CN111825654A

CN111825654A - Phenylmethylene piperidine derivatives, preparation method, intermediates and uses thereof

Info

Publication number: CN111825654A
Application number: CN201910317859.8A
Authority: CN
Inventors: 孟庆华; 王小虎
Original assignee: Beijing Coolling Biotechnology Co ltd
Current assignee: Beijing Coolling Biotechnology Co ltd
Priority date: 2019-04-19
Filing date: 2019-04-19
Publication date: 2020-10-27
Also published as: WO2020211836A1

Abstract

The invention discloses a benzylidene piperidine derivative, a preparation method, an intermediate and application thereof. Utensil for cleaning buttockIn particular, the present disclosure relates to compounds of formula (I) and processes for their preparation, intermediates used in the preparation of compounds of formula (I), and the use of compounds of formula (I) in the treatment and/or prevention of diseases associated with abnormal activation of ROR γ t. The compound of formula (I) can inhibit the receptor of ROR gamma t protein, regulate the differentiation of Th17 cells and inhibit the generation of IL-17, so that the compound can be used as a therapeutic drug for diseases related to abnormal activation of ROR gamma t.

Description

Phenylmethylene piperidine derivatives, preparation method, intermediates and uses thereof

Technical Field

The application belongs to the technical field of medicines, and relates to a benzylidene piperidine derivative with ROR gamma t inhibitory activity.

Background

Autoimmune diseases are mainly caused by a disorder of the immune system, in particular a dysfunction of T cells, leading to an abnormal recognition of the immune system, attack of self-tissues or antigens. Other inflammatory diseases, such as allergic diseases, are mainly caused by an excessive reaction of the immune system to foreign antigens. Over the last 10 years of research has shown that over-reaction of IL-17 expressing cells, particularly Th17 cells, can lead to a variety of human autoimmune diseases including rheumatoid arthritis, ankylosing spondylitis, psoriasis (colloquially referred to as psoriasis), multiple sclerosis and the like (Dong, 2014). In addition, studies have shown that Th17 cells also have important pathological roles in some allergic diseases, particularly in neutrophil-enriched asthma (Chang et al, 2017). Interestingly, studies have also found that IL-17 and Th17 cells expressing IL-17 are enriched in tumor tissues of various cancer patients (these cancers include colon, lung, liver, breast, ovary, pancreas, prostate, melanoma, etc.) and may have tumor-promoting or anti-tumor effects under various conditions (asadadeh et al, 2017). Therefore, some inhibitors or agonists against IL-17 or Th17 cells will likely be useful not only for the treatment of the above autoimmune or allergic diseases, but also for the clinical treatment of cancer.

Th17 cells were a third class of helper CD4 positive T cells, found in 2005 by professor Dongchen and professor Weaver et al, following Th1 and Th2 cells. Th17 cells predominantly express interleukins ((IL)) -17 and IL-17F (Harrington et al, 2005; Park et al, 2005), with IL-17 being considered to be the most prominent effector cytokine of Th17 cells. Under normal conditions, Th17 cells can recruit immune cells such as neutrophils and macrophages in a direct or indirect way by secreting chemokines and cytokines, resist infection of extracellular bacteria and fungi, and have important functions in mucosal immunity of human body by regulating the integrity of mucosal barrier. Abnormal, persistent activation of Th17 cells can lead to persistent inflammatory responses in the tissues and organs involved, causing various autoimmune diseases and affecting the disease course of various tumors (Asadzadeh et al, 2017).

Differentiation and development of Th17 cells are mainly controlled by a key primary transcription factor, ROR γ t, which directly regulates the expression of cytokines including IL-17 and IL-17F mainly through binding to sites of Th17 cell-associated genes (Ivanov et al, 2006; Yang et al, 2008). ROR γ t, also known as ROR γ 2, is one of two splice forms of the orphan receptor ROR γ 1 and ROR γ 2, where ROR γ 1 has some expression in muscle groups, liver, kidney and thymus tissues, while ROR γ t is mainly expressed in immune cells. It was found that genetic defects in ROR γ t, or blockade of ROR γ t function with small molecules, could lead to stunted development of Th17 cells and defective expression of IL-17, and resistance (insensitivity) to various mouse models of autoimmune diseases, including Experimental Autoimmune Encephalomyelitis (EAE) in mice, arthritis, psoriatic skin inflammation, etc. (Lai and Dong, 2016). In recent years, a plurality of monoclonal drugs against IL-17 and IL-17 receptors have shown good therapeutic effects in clinical trials of various human autoimmune diseases, and are approved by countries and regions such as Europe, America, Japan, and the like for the treatment of chronic inflammation such as moderate to severe psoriasis, psoriatic arthritis, ankylosing spondylitis, and the like (Lai and Dong, 2016). However, because monoclonal antibody drugs are expensive, the market urgently needs alternative drugs which are low in price, remarkable in curative effect and capable of benefiting the public patients, and therefore the key transcription factor ROR gamma t at the upstream of IL-17 also becomes an important hot drug target for treating Th17 related diseases.

Disclosure of Invention

One or more embodiments of the present application provide a benzylidene piperidine derivative. The phenmethyl piperidine derivative can target ROR gamma t, inhibit the activity of ROR gamma t and the differentiation and development of Th17 cells and the expression of IL-17, and can be used for treating related autoimmune diseases, inflammatory diseases or cancers.

