6-chloro-1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 63a (10 mg, 32.08. Mu. Mol, prepared according to published patent WO2020100027A 1) and 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 27c (14.11 mg, 48.11. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (6.11 mg, 32.08. Mu. Mol), N, N-dimethylethylenediamine (5.66 mg, 64.15. Mu. Mol) and potassium carbonate (17.73 mg, 128.30. Mu. Mol) were added and heated under argon atmosphere to 70℃for reaction for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6-chloro-2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 63b (8 mg, 15.27. Mu. Mol), yield 47.60%.

MS m/z(ESI):524.2[M+1] ⁺

Second step

tert-butyl

(R)-((2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(2-methylpyrrolidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(R) - ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6-chloro-2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 63b (8 mg, 15.27. Mu. Mol) and (R) -2-methylpyrrolidine hydrochloride (7.43 mg, 61.07. Mu. Mol) were dissolved in 1, 4-dioxane (2 mL), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (6.39 mg, 7.63. Mu. Mol) and cesium carbonate (14.92 mg, 45.80. Mu. Mol) were added in this order, and the mixture was stirred under argon gas at a temperature of 120℃for 8 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl (R) - ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 63C (7 mg, 12.22. Mu. Mol), yield 80.06%.

MS m/z(ESI):573.0[M+1] ⁺

Third step

(R) - ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 63c (7 mg, 12.22. Mu. Mol) was dissolved in dichloromethane (2 mL), and a 1, 4-dioxane solution of hydrogen chloride (4M, 122.23. Mu.L) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give (R) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 63 (4 mg, 6.82. Mu. Mol), yield 55.79%.

MS m/z(ESI):473.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.93(brs,2H),8.62(d,J＝8.4Hz,1H),8.09(t,J＝8.0Hz,1H),7.92(d,J＝7.6Hz,1H),6.74(s,1H),5.10(s,2H),4.41–4.25(m,3H),3.64(dd,J＝10.2,7.4Hz,2H),3.03(t,J＝7.4Hz,2H),2.77(t,J＝5.3Hz,3H),2.61(t,J＝7.5Hz,2H),2.15–1.94(m,3H),1.79–1.70(m,1H),1.74(s,6H),1.20(d,J＝6.2Hz,3H).

Example 64

6-(isopropyl(methyl)amino)-2-(6-(4-(2-methoxyphenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -2- (6- (4- (2-methoxyphenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(2-methoxyphenyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (2-methoxyphenyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (200 mg, 737.70. Mu. Mol) was dissolved in acetonitrile (7 mL) at room temperature, o-methoxyaniline 64a (454.25 mg,3.69mmol, 415.98. Mu. L) and glacial acetic acid (442.99 mg,7.38mmol, 422.30. Mu.L) were added, and the mixture was warmed to 90℃and reacted for 18 hours with stirring, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: C system) to give 2-bromo-6- (4- (2-methoxyphenyl) -4H-1,2, 4-triazol-3-yl) pyridine 64b (204 mg, 616.00. Mu. Mol) in a yield of 83.50%.

MS m/z(ESI):331.0[M+1] ⁺

Second step

tert-butyl

((6-(isopropyl(methyl)amino)-2-(6-(4-(2-methoxyphenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -2- (6- (4- (2-methoxyphenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 2-bromo-6- (4- (2-methoxyphenyl) -4H-1,2, 4-triazol-3-yl) pyridine 64b (95.04 mg, 286.99. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (81.99 mg, 430.49. Mu. Mol), N, N-dimethylethylenediamine (50.60 mg, 573.99. Mu. Mol) and potassium carbonate (99.16 mg, 717.49. Mu. Mol) were added and reacted under argon atmosphere at 70℃for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (4- (2-methoxyphenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 64C (113 mg, 128.35. Mu. Mol), in 89.44% yield.

MS m/z(ESI):599.3[M+1] ⁺

Third step

Tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (4- (2-methoxyphenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 64c (103 mg,172.04 μmol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (1.96 g,17.20 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -2- (6- (4- (2-methoxyphenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 64 (35 mg, 52.98. Mu. Mol), yield 30.79%.

MS m/z(ESI):499.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.97(brs,2H),8.79(s,1H),8.50(d,J＝8.3Hz,1H),8.07(t,J＝8.0Hz,1H),7.99(d,J＝7.6Hz,1H),7.62(t,J＝7.7Hz,1H),7.57(d,J＝8.2Hz,1H),7.25(t,J＝7.3Hz,2H),6.82(s,1H),5.00(p,J＝6.9Hz,1H),4.16(t,J＝5.8Hz,2H),3.85(s,2H),3.56(s,3H),2.90(s,3H),2.86(t,J＝5.3Hz,3H),1.15(d,J＝6.5Hz,6H).

Example 65

2-(6-(2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (2, 3-Dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

tert-butyl 4-bromo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

4-Bromo-2, 3-dihydro-1H-pyrrolo [2,3-c ] pyridine-1-carboxylic acid tert-butyl ester

4-Bromo-2, 3-dihydro-1H-pyrrolo [2,3-c ] pyridine 65a (250 mg,1.26mmol, commercially available) was dissolved in tetrahydrofuran (10 mL), 4-dimethylaminopyridine (76.72 mg, 627.99. Mu. Mol), triethylamine (635.46 mg,6.28 mmol) and di-tert-butyl dicarbonate (548.23 mg,2.51 mmol) were added in this order, and the mixture was heated to 50℃and reacted under stirring for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl 4-bromo-2, 3-dihydro-1H-pyrrolo [2,3-c ] pyridine-1-carboxylate 65b (250 mg, 835.66. Mu. Mol), in a yield of 66.53%.

MS m/z(ESI):299.0[M+1] ⁺

Second step

tert-butyl 4-(6-chloropyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

4- (6-Chloropyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [2,3-c ] pyridine-1-carboxylic acid tert-butyl ester

2-Chloro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine 56a (288.21 mg,1.20 mmol) and 4-bromo-2, 3-dihydro-1H-pyrrolo [2,3-c ] pyridine-1-carboxylic acid tert-butyl ester 65b (180 mg, 601.68. Mu. Mol) were dissolved in a mixed solvent of 1, 4-dioxane (7.5 mL) and water (1.5 mL), and 1, 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (44.03 mg, 60.17. Mu. Mol) and sodium hydrogen carbonate (151.63 mg,1.81 mmol) were added and reacted under argon atmosphere at a temperature elevated to 100℃for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: A system) to give tert-butyl 4- (6-chloropyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [2,3-c ] pyridine-1-carboxylate 65c (120 mg, 361.67. Mu. Mol), in 60.11% yield. MS m/z (ESI): 322.1[ M+1] ⁺

Third step

tert-butyl

4-(6-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-(isopropyl(methyl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

4- (6- (4- (((Tert-Butoxycarbonyl) (methyl) amino) methyl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [2,3-c ] pyridine-1-carboxylic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and tert-butyl 4- (6-chloropyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [2,3-c ] pyridine-1-carboxylate 65c (119.03 mg, 358.74. Mu. Mol) were dissolved in1, 4-dioxane (6 mL), tris (dibenzylideneacetone) dipalladium (13.14 mg, 14.35. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (16.61 mg, 28.70. Mu. Mol) and potassium phosphate (91.38 mg, 430.49. Mu. Mol) were added in this order and reacted for 4 hours at 120 ℃. The reaction solution was filtered under suction, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl 4- (6- (4- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [2,3-c ] pyridine-1-carboxylate 65d (50 mg, 77.67. Mu. Mol), yield 54.12%.

MS m/z(ESI):644.0[M+1] ⁺

Fourth step

4- (6- (4- (((Tert-Butoxycarbonyl) (methyl) amino) methyl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [2,3-c ] pyridine-1-carboxylic acid tert-butyl ester 65d (50 mg, 77.67. Mu. Mol) was dissolved in dichloromethane (2 mL), and a1, 4-dioxane solution of hydrogen chloride (4M, 776.67. Mu. L) was added, and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (2, 3-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 65 (12.51 mg, 21.78. Mu. Mol), yield 28.05%.

MS m/z(ESI):444.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.47(brs,1H),9.40(brs,2H),8.67–8.40(m,2H),8.12(t,J＝8.0Hz,1H),7.84(s,1H),7.80(d,J＝7.6Hz,1H),6.89(s,1H),5.21(s,2H),5.04(dd,J＝13.1,6.7Hz,1H),4.35(t,J＝5.9Hz,2H),3.79–3.74(m,2H),3.72-3.68(m,2H),2.92(d,J＝2.4Hz,3H),2.70(t,J＝5.3Hz,3H),1.16(dd,J＝6.7,2.7Hz,6H).

Example 66

2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-6-morpholino-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (5, 5-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6-morpholino-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

tert-butyl

((2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-morpholino-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (5, 5-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6-morpholino-1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6-chloro-2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 63b (15 mg, 28.63. Mu. Mol) and morpholine (49.88 mg, 572.50. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (11.98 mg, 14.31. Mu. Mol) and cesium carbonate (27.98 mg, 85.88. Mu. Mol) were added in this order, and stirred under argon gas at 120℃for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6-morpholino-1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 66a (10 mg, 17.40. Mu. Mol), yield 60.79%.

MS m/z(ESI):575.0[M+1] ⁺

Second step

Tert-butyl ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6-morpholino-1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 66a (10 mg, 17.40. Mu. Mol) was dissolved in dichloromethane (4 mL), and a1, 4-dioxane solution of hydrogen chloride (4M, 174.01. Mu.L) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6-morpholino-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 66 (5 mg, 8.50. Mu. Mol) in a yield of 48.82%.

MS m/z(ESI):475.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.01(brs,2H),8.62(d,J＝8.4Hz,1H),8.09(t,J＝8.0Hz,1H),7.92(d,J＝7.6Hz,1H),7.17(s,1H),5.12(s,2H),4.35(t,J＝5.9Hz,2H),3.74(d,J＝4.9Hz,4H),3.65(d,J＝5.0Hz,4H),3.03(t,J＝7.4Hz,2H),2.74(t,J＝5.2Hz,3H),2.61(t,J＝7.5Hz,2H),1.74(s,6H).

Example 67

6-(isopropyl(methyl)amino)-2-(6-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -2- (6- (5-methyl-4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (5-methyl-4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridine

2- (6-Bromopyridin-2-yl) -5-methyl-1, 3, 4-oxadiazole 67a (50 mg, 208.28. Mu. Mol, prepared according to WO2020100027A 1) and aniline 67b (116.38 mg,1.25mmol, 113.88. Mu.L) were dissolved in pyridine (4 mL), cooled to 0deg.C, trifluoroacetic acid (23.75 mg, 208.28. Mu. Mol, 15.95. Mu.L) was added, and the reaction was stirred at 100deg.C for 24 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: B system) to give 2-bromo-6- (5-methyl-4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridine 67c (50 mg, 158.65. Mu. Mol) in a yield of 76.17%.

MS m/z(ESI):315.0[M+1] ⁺

Second step

tert-butyl

((6-(isopropyl(methyl)amino)-2-(6-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -2- (6- (5-methyl-4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (25 mg, 71.75. Mu. Mol) and 2-bromo-6- (5-methyl-4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridine 67c (33.92 mg, 107.62. Mu. Mol) were dissolved in1, 4-dioxane (3 mL), tris (dibenzylidene-BASE acetone) dipalladium (65.70 mg, 71.75. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (41.52 mg, 71.75. Mu. Mol) and potassium phosphate (45.69 mg, 215.25. Mu. Mol) were added in this order and reacted for 2 hours at 80 ℃. The reaction mixture was filtered under suction, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (5-methyl-4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 67d (40 mg, 68.65. Mu. Mol), yield 95.68%.

MS m/z(ESI):583.4[M+1] ⁺

Third step

Tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (5-methyl-4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 67d (40 mg,68.65 μmol) was dissolved in dichloromethane (3 mL), cooled to 0 ℃, trifluoroacetic acid (23.48 mg,205.94 μmol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -2- (6- (5-methyl-4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 67 (12 mg, 20.03. Mu. Mol), yield 29.18%.

MS m/z(ESI):483.0[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.05(brs,2H),8.46(d,J＝8.1Hz,1H),8.09–7.97(m,2H),7.67(dd,J＝4.8,1.9Hz,3H),7.50(dd,J＝6.5,2.9Hz,2H),6.81(s,1H),5.07–4.94(m,1H),4.19(t,J＝5.6Hz,2H),3.83(s,2H),2.90(s,3H),2.86(t,J＝5.3Hz,3H),2.24(s,3H),1.15(d,J＝6.6Hz,6H).

Example 68

2-(6-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (4- (2-Chlorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (2-chlorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (200 mg, 737.70. Mu. Mol) was dissolved in acetonitrile (7 mL) at room temperature, o-chloroaniline 68a (282.33 mg,2.21mmol, 232.75. Mu.L) and glacial acetic acid (442.99 mg,7.38mmol, 422.30. Mu.L) were added, and the mixture was warmed to 90℃and reacted for 18 hours with stirring, and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 2-bromo-6- (4- (2-chlorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine 68b (122 mg, 327.77. Mu. Mol) in a yield of 44.43%.

MS m/z(ESI):334.8[M+1] ⁺

Second step

tert-butyl

((2-(6-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (4- (2-Chlorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 2-bromo-6- (4- (2-chlorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine 68b (96.31 mg, 286.99. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (81.99 mg, 430.49. Mu. Mol), N, N-dimethylethylenediamine (50.60 mg, 573.99. Mu. Mol) and potassium carbonate (99.16 mg, 717.49. Mu. Mol) were added and reacted under argon atmosphere at 70℃for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6- (4- (2-chlorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 68C (105 mg, 120.81. Mu. Mol), yield 84.19%.

MS m/z(ESI):603.3[M+1] ⁺

Third step

Tert-butyl ((2- (6- (4- (2-chlorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 68c (100 mg, 165.81. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (1.89 g,16.58 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (4- (2-chlorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 68 (30 mg, 46.18. Mu. Mol), in 27.85% yield.

MS m/z(ESI):503.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.01(brs,2H),8.91(s,1H),8.53(p,J＝3.9Hz,1H),8.09(dd,J＝4.7,0.9Hz,2H),7.86–7.77(m,2H),7.77–7.66(m,2H),6.82(s,1H),5.08–4.94(m,1H),4.18(s,2H),4.01–3.66(m,2H),2.90(s,3H),2.88(s,3H),1.15(d,J＝6.6Hz,6H).

Example 69

2-(6-(4-(2,6-difluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (4- (2, 6-Difluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(2,6-difluorophenyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (2, 6-difluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (300 mg,1.11 mmol) was dissolved in acetonitrile (6 mL) at room temperature, 2, 6-difluoroaniline 69a (428.59 mg,3.32mmol, 357.46. Mu.L) and glacial acetic acid (6 mL) were added, and the mixture was warmed to 100℃and reacted for 48 hours with stirring, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 2-bromo-6- (4- (2, 6-difluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine 69b (180 mg, 373.75. Mu. Mol) in 33.78% yield.

MS m/z(ESI):337.0[M+1] ⁺

Second step

tert-butyl

((2-(6-(4-(2,6-difluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (4- (2, 6-Difluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 2-bromo-6- (4- (2, 6-difluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine 69b (72.56 mg, 215.25. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (81.99 mg, 430.49. Mu. Mol), N, N-dimethylethylenediamine (50.60 mg, 573.99. Mu. Mol) and potassium carbonate (99.16 mg, 717.49. Mu. Mol) were added and reacted under argon atmosphere at 70℃for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl ((2- (6- (4- (2, 6-difluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 69c (68 mg, 104.53. Mu. Mol) in a yield of 72.85%.

MS m/z(ESI):605.2[M+1] ⁺

Third step

Tert-butyl ((2- (6- (4- (2, 6-difluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 69c (63 mg, 104.19. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (1.19 g,10.42 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (4- (2, 6-difluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 69 (47 mg, 69.34. Mu. Mol) in a yield of 66.55%.

MS m/z(ESI):505.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.10(s,1H),8.92(brs,2H),8.59(dt,J＝7.6,3.8Hz,1H),8.17–8.09(m,2H),7.86–7.77(m,1H),7.55(t,J＝8.2Hz,2H),6.83(s,1H),5.07–4.95(m,1H),4.16(t,J＝5.8Hz,2H),3.91(s,2H),2.90(s,3H),2.87(t,J＝5.3Hz,3H),1.15(d,J＝6.6Hz,6H).

Example 70

2-(6-(4-(2,6-dimethylphenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (4- (2, 6-Dimethylphenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(2,6-dimethylphenyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (2, 6-dimethylphenyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (200 mg, 737.70. Mu. Mol) was dissolved in acetonitrile (4 mL) at room temperature, and 2, 6-dimethylaniline 70a (446.97 mg,3.69mmol, 454.24. Mu. L) and glacial acetic acid (442.99 mg,7.38mmol, 422.30. Mu.L) were added, and the mixture was heated to 90℃and reacted under stirring for 18 hours, and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 2-bromo-6- (4- (2, 6-dimethylphenyl) -4H-1,2, 4-triazol-3-yl) pyridine 70b (119 mg, 256.66. Mu. Mol) in a yield of 34.79%.

MS m/z(ESI):329.0[M+1] ⁺

Second step

tert-butyl

((2-(6-(4-(2,6-dimethylphenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (4- (2, 6-Dimethylphenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 2-bromo-6- (4- (2, 6-dimethylphenyl) -4H-1,2, 4-triazol-3-yl) pyridine 70b (94.48 mg, 286.99. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), tris (dibenzylidene-BASE acetone) dipalladium (65.7 mg, 71.74. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (83.04 mg, 143.5. Mu. Mol) and potassium phosphate (91.38 mg, 430.49. Mu. Mol) were added in this order and reacted at 70℃for 32 hours. The reaction mixture was filtered under suction, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl ((2- (6- (4- (2, 6-dimethylphenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 70c (79 mg, 117.59. Mu. Mol) in 81.95% yield.

MS m/z(ESI):597.0[M+1] ⁺

Third step

Tert-butyl ((2- (6- (4- (2, 6-dimethylphenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 70c (74 mg,124.01 μmol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (1.41 g,12.40 mmol) was added, and stirred slowly to room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (4- (2, 6-dimethylphenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 70 (46 mg, 69.12. Mu. Mol) in a yield of 55.74%.

MS m/z(ESI):497.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.95(brs,2H),8.79(s,1H),8.57–8.50(m,1H),8.13–8.04(m,2H),7.48(dd,J＝8.3,6.8Hz,1H),7.38(d,J＝7.5Hz,2H),6.82(s,1H),5.07–4.94(m,1H),4.23(t,J＝5.9Hz,2H),3.82(s,2H),2.90(s,3H),2.89(t,J＝5.9Hz,3H),1.95(s,6H),1.15(d,J＝6.6Hz,6H).

Example 71

2-(6-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-8-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (3, 4-Dihydro-2H-pyrido [4,3-b ] [1,4] oxazin-8-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

tert-butyl 8-(6-chloropyridin-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxylate

8- (6-Chloropyridin-2-yl) -2, 3-dihydro-4H-pyrido [4,3-b ] [1,4] oxazine-4-carboxylic acid tert-butyl ester

8-Bromo-2, 3-dihydro-4H-pyrido [4,3-b ] [1,4] oxazine-4-carboxylic acid tert-butyl ester 71a (55.08 mg, 174.76. Mu. Mol, prepared according to published patent WO 2018183964A 1) and (6-chloropyridin-2-yl) boronic acid 71b (25 mg, 158.87. Mu. Mol, commercially available) were dissolved in a mixed solvent of 1, 4-dioxane (1 mL) and water (0.2 mL), and 1, 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (11.62 mg, 15.89. Mu. Mol) and potassium phosphate (101.17 mg, 476.61. Mu. Mol) were added and reacted at 80℃for 18 hours under argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give tert-butyl 8- (6-chloropyridin-2-yl) -2, 3-dihydro-4H-pyrido [4,3-b ] [1,4] oxazine-4-carboxylate 71c (17 mg, 48.88. Mu. Mol), yield 30.77%.