One or more embodiments of the present application provide compounds of formula (I)

Wherein

X is

R₁Is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen or cyano; the C1-C6 alkyl group, the C1-C6 haloalkyl group, the C1-C6 alkoxy group are each independently optionally substituted by one or more groups selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 alicyclic hydrocarbon group and 3-7 membered heterocycloalkyl;

each R is₂Independently is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen or cyano; the C1-C6 alkyl group, C1-C6 haloalkyl group are each independently optionally substituted with one or more groups selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 alicyclic hydrocarbon group, and 3-7 membered heterocycloalkyl group;

R₃is C1-C6 alkyl, C1-C6 alkoxy, C3-C7 alicyclic hydrocarbon, 3-7 membered heteroatom-containing alicyclic hydrocarbon, C5-C10 aryl, or 5-10 membered heteroaryl, wherein said C1-C6 alkyl, C1-C6 alkoxy, C3-C7 alicyclic hydrocarbon, 3-7 membered heteroatom-containing alicyclic hydrocarbon, C5-C10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano, acyl, carboxyl, hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, carbonyl, C3-C7 alicyclic hydrocarbon, 3-7 membered heterocycloalkyl, sulfonyl, C5-C10 aryl, and 5-10 membered heteroaryl;

R₄is C1-C6 alkyl, C1-C6 alkoxy, C3-C7 alicyclic hydrocarbon group, 3-7 membered alicyclic hydrocarbon group containing heteroatom, C5-C10 aryl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C7 alicyclic hydrocarbon group, 3-7 membered alicyclic hydrocarbon group containing heteroatom, C5-C10 aryl and 5-10 membered heteroaryl are respectively and independentlyOptionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, amino, cyano, acyl, carboxyl, hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, carbonyl, C3-C7 alicyclic hydrocarbon, 3-7 membered heterocycloalkyl, sulfonyl optionally substituted with C1-C3 alkyl, C5-C10 aryl, and 5-10 membered heteroaryl;

m is 0, 1 or 2;

p is 0 or 1;

or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

One or more embodiments of the present application provide pharmaceutical compositions containing a compound of formula (I) or a stereoisomer, enantiomer or tautomer of the compound or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

One or more embodiments of the present application provide the use of a compound of formula (I) or a stereoisomer, enantiomer or tautomer of the compound or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, enantiomer or tautomer of the compound or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the prophylaxis and/or treatment of a disease.

One or more embodiments of the present application provide the use of a compound of formula (I) or a stereoisomer, enantiomer or tautomer of the compound or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, enantiomer or tautomer of the compound or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the manufacture of an inhibitor of the ROR γ t receptor.

One or more embodiments of the present application provide the use of a compound of formula (I) or a stereoisomer, enantiomer or tautomer of such a compound or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or of a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, enantiomer or tautomer of such a compound or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the prophylaxis and/or treatment of a disease associated with abnormal activation of the ROR γ t receptor.

One or more embodiments of the present application provide the use of a compound of formula (I) or a stereoisomer, enantiomer or tautomer of the compound or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, enantiomer or tautomer of the compound or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the inhibition of the ROR γ t receptor.

Drawings

FIG. 1: example 4 Experimental Autoimmune Encephalomyelitis (EAE) in mice the number of days of immunization of the mice was plotted against the clinical score following administration of compound 31 at 10mg/kg body weight of the mice.

FIG. 2: example 4 Experimental Autoimmune Encephalomyelitis (EAE) in mice the number of days of immunization of the mice was plotted against the clinical score following administration of compound 31 at 30mg/kg body weight of the mice.

FIG. 3: example 4 Experimental Autoimmune Encephalomyelitis (EAE) in mice the number of days of immunization of the mice was plotted against the clinical score following administration of compound 31 at 100mg/kg body weight of the mice.

Detailed Description

Wherein

X is

R₁Is hydrogen, C1-C6 alkyl, C3-C7 alicyclic hydrocarbon group, C1-C6 halogenated alkyl, C1-C6 alkoxy, halogen or cyano; the C1-C6 alkyl, C3-C7 alicyclic hydrocarbon group, C1-C6 haloalkyl, C1-C6 alkoxy, each independently optionally substituted with one or more groups selected from C1-C6 alkyl, C1-C6 haloalkyl, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 alicyclic hydrocarbon group, 3-7 membered heterocycloalkyl;

each R is₂Independently C1-C6 alkyl C1-C6 haloalkyl, C3-C7 alicyclic hydrocarbon, C1-C6 alkoxy, halogen or cyano; the C1-C6 alkyl group, C3-C7 alicyclic hydrocarbon group, C1-C6 halogenated alkyl group are respectively and independently optionally substituted by one or more groups selected from C1-C6 alkyl group, C1-C6 halogenated alkyl group, cyano group, C1-C6 alkoxy group, C1-C6 halogenated alkoxy group, C3-C7 alicyclic hydrocarbon group and 3-7-membered heterocyclic alkyl group;

R₄is C1-C6 alkyl, C1-C6 alkoxy, C3-C7 alicyclic hydrocarbon, 3-7 membered alicyclic hydrocarbon containing hetero atom, C5-C10 aryl or 5-10 membered heteroaryl, wherein said C1-C6 alkyl, C1-C6 alkoxy, C3-C7 alicyclic hydrocarbon, 3-7 membered heteroatom-containing alicyclic hydrocarbon, C5-C10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, amino, cyano, acyl, carboxyl, hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, carbonyl, C3-C7 alicyclic hydrocarbon, 3-7 membered heterocycloalkyl, sulfonyl optionally substituted with C1-C3 alkyl, C5-C10 aryl, and 5-10 membered heteroaryl;

m is 0, 1 or 23;

p is 0 or 1;

In one or more embodiments of the present application, X is

In one or more embodiments of the present application, R₁Is hydrogen, C1-C6 alkyl, C3-C7 alicyclic hydrocarbon, C1-C6 halogenated alkyl, C1-C6 alkoxy or halogen. In one or more embodiments of the present application, R₁Is hydrogen, C1-C6 alkyl or halogen. In one or more embodiments of the present application, R₁Is methyl or Cl.