MS m/z(ESI):348.1[M+1] ⁺

Second step

tert-butyl

8-(6-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-(isopropyl(methyl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pyridin-2-yl)-2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-carboxylate

8- (6- (4- (((Tert-Butoxycarbonyl) (methyl) amino) methyl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -2, 3-dihydro-4H-pyrido [4,3-b ] [1,4] oxazine-4-carboxylic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (17.03 mg, 48.88. Mu. Mol) and tert-butyl 8- (6-chloropyridin-2-yl) -2, 3-dihydro-4H-pyrido [4,3-b ] [1,4] oxazine-4-carboxylate 71c (17 mg, 48.88. Mu. Mol) were dissolved in 1, 4-dioxane (1 mL), and tris (dibenzylidene-acetone) dipalladium (11.19 mg, 12.22. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (14.14 mg, 24.44. Mu. Mol) and potassium phosphate (31.13 mg, 146.64. Mu. Mol) were added in this order and heated to 70℃for 18 hours. The reaction solution was filtered under suction, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) successively to give tert-butyl 8- (6- (4- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -2, 3-dihydro-4H-pyrido [4,3-b ] [1,4] oxazine-4-carboxylate 71d (29 mg, 43.95. Mu. Mol), yield 89.92%.

MS m/z(ESI):660.2[M+1] ⁺

Third step

8- (6- (4- (((Tert-Butoxycarbonyl) (methyl) amino) methyl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -2, 3-dihydro-4H-pyrido [4,3-b ] [1,4] oxazine-4-carboxylic acid tert-butyl ester 71d (27 mg, 40.92. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (466.61 mg,4.09 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (3, 4-dihydro-2H-pyrido [4,3-b ] [1,4] oxazin-8-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 71 (6 mg, 10.42. Mu. Mol), yield 25.46%.

MS m/z(ESI):460.1[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.89(brs,2H),8.54(d,J＝8.3Hz,1H),8.45(s,1H),8.05(t,J＝8.0Hz,1H),8.02(s,1H),7.82(d,J＝7.6Hz,1H),6.90(s,1H),5.15(s,2H),5.08–4.98(m,1H),4.47(s,2H),4.37(t,J＝6.0Hz,2H),3.55–3.45(m,3H),2.92(s,3H),2.73(t,J＝5.3Hz,3H),1.16(d,J＝6.7Hz,6H).

Example 72

2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-6-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (5, 5-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6- (4-methylpiperazin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

tert-butyl

((2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(4-methylpiperazin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (5, 5-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (4-methylpiperazin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6-chloro-2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 63b (15 mg, 28.63. Mu. Mol) and N-methylpiperazine (57.34 mg, 572.50. Mu. Mol) were dissolved in 1, 4-dioxane (2 mL), and methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (11.98 mg, 14.31. Mu. Mol) and cesium carbonate (27.98 mg, 85.88. Mu. Mol) were added sequentially. Heating to 120 ℃ under the protection of argon, and stirring for reaction for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (4-methylpiperazin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 72a (10 mg, 17.02. Mu. Mol), yield 59.44%.

MS m/z(ESI):588.0[M+1] ⁺

Second step

Tert-butyl ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (4-methylpiperazin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 72a (10 mg, 17.02. Mu. Mol) was dissolved in dichloromethane (3 mL), and a1, 4-dioxane solution of hydrogen chloride (4M, 170.15. Mu.L) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6- (4-methylpiperazin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 72 (3 mg, 4.88. Mu. Mol), yield 28.66%.

MS m/z(ESI):488.3[M+1] ⁺

¹H NMR(400MHz,Methanol-d ₄)δ8.74(d,J＝8.4Hz,1H),8.09–8.01(m,1H),7.86(d,J＝7.6Hz,1H),7.32(d,J＝2.0Hz,1H),5.16(s,2H),4.71(s,2H),4.44(s,2H),3.63(s,2H),3.43–3.12(m,4H),3.15(t,J＝7.5Hz,2H),2.97(s,3H),2.90(s,3H),2.72(t,J＝7.5Hz,2H),1.81(s,6H).

Example 73

2-(6-(4-(2,4-difluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (4- (2, 4-Difluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(2,4-difluorophenyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (2, 4-difluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (300 mg,1.11 mmol) was dissolved in acetonitrile (6 mL) at room temperature, 2, 4-difluoroaniline 73a (428.59 mg,3.32mmol, 338.00. Mu.L) and glacial acetic acid (465.14 mg,7.75mmol, 443.41. Mu.L) were added, and the mixture was warmed to 90℃and reacted for 18 hours with stirring, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 2-bromo-6- (4- (2, 4-difluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine 73b (102 mg, 283.89. Mu. Mol) in 25.66% yield.

MS m/z(ESI):336.7[M+1] ⁺

Second step

tert-butyl

((2-(6-(4-(2,4-difluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (4- (2, 4-Difluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 2-bromo-6- (4- (2, 4-difluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridine 73b (72.56 mg, 215.25. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (81.99 mg, 430.49. Mu. Mol), N, N-dimethylethylenediamine (50.60 mg, 573.99. Mu. Mol) and potassium carbonate (99.16 mg, 717.49. Mu. Mol) were added and reacted under argon atmosphere at 70℃for 24 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl ((2- (6- (4- (2, 4-difluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 73c (67 mg, 87.97. Mu. Mol), yield 61.30%.

MS m/z(ESI):605.3[M+1] ⁺

Third step

Tert-butyl ((2- (6- (4- (2, 4-difluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 73c (61 mg, 100.88. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (1.15 g,10.09 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (4- (2, 4-difluorophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 73 (28 mg, 44.50. Mu. Mol), yield 44.11%.

MS m/z(ESI):505.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.98(brs,2H),8.95(s,1H),8.57(dd,J＝7.3,2.1Hz,1H), 8.16–8.06(m,2H),7.91(td,J＝8.8,5.9Hz,1H),7.77–7.67(m,1H),7.52–7.43(m,1H),6.84(s,1H),5.07–4.95(m,1H),4.14(t,J＝6.1Hz,2H),4.01(s,2H),2.91(s,3H),2.82(t,J＝5.3Hz,3H),1.15(d,J＝6.6Hz,6H).

Example 74

4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

4- (3, 8-Diazabicyclo [3.2.1] oct-3-yl) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

tert-butyl

4-chloro-6-(isopropyl(methyl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate

4-Chloro-6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxylic acid tert-butyl ester

4-Chloro-6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 74a (495mg, 2.07mmol, prepared according to published patent WO2020100027A 1) was dissolved in dichloromethane (20 mL), di-tert-butyl dicarbonate (901.41 mg,4.13mmol, 948.85. Mu.L) and 4-dimethylaminopyridine (126.15 mg,1.03 mmol) were added in sequence and the reaction stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 4-chloro-6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxylic acid tert-butyl ester 74b (680 mg,2.00 mmol), yield 96.90%.

MS m/z(ESI):340.2[M+1] ⁺

Second step

tert-butyl

4-(8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(isopropyl(methyl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate

4- (8- (Tert-Butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxylic acid tert-butyl ester

4-Chloro-6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxylic acid tert-butyl ester 74b (227 mg, 668.01. Mu. Mol) and 3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 74c (283.62 mg,1.34 mmol) were dissolved in1, 4-dioxane (5 mL), and methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (559.37 mg, 668.01. Mu. Mol) and potassium carbonate (184.65 mg,13.4 mmol) were added sequentially. Heating to 100 ℃ under the protection of argon, and stirring for reaction for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl 4- (8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxylate 74d (230 mg, 446.04. Mu. Mol), in 66.77% yield.

MS m/z(ESI):516.3[M+1] ⁺

Third step

4- (3, 8-Diazabicyclo [3.2.1] oct-3-yl) -6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(isopropyl(methyl)amino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

4- (8- (Tert-Butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxylic acid tert-butyl ester 74d (262 mg, 508.10. Mu. Mol) was dissolved in methanol (5 mL), and an ethyl acetate solution of hydrogen chloride (4M, 1.27 mL) was added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to give 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 74e (160 mg,507.27 μmol), 99.84% yield, which was directly used in the next reaction.

MS m/z(ESI):316.0[M+1] ⁺

Fourth step

tert-butyl

3-(6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

3- (6- (Isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

4- (3, 8-Diazabicyclo [3.2.1] oct-3-yl) -6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 74e (160 mg, 507.27. Mu. Mol) was dissolved in dichloromethane (10 mL), and di-tert-butyl dicarbonate (166.07 mg, 760.91. Mu. Mol, 174.81. Mu. L) and triethylamine (256.68 mg,2.54mmol, 353.55. Mu. L) were sequentially added thereto and the reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give tert-butyl 3- (6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate 74f (200 mg, 481.32. Mu. Mol), in a yield of 94.88%.

MS m/z(ESI):416.2[M+1] ⁺

Fifth step

tert-butyl

3-(2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

3- (2- (6- (5, 5-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

3- (6- (Isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 74f (50 mg, 120.33. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 27c (52.91 mg, 180.49. Mu. Mol) were dissolved in 1, 4-dioxane (5 mL), and cuprous iodide (11.43 mg, 60.16. Mu. Mol), N, N-dimethylethylenediamine (5.30 mg, 60.16. Mu. Mol, 6.57. Mu. L) and potassium carbonate (33.26 mg, 240.66. Mu. Mol) were added and reacted under argon atmosphere for 5 hours at 80 ℃. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 74g (40 mg, 63.72. Mu. Mol) of tert-butyl 3- (2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, yield 52.95%.

MS m/z(ESI):629.4[M+1] ⁺

Sixth step

4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one4-(3,8- Diazabicyclo [3.2.1] oct-3-yl) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

3- (2- (6- (5, 5-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 74g (40 mg, 63.72. Mu. Mol) was dissolved in methanol (5 mL), cooled to 0 ℃, and an ethyl acetate solution of hydrogen chloride (4M, 797.5. Mu.L) was added, slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 4- (3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 74 (15 mg, 26.09. Mu. Mol), yield 40.94%.

MS m/z(ESI):528.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.13(brs,2H),8.61(d,J＝8.4Hz,1H),8.05(t,J＝8.0Hz,1H),7.91(d,J＝7.7Hz,1H),6.34(s,1H),5.22(s,2H),4.81–4.69(m,1H),4.18(s,2H),4.00(d,J＝13.1Hz,2H),3.06–2.92(m,4H),2.83(s,3H),2.66–2.54(m,2H),1.98(s,6H),1.31–1.15(m,4H),1.13(d,J＝6.6Hz,6H).

Example 75

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(4-(4-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4- (4-methylpyridin-3-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(4-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (4-methylpyridin-3-yl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (300 mg,1.11 mmol) was dissolved in acetonitrile (6 mL) at room temperature, 4-methylpyridin-3-amine 75a (358.99 mg,3.32 mmol) and glacial acetic acid (465.14 mg,7.75mmol, 443.41. Mu.L) were added, the mixture was warmed to 90℃and stirred for 24 hours, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: G system) to give 2-bromo-6- (4- (4-methylpyridin-3-yl) -4H-1,2, 4-triazol-3-yl) pyridine 75b (97 mg, 305.92. Mu. Mol) in 27.65% yield.

MS m/z(ESI):316.0[M+1] ⁺

Second step

tert-butyl

((6-(isopropyl(methyl)amino)-2-(6-(4-(4-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -2- (6- (4- (4-methylpyridin-3-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 2-bromo-6- (4- (4-methylpyridin-3-yl) -4H-1,2, 4-triazol-3-yl) pyridine 75b (54.44 mg, 172.20. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (81.99 mg, 430.49. Mu. Mol), N, N-dimethylethylenediamine (50.60 mg, 573.99. Mu. Mol) and potassium carbonate (99.16 mg, 717.49. Mu. Mol) were added and reacted under argon atmosphere at 70℃for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (4- (4-methylpyridin-3-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 75c (85 mg, 139.06. Mu. Mol), yield 96.91%.

MS m/z(ESI):584.3[M+1] ⁺

Third step

Tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (4- (4-methylpyridin-3-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 75c (80 mg, 137.06. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (781.38 mg,6.85 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4- (4-methylpyridin-3-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 75 (35 mg, 56.83. Mu. Mol), yield 41.46%.

MS m/z(ESI):484.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.05(brs,2H),8.92(s,1H),8.77–8.70(m,2H),8.53(p,J＝3.9Hz,1H),8.10(d,J＝4.7Hz,2H),7.63(d,J＝5.0Hz,1H),6.82(s,1H),5.07–4.94(m,1H),4.25(s,2H),3.79(s,2H),2.90(s,3H),2.87(t,J＝5.4Hz,3H),2.01(s,3H),1.15(d,J＝6.6Hz,6H).

Example 76

4-((cyclopropylamino)methyl)-2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

4- ((Cyclopropylamino) methyl) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

4-((cyclopropylamino)methyl)-6-(isopropyl(methyl)amino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

4- ((Cyclopropylamino) methyl) -6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(6- (Isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate 76a (20 mg, 63.82. Mu. Mol, prepared according to published patent WO2020100027A 1) was dissolved in tetrahydrofuran (5 mL), and cyclopropylamine (36.44 mg, 638.22. Mu. Mol, 44.22. Mu. L) was then added and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure to give 4- ((cyclopropylamino) methyl) -6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 76b (17.51 mg, 63.82. Mu. Mol), in 100% yield, which was directly used in the next reaction.

MS m/z(ESI):275.2[M+1] ⁺

Second step

tert-butyl

cyclopropyl((6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)carbamate

Cyclopropyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester

4- ((Cyclopropylamino) methyl) -6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 76b (17.51 mg, 63.82. Mu. Mol) was dissolved in tetrahydrofuran (5 mL), di-tert-butyl dicarbonate (27.86 mg, 127.64. Mu. Mol) and triethylamine (12.92 mg, 127.64. Mu. Mol) were added in this order, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give tert-butyl cyclopropyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamate 76c (23 mg, 61.42. Mu. Mol), yield 96.24%.

MS m/z(ESI):375.0[M+1] ⁺

Third step

tert-butyl

cyclopropyl((2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)carbamate

Cyclopropyl ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester

Cyclopropyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester 76c (23 mg, 61.42. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 27c (27.01 mg, 92.13. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (5.83 mg, 30.71. Mu. Mol), N, N-dimethylethylenediamine (2.71 mg, 30.71. Mu. Mol, 3.35. Mu. L) and potassium carbonate (16.98 mg, 122.84. Mu. Mol) were added and heated to 80℃under argon atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl cyclopropyl ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) carbamate 76d (36 mg, 61.36. Mu. Mol), yield 99.90%.

MS m/z(ESI):587.4[M+1] ⁺

Fourth step

Cyclopropyl ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester 76d (36 mg,61.36 μmol) was dissolved in methanol (5 mL), cooled to 0 ℃, and an ethyl acetate solution of hydrogen chloride (4 m,153.39 μl) was added, followed by stirring for 3 hours after slowly warming to room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 4- ((cyclopropylamino) methyl) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 76 (20 mg, 40.28. Mu. Mol), yield 65.65%.

MS m/z(ESI):487.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.28(brs,2H),8.63(d,J＝8.0Hz,1H),8.14–8.05(m,1H),7.91(d,J＝7.6Hz,1H),6.94(s,1H),5.15(s,2H),5.08–4.96(m,1H),4.38(s,2H),3.03(t,J＝7.4Hz,2H),2.94(s,3H),2.89(s,1H),2.61(t,J＝7.6Hz,2H),1.75(s,6H),1.17(d,J＝6.7Hz, 6H),0.95–0.86(m,2H),0.86–0.76(m,2H).

Example 77

6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (7-Azabicyclo [2.2.1] heptan-7-yl) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-chloro-N,N-dimethylisonicotinamide

2- (7-Azabicyclo [2.2.1] heptan-7-yl) -6-chloro-N, N-dimethylisonicotinamide

2, 6-Dichloro-N, N-dimethylisonicotinamide 55a (1 g,4.56 mmol) was dissolved in dimethyl sulfoxide (20 mL), 7-azabicyclo [2.2.1] heptane 77a (1.86 g,13.69 mmol) and cesium fluoride (832.07 mg,5.48 mmol) were added, and the reaction was stirred at 100℃for 50 hours. After dilution with water (30 mL), ethyl acetate (20 mL. Times.3) was used for extraction, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (eluent: A system) to give 2- (7-azabicyclo [2.2.1] heptane-7-yl) -6-chloro-N, N-dimethylisonicotinamide 77b (1.02 g,3.65 mmol) in 79.87% yield.

MS m/z(ESI):280.1[M+1] ⁺

Second step

6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-chloro-3-formyl-N,N-dimethylisonicotinamide

6- (7-Azabicyclo [2.2.1] heptan-7-yl) -2-chloro-3-formyl-N, N-dimethylisonicotinamide

N, N-dimethylformamide (914.39 mg,12.51mmol, 968.64. Mu.L) was dissolved in1, 2-dichloroethane (20 mL), cooled to 0℃and phosphorus oxychloride (1.37 g,8.94mmol, 832.93. Mu.L) was slowly added dropwise thereto, and the mixture was stirred for 30 minutes after warming to room temperature. 2- (7-azabicyclo [2.2.1] heptan-7-yl) -6-chloro-N, N-dimethylisonicotinamide 77b (0.5 g,1.79 mmol) was dissolved in1, 2-dichloroethane (5 mL), and the reaction mixture was added dropwise thereto, and the temperature was raised to 75℃and the reaction was stirred for 18 hours. Saturated ammonium bicarbonate solution was added to adjust pH to alkaline, dichloromethane (20 mL. Times.3) was used for extraction, the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 6- (7-azabicyclo [2.2.1] heptan-7-yl) -2-chloro-3-formyl-N, N-dimethylisonicotinamide 77c (300 mg,974.74 mmol). The yield was 54.54%.

MS m/z(ESI):308.1[M+1] ⁺

Third step

(E)-6-(7-azabicyclo[2.2.1]heptan-7-yl)-3-(((tert-butylsulfinyl)imino)methyl)-2-chloro-N,N-dimethylisonicotinamide

(E) -6- (7-azabicyclo [2.2.1] heptan-7-yl) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-N, N-dimethylisonicotinamide

6- (7-Azabicyclo [2.2.1] heptan-7-yl) -2-chloro-3-formyl-N, N-dimethylisonicotinamide 77c (300 mg, 974.74. Mu. Mol) was dissolved in tetrahydrofuran (15 mL), cooled to 0 ℃, tert-butylsulfinamide (177.21 mg,1.46 mmol) and ethyl titanate (667.04 mg,2.92 mmol) were added, reacted at 50℃for 2 hours, cooled to room temperature, diluted with ethyl acetate (40 mL), saturated sodium bicarbonate solution (40 mL), stirred for 30 minutes, filtered, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give (E) -6- (7-azabicyclo [2.2.1] heptan-7-yl) -3- (((tert-butylsulfinyl) iminomethyl) -2-chloro-N, N-dimethylisonicotinamide (77.77 mg, 77. Mu. Mu.00%).

MS m/z(ESI):411.2[M+1] ⁺

Fourth step

6-(7-azabicyclo[2.2.1]heptan-7-yl)-4-chloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (7-Azabicyclo [2.2.1] heptan-7-yl) -4-chloro-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(E) -6- (7-azabicyclo [2.2.1] heptan-7-yl) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-N, N-dimethylisonicotinamide 77d (180 mg, 438.00. Mu. Mol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 ℃, lithium borohydride (2M, 438.00. Mu.L) was added, the reaction was continued with stirring at 0℃for 1 hour, sodium methoxide (354.91 mg,6.57mmol, 365.89. Mu.L) was added, the reaction was quenched by adding water (10 mL) slowly warmed to room temperature for 5 hours, ethyl acetate (15 mL. Times.3) was extracted, the organic phase was combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 6- (7-azabicyclo [2.2.1] heptan-7-yl) -4-chloro-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine (84.98 mg, 84.98%).

MS m/z(ESI):264.1[M+1] ⁺

Fifth step

methyl

6-(7-azabicyclo[2.2.1]heptan-7-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

6- (7-Azabicyclo [2.2.1] heptan-7-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carboxylic acid methyl ester

6- (7-Azabicyclo [2.2.1] heptan-7-yl) -4-chloro-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 77e (98 mg, 371.60. Mu. Mol) was dissolved in methanol (10 mL), triethylamine (75.21 mg, 743.21. Mu. Mol) and 1, 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (64.35 mg, 37.16. Mu. Mol) were added thereto, and the mixture was stirred under carbon monoxide atmosphere at a temperature of 60℃for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give methyl 6- (7-azabicyclo [2.2.1] heptan-7-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carboxylate 77f (81 mg, 281.92. Mu. Mol), in a yield of 75.87%.

MS m/z(ESI):288.1[M+1] ⁺

Sixth step

6-(7-azabicyclo[2.2.1]heptan-7-yl)-4-(hydroxymethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (7-Azabicyclo [2.2.1] heptan-7-yl) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

Methyl 6- (7-azabicyclo [2.2.1] heptan-7-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridine-4-carboxylate 77f (81 mg, 281.92. Mu. Mol) was dissolved in tetrahydrofuran (10 mL), a solution of lithium borohydride in tetrahydrofuran (2M, 704.81. Mu.L) was slowly added dropwise thereto, the mixture was stirred for 2 hours after warming to room temperature, water (1 mL) was added thereto, the reaction mixture was quenched, and the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 77g (70 mg,269. Mu. Mol) of 6- (7-azabicyclo [2.2.1] heptan-7-yl) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-1-one in a yield of 95.75%.

MS m/z(ESI):260.0[M+1] ⁺

Seventh step

(6-(7-azabicyclo[2.2.1]heptan-7-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methylmethanesulfonate

(6- (7-Azabicyclo [2.2.1] heptan-7-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate

77G (70 mg, 269.95. Mu. Mol) of 6- (7-azabicyclo [2.2.1] heptan-7-yl) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one was dissolved in tetrahydrofuran (5 mL), cooled to 0 ℃, triethylamine (32.78 mg, 323.95. Mu. Mol) and methylsulfonyl chloride (61.85 mg, 539.91. Mu. Mol, 41.79. Mu. L) were added, respectively, and stirring was continued at 0℃for 2 hours, the reaction was quenched with saturated sodium bicarbonate solution (2 mL), extracted with ethyl acetate (10 mL. Times.3), the organic phase was combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (6- (7-azabicyclo [2.2.1] heptan-7-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methylmethanesulfonate 77H (70 mg, 207.47. Mu. For further direct reaction in 76.85% yield.

MS m/z(ESI):338.1[M+1] ⁺

Eighth step

6-(7-azabicyclo[2.2.1]heptan-7-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (7-Azabicyclo [2.2.1] heptan-7-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(6- (7-Azabicyclo [2.2.1] heptan-7-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate 77H (70 mg, 207.47. Mu. Mol) was dissolved in tetrahydrofuran (10 mL), a solution of methylamine in tetrahydrofuran (2M, 2.07 mL) was added, and the reaction mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure to give 6- (7-azabicyclo [2.2.1] heptan-7-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 77i (56 mg, 205.62. Mu. Mol) in 99.11% yield, which was used directly in the next step.

MS m/z(ESI):273.2[M+1] ⁺

Ninth step

tert-butyl

((6-(7-azabicyclo[2.2.1]heptan-7-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (7-Azabicyclo [2.2.1] heptan-7-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

6- (7-Azabicyclo [2.2.1] heptan-7-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 77i (56 mg, 205.62. Mu. Mol) was dissolved in tetrahydrofuran (10 mL), triethylamine (31.21 mg, 308.43. Mu. Mol) and di-tert-butyl dicarbonate (49.36 mg, 226.18. Mu. Mol) were added, respectively, and the reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give ((6- (7-azabicyclo [2.2.1] heptan-7-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 77j (57 mg, 153.04. Mu. Mol) in a yield of 74.43%.

MS m/z(ESI):373.2[M+1] ⁺

Tenth step

tert-butyl

((6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (7-Azabicyclo [2.2.1] heptan-7-yl) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (7-azabicyclo [2.2.1] heptan-7-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 77j (50 mg, 134.24. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 27c (47.23 mg, 161.09. Mu. Mol) were dissolved in1, 4-dioxane (6 mL), and cuprous iodide (5.10 mg, 26.85. Mu. Mol), N, N-dimethylethylenediamine (2.37 mg, 26.85. Mu. Mol) and potassium carbonate (22.26 mg, 161.09. Mu. Mol) were added and reacted under argon atmosphere at 60℃for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (7-azabicyclo [2.2.1] heptan-7-yl) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 77k (50 mg, 85.51. Mu. Mol), yield 63.70%.

MS m/z(ESI):585.3[M+1] ⁺

Eleventh step

Tert-butyl ((6- (7-azabicyclo [2.2.1] heptan-7-yl) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 77k (50 mg, 85.51. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, and trifluoroacetic acid (48.75 mg, 427.56. Mu. Mol) was added, slowly warmed to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (7-azabicyclo [2.2.1] heptan-7-yl) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 77 (20 mg, 32.34. Mu. Mol), yield 37.82%.

MS m/z(ESI):485.2[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.93(brs,2H),8.61(d,J＝8.1Hz,1H),8.14–8.07(m,1H),7.92(d,J＝7.6Hz,1H),7.24(s,1H),5.11(s,2H),4.77(s,2H),4.34(t,J＝5.9Hz,2H),3.03(t,J＝7.4Hz,2H),2.75(t,J＝5.4Hz,3H),2.60(t,J＝7.4Hz,2H),1.73(s,6H),1.72–1.65(m,4H),1.50(d,J＝7.0Hz,4H).

Example 78

2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(3,5-dimethylpiperidin-1-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (5, 5-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (3, 5-dimethylpiperidin-1-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-chloro-6-(3,5-dimethylpiperidin-1-yl)-N,N-dimethylisonicotinamide

2-Chloro-6- (3, 5-dimethylpiperidin-1-yl) -N, N-dimethylisonicotinamide

2, 6-Dichloro-N, N-dimethylisonicotinamide 55a (600 mg,2.74 mmol) was dissolved in acetonitrile (10 mL), 3, 5-dimethylpiperidine 78a (1.86 g,13.69 mmol) was added, and the mixture was warmed to 100℃and stirred for 5 hours with sealing. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 2-chloro-6- (3, 5-dimethylpiperidin-1-yl) -N, N-dimethylisonicotinamide 78b (800 mg,2.70 mmol) in 98.74% yield.

MS m/z(ESI):296.2[M+1] ⁺

Second step

2-chloro-6-(3,5-dimethylpiperidin-1-yl)-3-formyl-N,N-dimethylisonicotinamide

2-Chloro-6- (3, 5-dimethylpiperidin-1-yl) -3-formyl-N, N-dimethylisonicotinamide

N, N-dimethylformamide (691.84 mg,9.47mmol, 736.00. Mu.L) was dissolved in 1, 2-dichloroethane (10 mL), cooled to 0℃and phosphorus oxychloride (1.45 g,9.47mmol, 884.98. Mu.L) was slowly added dropwise thereto, and the mixture was stirred for 30 minutes after warming to room temperature. 2-chloro-6- (3, 5-dimethylpiperidin-1-yl) -N, N-dimethylisonicotinamide 78b (700 mg,2.37 mmol) was dissolved in 1, 2-dichloroethane (3 mL), and the reaction mixture was added dropwise thereto, and the temperature was raised to 75℃and the reaction was stirred for 5 hours. Saturated ammonium bicarbonate solution was added to adjust pH to alkaline, dichloromethane (15 mL. Times.3) was used for extraction, the organic phases were combined, washed with water (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 2-chloro-6- (3, 5-dimethylpiperidin-1-yl) -3-formyl-N, N-dimethylisonicotinamide 78c (700 mg,2.16 mmol). The yield was 91.35%.

MS m/z(ESI):324.2[M+1] ⁺

Third step

(E)-3-(((tert-butylsulfinyl)imino)methyl)-2-chloro-6-(3,5-dimethylpiperidin-1-yl)-N,N-dimethylisonicotinamide

(E) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-6- (3, 5-dimethylpiperidin-1-yl) -N, N-dimethylisonicotinamide

2-Chloro-6- (3, 5-dimethylpiperidin-1-yl) -3-formyl-N, N-dimethylisonicotinamide 78c (700 mg,2.16 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0℃and tert-butylsulfinamide (393.00 mg,3.24 mmol) and ethyl titanate (1.48 g,6.49mmol,1.36 mL) were added, reacted for 3 hours at 50℃cooled to room temperature, diluted with ethyl acetate, saturated sodium bicarbonate solution (40 mL) was added, stirred for 30 minutes, filtered, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give (E) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-6- (3, 5-dimethylpiperidin-1-yl) -N, N-dimethylisonicotinamide 78d (mg, 2.900 mmol) in 97.50% yield.

MS m/z(ESI):427.0[M+1] ⁺

Fourth step

4-chloro-6-(3,5-dimethylpiperidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

4-Chloro-6- (3, 5-dimethylpiperidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(E) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-6- (3, 5-dimethylpiperidin-1-yl) -N, N-dimethylisonicotinamide 78d (900 mg,2.11 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0℃and lithium borohydride (91.81 mg,4.22 mmol) was added, the reaction was continued with stirring at 0℃for 1 hour, sodium methoxide (1.14 g,21.08 mmol) was added, the reaction was stirred slowly at room temperature for 5 hours, water (5 mL) was added to quench the reaction, ethyl acetate (15 mL. Times.3) was extracted, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 4-chloro-6- (3, 5-dimethylpiperidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one (39 mg, 5mmol, 66.99% yield).

MS m/z(ESI):280.0[M+1] ⁺

Fifth step

methyl

6-(3,5-dimethylpiperidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

6- (3, 5-Dimethylpiperidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carboxylic acid methyl ester

4-Chloro-6- (3, 5-dimethylpiperidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 78e (399mg, 1.41 mmol) was dissolved in methanol (10 mL), triethylamine (428.61 mg,4.24mmol, 590.37. Mu.L) and 1, 1-bis (diphenylphosphine) iron-palladium dichloride (103.31 mg, 141.19. Mu. Mol) were added thereto, and the reaction was stirred under carbon monoxide atmosphere at 60℃for 18 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give methyl 6- (3, 5-dimethylpiperidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carboxylate 78f (365 mg,1.20 mmol), yield 85.22%.

MS m/z(ESI):304.1[M+1] ⁺

Sixth step

6-(3,5-dimethylpiperidin-1-yl)-4-(hydroxymethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (3, 5-Dimethylpiperidin-1-yl) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

Methyl 6- (3, 5-dimethylpiperidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridine-4-carboxylate 78f (365 mg,1.20 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0℃and lithium borohydride (52.41 mg,2.41 mmol) was slowly added dropwise, stirred for 18 hours after warming to room temperature, quenched with water (1 mL), the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: C system) to give 78g (250 mg, 907.95. Mu. Mol) of 6- (3, 5-dimethylpiperidin-1-yl) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-1-one, the yield was 75.46%.

MS m/z(ESI):276.1[M+1] ⁺

Seventh step

(6-(3,5-dimethylpiperidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methylmethanesulfonate

(6- (3, 5-Dimethylpiperidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate

78G (250 mg, 907.95. Mu. Mol) of 6- (3, 5-dimethylpiperidin-1-yl) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one was dissolved in tetrahydrofuran (10 mL), cooled to 0℃and triethylamine (367.50 mg,3.63mmol, 506.20. Mu.L) and methylsulfonyl chloride (208.01 mg,1.82mmol, 140.55. Mu.L) were added, respectively, and stirring was continued at 0℃for 2 hours, the reaction was quenched with saturated sodium bicarbonate solution (2 mL), extracted with ethyl acetate (10 mL. Times.3), the organic phase was combined, washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give (6- (3, 5-dimethylpiperidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-methylsulfonate (57 mg, 25. Mu.57 mol) in yield of 57H (57 mg, 52%).

MS m/z(ESI):354.2[M+1] ⁺

Eighth step

6-(3,5-dimethylpiperidin-1-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (3, 5-Dimethylpiperidin-1-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(6- (3, 5-Dimethylpiperidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate 78H (120 mg, 339.52. Mu. Mol) was dissolved in methylene chloride (10 mL), a solution of methylamine in ethanol (content 30-33%,105.45mg,3.40 mmol) was added thereto, the reaction mixture was stirred at room temperature for 18 hours, and the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: B system) to give 6- (3, 5-dimethylpiperidin-1-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 78i (30 mg, 104.03. Mu. Mol), yield 30.64%.

MS m/z(ESI):289.2[M+1] ⁺

Ninth step

tert-butyl

((6-(3,5-dimethylpiperidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (3, 5-Dimethylpiperidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

6- (3, 5-Dimethylpiperidin-1-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 78i (40 mg, 138.70. Mu. Mol) was dissolved in methylene chloride (5 mL), triethylamine (28.07 mg, 277.41. Mu. Mol, 38.66. Mu.L) and di-tert-butyl dicarbonate (60.54 mg, 277.41. Mu. Mol, 63.73. Mu. L) were sequentially added, the reaction mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give ((6- (3, 5-dimethylpiperidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 78j (33 mg, 84.94. Mu. Mol), yield 61.24%.

MS m/z(ESI):389.3[M+1] ⁺

Tenth step

tert-butyl

((2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(3,5-dimethylpiperidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (5, 5-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (3, 5-dimethylpiperidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (3, 5-dimethylpiperidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 78j (33 mg, 84.94. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 27c (37.35 mg, 127.41. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (8.07 mg, 42.47. Mu. Mol), N, N-dimethylethylenediamine (3.74 mg, 42.47. Mu. Mol), 4.64. Mu. L) and potassium carbonate (23.48 mg, 169.88. Mu. Mol) were added and reacted under argon atmosphere at 100℃for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (3, 5-dimethylpiperidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 78k (30 mg, 24.97. Mu. Mol) in 29.40% yield.

MS m/z(ESI):601.3[M+1] ⁺

Eleventh step

Tert-butyl ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (3, 5-dimethylpiperidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 78k (30 mg, 24.97. Mu. Mol) was dissolved in methanol (5 mL), cooled to 0 ℃, and an ethyl acetate solution of hydrogen chloride (18.23 mg, 499.37. Mu. Mol) was added, and stirred for 1 hour after slowly warming to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (3, 5-dimethylpiperidin-1-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 78 (5 mg, 9.74. Mu. Mol), yield 19.50%.

MS m/z(ESI):501.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.61(d,J＝8.4Hz,1H),8.09(t,J＝8.1Hz,1H),7.92(d,J＝7.6Hz,1H),7.13(s,1H),5.11(s,2H),4.49(d,J＝12.9Hz,2H),4.27(s,2H),3.02(t,J＝7.4Hz,2H),2.93(q,J＝7.3Hz,2H),2.71(s,3H),2.60(t,J＝7.5Hz,2H),2.36(t,J＝12.1Hz,2H),1.67–1.51(m,2H),1.16(t,J＝7.2Hz,6H),0.95(d,J＝6.5Hz,6H).

Example 79

2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-4-(piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (5, 5-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- (piperazin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

tert-butyl

4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-(isopropyl(methyl)amino)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxylate

4- (4- (Tert-Butoxycarbonyl) piperazin-1-yl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxylic acid tert-butyl ester

4-Chloro-6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxylic acid tert-butyl ester 74b (80 mg, 235.42. Mu. Mol) and piperazine-1-carboxylic acid tert-butyl ester 79a (87.69 mg, 470.84. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (19.71 mg, 23.54. Mu. Mol) and potassium carbonate (65.08 mg, 470.84. Mu. Mol) were added in this order, and the mixture was heated to 100℃under argon atmosphere and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl 4- (4- (tert-butoxycarbonyl) piperazin-1-yl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxylate 79b (100 mg, 204.25. Mu. Mol), in a yield of 86.76%.

MS m/z(ESI):490.3[M+1] ⁺

Second step

6-(isopropyl(methyl)amino)-4-(piperazin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- (piperazin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

4- (4- (Tert-Butoxycarbonyl) piperazin-1-yl) -6- (isopropyl (methyl) amino) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxylic acid tert-butyl ester 79b (100 mg, 204.25. Mu. Mol) was dissolved in dichloromethane (10 mL), and a1, 4-dioxane solution of hydrogen chloride (4M, 0.5 mL) was added and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to give 6- (isopropyl (methyl) amino) -4- (piperazin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 79c (59 mg,203.89 mmol), 99.82% yield, which was directly used in the next reaction.

MS m/z(ESI):290.3[M+1] ⁺

Third step

tert-butyl

4-(6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)piperazine-1-carboxylate

4- (6- (Isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

6- (Isopropyl (methyl) amino) -4- (piperazin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 79c (59 mg,203.89 mmol) was dissolved in tetrahydrofuran (15 mL), di-tert-butyl dicarbonate (89.00 mg, 407.78. Mu. Mol) and triethylamine (24.76 mg, 244.67. Mu. Mol) were added in this order, and the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give tert-butyl 4- (6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) 1-carboxylate 79d (68 mg,174.59 μmol), yield 85.63%.

MS m/z(ESI):390.2[M+1] ⁺

Fourth step

tert-butyl

4-(2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)piperazine-1-carboxylate

4- (2- (6- (5, 5-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

4- (6- (Isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester 79d (68 mg, 174.59. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 27c (61.42 mg, 209.50. Mu. Mol) were dissolved in1, 4-dioxane (6 mL), and cuprous iodide (48.26 mg, 349.17. Mu. Mol), N, N-dimethylethylenediamine (3.08 mg, 34.92. Mu. Mol) and potassium carbonate (48.26 mg, 349.17. Mu. Mol) were added and reacted for 18 hours under argon atmosphere at 80 ℃. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl 4- (2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) piperazine-1-carboxylate 79e (86 mg, 142.92. Mu. Mol), in a yield of 81.86%.

MS m/z(ESI):602.3[M+1] ⁺

Fifth step

4- (2- (6- (5, 5-Dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester 79e (86 mg, 142.92. Mu. Mol) was dissolved in dichloromethane (6 mL), cooled to 0 ℃, and trifluoroacetic acid (65.18 mg, 571.67. Mu. Mol) was added and stirred for 1 hour after slow warming to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -4- (piperazin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 79 (33 mg, 53.01. Mu. Mol) in a yield of 37.09%.