In one or more embodiments of the present application, each R₂Independently C1-C6 alkyl, C3-C7 alicyclic hydrocarbon, C1-C6 haloalkyl, C1-C6 alkoxy or halogen. In one or more embodiments of the present application, each R₂Independently a halogen. In one or more embodiments of the present application, each R₂Independently F and Cl. In one or more embodiments of the present application, when m is 1 or 2, at least one R₂At R₁And (4) contraposition.

In one or more embodiments of the present application, R₄Is C3-C7 alicyclic hydrocarbon group, 3-7 membered alicyclic hydrocarbon group containing hetero atom, C5-C10 aryl group or 5-10 membered heteroaryl group; the C3-C7 alicyclic hydrocarbon group, the 3-7 membered heteroatom-containing alicyclic hydrocarbon group, the C5-C10 aryl group or the 5-10 membered heteroaryl group are each independently optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, amino, cyano, acyl, carboxyl, hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, carbonyl, C3-C7 alicyclic hydrocarbon group, the 3-7 membered heteroatom-containing alicyclic hydrocarbon group and sulfonyl optionally substituted with C1-C3 alkyl.

In one or more embodiments of the present application, R₄Is 3-7 membered alicyclic hydrocarbon group containing heteroatom, C5-C10 aryl or 5-10 membered heteroaryl, the 3-7 membered alicyclic hydrocarbon group containing heteroatom, C5-C10 aryl or 5-10 membered heteroaryl is optionally substituted by one or more groups selected from halogen, C1-C6 alkyl, cyano, C1-C6 alkoxy, carbonyl, C3-C7 alicyclic hydrocarbon group and is optionally substituted by one or more groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, carbonylC1-C3 alkyl substituted sulfonyl.

In one or more embodiments of the present application, R₄Is optionally substituted by one or more of F, Cl, C1-C3 alkyl and cyano

C5-C10 aryl or 5-10 membered heteroaryl.

In one or more embodiments of the present application, R₄Is preferably R₄Is optionally substituted by one or more of F, Cl, C1-C3 alkyl and cyano

C5-C10 aryl or 5-10 membered heteroaryl.

In one or more embodiments of the present application, R₄Is composed of

In one or more embodiments of the present application, R₃Is C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, or 5-10 membered heteroaryl; the C1-C6 alkyl, C1-C6 alkoxy, C3-C7 alicyclic hydrocarbon, 3-7 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C1-C6 alkyl.

In one or more embodiments of the present application, R₃Is C1-C4 alkyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, or 5-6 membered heteroaryl; the C1-C4 alkyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted with fluoro, C1-C3 fluoroalkyl, C1-C6 alkoxy, C1-C3 fluoroalkoxy, or C1-C6 alkyl.

In one or more embodiments of the present application, R₃Is composed of

In one or more embodiments of the present application, R₁Is C1-C6 alkyl; r₂Is halogen; r₃Is C1-C6 alkyl or C3-C7 alicyclic hydrocarbon optionally substituted by halogen; x is

R₄Is C5-C10 aryl or 5-10 membered heteroaryl optionally substituted with one or more of halogen, C1-C6 alkyl and cyano; m is 1; p is 0 or 1.

In one or more embodiments of the present application, R₁Is methyl; r₂Is Cl or F; r₃Is isopropyl, cyclopropyl, cyclopentyl or cyclohexyl optionally substituted with one or more F; x is

R₄Is phenyl, pyridyl or substituted by one or more of F, methyl and cyano

m is 1; p is 0 or 1;

in one or more embodiments of the present application, R₁Is methyl; r₂Is Cl or F; r₃Is isopropyl, cyclopropyl, cyclopentyl or cyclohexyl optionally substituted with one or two F; x is

R₄Is pyridyl optionally substituted by one F, methyl and cyano group or

m is 1; p is 0 or 1.

In one or more embodiments of the present application, the compounds of formula (I) are of the structure:

x, R therein₁、R₂And R₃As defined above.

One or more embodiments of the present application provide the following compounds, or stereoisomers, enantiomers or tautomers thereof, or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, whose structures are shown in table 1:

compound 1

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-methylnicotinamide

Compound 2

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-fluoro-6-methylnicotinamide

Compound 3

N- (5-chloro-3 ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzamide

Compound 4

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -2-methylisonicotinamide

Compound 5

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyanonicotinamide

Compound 6

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -1-methyl-6-oxo-1, 6-dihydropyridazine-4-carboxamide

Compound 7

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -4-cyanobenzamide

Compound 8

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyano-5-hydroxybenzamide

Compound 9

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl-2-tolyl) -1-ethyl-6-oxo-1, 6-dihydropyridazine-4-carboxamide

Compound 10

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -1-cyclopropyl-6-oxo-1, 6-dihydropyridazine-4-carboxamide

Compound 11

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) imidazo [1,2-a ] pyridine-7-carboxamide