MS m/z(ESI):502.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ(brs,2H),8.64(d,J＝8.4Hz,1H),8.07(t,J＝8.0Hz,1H),7.92(d,J＝7.6Hz,1H),6.37(s,1H),5.20(s,2H),4.77(p,J＝6.7Hz,1H),3.78–3.70(m,4H),3.25(s,4H),3.02(t,J＝7.5Hz,2H),2.85(s,3H),2.60(t,J＝7.5Hz,2H),1.72(s,6H),1.14(d,J＝6.7Hz,6H).

Example 80

(R)-4-((methylamino)methyl)-6-(2-methylpyrrolidin-1-yl)-2-(6-(4-(1-(trifluoromethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(R) -4- ((methylamino) methyl) -6- (2-methylpyrrolidin-1-yl) -2- (6- (4- (1- (trifluoromethyl) cyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

(R)-2-chloro-N,N-dimethyl-6-(2-methylpyrrolidin-1-yl)isonicotinamide

(R) -2-chloro-N, N-dimethyl-6- (2-methylpyrrolidin-1-yl) isonicotinamide

2, 6-Dichloro-N, N-dimethylisonicotinamide 55a (3.95 g,18.03 mmol) was dissolved in dimethyl sulfoxide (25 mL), and (R) -2-methylpyrrolidine hydrochloride 80a (3.29 g,27.05 mmol) and cesium fluoride (8.22 g,54.09 mmol) were added, and the mixture was warmed to 100℃and stirred for 5 hours with sealing. Water (75 mL) and ethyl acetate (50 mL) were added to dilute the mixture, the aqueous phase was extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with water (75 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give (R) -2-chloro-N, N-dimethyl-6- (2-methylpyrrolidin-1-yl) isonicotinamide 80b (4.8 g,17.93 mmol) in 99.42% yield.

MS m/z(ESI):268.1[M+1] ⁺

Second step

(R)-2-chloro-3-formyl-N,N-dimethyl-6-(2-methylpyrrolidin-1-yl)isonicotinamide

(R) -2-chloro-3-formyl-N, N-dimethyl-6- (2-methylpyrrolidin-1-yl) isonicotinamide

N, N-dimethylformamide (5.24 g,71.71mmol,5.58 mL) was dissolved in 1, 2-dichloroethane (100 mL), cooled to 0℃and phosphorus oxychloride (10.99 g,71.71mmol,6.70 mL) was slowly added dropwise, and the mixture was stirred for 30 minutes after warming to room temperature. (R) -2-chloro-N, N-dimethyl-6- (2-methylpyrrolidin-1-yl) isonicotinamide 80b (4.8 g,17.93 mmol) was dissolved in 1, 2-dichloroethane (30 mL), and the solution was added dropwise to the reaction mixture, and the mixture was heated to 75℃and stirred for 18 hours. Saturated ammonium bicarbonate solution was added to adjust pH to alkaline, dichloromethane (150 mL. Times.3) was added to extract, the organic phases were combined, washed with water (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give (R) -2-chloro-3-formyl-N, N-dimethyl-6- (2-methylpyrrolidin-1-yl) isonicotinamide 80c (4 g,13.52 mmol) in 75.44% yield.

MS m/z(ESI):296.1[M+1] ⁺

Third step

3-((E)-((tert-butylsulfinyl)imino)methyl)-2-chloro-N,N-dimethyl-6-((R)-2-methylpyrrolidin-1-yl)isonicotinamide

3- ((E) - ((tert-butylsulfinyl) imino) methyl) -2-chloro-N, N-dimethyl-6- ((R) -2-methylpyrrolidin-1-yl) isonicotinamide

(R) -2-chloro-3-formyl-N, N-dimethyl-6- (2-methylpyrrolidin-1-yl) isonicotinamide 80c (270 mg, 912.89. Mu. Mol) was dissolved in tetrahydrofuran (10 mL), cooled to 0℃and tert-butylsulfinamide (165.96 mg,1.37 mmol) and ethyl titanate (624.71 mg,2.74mmol, 574.19. Mu.L) were added, reacted at 50℃for 3 hours, cooled to room temperature, diluted with ethyl acetate, saturated aqueous sodium bicarbonate (50 mL) was added, stirred for 30 minutes, filtered, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (eluent: A system) to give 3- ((E) - ((tert-butylsulfinyl) imino) methyl) -2-chloro-N, N-dimethyl-6- ((R) -2-methylpyrrolidin-1-yl) isonicotinamide 80d (300 mg, 82.37. Mu.97% yield.

MS m/z(ESI):399.2[M+1] ⁺

Fourth step

(R)-4-chloro-6-(2-methylpyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(R) -4-chloro-6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

3- ((E) - ((tert-butylsulfinyl) imino) methyl) -2-chloro-N, N-dimethyl-6- ((R) -2-methylpyrrolidin-1-yl) isonicotinamide 80d (6 g,15.04 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0℃and lithium borohydride (655.12 mg,30.08 mmol) was added, the reaction was continued with stirring at 0℃for 1 hour, sodium methoxide (12.19 g,225.59 mmol) was added, stirred slowly to room temperature for 5 hours, quenched with water (30 mL), extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with water (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give (R) -4-chloro-6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one (35.36 g, 35.13 mmol), yield 80.35.35 mmol).

MS m/z(ESI):252.1[M+1] ⁺

Fifth step

methyl

(R)-6-(2-methylpyrrolidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

(R) -6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carboxylic acid methyl ester

(R) -4-chloro-6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 80e (2.61 g,10.37 mmol) was dissolved in methanol (16 mL), triethylamine (3.15 g,31.11mmol,4.34 mL) was added, and 1, 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (1.80 g,1.04 mmol) was stirred under carbon monoxide atmosphere at a temperature of 60℃for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give methyl (R) -6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carboxylate 80f (2.48 g,9.01 mmol), in a yield of 86.88%.

MS m/z(ESI):276.2[M+1] ⁺

Sixth step

(R)-4-(hydroxymethyl)-6-(2-methylpyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(R) -4- (hydroxymethyl) -6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(R) -6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridine-4-carboxylic acid methyl ester 80f (2.71 g,9.84 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to 0 ℃, lithium borohydride (428.79 mg,19.69 mmol) was slowly added dropwise, stirred for 18 hours after warming to room temperature, water (1 mL) was added to quench the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 80g (2.3 g,9.30 mmol) of (R) -4- (hydroxymethyl) -6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-1-one, and the yield was 94.48%.

MS m/z(ESI):248.2[M+1] ⁺

Seventh step

(R)-(6-(2-methylpyrrolidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methylmethanesulfonate

(R) - (6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate

80G (850 mg,3.44 mmol) of (R) -4- (hydroxymethyl) -6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one was dissolved in tetrahydrofuran (100 mL), cooled to 0℃and triethylamine (1.74 g,17.19 mmol) and methylsulfonyl chloride (1.18 g,10.31 mmol) were added, respectively, stirring was continued for 1 hour at 0℃and the reaction was quenched with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with water (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 80H (1.1 g,3.38 mmol) of (R) - (6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methylsulfonate, which was used directly in the next reaction.

MS m/z(ESI):326.1[M+1] ⁺

Eighth step

(R)-4-((methylamino)methyl)-6-(2-methylpyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(R) -4- ((methylamino) methyl) -6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(R) - (6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate 80H (1.1 g,3.38 mmol) was dissolved in dichloromethane (80 mL), an ethanol solution of methylamine (content 30-33%,10.50g,101.42 mmol) was added, stirred at room temperature for 2 hours, and the reaction mixture was concentrated under reduced pressure to give (R) -4- ((methylamino) methyl) -6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 80i (870 mg,3.34 mmol) in 98.85% yield.

MS m/z(ESI):261.2[M+1] ⁺

Ninth step

tert-butyl

(R)-methyl((6-(2-methylpyrrolidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)carbamate

(R) -methyl ((6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester

(R) -4- ((methylamino) methyl) -6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 80i (79mg, 3.04 mmol) was dissolved in tetrahydrofuran (20 mL), triethylamine (615.69 mg,6.08mmol, 848.06. Mu.L) and di-tert-butyl dicarbonate (1.33 g,6.08mmol,1.40 mL) were added respectively, the reaction mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl (R) -methyl ((6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamate 80j (900 mg,2.50 mmol) in 82.07% yield.

MS m/z(ESI):361.1[M+1] ⁺

Tenth step

tert-butyl

(R)-methyl((6-(2-methylpyrrolidin-1-yl)-1-oxo-2-(6-(4-(1-(trifluoromethyl)cyclopropyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)carbamate

(R) -methyl ((6- (2-methylpyrrolidin-1-yl) -1-oxo-2- (6- (4- (1- (trifluoromethyl) cyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester

(R) -methyl ((6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester 80j (50 mg, 138.72. Mu. Mol) and 2-bromo-6- (4- (1- (trifluoromethyl) cyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridine 59b (92.41 mg, 277.43. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (79.26 mg, 416.15. Mu. Mol), N, N-dimethylethylenediamine (48.91 mg, 554.86. Mu. Mol, 60.61. Mu. L) and potassium carbonate (95.86 mg, 693.58. Mu. Mol) were added and heated to 70℃under argon atmosphere for reaction for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl (R) -methyl ((6- (2-methylpyrrolidin-1-yl) -1-oxo-2- (6- (4- (1- (trifluoromethyl) cyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamate 80k (52 mg, 51.78. Mu. Mol) in a yield of 37.32%.

MS m/z(ESI):613.3[M+1] ⁺

Eleventh step

(R) -methyl ((6- (2-methylpyrrolidin-1-yl) -1-oxo-2- (6- (4- (1- (trifluoromethyl) cyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester 80k (45 mg, 73.45. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (418.75 mg,3.67 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give (R) -4- ((methylamino) methyl) -6- (2-methylpyrrolidin-1-yl) -2- (6- (4- (1- (trifluoromethyl) cyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 80 (15 mg, 23.06. Mu. Mol), yield 31.39%.

MS m/z(ESI):513.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.04(s,1H),8.90(brs,2H),8.70(d,J＝8.4Hz,1H),8.17–8.09(m,1H),7.91(d,J＝7.5Hz,1H),6.75(s,1H),5.05(s,2H),4.34(d,J＝6.3Hz,1H),4.27(s,2H),3.64(t,J＝8.9Hz,1H),3.46–3.36(m,1H),2.75(s,3H),2.58–2.54(m,1H),2.17– 1.95(m,3H),1.88–1.80(m,2H),1.79–1.68(m,2H),1.20(d,J＝6.2Hz,3H).

Example 81

2-(3-(6-(6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pyridin-2-yl)-4H-1,2,4-triazol-4-yl)benzonitrile

2- (3- (6- (6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -4H-1,2, 4-triazol-4-yl) benzonitrile

First step

2-bromo-6-(4-(2-bromophenyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (2-bromophenyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (1G, 3.69 mmol) was dissolved in acetonitrile (50 mL) at room temperature, 2-bromoaniline 81a (3.17G, 18.44 mmol) and glacial acetic acid (2.21G, 36.88mmol,2.11 mL) were added, the mixture was warmed to 90℃and stirred for 18 hours, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: G system) to give 2-bromo-6- (4- (2-bromophenyl) -4H-1,2, 4-triazol-3-yl) pyridine 81b (126 mg, 267.89. Mu. Mol) in 7.26% yield.

MS m/z(ESI):378.9[M+1] ⁺

Second step

tert-butyl

((2-(6-(4-(2-bromophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (4- (2-Bromophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (60 mg, 172.20. Mu. Mol) and 2-bromo-6- (4- (2-bromophenyl) -4H-1,2, 4-triazol-3-yl) pyridine 81b (119.98 mg, 189.42. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (98.38 mg, 516.59. Mu. Mol), N, N-dimethylethylenediamine (60.72 mg, 688.79. Mu. Mol) and potassium carbonate (119.00 mg, 860.98. Mu. Mol) were added and reacted under argon atmosphere at 70℃for 24 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl ((2- (6- (4- (2-bromophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 81c (100 mg, 135.14. Mu. Mol), yield 78.48%.

MS m/z(ESI):647.3[M+1] ⁺

Third step

tert-butyl

((2-(6-(4-(2-cyanophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(isopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (4- (2-Cyanophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((2- (6- (4- (2-bromophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 81c (40 mg, 61.77. Mu. Mol) was dissolved in N-methylpyrrolidone (2 mL), zinc cyanide (36.27 mg, 308.85. Mu. Mol) and tetrakis (triphenylphosphine) palladium (17.84 mg, 15.44. Mu. Mol) were added in this order, and the reaction was heated to 120℃under argon atmosphere with microwave stirring for 4 hours. After the reaction solution was cooled to 0℃and quenched with an aqueous solution of ferrous sulfate (5 mL), diluted with water (20 mL), extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl ((2- (6- (4- (2-cyanophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 81d (40 mg, 57.84. Mu. Mol) in 93.64% yield.

MS m/z(ESI):594.3[M+1] ⁺

Fourth step

Tert-butyl ((2- (6- (4- (2-cyanophenyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 81d (35 mg, 58.95. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (67.22 mg, 589.55. Mu. Mol) was added, and the mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 81 (18 mg, 28.35. Mu. Mol) of 2- (3- (6- (6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -4H-1,2, 4-triazol-4-yl) benzonitrile in a yield of 48.09%.

MS m/z(ESI):494.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.05(s,1H),8.90(brs,2H),8.59–8.53(m,1H),8.21(dd,J＝7.7,1.5Hz,1H),8.16–8.10(m,2H),8.08–8.01(m,1H),7.94–7.87(m,2H),6.83(s,1H),5.06–4.93(m,1H),4.20–4.08(m,2H),3.77(s,2H),2.90(s,3H),2.88(t,J＝5.3Hz,3H),1.15(d,J＝6.6Hz,6H).

Example 82

6-(cyclopropyl(methyl)amino)-2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Cyclopropyl (methyl) amino) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-chloro-6-(cyclopropyl(methyl)amino)-N,N-dimethylisonicotinamide

2-Chloro-6- (cyclopropyl (methyl) amino) -N, N-dimethylisonicotinamide

2, 6-Dichloro-N, N-dimethylisonicotinamide 55a (400 mg,1.83 mmol) was dissolved in dimethyl sulfoxide (5 mL), N-methylcyclopropylamine hydrochloride 82a (196.44 mg,1.83 mmol) and cesium fluoride (832.07 mg,5.48 mmol) were added, and the mixture was heated to 100℃and stirred for 20 hours. Water (5 mL) and ethyl acetate (10 mL) were added to dilute the mixture, the aqueous phase was extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 2-chloro-6- (cyclopropyl (methyl) amino) -N, N-dimethylisonicotinamide 82b (460 mg,1.81 mmol) in 99.29% yield.

MS m/z(ESI):254.1[M+1] ⁺

Second step

2-chloro-6-(cyclopropyl(methyl)amino)-3-formyl-N,N-dimethylisonicotinamide

2-Chloro-6- (cyclopropyl (methyl) amino) -3-formyl-N, N-dimethylisonicotinamide

N, N-dimethylformamide (345.68 mg,4.73mmol, 366.18. Mu.L) was dissolved in 1, 2-dichloroethane (20 mL), cooled to 0℃and phosphorus oxychloride (725.17 mg,4.73mmol, 440.83. Mu.L) was slowly added dropwise thereto, and after warming to room temperature, it was stirred for 30 minutes, 2-chloro-6- (cyclopropyl (methyl) amino) -N, N-dimethylisonicotinamide 82b (400 mg,1.58 mmol) was dissolved in 1, 2-dichloroethane (5 mL), and the reaction mixture was added dropwise thereto, and the temperature was raised to 75℃and stirred for 18 hours. Saturated ammonium bicarbonate aqueous solution was added to adjust pH to basicity, dichloromethane (30 mL. Times.3) was added to extract, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 2-chloro-6- (cyclopropyl (methyl) amino) -3-formyl-N, N-dimethylisonicotinamide 82c (270 mg, 958.34. Mu. Mol) in a yield of 60.79%.

MS m/z(ESI):282.1[M+1] ⁺

Third step

(E)-3-(((tert-butylsulfinyl)imino)methyl)-2-chloro-6-(cyclopropyl(methyl)amino)-N,N-dimethylisonicotinamide

(E) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-6- (cyclopropyl (methyl) amino) -N, N-dimethylisonicotinamide

2-Chloro-6- (cyclopropyl (methyl) amino) -3-formyl-N, N-dimethylisonicotinamide 82c (270 mg, 958.34. Mu. Mol) was dissolved in tetrahydrofuran (15 mL), cooled to 0 ℃, tert-butylsulfinamide (348.45 mg,2.88 mmol) and ethyl titanate (655.82 mg,2.88 mmol) were added, heated to 50℃for 2 hours, cooled to room temperature, ethyl acetate (20 mL) was diluted, saturated sodium bicarbonate solution (10 mL) was added, stirred for 30 minutes, filtered, ethyl acetate (20 mL. Times.3) was extracted, the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue which was purified by silica gel column chromatography (eluent: A system) to give (E) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-6- (cyclopropyl (methyl) amino) -N, N-dimethylisonicotinamide 82d (320 mg, 831.34. Mu. Mol), yield 86.75%.

MS m/z(ESI):386.2[M+1] ⁺

Fourth step

4-chloro-6-(cyclopropyl(methyl)amino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

4-Chloro-6- (cyclopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(E) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-6- (cyclopropyl (methyl) amino) -N, N-dimethylisonicotinamide 82d (320 mg, 831.34. Mu. Mol) was dissolved in tetrahydrofuran (8 mL), cooled to 0 ℃, lithium borohydride (36.21 mg,1.66 mmol) was added, the reaction was continued with stirring at 0℃for 1 hour, sodium methoxide (673.63 mg,12.47 mmol) was added, stirred slowly to room temperature for 5 hours, quenched with water (1 mL), extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 4-chloro-6- (cyclopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 82E (133 mg, 559.56. Mu.%), yield of 31%.

MS m/z(ESI):238.1[M+1] ⁺

Fifth step

methyl

6-(cyclopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

6- (Cyclopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carboxylic acid methyl ester

4-Chloro-6- (cyclopropyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 82e (130 mg, 546.94. Mu. Mol) was dissolved in methanol (5 mL), triethylamine (110.69 mg,1.09 mmol) and 1, 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (189.43 mg, 109.39. Mu. Mol) were added thereto, and the reaction was stirred under carbon monoxide atmosphere at 60℃for 18 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give methyl 6- (cyclopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carboxylate 82f (113 mg, 432.49. Mu. Mol), in 79.07% yield.

MS m/z(ESI):262.2[M+1] ⁺

Sixth step

6-(cyclopropyl(methyl)amino)-4-(hydroxymethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Cyclopropyl (methyl) amino) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

Methyl 6- (cyclopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridine-4-carboxylate 82f (113 mg, 432.49. Mu. Mol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 ℃, lithium borohydride (18.84 mg, 864.99. Mu. Mol) was slowly added dropwise, cooled to room temperature, stirred for 2 hours after cooling to room temperature, water (1 mL) was added to quench the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 82g (100 mg, 428.70. Mu. Mol) of 6- (cyclopropyl (methyl) amino) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-1-one in 99.12% yield.