Compound 12

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) - [1,2,4] triazolo [1,5-a ] pyridine-7-carboxamide

Compound 13

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -2-cyclopropylpyrimidine-5-carboxamide

Compound 14

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-2-fluorobenzamide

Compound 15

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyano-2-fluorobenzamide

Compound 16

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3- (methylsulfonyl) benzamide

Compound 17

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-methoxypyridazine-4-carboxamide

Compound 18

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 19

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -2-cyclopropylthiazole-5-carboxamide

Compound 20

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -1-cyclopropyl-1H-pyrazole-4-carboxamide

Compound 21

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-methoxybenzamide

Compound 22

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-methoxycyclobutylamide

Compound 23

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-phenylpropanamide

Compound 24

N- (5-chloro-2-methyl-3- ((1- (tetrahydro-2H-pyran-4-carbonyl) piperidin-4-ylidene) methyl) phenyl) 3-cyanobenzamide

Compound 25

N- (5-chloro-3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzamide

Compound 26

N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzamide

Compound 27

N- (3- ((1- (bicyclo [3.1.0] N-hexane-3-carbonyl) piperidin-4-ylidene) methyl) -5-chloro-2-tolyl) -3-cyanobenzamide

Compound 28

N- (5-chloro-3- ((1- (3, 3-difluorocyclobutylcarbonyl) piperidin-4-ylidene) methyl-2-tolyl) -3-cyanobenzamide

Compound 29

N- (3- ((1- (2- (bicyclo [1.1.1] pentan-1-yl) acetyl) piperidin-4-ylidene) methyl) -5-chloro-2-tolyl) -3-cyanobenzamide

Compound 30

N- (3- ((1- (2- (bicyclo [1.1.1] pentan-1-yl) acetyl) piperidin-4-ylidene) methyl) -5-chloro-2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 31

N- (5-chloro-3- ((1- (4, 4-difluorocyclohexylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 32

N- (5-chloro-3- ((1- (4, 4-difluorocyclohexylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzamide

Compound 33

N- (5-chloro-2-methyl-3- ((1- (thiophene-2-carbonyl) piperidin-4-ylidene) methyl) phenyl) -3-cyanobenzamide

Compound 34

N- (5-chloro-3- ((1- (2-cyclobutylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 35

N- (5-chloro-3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyanonicotinamide

Compound 36

N- (5-chloro-3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 37

5-chloro-N- (5-chloro-3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-methylnicotinamide

Compound 38

N- (5-chloro-2-methyl-3- ((1- (3,3, 3-trifluoropropionyl) piperidin-4-ylidene) methyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 39

N- (5-chloro-2-methyl-3- ((1- (tetrahydrofuran-3-carbonyl) piperidin-4-ylidene) methyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 40

N- (5-chloro-3- ((1- (3, 3-dimethylcyclobutylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 41

N- (5-chloro-3- ((1- (1-fluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 42

N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 43

(R) -N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 44

(S) -N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 45

N- (5-chloro-2-methyl-3- ((1- (tetrahydrofuran-2-carbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 46

N- (5-chloro-3- ((1-isobutyrylpiperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 47

N- (5-chloro-2-methyl-3- ((1- (3-methylbutyryl) piperidin-4-ylidene) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 48

N- (5-chloro-3- ((1- (2-fluoro-2-methylpropionyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 49

N- (5-chloro-3- ((1- (cyclobutylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 50

N- (5-chloro-3- ((1- (1-fluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-6-methylnicotinamide

Compound 51

(R) -N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-6-methylnicotinamide

Compound 52

(S) -N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-6-methylnicotinamide

Compound 53

N- (5-chloro-3- ((1-isobutyrylpiperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-6-methylnicotinamide

Compound 54

N- (5-chloro-3- (1- (4, 4-difluoropiperidine-1-carbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 55

N- (5-chloro-3- ((1- (3, 3-difluorotetrahydropyrrole-1-carbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzamide

Compound 56

N- (5-chloro-2-methyl-3- ((1- (tetrahydropyrrole-1-carbonyl) piperidin-4-ylidene) methyl) phenyl) -3-cyanobenzamide

Compound 57

4- (5-chloro-3- (3-cyanobenzamide) -2-methylbenzylidene) piperidine-1-carboxylic acid isopropyl ester

Compound 58

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzenesulfonamide

Compound 59

1- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3- (pyridin-2-yl) urea

Compound 60

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 61

N- (5-chloro-3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 62

N- (5-chloro-3- ((1- (2-cyclobutylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 63

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-6-methylnicotinamide

Compound 64

N- (5-chloro-3- ((1- (2-cyclopropaneacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-6-methylnicotinamide

Compound 65

N- (5-chloro-3- ((1- (2-cyclobutylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-6-methylnicotinamide

Compound 66

N- (5-chloro-3- ((1- (4, 4-difluorocyclohexylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-6-methylnicotinamide

Compound 67

6-chloro-N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 68

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-oxo-1, 6-dihydropyridazine-4-carboxamide

Compound 69

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -2-cyano-6-methoxynicotinamide

Compound 70

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 71

3-cyano-N- (3- (1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -5-fluoro-2-tolyl) benzamide

Compound 72

N- (2-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) phenyl) -3-cyanobenzamide

Compound 73

3-cyano-N- (3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) benzamide

Compound 74

6-cyano-N- (3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -5-fluoro-2-tolyl) -1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 75

6-cyano-N- (3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -5-fluoro-2-tolyl) -1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 76

6-cyano-N- (5-fluoro-3- ((1-isobutyrylpiperidin-4-ylidene) methyl) -2-tolyl) -1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 77

(R) -6-cyano-N- (3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -5-fluoro-2-tolyl) -1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Compound 78

5-chloro-N- (3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -5-fluoro-2-tolyl) -6-methylnicotinamide

Compound 79

5-cyano-N- (3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -5-fluoro-2-tolyl) -6-methylnicotinamide

Compound 80

5-cyano-N- (3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -5-fluoro-2-tolyl) -6-methylnicotinamide

Compound 81

5-cyano-N- (5-fluoro-3- ((1-isobutyrylpiperidin-4-ylidene) methyl) -2-tolyl) -6-methylnicotinamide

Compound 82

(R) -5-cyano-N- (3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -5-fluoro-2-tolyl) -6-methylnicotinamide

Table 1 the numbering and structure of typical compounds of formula (I) of the present application are:

synthesis of

In one or more embodiments of the present application, compounds of formula (I) may be prepared by the steps shown in scheme a or scheme B:

scheme A

Step 1

i) Nitrifying the substituted compound of the formula (I-A) with mixed acid to obtain a compound of the formula (I-B), wherein the mixed acid is a mixture of concentrated nitric acid and concentrated sulfuric acid;

ii) reducing the compound of formula (I-B) with borane to give a compound of formula (I-C);

iii) carrying out substitution reaction on the compound of the formula (I-C), carbon tetrabromide and triphenylphosphine to obtain a compound of the formula (I-D);

iv) subjecting the compound of formula (I-D) to an addition reaction with triphenylphosphine to obtain a ylide reagent compound of formula (I-E);

v) carrying out a Wittig reaction on the compound of the formula (I-E) and 4-oxypiperidine-1-carboxylic acid tert-butyl ester under a basic condition to obtain the compound of the formula (I-F).

In one or more embodiments, the reduction in step ii) is performed in THF.

In one or more embodiments, the alkaline conditions in step v) are generated from NaH.

In one or more embodiments, the Wittig reaction in step v) is performed in DMSO.

Wherein R is₁、R₂And m is as defined above for formula (I).

Step 2

Removing the protecting group from the compound of formula (I-F) to obtain a compound of formula (I-G) or a salt thereof;

wherein R is₁、R₂And m is as defined above for formula (I).

Step 3

Reacting a compound of formula (I-G) or a salt thereof (e.g., hydrochloride or trifluoroacetate) with R₃COR₅Carrying out condensation reaction to obtain a compound shown as a formula (I-H);

wherein R is₁、R₂、R₃M and p are as defined above for formula (I).

Step 4

Reducing the compound of formula (I-H) with iron powder to obtain the compound of formula (I-I);

wherein R is₁、R₂、R₃M and p are as defined above for formula (I).

Step 5

The compounds of formula (I-I) are each independently of R₄COR₆、R₄NCO and R₄SO₂Cl₂Carrying out urethane exchange reaction, addition reaction or condensation reaction on the compound to obtain a compound shown in a formula (I);

wherein: x, R₁、R₂、R₃、R₄M and p are as defined above for formula (I); r₅Groups conventionally used in the art for conducting urethane exchange reactions, for example, hydroxyl groups, halogens such as chlorine, methoxy groups, ethoxy groups, and the like.

Scheme B

Step 1

Reducing the compound of formula (I-F) with iron powder to obtain a compound of formula (I-J);

wherein: r₁、R₂And m is as defined in formula (I) above; compounds of formula (I-F) were prepared according to the procedure of scheme A, step 1.

In step 1 of this scheme, compounds of formula (I-J) can also be prepared using the following scheme:

subjecting the intermediate compound of formula (I-M) to a coupling reaction with the intermediate compound of formula (I-N) to obtain an intermediate compound of formula (I-J);

wherein: r₁、R₂And m is as defined for formula (I); intermediate compounds of formula (I-M) and intermediate compounds of formula (I-N) may be prepared using methods conventionally used in the art, and intermediate compounds of formula (I-M) and intermediate compounds of formula (I-N) may be prepared by the reaction schemes shown above.

Step 2

Reacting a compound of formula (I-J) with R₄COR₆Carrying out a reaction to obtain a compound of formula (I-K);

wherein: r₁、R₂、R₄X and m are as defined above for formula (I); r₅Selected from hydroxy, halogen (e.g. chlorine), alkoxy (e.g. methoxy, ethoxy).

Step 3

Removing Boc protection from the compound of formula (I-K) to obtain a compound of formula (I-L) or a salt thereof;

wherein: r₁、R₂X and m are as defined in formula (I).

Step 4

Reacting a compound of formula (I-L) or a salt thereof (e.g., hydrochloride or trifluoroacetate) with R₃COR₅Carrying out condensation reaction to obtain a compound shown in a formula (I);

wherein: r₁-R₃X, m and p are as defined in formula (I).

The above synthetic schemes are only examples of the preparation methods of some compounds in the present application, and according to the well-known technique in the art, the skilled person can synthesize the compounds in the present application by similar methods based on the above synthetic schemes.

Intermediates

In one or more embodiments of the present application, there is also provided a compound of formula (I-F), a compound of formula (I-G), a compound of formula (I-H), respectively

Wherein: r₁-R₃M and p are as defined in formula (I).

In one or more embodiments of the present application, there is provided an intermediate compound of formula (I-I),

wherein: r₁-R₃M and p are as defined in formula (I).