MS m/z(ESI):234.2[M+1] ⁺

Seventh step

(6-(cyclopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methylmethanesulfonate

(6- (Cyclopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate

82G (100 mg, 428.70. Mu. Mol) of 6- (cyclopropyl (methyl) amino) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one was dissolved in tetrahydrofuran (10 mL), cooled to 0℃and triethylamine (65.07 mg, 643.04. Mu. Mol) and methanesulfonyl chloride (98.21 mg, 857.39. Mu. Mol) were added, respectively, stirring was continued at 0℃for 1 hour, the reaction was quenched with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (6- (cyclopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methylmesylate 82H (40 mg, 158.91. Mu. Mol), which was directly used for the next reaction.

MS m/z(ESI):252.0[M+1] ⁺

Eighth step

6-(cyclopropyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Cyclopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(6- (Cyclopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate 82H (30 mg, 119.18. Mu. Mol) was dissolved in tetrahydrofuran (5 mL), a solution of methylamine in tetrahydrofuran (2M, 74.03mg,2.38 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure to give 6- (cyclopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 82i (25 mg, 101.50. Mu. Mol) in a yield of 85.16%.

MS m/z(ESI):247.2[M+1] ⁺

Ninth step

tert-butyl

((6-(cyclopropyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(6- (Cyclopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

6- (Cyclopropyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 82i (25 mg, 101.50. Mu. Mol) was dissolved in tetrahydrofuran (4 mL), triethylamine (10.27 mg, 101.50. Mu. Mol) and di-tert-butyl dicarbonate (22.15 mg, 101.50. Mu. Mol) were added, respectively, and the reaction mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give ((6- (cyclopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 82j (30 mg, 86.60. Mu. Mol), yield 85.32%.

MS m/z(ESI):347.2[M+1] ⁺

Tenth step

tert-butyl

((6-(cyclopropyl(methyl)amino)-2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate((6-( Cyclopropyl (methyl) amino) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (cyclopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 82j (5 mg, 14.43. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 27c (4.23 mg, 14.43. Mu. Mol) were dissolved in1, 4-dioxane (3 mL), and cuprous iodide (274.23. Mu.g, 1.44. Mu. Mol), N, N-dimethylethylenediamine (127.23. Mu.g, 1.44. Mu. Mol) and potassium carbonate (3.99 mg, 28.87. Mu. Mol) were added and reacted for 2 hours under argon atmosphere at 80 ℃. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (cyclopropyl (methyl) amino) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 82k (5 mg, 8.95. Mu. Mol), yield 62.01%.

MS m/z(ESI):602.3[M+1] ⁺

Eleventh step

Tert-butyl ((6- (cyclopropyl (methyl) amino) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 82k (5 mg, 8.95. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, and trifluoroacetic acid (2.04 mg, 17.90. Mu. Mol) was added, followed by stirring for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (cyclopropyl (methyl) amino) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 82 (3 mg, 5.13. Mu. Mol), in a yield of 57.33%.

MS m/z(ESI):459.2[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.62(dd,J＝8.4,0.9Hz,1H),8.44(brs,2H),8.09(t,J＝8.0Hz,1H),7.93(dd,J＝7.6,0.9Hz,1H),7.23(s,1H),5.32(t,J＝4.9Hz,1H),5.16(s,2H),4.20(s,2H),3.31–3.27(m,1H),3.20(s,3H),3.01(t,J＝7.5Hz,2H),2.90(q,J＝7.2Hz,2H),2.05–1.94(m,2H),1.75(s,6H),1.02–0.94(m,2H),0.68–0.61(m,2H).

Example 83

6-(cyclopentyl(methyl)amino)-2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Cyclopentyl (methyl) amino) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-chloro-6-(cyclopentyl(methyl)amino)-N,N-dimethylisonicotinamide

2-Chloro-6- (cyclopentyl (methyl) amino) -N, N-dimethylisonicotinamide

2, 6-Dichloro-N, N-dimethylisonicotinamide 55a (1.34 g,6.12 mmol) was dissolved in dimethyl sulfoxide (20 mL), N-methylcyclopentylamine 83a (909.94 mg,9.18 mmol) and potassium fluoride (1.07 g,18.35 mmol) were added, and the reaction was stirred for 2 hours with microwave heating to 150 ℃. Water (20 mL) and ethyl acetate (50 mL) were added to dilute the mixture, the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 2-chloro-6- (cyclopentyl (methyl) amino) -N, N-dimethylisonicotinamide 83b (1.64 g,5.82 mmol) in 95.15% yield.

MS m/z(ESI):282.1[M+1] ⁺

Second step

2-chloro-6-(cyclopentyl(methyl)amino)-3-formyl-N,N-dimethylisonicotinamide

2-Chloro-6- (cyclopentyl (methyl) amino) -3-formyl-N, N-dimethylisonicotinamide

N, N-dimethylformamide (1.70 g,23.28mmol,1.81 mL) was dissolved in 1, 2-dichloroethane (20 mL), cooled to 0deg.C, phosphorus oxychloride (3.57 g,23.28mmol,2.18 mL) was slowly added dropwise, and the mixture was stirred for 30 minutes after warming to room temperature. 2-chloro-6- (cyclopentyl (methyl) amino) -N, N-dimethylisonicotinamide 83b (1.64 g,5.82 mmol) was dissolved in 1, 2-dichloroethane (5 mL), and the reaction mixture was added dropwise thereto, and the temperature was raised to 75℃and the reaction was stirred for 5 hours. Saturated ammonium bicarbonate solution was added to adjust pH to basicity, dichloromethane (150 mL. Times.3) was used for extraction, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 2-chloro-6- (cyclopentyl (methyl) amino) -3-formyl-N, N-dimethylisonicotinamide 83c (1.04 g,3.36 mmol) in 57.68% yield.

MS m/z(ESI):310.1[M+1] ⁺

Third step

(E)-3-(((tert-butylsulfinyl)imino)methyl)-2-chloro-6-(cyclopentyl(methyl)amino)-N,N-dimethylisonicotinamide

(E) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-6- (cyclopentyl (methyl) amino) -N, N-dimethylisonicotinamide

2-Chloro-6- (cyclopentyl (methyl) amino) -3-formyl-N, N-dimethylisonicotinamide 83c (1.04 g,3.36 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to 0 ℃, tert-butylsulfinamide (610.32 mg,5.04 mmol) and ethyl titanate (2.30 g,10.07mmol,2.11 mL) were added, the reaction was warmed to 50℃for 3 hours, cooled to room temperature, ethyl acetate was diluted, saturated sodium bicarbonate solution (50 mL) was added, stirred for 30 minutes, filtered, ethyl acetate (50 mL. Times.3) was extracted, the organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give (E) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-6- (cyclopentyl (methyl) amino) -N, N-dimethylisonicotinamide 83d (1.3 g,3.15 mmol), yield 93.77%.

MS m/z(ESI):413.2[M+1] ⁺

Fourth step

4-chloro-6-(cyclopentyl(methyl)amino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

4-Chloro-6- (cyclopentyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(E) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-6- (cyclopentyl (methyl) amino) -N, N-dimethylisonicotinamide 83d (1.3 g,3.15 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 ℃, lithium borohydride (137.12 mg,6.30 mmol) was added, the reaction was continued with stirring at 0℃for 1 hour, sodium methoxide (1.70 g,31.48 mmol) was added, the reaction was stirred slowly at room temperature for 15 hours, quenched with water (2 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 4-chloro-6- (cyclopentyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 83E (0 mg,2. 66.94% yield).

MS m/z(ESI):266.1[M+1] ⁺

Fifth step

methyl

6-(cyclopentyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

6- (Cyclopentyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carboxylic acid methyl ester

4-Chloro-6- (cyclopentyl (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 83e (560 mg,2.11 mmol) was dissolved in methanol (15 mL), triethylamine (639.72 mg,6.32mmol, 881.16. Mu.L) and 1, 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (364.93 mg, 210.73. Mu. Mol) were added thereto, and the mixture was stirred under carbon monoxide atmosphere at 60℃for 18 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give methyl 6- (cyclopentyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carboxylate 83f (600 mg,2.07 mmol), in a yield of 98.41%.

MS m/z(ESI):290.0[M+1] ⁺

Sixth step

6-(cyclopentyl(methyl)amino)-4-(hydroxymethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Cyclopentyl (methyl) amino) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

Methyl 6- (cyclopentyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridine-4-carboxylate 83f (600 mg,2.07 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 ℃, lithium borohydride (90.33 mg,4.15 mmol) was slowly added dropwise, the reaction was quenched by adding water (1 mL) for 18 hours after warming to room temperature, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 83g (326 mg,1.25 mmol) of 6- (cyclopentyl (methyl) amino) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-1-one in a yield of 60.16%.

MS m/z(ESI):261.8[M+1] ⁺

Seventh step

(6-(cyclopentyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methylmethanesulfonate

(6- (Cyclopentyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate

83G (100 mg, 382.67. Mu. Mol) of 6- (cyclopentyl (methyl) amino) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one was dissolved in tetrahydrofuran (10 mL), cooled to 0℃and triethylamine (154.89 mg,1.53mmol, 213.35. Mu.L) and methylsulfonyl chloride (87.67 mg, 765.35. Mu. Mol, 59.24. Mu.L) were added, respectively, and stirring was continued at 0℃for 1 hour, the reaction was quenched with saturated sodium bicarbonate solution (2 mL), extracted with ethyl acetate (15 mL. Times.3), the organic phases were combined, washed with water (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent: A system) to give (6- (cyclopentyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methylsulfonate (83 mg, 99.32. Mu.07% yield.

MS m/z(ESI):339.8[M+1] ⁺

Eighth step

6-(cyclopentyl(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Cyclopentyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(6- (Cyclopentyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate 83H (129 mg, 380.07. Mu. Mol) was dissolved in tetrahydrofuran (100 mL), an ethanol solution of methylamine (content 30-33%,1.18g,11.40 mmol) was added, stirred at room temperature for 18 hours, and the reaction mixture was concentrated under reduced pressure to give 6- (cyclopentyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 83i (100 mg, 364.48. Mu. Mol) in a yield of 95.90%.

MS m/z(ESI):275.2[M+1] ⁺

Ninth step

tert-butyl

((6-(cyclopentyl(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(6- (Cyclopentyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

6- (Cyclopentyl (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 83i (100 mg, 364.48. Mu. Mol) was dissolved in tetrahydrofuran (10 mL), triethylamine (73.76 mg, 728.97. Mu. Mol, 101.60. Mu.L) and di-tert-butyl dicarbonate (159.10 mg, 728.97. Mu. Mol, 167.47. Mu. L) were added, respectively, the reaction mixture was stirred at room temperature for 2 hours, and the resulting residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: A system) to give (6- (cyclopentyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl 83j (135 mg, 360.50. Mu. Mol), yield 98.91%.

MS m/z(ESI):375.0[M+1] ⁺

Tenth step

tert-butyl

((6-(cyclopentyl(methyl)amino)-2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate((6-( Cyclopentyl (methyl) amino) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl (6- (cyclopentyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 83j (135 mg, 360.50. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 27c (116.25 mg, 396.55. Mu. Mol) were dissolved in1, 4-dioxane (10 mL), and cuprous iodide (34.25 mg, 180.25. Mu. Mol), N, N-dimethylethylenediamine (15.89 mg, 180.25. Mu. Mol, 19.69. Mu. L) and potassium carbonate (99.65 mg, 721.01. Mu. Mol) were added and reacted under argon atmosphere at 80℃for 6 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give tert-butyl ((6- (cyclopentyl (methyl) amino) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-C ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-4-yl) methyl) (methyl) carbamate 83k (200 mg, 184.07. Mu. Mol), yield 51.06%.

MS m/z(ESI):587.4[M+1] ⁺

Eleventh step

Tert-butyl ((6- (cyclopentyl (methyl) amino) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 83k (200 mg, 184.07. Mu. Mol) was dissolved in methanol (10 mL), cooled to 0 ℃, and a solution of hydrogen chloride in ethyl acetate (671.86 mg,18.41 mmol) was added, followed by stirring for 1 hour after slowly warming to room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (cyclopentyl (methyl) amino) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 83 (80 mg, 132.14. Mu. Mol), and a yield of 71.79%.

MS m/z(ESI):487.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.35–9.12(m,2H),8.64(d,J＝8.3Hz,1H),8.11(t,J＝8.0Hz,1H),7.93(d,J＝7.6Hz,1H),6.94(s,1H),5.16(d,J＝8.1Hz,1H),5.12(s,2H),4.29(t,J＝5.9Hz,2H),3.08(t,J＝7.4Hz,2H),2.96(s,3H),2.73(t,J＝5.4Hz,3H),2.63(t,J＝7.4Hz,2H),1.92–1.80(m,2H),1.76(s,6H),1.75–1.68(m,2H),1.68–1.51(m,4H).

Example 84

(R)-2-(6-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-6-(2-methylpyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(R) -2- (6- (5-methyl-4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

tert-butyl

(R)-methyl((2-(6-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(2-methylpyrrolidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)carbamate

(R) -methyl ((2- (6- (5-methyl-4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester

(R) -methyl ((6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester 80j (50 mg, 138.72. Mu. Mol) and 2-bromo-6- (5-methyl-4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridine 67c (87.44 mg, 277.43. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (79.26 mg, 416.15. Mu. Mol), N, N-dimethylethylenediamine (48.91 mg, 554.86. Mu. Mol, 60.61. Mu. L) and potassium carbonate (95.86 mg, 693.58. Mu. Mol) were added and reacted under argon atmosphere at 80℃for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl (R) -methyl ((2- (6- (5-methyl-4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamate 84a (62 mg, 104.25. Mu. Mol), yield 75.16%.

MS m/z(ESI):595.4[M+1] ⁺

Second step

(R) -methyl ((2- (6- (5-methyl-4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester 84a (55 mg, 92.48. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (527.24 mg,4.62 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give (R) -2- (6- (5-methyl-4-phenyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 84 (28 mg, 45.47. Mu. Mol), yield 49.17%. MS m/z (ESI): 495.3[ M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.96(brs,2H),8.46(dd,J＝8.2,1.1Hz,1H),8.09–7.96(m,2H),7.71–7.62(m,3H),7.56–7.46(m,2H),6.64(s,1H),4.36–4.26(m,1H),4.24–4.15(m, 2H),3.83(d,J＝1.6Hz,2H),3.65–3.56(m,1H),3.41–3.31(m,1H),2.88(t,J＝5.1Hz,3H),2.24(s,3H),2.15–1.92(m,3H),1.76–1.68(m,1H),1.17(d,J＝6.2Hz,3H).

Example 85

2-(6-(4-(2-fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-6-((R)-2-methylpyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (4- (2-Fluorophenyl) -5-methyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6- ((R) -2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(2-fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (2-fluorophenyl) -5-methyl-4H-1, 2, 4-triazol-3-yl) pyridine

2- (6-Bromopyridin-2-yl) -5-methyl-1, 3, 4-oxadiazole 67a (100 mg, 416.56. Mu. Mol) and 2-fluoroaniline 49a (231.44 mg,2.08mmol, 201.08. Mu.L) were dissolved in pyridine (2 mL), cooled to 0℃and trifluoroacetic acid (47.50 mg, 416.57. Mu. Mol) was added thereto, and the mixture was heated to 100℃and stirred for 48 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: B system) to give 2-bromo-6- (4- (2-fluorophenyl) -5-methyl-4H-1, 2, 4-triazol-3-yl) pyridine 85a (120 mg, 294.45. Mu. Mol) in a yield of 70.69%.

MS m/z(ESI):333.0[M+1] ⁺

Second step

tert-butyl

((2-(6-(4-(2-fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-((R)-2-methylpyrrolidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((2- (6- (4- (2-Fluorophenyl) -5-methyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- ((R) -2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

(R) -methyl ((6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester 80j (50 mg, 138.72. Mu. Mol) and 2-bromo-6- (4- (2-fluorophenyl) -5-methyl-4H-1, 2, 4-triazol-3-yl) pyridine 85a (92.43 mg, 277.43. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (79.26 mg, 416.15. Mu. Mol), N, N-dimethylethylenediamine (48.91 mg, 554.86. Mu. Mol, 60.61. Mu. L) and potassium carbonate (95.86 mg, 693.58. Mu. Mol) were added and heated to 80℃under argon atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl ((2- (6- (4- (2-fluorophenyl) -5-methyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- ((R) -2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 85b (85 mg, 126.27. Mu. Mol), in a yield of 91.03%.

MS m/z(ESI):613.3[M+1] ⁺

Third step

Tert-butyl ((2- (6- (4- (2-fluorophenyl) -5-methyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- ((R) -2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 85b (80 mg, 130.57. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (744.38 mg,6.53 mmol) was added, and after slow warming to room temperature, stirring was performed for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (4- (2-fluorophenyl) -5-methyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6- ((R) -2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 85 (78 mg, 121.88. Mu. Mol) in a yield of 93.35%.

MS m/z(ESI):513.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.00(brs,2H),8.51(dd,J＝7.5,1.9Hz,1H),8.11–8.02(m,2H),7.81–7.71(m,2H),7.66–7.52(m,2H),6.65(s,1H),4.38–4.25(m,1H),4.19(s,2H),3.90(dd,J＝17.1,5.3Hz,1H),3.79(dd,J＝17.1,6.5Hz,1H),3.61(t,J＝8.8Hz,1H),3.43–3.31(m,1H),2.89(t,J＝5.4Hz,3H),2.26(s,3H),2.13–1.93(m,3H),1.78–1.67(m,1H),1.17(d,J＝6.2Hz,3H).

Example 86

2-(6-(5-methyl-4-(o-tolyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-6-((R)-2-methylpyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

2- (6- (5-Methyl-4- (o-tolyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6- ((R) -2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(5-methyl-4-(o-tolyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (5-methyl-4- (o-tolyl) -4H-1,2, 4-triazol-3-yl) pyridine

2- (6-Bromopyridin-2-yl) -5-methyl-1, 3, 4-oxadiazole 67a (100 mg, 416.57. Mu. Mol) and o-toluidine 60a (223.18 mg,2.08 mmol) were dissolved in pyridine (2 mL), cooled to 0℃and trifluoroacetic acid (47.50 mg, 416.57. Mu. Mol) was added thereto, and the mixture was stirred at 100℃for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: B system) to give 2-bromo-6- (5-methyl-4- (o-tolyl) -4H-1,2, 4-triazol-3-yl) pyridine 86a (108 mg, 276.11. Mu. Mol) in 66.28% yield.

MS m/z(ESI):329.1[M+1] ⁺

Second step

tert-butyl

methyl((2-(6-(5-methyl-4-(o-tolyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-((R)-2-methylpyrrolidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)carbamate

Methyl ((2- (6- (5-methyl-4- (o-tolyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- ((R) -2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester

(R) -methyl ((6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester 80j (50 mg, 138.72. Mu. Mol) and 2-bromo-6- (5-methyl-4- (o-tolyl) -4H-1,2, 4-triazol-3-yl) pyridine 86a (91.33 mg, 277.43. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), and cuprous iodide (79.26 mg, 416.15. Mu. Mol), N, N-dimethylethylenediamine (48.91 mg, 554.86. Mu. Mol, 60.61. Mu. L) and potassium carbonate (95.86 mg, 693.58. Mu. Mol) were added and reacted under argon atmosphere at 80℃for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl methyl ((2- (6- (5-methyl-4- (o-tolyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- ((R) -2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamate 86b (80 mg, 131.42. Mu. Mol), in 94.74% yield.