In some embodiments, the compounds of formula (I-I) include, but are not limited to, the following compounds:

in one or more embodiments of the present application, there is also provided a compound of formula (I-J) and a compound of formula (I-K), respectively

Wherein: r₁、R₂X and m are as defined in formula (I).

In one or more embodiments of the present application, there is also provided a compound of formula (I-L)

Wherein: r₁、R₂X and m are as defined in formula (I).

One or more embodiments of the present application also provide a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, enantiomer or tautomer thereof or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination with one or more pharmaceutically acceptable excipients and/or carriers.

One or more embodiments of the present application also provide the use of a compound of formula (I) or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as a medicament, or for the treatment of a disease.

One or more embodiments of the present application also provide the use of a compound of formula (I) or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of an inhibitor of the ROR γ t receptor.

One or more embodiments of the present application also provides a use of a compound of formula (I) or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the manufacture of a medicament for the prevention and/or treatment of a disease associated with abnormal activation of the ROR γ t receptor.

In one or more embodiments of the present application, the above-mentioned diseases associated with abnormal activation of ROR γ t receptor include autoimmune diseases, allergic diseases and cancer.

In one or more embodiments of the present application, the diseases associated with abnormal activation of the ROR γ t receptor include dandruff (Psoriasis), Psoriatic Arthritis (Psoriatic Arthritis), rheumatoid Arthritis (Rheumatoid Arthritis), Ankylosing Spondylitis (alkylosing spinelitis), multiple sclerosis (multiple sclerosis), Sjogren's Syndrome, Dry Eye Syndrome (Dry Eye Syndrome), Graft-versus-host Disease (Graft-versus-host Disease), Inflammatory Bowel Disease (Inflammatory Bowel Disease), chronic Obstructive Pulmonary Disease (Chronic Obstructive Pulmonary Disease), Asthma (Asthma), Autoimmune Uveitis (Autoimmune Uveitis), Autoimmune Hepatitis (Autoimmune Hepatitis), Autoimmune thyroiditis (Autoimmune thyroiditis), Autoimmune Nephritis (Autoimmune Nephritis), Atopic Dermatitis (Atopic Dermatitis), prostatitis (prostate Hyperplasia), and prostate cancer (therapy-refractory prostate cancer).

One or more embodiments of the present application also provide the use of a compound of formula (I) or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for inhibiting the ROR γ t receptor.

As will be described in greater detail below in connection with the detailed description, a compound of formula (I) of the present application, or a stereoisomer, enantiomer or tautomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is effective for inhibiting the ROR γ t protein receptor, thereby modulating the differentiation of Th17 cells and inhibiting the production of IL-17. The compounds of formula (I) of the present application are therefore useful as preferred therapeutic agents for the treatment of diseases associated with abnormal activation of the ROR gamma t receptor.

Definition of

As used in the specification and the appended claims, unless specified to the contrary, the terms of the present application have the meanings indicated below:

the term "compound" includes all stereoisomers, geometric isomers, tautomers. The "compounds" described herein may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, individual enantiomers and diastereomers or other stereoisomeric forms or mixtures thereof. The compounds containing asymmetric carbon atoms can be isolated in optically pure form or as racemates. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents. As used herein, "compound" also includes geometric isomeric forms, which refers to compounds having different cis-trans isomerism without chirality at the double bond or at the ring substituents. The term "compound" as used herein also includes tautomeric forms. Tautomeric forms may result from the exchange of one single bond with an adjacent double bond and the concomitant migration of one proton.

The compounds herein, whether intermediates or compounds of formula (I), may also be isotopically labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds are considered to be within the scope herein. Examples of isotopes in the compounds herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, each having the same proton number but a different mass number between isotopes.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "amino" refers to the group-NH₂。

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

The term "hydroxy" refers to-OH.

The term "carboxyl" refers to-COOH.

"mercapto" groups refer to "-SH" groups.

A "carbonyl" group refers to a C ═ O group.

An "isocyanato" group refers to an "-NCO" group.

A "thiocyanate" group refers to an "-CNS" group.

"isothiocyanato" group refers to the "-NCS" group.

"CA to CB" or "CA-CB" refers to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in an aryl, heteroaryl group, where "A" and "B" are integers. That is, alkyl, alkenyl, alkynyl, aryl, heteroaryl groups may contain from "a" to "B" carbon atoms. Thus, for example, a "C1 to C4 alkyl" or "C1-C4 alkyl" group refers to all alkyl groups having 1 to 4 carbons, i.e., CH₃-、CH₃CH₂-、CH₃CH₂CH₂-、(CH₃)₂CH-、CH₃CH₂CH₂CH₂-、CH₃CH₂CH(CH₃) -and (CH)₃)₃C-。

The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group consisting of carbon and hydrogen atoms, such as C1-C20 alkyl, preferably C1-C6 alkyl. C1-C20 alkyl refers to alkyl groups having 1 to 20 carbon atoms, such as alkyl groups having 1,2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), hexyl (e.g., n-hexyl), and the like. The alkyl group may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxy, aryl, heteroaryl, amine, halogen, sulfonyl, sulfinyl, phosphonyl, and the like.

"alkenyl" refers to a hydrocarbon group containing one or more double bonds in a straight or branched hydrocarbon chain. Alkenyl groups may be unsubstituted or substituted. An alkenyl group may have 1 to 20 carbon atoms, and whenever appearing herein, numerical ranges such as "1 to 20" refer to each integer in the given range; for example, "1 to 20 carbon atoms" refers to an alkenyl group that may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 carbon atoms, or 20 carbon atoms.

"alkynyl" refers to a hydrocarbon group containing one or more triple bonds in a straight or branched hydrocarbon chain. Alkynyl groups may be unsubstituted or substituted. Alkynyl groups can have 1 to 20 carbon atoms, and whenever appearing herein, numerical ranges such as "1 to 20" refer to each integer in the given range; for example, "1 to 20 carbon atoms" refers to an alkynyl group that may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 carbon atoms, or 20 carbon atoms.

The term "alicyclic hydrocarbon group" refers to a saturated (i.e., "alicyclic alkyl group") or unsaturated monocyclic, fused, spiro, or bridged ring consisting of carbon atoms (e.g., 3, 4,5, 6, 7, 8, 9, or 10 carbon atoms) and hydrogen atoms. Examples of the alicyclic hydrocarbon group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, spiro [3.4] octyl, bicyclo [1.1.1] pentyl, and bicyclo [3.1.0] hexyl. Alicyclic hydrocarbon groups include alicyclic alkyl (cycloalkyl).

The term "heteroatom-containing alicyclic hydrocarbon group" refers to saturated (heterocycloalkyl) or unsaturated non-aromatic monocyclic, fused, bridged and spiro rings containing one or more (e.g., 1,2, 3 or 4) heteroatoms. Wherein the heteroatom is typically N, O, S or

The heteroatom-containing alicyclic hydrocarbon group may be a 3-to 10-membered (e.g., containing 3, 4,5, 6, 7, 8, 9, or 10 ring atoms) monocyclic or bicyclic or tricyclic ring. Examples of heteroatom-containing alicyclic hydrocarbon groups include, but are not limited to, piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, and the like. The heteroatom-containing alicyclic hydrocarbon group may be unsubstituted or substituted with one or more substituents including, but not limited to, halogen, alkyl, haloalkyl, amino, cyano, hydroxy, alkoxy, haloalkoxy, carbonyl, alicyclic hydrocarbon, heteroatom-containing alicyclic hydrocarbon, sulfonyl optionally substituted with C1-C3 alkyl, aryl, heteroaryl, and the like. For example, when the heteroatom-containing alicyclic hydrocarbon group is substituted with a carbonyl group, it may be 2-oxo-1, 2-dihydropyridinyl

Or "3-oxo-1, 2-dihydropyridazinyl group

The heteroatom-containing alicyclic hydrocarbon group includes a heterocycloalkyl group.

The term "aryl" refers to an all-carbon monocyclic or all-carbon fused ring having a fully conjugated pi-electron system, typically having 5 to 14 carbon atoms, e.g., 6, 10, 12, 14 carbon atoms. Aryl groups may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carboxy, aryl, aralkyl, amine, halo, sulfonyl, sulfinyl, phosphonyl. Examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

The term "heteroaryl" refers to a monocyclic or fused ring having 6 to 12 ring atoms (e.g., 6, 10, 12, 14 ring atoms) containing 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from N, O, S, the remaining ring atoms being C, and having a fully conjugated pi-electron system including, but not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, benzimidazole, benzotriazole, and the like. Heteroaryl groups may be unsubstituted or substituted, and include, but are not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxy, aryl, aralkyl, amine, halo, sulfonyl, sulfinyl, phosphonyl. For example, when the heteroaryl group is substituted with a hydroxy group, it may be piperidin-2-ol

Or pyridazin-3-ols

"alkoxy" refers to the formula-OR, wherein R is alkyl as defined herein. A non-limiting list of alkoxy groups is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy. Alkoxy groups may be substituted or unsubstituted.

"acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, or aryl as a substituent attached through a carbonyl group. Examples include formyl, acetyl, propionyl, benzoyl and acryloyl. Acyl groups may be substituted or unsubstituted.

"haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with a halogen (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. Haloalkyl groups may be substituted or unsubstituted.

"haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced with a halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. Haloalkoxy groups may be substituted or unsubstituted.

"arylthio" refers to RS-, where R is aryl, such as but not limited to phenyl. The arylthio group may be substituted or unsubstituted.

A "thiocarbonyl" group refers to a "-C (═ S) R" group, where R is as defined for R in the O-carboxy group. The thiocarbonyl group may be substituted or unsubstituted.

The "trihalomethanesulfonyl" group means "X₃CSO₂- "groups in which each X is halogen.

The "trihalomethanesulfonamido" group is defined as "X₃CS(O)₂N(R_A) - "groups in which each X is halogen and R_AIs hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, (heteroaryl) alkyl or (heteroalicyclic) alkyl.

"alkylthio" groups refer to "-SR" groups, where R can be alkyl (in which case "alkylthio" is "alkylthio"), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl) alkyl, or (heteroalicyclyl) alkyl. The hydrocarbylthio group may be substituted or unsubstituted.

A "sulfinyl" group refers to a "-S (═ O) -R" group, where R is as defined for R in the hydrocarbylthio group. Sulfinyl groups may be substituted or unsubstituted.

The "sulfonyl" group means "SO₂R' group, wherein R is as defined for R in the hydrocarbylthio group. Sulfonyl radicalThe radicals may be substituted or unsubstituted.

"DMSO" refers to dimethyl sulfoxide.

"C-acylamino" radical means "-C (═ O) N (R)_AR_B) "group, wherein R_AAnd R_BCan independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, (heteroaryl) alkyl, or (heteroalicyclic) alkyl. The C-acylamino group may be substituted or unsubstituted.