MS m/z(ESI):609.3[M+1] ⁺

Third step

Methyl ((2- (6- (5-methyl-4- (o-tolyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- ((R) -2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester 86b (75 mg, 123.21. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (702.40 mg,6.16 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 2- (6- (5-methyl-4- (o-tolyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6- ((R) -2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 86 (64 mg, 100.97. Mu. Mol), in a yield of 81.95%.

MS m/z(ESI):509.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.95(brs,2H),8.53–8.43(m,1H),8.07–7.99(m,2H),7.64–7.54(m,2H),7.54–7.48(m,1H),7.44(d,J＝7.7Hz,1H),6.64(s,1H),4.35–4.27(m,1H),4.27–4.15(m,2H),3.90–3.74(m,2H),3.65–3.57(m,1H),3.42–3.28(m,1H),2.90(t,J＝5.3Hz,3H),2.15(s,3H),2.14–1.95(m,3H),1.95(d,J＝2.0Hz,3H),1.76–1.69(m,1H),1.17(d,J＝6.2Hz,3H).

Examples 87-128 were synthesized according to the synthesis method of examples 1-86 of the present invention. The profile parameters for examples 87-128 are shown in the following table:

Example 130

6-(isopropyl(methyl)amino)-4-((methylamino)methyl)-2-(6-(4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- (Isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4- (1-methylcyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (1-methylcyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (200 mg, 737.70. Mu. Mol) was dissolved in acetonitrile (5 mL) at room temperature, 1-methylcyclopropylamine hydrochloride 130a (238.09 mg,2.21 mmol) and glacial acetic acid (442.99 mg,7.38mmol, 422.30. Mu.L) were added, the mixture was warmed to 90℃and stirred for 12 hours, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: G system) to give 2-bromo-6- (4- (1-methylcyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridine 130b (191 mg, 587.16. Mu. Mol) in a yield of 79.59%.

MS m/z(ESI):279.0[M+1] ⁺

Second step

tert-butyl

((6-(isopropyl(methyl)amino)-2-(6-(4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- (Isopropyl (methyl) amino) -2- (6- (4- (1-methylcyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (isopropyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 2b (50 mg, 143.50. Mu. Mol) and 2-bromo-6- (4- (1-methylcyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridine 130b (60.08 mg, 215.25. Mu. Mol) were dissolved in1, 4-dioxane (2 mL), tris (dibenzylidene-BASE acetone) dipalladium (32.85 mg, 35.87. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (41.52 mg, 71.75. Mu. Mol) and potassium phosphate (91.38 mg, 430.49. Mu. Mol) were added in this order and reacted at 80℃for 16 hours. LCMS monitored the reaction, and after completion of the reaction, the reaction was filtered with suction and concentrated, and the resulting residue was purified by column chromatography over silica gel (eluent: a system) to give tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (4- (1-methylcyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 130c (75 mg,97.82 μmol) in 68.17% yield.

MS m/z(ESI):547.2[M+1] ⁺

Third step

Tert-butyl ((6- (isopropyl (methyl) amino) -2- (6- (4- (1-methylcyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 130c (70 mg,128.05 μmol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, trifluoroacetic acid (730.01 mg,6.40 mmol) was added, and stirred for 12 hours after slowly warming to room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- (isopropyl (methyl) amino) -4- ((methylamino) methyl) -2- (6- (4- (1-methylcyclopropyl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 130 (70 mg, 121.37. Mu. Mol), yield 94.78%.

MS m/z(ESI):447.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.96(brs,1H),8.83(s,1H),8.68(dd,J＝8.5,0.9Hz,1H),8.16–8.06(m,1H),7.86(dd,J＝7.6,0.9Hz,1H),6.91(s,1H),5.11(s,2H),5.08–4.98(m,1H),4.33(t,J＝5.9Hz,2H),2.93(s,3H),2.74(t,J＝5.3Hz,3H),1.79(s,3H),1.16(d,J＝6.7Hz,6H),1.04(s,4H).

Example 131

(R)-2-(6-(4-(1-isopropyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-6-(2-methylpyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(R) -2- (6- (4- (1-isopropyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-bromo-6-(4-(1-isopropyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)pyridine

2-Bromo-6- (4- (1-isopropyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridine

(E) -N' - (6-bromopyridyl formyl) -N, N-dimethylformamide 9a (370 mg,1.36 mmol) was dissolved in glacial acetic acid (5 mL) at room temperature, 1-isopropyl-1H-pyrazol-5-amine 131a (200 mg,1.60mmol, commercially available) was added, the mixture was warmed to 100℃and reacted for 8 hours under stirring, and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: G system) to give 2-bromo-6- (4- (1-isopropyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridine 131b (300 mg, 900.40. Mu. Mol) in a yield of 65.98%.

MS m/z(ESI):333.0[M+1] ⁺

Second step

tert-butyl

(R)-((2-(6-(4-(1-isopropyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(2-methylpyrrolidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(R) - ((2- (6- (4- (1-isopropyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

(R) -methyl ((6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester 80J (30 mg, 83.23. Mu. Mol) and 2-bromo-6- (4- (1-isopropyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridine 131b (55.46 mg, 166.46. Mu. Mol) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (9.24 mg, 41.61. Mu. Mol), N, N-dimethylethylenediamine (3.67 mg, 41.61. Mu. Mol) and potassium carbonate (23.01 mg, 166.46. Mu. Mol) were added and reacted under argon atmosphere at 95℃for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl (R) - ((2- (6- (4- (1-isopropyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 131c (30 mg, 49.94. Mu. Mol), yield 60.00%.

MS m/z(ESI):613.4[M+1] ⁺

Third step

(R) - ((2- (6- (4- (1-isopropyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 131c (30 mg, 48.96. Mu. Mol) was dissolved in methanol (10 mL), cooled to 0℃and an ethyl acetate solution of hydrogen chloride (4.9 mL,4.90mmol, 1M) was added, followed by stirring for 1 hour after slowly warming to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give (R) -2- (6- (4- (1-isopropyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 131 (8 mg, 12.64. Mu. Mol), yield 25.81%.

MS m/z(ESI):513.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.08(s,1H),8.99(brs,2H),8.54(dd,J＝7.1,2.2Hz,1H),8.19–8.06(m,2H),7.89(d,J＝2.0Hz,1H),6.69(s,1H),6.67(d,J＝1.9Hz,1H),4.38–4.23(m,3H),4.12(s,2H),4.08–3.95(m,2H),3.68–3.57(m,1H),2.86(t,J＝5.4Hz,3H),2.17–1.92(m,3H),1.78–1.67(m,1H),1.24(d,J＝6.7Hz,6H),1.18(d,J＝6.2Hz,3H).

Example 132

(S)-3-(6-(6-(cyclopentyl(methyl)amino)-4-((methylamino)methyl)-1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)pyridin-2-yl)-4-methyloxazolidin-2-one

(S) -3- (6- (6- (cyclopentyl (methyl) amino) -4- ((methylamino) methyl) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -4-methyl oxazolidin-2-one

First step

tert-butyl

(S)-((6-(cyclopentyl(methyl)amino)-2-(6-(4-methyl-2-oxooxazolidin-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(S) - ((6- (cyclopentyl (methyl) amino) -2- (6- (4-methyl-2-oxooxazolidin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- (cyclopentyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 83J (69.63 mg, 185.95. Mu. Mol) and (S) -3- (6-bromopyridin-2-yl) -4-methyl oxazolidin-2-one 132a (95.61 mg, 371.90. Mu. Mol, prepared according to published patent WO2020100027A 1) were dissolved in1, 4-dioxane (5 mL), and cuprous iodide (17.71 mg, 92.97. Mu. Mol), N, N-dimethylethylenediamine (8.20 mg, 92.97. Mu. Mol) and potassium carbonate (51.40 mg, 371.90. Mu. Mol) were added and heated under argon atmosphere to 95℃for reaction for 12 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl (S) - ((6- (cyclopentyl (methyl) amino) -2- (6- (4-methyl-2-oxooxazolid in-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 132b (100 mg, 54.48. Mu. Mol), yield 29.30%.

MS m/z(ESI):551.3[M+1] ⁺

Second step

(S) - ((6- (cyclopentyl (methyl) amino) -2- (6- (4-methyl-2-oxooxazolidin-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 132b (50 mg, 90.80. Mu. Mol) was dissolved in methanol (10 mL), cooled to 0℃and then a solution of hydrogen chloride in ethyl acetate (165.71 mg,4.54 mmol) was added and stirred for 1 hour after slowly warming to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give (S) -3- (6- (6- (cyclopentyl (methyl) amino) -4- ((methylamino) methyl) -1-oxo-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridin-2-yl) -4-methyl oxazolidin-2-one 132 (26 mg, 45.59. Mu. Mol), in 50.21% yield.

MS m/z(ESI):451.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.18(d,J＝4.7Hz,2H),8.23(d,J＝8.0Hz,1H),7.95(t,J＝8.1Hz,1H),7.81(d,J＝8.1Hz,1H),6.91(s,1H),5.20–5.11(m,1H),5.11(d,J＝17.1Hz,1H),5.00(d,J＝17.2Hz,1H),4.98–4.89(m,1H),4.60(t,J＝8.3Hz,1H),4.34(td,J＝5.9,3.4Hz,2H),4.16(dd,J＝8.4,3.9Hz,1H),2.95(s,3H),2.72(t,J＝5.4Hz,3H),1.90–1.79(m,2H),1.78–1.67(m,2H),1.67–1.52(m,4H),1.48(d,J＝6.2Hz,3H).

Example 133

(R)-2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-6-(3-methylmorpholino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(R) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6- (3-methylmorpholine) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

(R)-2-chloro-N,N-dimethyl-6-(3-methylmorpholino)isonicotinamide

(R) -2-chloro-N, N-dimethyl-6- (3-methylmorpholine) isonicotinamide

2, 6-Dichloro-N, N-dimethylisonicotinamide 55a (2 g,9.13 mmol) was dissolved in dimethyl sulfoxide (10 mL), and (R) -3-methylmorpholine 133a (1.39 g,13.69mmol,1.55 mL) and potassium fluoride (1.59 g,27.39 mmol) were added and the mixture was heated to 150℃with microwaves and stirred for 6 hours. Water (20 mL) and ethyl acetate (50 mL) were added to dilute the mixture, the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give (R) -2-chloro-N, N-dimethyl-6- (3-methylmorpholino) isonicotinamide 133b (2.5 g,8.81 mmol) in 96.50% yield.

MS m/z(ESI):284.1[M+1] ⁺

Second step

(R)-2-chloro-3-formyl-N,N-dimethyl-6-(3-methylmorpholino)isonicotinamide

(R) -2-chloro-3-formyl-N, N-dimethyl-6- (3-methylmorpholino) isonicotinamide

N, N-dimethylformamide (2.58 g,35.24mmol,2.74 mL) was dissolved in 1, 2-dichloroethane (50 mL), cooled to 0℃and phosphorus oxychloride (5.40 g,35.24mmol,3.29 mL) was slowly added dropwise thereto, stirred for 30 minutes after warming to room temperature, and (R) -2-chloro-N, N-dimethyl-6- (3-methylmorpholino) isonicotinamide 133b (2.5 g,8.81 mmol) was dissolved in 1, 2-dichloroethane (8 mL), and the mixture was added dropwise thereto, and the temperature was raised to 75℃and stirred for reaction for 18 hours. Saturated ammonium bicarbonate aqueous solution was added to adjust pH to basicity, dichloromethane (150 mL. Times.3) was added to extract, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give (R) -2-chloro-3-formyl-N, N-dimethyl-6- (3-methylmorpholino) isonicotinamide 133c (2.34 g,7.51 mmol) in 85.19% yield.

MS m/z(ESI):312.1[M+1] ⁺

Third step

3-((E)-((tert-butylsulfinyl)imino)methyl)-2-chloro-N,N-dimethyl-6-((R)-3-methylmorpholino)isonicotinamide

3- ((E) - ((tert-butylsulfinyl) imino) methyl) -2-chloro-N, N-dimethyl-6- ((R) -3-methylmorpholino) isonicotinamide

(R) -2-chloro-3-formyl-N, N-dimethyl-6- (3-methylmorpholino) isonicotinamide 133c (2.34 g,7.51 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0℃and tert-butylsulfinamide (1.36 g,11.26 mmol) and ethyl titanate (5.14 g,22.52mmol,4.72 mL) were added, heated to 50℃for 3 hours, cooled to room temperature, diluted with ethyl acetate, saturated aqueous sodium bicarbonate (50 mL) was added, stirred for 30 minutes, filtered, extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (eluent: A system) to give 3- ((E) - ((tert-butylsulfinyl) imino) methyl) -2-chloro-N, N-dimethyl-6- ((R) -3-methylmorpholino) isonicotinamide 133d (3.11 g,7.49 mmol) in 100.49 mmol) with a yield of 100.00%.

MS m/z(ESI):414.8[M+1] ⁺

Fourth step

(R)-4-chloro-6-(3-methylmorpholino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(R) -4-chloro-6- (3-methylmorpholino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

3- ((E) - ((tert-butylsulfinyl) imino) methyl) -2-chloro-N, N-dimethyl-6- ((R) -3-methylmorpholino l) isonicotinamide 133d (3.11 g,7.49 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0℃and lithium borohydride (326.48 mg,14.99 mmol) was added, the reaction was continued with stirring at 0℃for 1 hour, sodium methoxide (6.07 g,112.42 mmol) was added, the reaction was stirred slowly at room temperature for 5 hours, quenched with water (20 mL), extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give (R) -4-chloro-6- (3-methylmorpholino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 133E (1.4 g, 5.23 mmol), 69% yield.

MS m/z(ESI):268.1[M+1] ⁺

Fifth step

methyl(R)-6-(3-methylmorpholino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

(R) -6- (3-methylmorpholine) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carboxylic acid methyl ester

(R) -4-chloro-6- (3-methylmorpholino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 133e (1.4 g,5.23 mmol) was dissolved in methanol (50 mL), triethylamine (1.59 g,15.69mmol,2.19 mL) and 1, 1-bis (diphenylphosphine) iron-bis-palladium dichloride (905.60 mg, 522.95. Mu. Mol) were added thereto, and the mixture was stirred under carbon monoxide atmosphere at 60℃for 18 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give (R) -6- (3-methylmorpholine) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carboxylic acid methyl ester 133f (1.27 g,4.36 mmol), yield 83.37%.

MS m/z(ESI):292.2[M+1] ⁺

Sixth step

(R)-4-(hydroxymethyl)-6-(3-methylmorpholino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(R) -4- (hydroxymethyl) -6- (3-methylmorpholino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(R) -6- (3-methylmorpholino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridine-4-carboxylic acid methyl ester 133f (1.27 g,4.36 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to 0℃and lithium borohydride (181.19 mg,8.32 mmol) was slowly added dropwise thereto, cooled to room temperature, stirred for 18 hours, quenched with water (2 mL), and the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give 133g (82mg, 3.11 mmol) of (R) -4- (hydroxymethyl) -6- (3-methylmorpholino) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-1-one in 74.88% yield.

MS m/z(ESI):264.1[M+1] ⁺

Seventh step

(R)-(6-(3-methylmorpholino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methylmethanesulfonate

(R) - (6- (3-methylmorpholino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate

(R) -4- (hydroxymethyl) -6- (3-methylmorpholino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 133g (720 mg,2.73 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to 0℃and triethylamine (1.11 g,10.94mmol,1.52 mL) and methylsulfonyl chloride (626.50 mg,5.47mmol, 423.31. Mu.L) were added, respectively, stirring was continued at 0℃for 3 hours, the reaction was quenched with saturated aqueous sodium bicarbonate (10 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (eluent: A system) to give (R) - (6- (3-methylmorpholino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methylsulfonate H (900 mg, 2.41 mmol), yield 96.41%.

MS m/z(ESI):342.2[M+1] ⁺

Eighth step

(R)-4-((methylamino)methyl)-6-(3-methylmorpholino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1- one

(R) -4- ((methylamino) methyl) -6- (3-methylmorpholino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(R) - (6- (3-methylmorpholino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methylsulfonate 133H (900 mg,2.64 mmol) was dissolved in tetrahydrofuran (50 mL), a solution of methylamine in ethanol (content 30-33%,13.65g,131.82 mmol) was added, stirred at room temperature for 18 hours, and the reaction mixture was concentrated under reduced pressure to give (R) -4- ((methylamino) methyl) -6- (3-methylmorpholino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 133i (328 mg,2.63 mmol) in 99.93% yield.

MS m/z(ESI):277.1[M+1] ⁺

Ninth step

tert-butyl

(R)-methyl((6-(3-methylmorpholino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)carbamate

(R) -methyl ((6- (3-methylmorpholine) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester

(R) -4- ((methylamino) methyl) -6- (3-methylmorpholino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 133i (178 mg,2.63 mmol) was dissolved in tetrahydrofuran (20 mL), triethylamine (533.17 mg,5.27mmol, 734.39. Mu.L) and di-tert-butyl dicarbonate (1.15 g,5.27mmol,1.21 mL) were added respectively, the reaction mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent: A system) to give (R) -methyl ((6- (3-methylmorpholino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester 133J (762 mg,2.02 mmol) in a yield of 76.81%.

MS m/z(ESI):377.3[M+1] ⁺

Tenth step

tert-butyl

(R)-((2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-6-(3-methylmorpholino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

(R) - ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (3-methylmorpholino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl (R) -methyl ((6- (3-methylmorpholino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamate 133J (100 mg, 265.64. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 27c (85.66 mg, 292.20. Mu. Mol) were dissolved in1, 4-dioxane (10 mL), and cuprous iodide (25.24 mg, 132.82. Mu. Mol), N, N-dimethylethylenediamine (11.71 mg, 132.82. Mu. Mol, 14.51. Mu. L) and potassium carbonate (73.43 mg, 531.28. Mu. Mol) were added and heated to 100℃under argon atmosphere for reaction for 8 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl (R) - ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (3-methylmorpholine) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 133k (90 mg, 152.88. Mu. Mol), yield 57.55%.

MS m/z(ESI):589.4[M+1] ⁺

Eleventh step

(R) - ((2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -6- (3-methylmorpholino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 133k (90 mg, 152.88. Mu. Mol) was dissolved in methanol (10 mL), cooled to 0℃and then a solution of hydrogen chloride in ethyl acetate (558.01 mg,15.29 mmol) was added and stirred for 1 hour after slowly warming to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give (R) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6- (3-methylmorpholine) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 133 (30 mg, 49.29. Mu. Mol), in a yield of 32.24%.

MS m/z(ESI):489.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.09(brs,2H),8.63(d,J＝8.3Hz,1H),8.10(t,J＝8.0Hz,1H),7.92(d,J＝7.6Hz,1H),7.09(s,1H),5.11(s,2H),4.61–4.51(m,1H),4.34(t,J＝5.9Hz,2H),4.14(d,J＝13.5Hz,1H),3.99(dd,J＝11.3,3.6Hz,1H),3.77(d,J＝11.3Hz,1H),3.66(dd,J＝11.3,3.0Hz,1H),3.51(td,J＝11.8,3.0Hz,1H),3.20–3.10(m,1H),3.05(t,J＝7.4Hz,2H),2.74(t,J＝5.3Hz,3H),2.62(t,J＝7.4Hz,2H),1.75(s,6H),1.16(d,J＝6.6Hz,3H).

Example 134

(R)-2-(6-(4-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-6-(2-methylpyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

(R) -2- (6- (4- (1-methyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

tert-butyl

(R)-methyl((2-(6-(4-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(2-methylpyrrolidin-1-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)carbamate

(R) -methyl ((2- (6- (4- (1-methyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester

(R) -methyl ((6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester 80J (118.13 mg, 327.73. Mu. Mol) and 2-bromo-6- (4- (1-methyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridine 61b (100 mg, 327.73. Mu. Mol) were dissolved in1, 4-dioxane (10 mL), and cuprous iodide (31.13 mg, 163.86. Mu. Mol), N, N-dimethylethylenediamine (14.44 mg, 163.86. Mu. Mol) and potassium carbonate (90.59 mg, 655.45. Mu. Mol) were added and reacted for 2 hours under argon atmosphere at 80 ℃. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl (R) -methyl ((2- (6- (4- (1-methyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamate 134a (80 mg, 136.83. Mu. Mol), yield 41.75%.

MS m/z(ESI):585.3[M+1] ⁺

Second step

(R) -methyl ((2- (6- (4- (1-methyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -6- (2-methylpyrrolidin-1-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) carbamic acid tert-butyl ester 134a (80 mg, 136.83. Mu. Mol) was dissolved in dichloromethane (10 mL), cooled to 0 ℃, trifluoroacetic acid (46.80 mg, 410.49. Mu. Mol) was added, and the mixture was stirred for 1 hour after slowly warming to room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give (R) -2- (6- (4- (1-methyl-1H-pyrazol-5-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -6- (2-methylpyrrolidin-1-yl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 134 (25 mg, 41.48. Mu. Mol), in a yield of 30.31%.

MS m/z(ESI):485.3[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ9.06(brs,2H),8.99(s,1H),8.57(dd,J＝6.7,2.6Hz,1H),8.16–8.06(m,2H),7.77(d,J＝2.1Hz,1H),6.68(s,1H),6.61(d,J＝2.0Hz,1H),4.36(s,2H),4.37–4.28(m,1H),4.11(s,2H),3.69(s,3H),3.62(t,J＝8.9Hz,1H),3.44–3.35(m,1H),2.86(s,3H),2.14–1.91(m,3H),1.79–1.65(m,1H),1.18(d,J＝6.2Hz,3H).

Example 135

6-((cyclopentylmethyl)(methyl)amino)-2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- ((Cyclopentylmethyl) (methyl) amino) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

First step

2-chloro-6-((cyclopentylmethyl)(methyl)amino)-N,N-dimethylisonicotinamide

2-Chloro-6- ((cyclopentylmethyl) (methyl) amino) -N, N-dimethylisonicotinamide

2, 6-Dichloro-N, N-dimethylisonicotinamide 55a (483.81 mg,2.21 mmol) was dissolved in dimethyl sulfoxide (30 mL), 1-cyclopentyl-N-methyl methylamine 135a (250 mg,2.21 mmol) and potassium fluoride (670.94 mg,4.42 mmol) were added, and the mixture was heated to 100℃with microwaves and stirred for 2 hours. Water (30 mL) and ethyl acetate (50 mL) were added to dilute the mixture, the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 2-chloro-6- ((cyclopentylmethyl) (methyl) amino) -N, N-dimethylisonicotinamide 135b (360 mg,1.22 mmol) in 55.11% yield.

MS m/z(ESI):296.2[M+1] ⁺

Second step

2-chloro-6-((cyclopentylmethyl)(methyl)amino)-3-formyl-N,N-dimethylisonicotinamide

2-Chloro-6- ((cyclopentylmethyl) (methyl) amino) -3-formyl-N, N-dimethylisonicotinamide

N, N-dimethylformamide (864.80 mg,11.83mmol, 916.11. Mu.L) was dissolved in 1, 2-dichloroethane (30 mL), cooled to 0℃and phosphorus oxychloride (1.81 g,11.83mmol,1.10 mL) was slowly added dropwise thereto, and the mixture was stirred for 30 minutes after warming to room temperature. 2-chloro-6- ((cyclopentylmethyl) (methyl) amino) -N, N-dimethylisonicotinamide 135b (350 mg,1.18 mmol) was dissolved in 1, 2-dichloroethane (5 mL), and the solution was added dropwise thereto, and the temperature was raised to 75℃and the reaction was stirred for 18 hours. Saturated ammonium bicarbonate solution was added to adjust pH to alkaline, dichloromethane (50 mL. Times.3) was added to extract, the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give 2-chloro-6- ((cyclopentylmethyl) (methyl) amino) -3-formyl-N, N-dimethylisonicotinamide 135c (200 mg, 617.63. Mu. Mol) in 52.20% yield.

MS m/z(ESI):324.2[M+1] ⁺

Third step

(E)-3-(((tert-butylsulfinyl)imino)methyl)-2-chloro-6-((cyclopentylmethyl)(methyl)amino)-N,N-dimethylisonicotinamide

(E) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-6- ((cyclopentylmethyl) (methyl) amino) -N, N-dimethylisonicotinamide

2-Chloro-6- ((cyclopentylmethyl) (methyl) amino) -3-formyl-N, N-dimethylisonicotinamide 135c (200 mg, 617.63. Mu. Mol) was dissolved in tetrahydrofuran (4 mL), cooled to 0 ℃, tert-butylsulfinamide (224.57 mg,1.85 mmol) and ethyl titanate (422.66 mg,1.85 mmol) were added, the reaction was warmed to 50℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, saturated sodium bicarbonate solution (10 mL) was added, stirred for 30 minutes, filtered, extracted with ethyl acetate (15 mL. Times.3), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give (E) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-6- ((cyclopentylmethyl) (methyl) amino) -N, N-dimethylisonicotinamide 135d (80 mg, 187.35. Mu. Mol) in 30.33% yield.

MS m/z(ESI):427.2[M+1] ⁺

Fourth step

4-chloro-6-((cyclopentylmethyl)(methyl)amino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

4-Chloro-6- ((cyclopentylmethyl) (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(E) -3- (((tert-butylsulfinyl) imino) methyl) -2-chloro-6- ((cyclopentylmethyl) (methyl) amino) -N, N-dimethylisonicotinamide 135d (80 mg, 187.35. Mu. Mol) was dissolved in tetrahydrofuran (15 mL), cooled to 0 ℃, lithium borohydride (326.48 mg,14.99 mmol) was added, the reaction was continued with stirring at 0℃for 1 hour, sodium methoxide (151.81 mg,2.81 mmol) was added, stirred slowly at room temperature for 5 hours, quenched with water (1 mL), extracted with ethyl acetate (15 mL. Times.3), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (eluent: A system) to give 4-chloro-6- ((cyclopentylmethyl) (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 135E (52 mg, 185.87. Mu. Mol), yield 99.21%.

MS m/z(ESI):280.1[M+1] ⁺

Fifth step

methyl

6-((cyclopentylmethyl)(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

6- ((Cyclopentylmethyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carboxylic acid methyl ester

4-Chloro-6- ((cyclopentylmethyl) (methyl) amino) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 135e (50 mg, 178.72. Mu. Mol) was dissolved in methanol (5 mL), triethylamine (36.17 mg, 357.44. Mu. Mol) and 1, 1-bis (diphenylphosphine) di-iron palladium dichloride (92.85 mg, 53.62. Mu. Mol) were added, and the reaction was stirred under carbon monoxide atmosphere at 60℃for 18 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give methyl 6- ((cyclopentylmethyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridine-4-carboxylate 135f (50 mg, 164.82. Mu. Mol), in 92.22% yield.

MS m/z(ESI):304.2[M+1] ⁺

Sixth step

6-((cyclopentylmethyl)(methyl)amino)-4-(hydroxymethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- ((Cyclopentylmethyl) (methyl) amino) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

Methyl 6- ((cyclopentylmethyl (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridine-4-carboxylate 135f (50 mg, 164.82. Mu. Mol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 ℃, lithium borohydride (7.18 mg, 329.65. Mu. Mol) was slowly added dropwise, cooled to room temperature, stirred for 1 hour after cooling to room temperature, water (1 mL) was added to quench the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: C system) to give 135g (36 mg, 130.74. Mu. Mol) of 6- ((cyclopentylmethyl) (methyl) amino) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-C ] pyridin-1-one in a yield of 79.32%.

MS m/z(ESI):276.2[M+1] ⁺

Seventh step

(6-((cyclopentylmethyl)(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl methanesulfonate

(6- ((Cyclopentylmethyl) (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate

135G (36 mg, 130.74. Mu. Mol) of 6- ((cyclopentylmethyl) (methyl) amino) -4- (hydroxymethyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one was dissolved in tetrahydrofuran (10 mL), cooled to 0℃and triethylamine (26.46 mg, 261.49. Mu. Mol, 36.35. Mu.L) and methanesulfonyl chloride (22.47 mg, 196.12. Mu. Mol, 15.18. Mu.L) were added, respectively, and stirring was continued at 0℃for 3 hours, the reaction was quenched with saturated sodium bicarbonate solution (2 mL), extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (eluent: A system) to give (6- ((cyclopentylmethyl) (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methanesulfonate (15 mg, 42.44. Mu.46. Mu.g, yield).

MS m/z(ESI):354.2[M+1] ⁺

Eighth step

6-((cyclopentylmethyl)(methyl)amino)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

6- ((Cyclopentylmethyl) (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one

(6- ((Cyclopentylmethyl) (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl methanesulfonate 135H (15 mg, 42.44. Mu. Mol) was dissolved in tetrahydrofuran (5 mL), an ethanol solution of methylamine (content 30-33%,13.18mg, 424.41. Mu. Mol) was added, and the reaction mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure to give 6- ((cyclopentylmethyl) (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 135i (12.2 mg, 42.44. Mu. Mol) in 100.00% yield.

MS m/z(ESI):289.1[M+1] ⁺

Ninth step

tert-butyl

((6-((cyclopentylmethyl)(methyl)amino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- ((Cyclopentylmethyl) (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

6- ((Cyclopentylmethyl) (methyl) amino) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 135i (12.2 mg, 42.44. Mu. Mol) was dissolved in tetrahydrofuran (4 mL), triethylamine (8.42 mg, 83.22. Mu. Mol) and di-tert-butyl dicarbonate (18.16 mg, 83.22. Mu. Mol) were added, respectively, and the reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: A system) to give ((6- ((cyclopentylmethyl) (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester 135J (16 mg, 41.18. Mu. Mol), yield 98.97%.

MS m/z(ESI):389.2[M+1] ⁺

Tenth step

tert-butyl

((6-((cyclopentylmethyl)(methyl)amino)-2-(6-(5,5-dimethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate

((6- ((Cyclopentylmethyl) (methyl) amino) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamic acid tert-butyl ester

Tert-butyl ((6- ((cyclopentylmethyl) (methyl) amino) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 135J (16 mg, 41.18. Mu. Mol) and 3- (6-bromopyridin-2-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazole 27c (24.15 mg, 82.37. Mu. Mol) were dissolved in 1, 4-dioxane (2 mL), and tris (dibenzylidene-BASE acetone) dipalladium (3.77 mg, 4.12. Mu. Mol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (2.38 mg, 4.12. Mu. Mol) and potassium phosphate (26.23 mg, 123.55. Mu. Mol) were added in this order and reacted for 1 hour at 100 ℃. The reaction solution was filtered with suction, concentrated, and the obtained residue was purified by silica gel column chromatography (eluent: A system) successively to give tert-butyl ((6- ((cyclopentylmethyl) (methyl) amino) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 135k (13 mg, 21.64. Mu. Mol), yield 52.54%.

MS m/z(ESI):601.3[M+1] ⁺

Eleventh step

Tert-butyl ((6- ((cyclopentylmethyl) (methyl) amino) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -1-oxo-2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-4-yl) methyl) (methyl) carbamate 135k (10 mg, 16.65. Mu. Mol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, and trifluoroacetic acid (3.80 mg, 33.29. Mu. Mol) was added and stirred for 1 hour after slowly warming to room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography (eluent: G system) to give 6- ((cyclopentylmethyl) (methyl) amino) -2- (6- (5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -4- ((methylamino) methyl) -2, 3-dihydro-1H-pyrrolo [3,4-c ] pyridin-1-one 135 (4 mg, 5.98. Mu. Mol), yield 35.92%.

MS m/z(ESI):501.1[M+1] ⁺

¹H NMR(400MHz,DMSO-d ₆)δ8.62(d,J＝8.3Hz,1H),8.06(t,J＝8.0Hz,1H),7.92(d,J＝7.5Hz,1H),6.77(s,1H),5.32(t,J＝4.9Hz,1H),5.17(s,2H),4.00–3.86(m,2H),3.58(d,J＝7.3Hz,2H),3.30(s,3H),3.09(s,3H),3.01(t,J＝7.5Hz,2H),2.60(t,J＝7.4Hz,2H),2.36–2.31(m,1H),1.75(s,6H),1.69–1.58(m,4H),1.56–1.41(m,4H).

Biological evaluation

Test example 1 test of the Compounds of the invention for HPK1 kinase inhibitory Activity

The following methods were used to determine the extent of inhibition of recombinant human HPK1 kinase activity by the compounds of the invention under in vitro conditions. The method uses ADP-Glo ^TM KINASE ASSAY kit (cat No. V9102) from Promega company. The kit is a luminescent kinase detection kit and is used for detecting the content of ADP generated by kinase reaction, wherein the content of ADP is positively correlated with the kinase activity, and the content of the ADP is measured to reflect the inhibition strength of a compound on the HPK1 kinase activity. For detailed experimental procedures reference is made to the kit instructions.

The experimental procedure is briefly described as follows: the test compound was first dissolved in DMSO to prepare a stock solution, and then a buffer (20 mM MgCl ₂, 50. Mu.M DTT,0.1mg/ml BSA,40mM Tris,pH7.4) was prepared according to the buffer formulation provided in the reagent instructions, and the buffer was used for gradient dilution, and the final concentration of the test compound in the reaction system was in the range of 1000nM to 0.02nM. The reaction was performed in 384 well microplates, first compound and recombinant human HPK1 protein (final concentration 1 ng/. Mu.L, available from SIGNALCHEM, cat# M23-11G-10) were added to the wells and incubated at room temperature for 5 minutes, then ATP solution (final concentration 10. Mu.M) and substrate MBP (final concentration 0.2ug/uL, available from SIGNALCHEM, cat# M42-51N) were added to the reaction solution and incubated with shaking at room temperature for 60 minutes. Subsequently, 5. Mu.L of ADP-Glo Reagent was added to the reaction system, and incubation was continued at room temperature with shaking for 40 minutes. Then 10 μ L Kinase Detection Reagent was added to the reaction and incubation was continued with shaking for 30 minutes at room temperature. After the incubation, the chemiluminescent intensity value of each well was measured in a luminometer in the luminometer mode. The percent inhibition of compounds at each concentration was calculated by comparison with the luminescence intensity of the control group (0.1% dmso) and nonlinear regression analysis was performed by GRAPHPAD PRISM software on the compound concentration vs. inhibition to obtain IC ₅₀ values for the compounds, see table 1.

TABLE 1 IC50 data for compounds of the invention inhibiting HPK1 kinase activity

ConclusionAs can be seen from Table 1, the compounds of the present invention have a better inhibitory effect on HPK1 kinase.

Test example 2 determination of the inhibitory Activity of the Compounds of the invention against p-SLP76S376 in Jurkat cells

The following method was used to determine the inhibitory activity of the compounds of the present invention on p-SLP76S376 in Jurkat cells. The method uses a Phospho-SLP-76 (Ser 376) cell kit (product number 63ADK076 PEG) from Cisbio, and the detailed experimental procedure can be referred to the kit instructions. Jurkat cells were purchased from the China academy of sciences of Shanghai life sciences center for cell resources.

The experimental procedure is briefly described as follows: jurkat cells were cultured in RPMI 1640 complete medium containing 10% fetal bovine serum, 100U penicillin, 100 μg/mL streptomycin, and 1mM Sodium Pyruvate. mu.L of Jurkat cells (100000 per well) were plated in 384 well plates and the medium was complete and incubated in a 5% CO2 incubator at 37 ℃. Dissolving a test compound in DMSO to prepare a10 mM stock solution, diluting with RPMI 1640 complete medium, adding 2 mu L of RPMI 1640 complete medium containing the test compound with corresponding concentration into each well, and placing the test compound in a cell culture box for culture for 1 hour, wherein the final concentration of the test compound in the system is 10000nM-0.01 nM; subsequently, 2. Mu.l of Anti-human CD3 (5 ug/ml) was added and incubated in a cell incubator for 30 minutes; then 4. Mu.L of lysate was added for 45 min, and finally 4. Mu.L of Phospho-SLP-76Cryptate antibody and Phospho-SLP-76d2 anti-body were added and incubated overnight at room temperature. Fluorescence intensities at excitation wavelengths of 304nM were measured on an microplate reader in TF-FRET mode, with emission wavelengths of 620nM and 665nM for each well, and the fluorescence intensity ratio for each well 665/620 was calculated. The percent inhibition of the test compounds at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group (0.1% dmso), and nonlinear regression analysis was performed by GRAPHPAD PRISM software on the values of the inhibition with the test compound concentration to obtain IC ₅₀ values for the compounds, see table 2.

TABLE 2 IC ₅₀ data for the inhibitory Activity of the inventive Compounds on p-SLP76S376 in Jurkat cells

Examples numbering	IC ₅₀(nM)
5	207.3
6	257

7	407
9	148.3
10	429.7
13	632
27	136.2
30	232.2
31	486
34	142.7
35	167.2
39	313.3
45	280.5
46	301
49	50.17
50	133.2
51	139
52	81.34
55	65.89
57	94.48
59	109.9
60	99.86
61	50.08
62	255.7
63	91.55
64	139.1
65	139.3
66	81.41
67	314.6
68	118.1
69	81.08
70	435.7
73	112.8
75	69.5
80	237.8
81	238
83	143.3

84	463.9
85	366.9
86	389.7
130	52.79
132	187.7
133	98.1

ConclusionAs can be seen from Table 2, the compounds of the present invention have a good inhibitory effect on p-SLP76S376 in Jurkat cells.

Test example 3 determination of the ability of the Compounds of the invention to activate IL2 Release in Jurkat cells

The following methods were used to determine the ability of the compounds of the invention to activate IL2 release in Jurkat cells. The method uses the Human IL2kit from CisbioKit (cat No. 62HIL02 PEG), for detailed experimental procedures reference is made to the kit instructions. Jurkat cells were purchased from the China academy of sciences of Shanghai life sciences center for cell resources.

The experimental procedure is briefly described as follows: jurkat cells were cultured in RPMI 1640 complete medium containing 10% fetal bovine serum, 100U penicillin, 100 μg/mL streptomycin, and 1mM Sodium Pyruvate. mu.L of Jurkat cells (50000 per well) were plated in 384-well plates and the medium was complete and incubated in a 5% CO2 incubator at 37 ℃. Dissolving a test compound in DMSO to prepare a10 mM stock solution, diluting the stock solution by using RPMI 1640 complete medium, adding 4uL of the RPMI 1640 complete medium containing the test compound with corresponding concentration into each well, and placing the test compound in a cell culture box for culture for 30 minutes, wherein the final concentration of the test compound in the system is 10000nM-41 nM; subsequently, 4. Mu.l of Anti-human CD3 (5 ug/ml) and Anti-human CD28 (5 ug/ml) were added and incubated in a cell incubator for 4 hours; subsequently, 4. Mu.L of IL2Eu Cryptate Antibody and IL2d2 anti-body were added and incubated overnight at room temperature. Fluorescence intensities at excitation wavelengths of 304nM were measured on an microplate reader in TF-FRET mode, with emission wavelengths of 620nM and 665nM for each well, and the fluorescence intensity ratio for each well 665/620 was calculated. For data analysis, control group (0.1% dmso) was set to activate 0%,3 μm positive control (3 μm 1787) was set to activate 100%, the activation ratio of test compound at each concentration was calculated, and nonlinear regression analysis was performed by GRAPHPAD PRISM software at test compound concentration vs. value-activation ratio to obtain EC ₅₀ values of compounds, see table 3.

TABLE 3 data on the ability of compounds of the invention to activate IL2 release in Jurkat cells EC ₅₀

Examples numbering	EC ₅₀(nM)	Max(％)
3	432.2	62.52
4	479.10	94.71
5	374.60	118.53
6	497.2	82.64
9	199.4	100.31
17	338.6	95.85
18	341.1	95.55
27	123.6	106.05
30	420.7	124.3
33	406.6	62.13

34	154	66.03
35	169	90.94
36	459.3	102
49	95.17	116.00
50	127.4	87.49
51	127.8	71.22
52	160.4	81.18
55	128.2	97.29
57	136.5	91.26
59	99.02	66.11
60	129.6	106.78
61	78.94	148.39
63	92.02	114.5
64	142.9	105.29
65	218.0	171.1
66	68.6	119.8
67	145	98.38
68	128.5	127.05
69	73.34	136.17
73	127.9	107.82
75	90.16	118.82
77	384.7	131.92
81	354.9	99.73
83	251.6	79.41
84	395.7	104.45
85	250.4	101.99
86	361.6	85.06
130	66.44	73.17
132	329.2	172.8
133	103.5	123.21
134	170.5	93.2

Conclusionfrom Table 3, it can be seen that the compounds of the present invention have a better activating ability for IL2 release in Jurkat cells.

Test example 4, ICR mouse pharmacokinetic study of Compound of the invention

1. Purpose of experiment

The compound of the invention is administrated by measuring the liquid chromatography/mass spectrometry (LC/MS/MS) method by taking ICR mice as test animals, and the drug concentration in plasma at different times is measured to study the pharmacokinetic characteristics of the compound of the invention in the mice.

2. Experimental protocol

2.1 Experimental drugs and animals;

Compounds of the invention

ICR mice, male, 29.0-33.8 g, purchased from Peking Vitre Liwa laboratory animal technologies Co.

2.2 Pharmaceutical formulation

Weighing a proper amount of medicine, adding a proper amount of DMA (direct memory access) 30%Solutol HS 15:Saline =5:5:90 (v/v/v), and carrying out vortex oscillation and ultrasonic preparation to prepare a 1mg/kg solution;

2.3 administration of drugs

ICR mice, the test compound(s) were gavaged (9) and fed (PO, administered at a dose of 10mg/kg, administered at a volume of 10 mL/kg) after an overnight fast for 4 hours.

3. Operation of

About 0.1mL of blood was collected via orbital veins before and after administration for 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours, and heparin sodium was anticoagulated. After blood sample collection, the plasma was centrifuged (centrifugation conditions: 1500g,10 min). The collected plasma was stored at-40 to-20℃prior to analysis.

LC-MS/MS was used to determine the amount of test compound in the plasma of mice following intragastric administration.

3. Pharmacokinetic parameter results

The pharmacokinetic parameters of the compounds of the invention are shown in the following table.

TABLE 4 pharmacokinetic results

Conclusion: the compound has higher blood concentration and area under the curve, long half-life period and better pharmacokinetic property.

Test example 5 compounds for hERG potassium channel inhibition activity test

1. Cell culture

1.1 Cells used in this assay were CHO cell lines transfected with hERG cDNA and stably expressing hERG channels (supplied by Denmark Sophion Bioscience, inc.), with a cell number of P17. Cells were cultured in medium containing the following ingredients (all from Invitrogen): ham's F medium, 10% (v/v) inactivated fetal bovine serum, 100 μg/mL hygromycin B,100 μg/ML GENETICIN.

1.2CHO hERG cells were grown in dishes containing the above medium and cultured in an incubator containing 5% CO ₂ at 37 ℃. 24 to 48 hours prior to electrophysiological experiments, CHO hERG cells were transferred to round glass plates placed in petri dishes and grown in the same culture broth and culture conditions as above. The density of CHO hERG cells on each circular slide needs to be such that the vast majority of cells are independent, single.

2. Experimental solution

The solutions of table 5 (recommended by Sophion) were used for electrophysiological recording.

TABLE 5 composition of intracellular and extracellular fluids

3. Electrophysiological recording procedure

3.1 Electrophysiological recording System

A fully automated QPatch system (Sophion, denmark) was used to record whole cell currents. The cells were clamped at a voltage of-80 mV. The cell clamp voltage depolarized to +20mV to activate the hERG potassium channel, and after 2.5 seconds was clamped to-50 mV to eliminate inactivation and generate an outward tail current. The tail current peak is used as a value for hERG current magnitude.

3.2QPatch Experimental procedure

After the initial stage of achieving the whole cell arrangement state of rupture of membranes, the cells were recorded for at least 120 seconds to reach stability. The voltage pattern described above was then applied to the cells every 15 seconds throughout the process. Only stable cells are allowed into the course of drug treatment in the above parameter threshold record. An external solution containing 0.1% dimethyl sulfoxide (solvent) was applied to the cells, a baseline was established, and the current was allowed to stabilize for 3 minutes. After the addition of the compound solution, the cells remain in the test environment until the effect of the compound reaches a steady state or is limited to 4 minutes. In test experiments with different gradients of compound concentration, the compound was added to the clamped cells from low to high concentration. After completion of the compound test, the cells were washed with an external solution until the current was restored to a stable state.

4. Preparation of Compounds

4.1 10MM stock solution of compound was diluted in a gradient dilution with extracellular fluid to a final mu M concentration.

The highest test concentration of 4.2 was 30. Mu.M, followed by a total of 6 concentrations of 30, 10, 3, 1, 0.3 and 0.1. Mu.M.

4.3 The final concentration of DMSO in the compound solutions of other concentrations was 0.1% except for the 30. Mu.M compound DMSO of 0.3%. All compound solutions were subjected to conventional 5 to 10 minute sonication and shaking to ensure complete dissolution of the compound.

5. Data analysis

Test data were analyzed by QPatch analysis software supplied by Sophion, excel, GRAPHPAD PRISM, etc.

6. Quality control

Reagent: the experimental reagents used were purchased from Sigma company.

The test data in the report need to meet the following criteria:

The membrane resistance Rm is more than 100MΩ;

An access resistance (Ra) <15mΩ;

tail current amplitude >200pA;

Cell hERG current spontaneous reduction (rundown) per minute <2%;

Leakage current less than 200pA or less than 10% of hERG current peak (during 90% of the recording time);

the inhibitory effect of multiple concentrations CISAPRIDE on hERG channel was positive control.

7. Experimental results

The results of inhibition of hERG current by the compounds of the present invention and the comparative examples are shown in table 6.

Results of inhibition of hERG currents by the compounds of Table 6

Numbering of compounds	Inhibition by 1. Mu.M (%)
Comparative example 1	14.47
Compound 4	-0.31
Compound 35	3.17
Compound 57	7.90
Compound 59	4.87

Conclusion: inhibition of the cardiac hERG potassium channel by drugs is the primary cause of QT prolongation syndrome by drugs. From experimental results, compared with comparative example 1, the compound of the embodiment of the invention has no obvious inhibition effect on cardiac hERG potassium ion channel, and can avoid toxic and side effects of the heart at high dosage.

Wherein, comparative example 1 was prepared according to example 6 of WO2020100027A1, the specific structure is as follows:

test example 6 study of the metabolic stability of Compounds of the invention in mouse liver microsomes

1. Purpose of experiment

The purpose of this experimental study was to investigate the metabolic stability of the compounds of the invention in mouse liver microsomes.

2. Reagent information

Name of the name	Suppliers (suppliers)
Mouse liver microsome	Corning Co Ltd
Midazolam maleate	Chinese food and drug testing institute
NADPH	Roche Switzerland Co
Monopotassium phosphate	National medicine group chemical reagent Co., ltd
Dipotassium hydrogen phosphate	National medicine group chemical reagent Co., ltd

Magnesium chloride (MgCl ₂)	National medicine group chemical reagent Co., ltd
Verapamil hydrochloride	Chinese food and drug testing institute
Glibenclamide	Chinese food and drug testing institute
DMSO	Amresco Co Ltd
Methanol	Honeywell Co Ltd
Acetonitrile	Honeywell Co Ltd
Formic acid	Shanghai Ala Biochemical technology Co.Ltd

3. Experimental protocol

The test compound was incubated with mouse liver microsomes and the reaction was initiated by the addition of coenzyme NADPH. The reaction was stopped by withdrawing 20. Mu.L of the incubation and transferring to 200. Mu.L of acetonitrile containing internal standard at 0, 5, 15, 30 and 60 minutes. After protein precipitation, the supernatant was removed by centrifugation at 3,700rpm for 10 minutes. The supernatant was diluted 1:1 with water and analyzed by LC-MS/MS method. The in vitro intrinsic clearance was calculated from the clearance half-life of the test compound in the incubation system. Midazolam as an internal reference compound was incubated in2 parts in parallel. The incubation conditions are summarized in the following table:

4. Data analysis

The ratio of analyte/internal standard peak area (a _analyte/A _IS) will be determined by the instrument and the percent remaining (% Control) calculated from the ratio of a _analyte/A _IS in the sample at the non-zero time point to the sample at the zero time point. Ln (% Control) is plotted against incubation time and fitted linearly. The clearance constant (k, min ^-1) and clearance half-life (T _1/2, min) of the test compound were calculated from the following equations.

k＝-slope

T _1/2＝0.693/k

4. Experimental results

The relevant parameters of the liver microsome stability of the compound of the invention are shown in the following table:

Numbering of compounds	Half-life period /(T _1/2，min)
Comparative example 1	80.85
27	135.3
59	168.75
61	104.01
63	164.4

Conclusion: compared with comparative example 1, the compound of the invention has obviously prolonged half life and obviously improved stability of mouse liver microsomes.

Claims

A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

Wherein:

R ¹ and R ² are the same or different and are each independently selected from a hydrogen atom, alkyl, halogen, nitro, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸ or-S (O) _rR ⁶; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸、-CH ₂NHC(O)OR ⁶、-CH ₂NR ⁷R ⁸, or-S (O) _rR ⁶;

R ^A is selected from hydrogen, halogen, hydroxy, cyano, alkyl or alkoxy; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; r ^A is preferably a hydrogen atom;

R ³ is selected from a hydrogen atom, halogen, alkyl or alkoxy; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; r ³ is preferably a hydrogen atom;

R ⁴ is selected from the following groups:

(i) A 6-14 membered fused ring, a 5-6 membered aryl group, or a 7-11 membered heterocyclyl group, wherein said 6-14 membered fused ring, 5-6 membered aryl group, or 7-11 membered heterocyclyl group is optionally further substituted with one or more R ^a;

R ^a, which are identical or different, are independently selected from a hydrogen atom, alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸、-CH ₂NHC(O)OR ⁶、-CH ₂NR ⁷R ⁸ or-S (O) rR ⁶; wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸、-CH ₂NHC(O)OR ⁶、-CH ₂NR ⁷R ⁸ or-S (O) rR ⁶;

(ii) A 4-6 membered heterocyclyl or a 5-10 membered heteroaryl, wherein said 4-6 membered heterocyclyl or 5-10 membered heteroaryl is substituted with one or more R ^b;

R ^b, which are the same or different, are independently selected from the group consisting of hydrogen, alkyl, oxo, -S (O) _rR ⁶, -L-aryl, -L-heterocyclyl, -L-cycloalkyl, -L-fused ring, or-L-heteroaryl, wherein said aryl, heterocyclyl, fused ring, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyalkyl, benzyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸、 -CH ₂NHC(O)OR ⁶、-CH ₂NR ⁷R ⁸, or-S (O) _rR ⁶, wherein said cycloalkyl is further substituted with one or more substituents selected from the group consisting of alkyl, halogen, oxo, or haloalkyl;

Provided that at least one R ^b is selected from the group consisting of-S (O) _rR ⁶, -L-aryl, -L-heterocyclyl, -L-cycloalkyl, -L-fused ring, or-L-heteroaryl;

Each L is independently selected from a bond, -C ₁-C ₆ alkylene, or-C ₁-C ₆ alkyleneoxy; wherein said alkylene or alkyleneoxy group is optionally further substituted with one or more substituents selected from alkyl, halogen or hydroxy; preferably, L is selected from the group consisting of a bond, -CH ₂ -, or-CH ₂ O-;

Or two R ^b together with the same carbon atom to which they are attached form a-C (O) -;

(iii) -NR ^cR ^d、-C(O)NHCH ₂R ^g OR-OR ^f, wherein R ^c、R ^d、R ^f、R ^g, equal OR different, are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a fused ring, -C (O) R ⁶、-C(O)OR ⁶ OR-S (O) _rR ⁶, wherein said alkyl group, cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group OR a fused ring is optionally further substituted with one OR more substituents selected from alkyl group, hydroxyalkyl group, halogen, nitro group, cyano group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group 、＝O、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸、-CH ₂NHC(O)OR ⁶、-CH ₂NR ⁷R ⁸、P(O)R ⁷R ⁸ OR-S (O) _rR ⁶;

R ⁵ is selected from the group consisting of hydrogen, hydroxy, halogen, cyano, alkyl, or alkoxy, wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, alkyl, or alkoxy;

Or R ⁴ and R ⁵ together with the atoms to which they are attached form a heterocyclyl, heteroaryl, or fused ring; the heterocyclyl, heteroaryl, or fused ring is optionally further substituted with one or more R ^e;

R ^e is substituted with a substituent selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸、-CH ₂NHC(O)OR ⁶、-CH ₂NR ⁷R ⁸, or-S (O) rR ⁶; wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-OR ⁶、-C(O)R ⁶、-C(O)OR ⁶、-NHC(O)R ⁶、-NHC(O)OR ⁶、-NR ⁷R ⁸、-C(O)NR ⁷R ⁸、-CH ₂NHC(O)OR ⁶、-CH ₂NR ⁷R ⁸ or-S (O) rR ⁶;

R ⁶ is selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-C(O)R ⁹、-C(O)OR ⁹、-OC(O)R ⁹、-NR ¹⁰R ¹¹、-C(O)NR ¹⁰R ¹¹、-SO ₂NR ¹⁰R ¹¹, or-NR ¹⁰C(O)R ¹¹;

R ⁷ and R ⁸ are each independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-C(O)R ⁹、-C(O)OR ⁹、-OC(O)R ⁹、-NR ¹⁰R ¹¹、-C(O)NR ¹⁰R ¹¹、-SO ₂NR ¹⁰R ¹¹, or-NR ¹⁰C(O)R ¹¹;

Or R ⁷ and R ⁸ together with the atoms to which they are attached form a 4-8 membered heterocyclyl wherein the 4-8 membered heterocyclyl contains one or more N, O or S (O) _r groups and said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-C(O)R ⁹、-C(O)OR ⁹、-OC(O)R ⁹、-NR ¹⁰R ¹¹、-C(O)NR ¹⁰R ¹¹、-SO ₂NR ¹⁰R ¹¹ or-NR ¹⁰C(O)R ¹¹;

R ⁹、R ¹⁰ and R ¹¹ are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl group, heteroaryl group, carboxyl group, or carboxylate group;

r is selected from 0, 1 or 2.
The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (II), (III), or (IV):

Wherein:

Ring A is selected from 6-14 membered fused ring, 5-6 membered aryl or 7-11 membered heterocyclyl;

ring B is selected from 4-6 membered heterocyclyl or 5-10 membered heteroaryl;

ring C is selected from heterocyclyl, heteroaryl or fused ring;

m is selected from 0,1,2 or 3;

n is selected from 1,2 or 3;

p is selected from 0,1,2 or 3.

R ¹、R ²、R ^a、R ^b and R ^e are as defined in claim 1.
The compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (V), (VI), or (VII):

Wherein R ¹、R ²、R ^c、R ^d、R ^f and R ^g are as defined in claim 1.
A compound of formula (II) according to claim 2, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound of formula (II-1), (II-2), (II-3) or (II-4), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

Wherein:

ring D is selected from 3-8 membered heterocyclyl or 6-11 membered fused ring;

Ring E is selected from a 5-8 membered aryl, a 5-8 membered heteroaryl or a 6-9 membered fused ring;

Ring F is selected from 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;

q is selected from 0,1,2 or 3;

R ¹、R ² and R ^a are as defined in claim 2.
A compound of formula (III) according to claim 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (III-1) or (III-2):

Wherein R ¹、R ² and R ^b are as defined in claim 2.
A compound of formula (II) according to claim 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring a is selected from:
a compound according to claim 2 of formula (II-1) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein

Selected from:
a compound of formula (IV) according to claim 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring C is selected from:
a compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from heterocyclyl, heteroaryl, or-NR ⁷R ⁸; wherein the heterocyclyl or heteroaryl is optionally further substituted with one or more alkyl groups.

R ⁷ and R ⁸ are each independently selected from a hydrogen atom, an alkyl group, preferably methyl, or a cycloalkyl group, preferably cyclopropyl or cyclopentyl, wherein the alkyl group is optionally further substituted by a cycloalkyl group.
The compound of claim 9, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from
A compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

R ² is selected from alkyl, heteroaryl, heterocyclyl or-C (O) NR ⁷R ⁸; wherein said alkyl, heteroaryl or heterocyclyl is optionally further substituted with one or more alkyl or-NR ⁷R ⁸;

Preferably, R ² is selected from-CH ₂NR ⁷R ⁸;

R ⁷ and R ⁸ are each independently selected from a hydrogen atom, an alkyl group, preferably a methyl group, or a cycloalkyl group, preferably a cyclopropyl group or a cyclopentyl group.
The compound of claim 11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

r ² is selected from
A compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is:
A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Use of a compound according to any one of claims 1 to 13, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the preparation of an HPK1 inhibitor.
Use of a compound according to any one of claims 1 to 13, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the manufacture of a medicament for the treatment of a disease mediated by HPK1, wherein the disease mediated by HPK1 is preferably an inflammation, autoimmune disease or tumor, wherein the autoimmune disease is preferably systemic lupus erythematosus or psoriasis; wherein the tumor is preferably a hematological malignancy and a solid malignancy.
The use of claim 16, wherein the tumor is selected from the group consisting of acute myelogenous leukemia, bladder epithelial cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, blastoma, retinoblastoma, sarcoma, prostate cancer, cholangiocarcinoma, esophageal cancer, gastric cancer, liver cancer, glioma, cervical cancer, ovarian cancer, head and neck cancer, and multiple myeloma.
Use of a compound according to any one of claims 1 to 13, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the manufacture of a medicament for the treatment of inflammation, autoimmune diseases or neoplasms, wherein the autoimmune disease is preferably systemic lupus erythematosus or psoriasis; wherein the tumor is preferably a hematological malignancy and a solid malignancy.
The use of claim 18, wherein the tumor is selected from the group consisting of acute myelogenous leukemia, bladder epithelial cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, blastoma, retinoblastoma, sarcoma, prostate cancer, cholangiocarcinoma, esophageal cancer, gastric cancer, liver cancer, glioma, cervical cancer, ovarian cancer, head and neck cancer, and multiple myeloma.