An "N-acylamino" group is intended to mean "RC (═ O) N (R)_A) - "group, wherein R and R_ACan independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, (heteroaryl) alkyl, or (heteroalicyclic) alkyl. The N-acylamino group may be substituted or unsubstituted.

"S-sulfonylamino" group means "-SO₂N(R_AR_B) "group, wherein R_AAnd R_BCan independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, (heteroaryl) alkyl, or (heteroalicyclic) alkyl. The S-sulfonylamino group may be substituted or unsubstituted.

The "N-sulfonylamino" group means "RSO₂N(R_A) - "group, wherein R and R_ACan independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, (heteroaryl) alkyl, or (heteroalicyclic) alkyl. The N-sulfonylamino group may be substituted or unsubstituted.

An "O-carbamoyl" group means "-OC (═ O) N (R)_AR_B) "group, wherein R_AAnd R_BCan independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, (heteroaryl) alkyl, or (heteroalicyclic) alkyl. The O-carbamoyl group may be substituted or unsubstituted.

An "N-carbamoyl" group refers to "ROC (═ O) N (R)_A) - "group, wherein R and R_ACan independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, (heteroaryl) alkyl, or (heteroalicyclic) alkyl. The N-carbamoyl group may be substituted or unsubstituted.

An "O-thiocarbamoyl" group means "-OC (═ S) -N (R)_AR_B) "group, wherein R_AAnd R_BCan independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, (heteroaryl) alkyl, or (heteroalicyclic) alkyl. The O-thiocarbamoyl group may be substituted or unsubstituted.

An "N-thiocarbamoyl" group is intended to mean "ROC (═ S) N (R)_A) - "group, wherein R and R_ACan independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, (heteroaryl) alkyl, or (heteroalicyclic) alkyl. The N-thiocarbamoyl group may be substituted or unsubstituted.

The term "optionally" refers to the presence or absence.

When a group is described as "optionally substituted," then the group may be unsubstituted or substituted with one or more of the substituents shown. Similarly, when a group is described as "unsubstituted or substituted," if substituted, the substituents can be selected from one or more of the substituents shown. If no substituents are indicated, then said "optionally substituted" or "substituted" groups may be individually and independently substituted with one or more groups selected from: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic) alkyl, hydroxy, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halo, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonamido, N-sulfonamido, carboxy, isocyanato, thiocyanate, isothiocyanato, nitro, silyl, alkylthio, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido and amino.

The term "covalent bond" refers to the interaction between atoms through a common pair of electrons.

The term "treatment" means any treatment of a disease in a mammal, including: (1) preventing disease, even if the symptoms of the clinical disease do not develop; (2) inhibiting disease, i.e., arresting the development of clinical symptoms; (3) alleviating the disease, i.e. resolution of clinical symptoms.

The term "pharmaceutical composition" refers to a formulation of one or more compounds herein with carriers, excipients or adjuvants commonly acceptable in the art, for example, for use in the delivery of biologically active compounds to an organism (e.g., a human). For example, the purpose of a pharmaceutical composition is to facilitate administration delivery of the organism.

The term "pharmaceutically acceptable excipient and/or carrier" or "pharmaceutically acceptable excipient and/or carrier" refers to a substance that is co-administered with and facilitates administration of an active ingredient, including, but not limited to, any glidant, sweetener, diluent, preservative, fuel/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is acceptable for use in humans or animals (e.g., livestock) as permitted by the national food and drug administration. Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

The pharmaceutical composition described herein can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.

The pharmaceutical compositions described herein may be manufactured by methods well known in the art, such as by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.

Routes of administration of the compounds described herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. Preferred routes of administration are oral, intravenous, intramuscular, and intra-organ injections of diseased organs (e.g., eye, prostate, etc.).

For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable carriers well known in the art. The compounds herein can be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like, for oral administration to a patient. For example, for pharmaceutical compositions intended for oral administration, tablets may be obtained in the following manner: the active ingredient is combined with one or more solid carriers, the resulting mixture is granulated if necessary, and a small amount of excipients is added if necessary to process the mixture or granules to form tablets or cores. The core may be combined with an optional enteric coating material and processed into a coated dosage form more readily absorbed by an organism (e.g., a human).

The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not destroy the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. The drug salts can be obtained by reacting the compounds with inorganic acids such as hydrohalic acids (e.g., hydrochloric or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, for example an ammonium salt, an alkali metal salt such as a sodium or potassium salt, such as a calcium or calcium saltAlkaline earth metal salts of magnesium salts, e.g. dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, C₁-C₇Alkylamines, cyclohexylamine, triethanolamine, organic base salts of ethylenediamine, and salts with amino acids such as arginine and lysine.

Unless otherwise specified, the terms and phrases used in this application, and variations thereof, particularly in the appended claims, should be construed as open ended as opposed to limiting. As an example of the foregoing, the term "comprising" should be understood to mean "including, without limitation," synonymous with and inclusive of or open-ended, and not exclude additional, unrecited elements or method steps; the term "having" should be interpreted as "having at least".

The technical solution of the present invention will be further described with reference to the following specific examples. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present disclosure, as various changes may be made therein without departing from the spirit and scope of the disclosure.

In the methods of preparing the target compounds provided herein, the structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass spectrometry (LC-MS). NMR shift () at 10^-6The units in (ppm) are given. NMR measurements were performed using a ZKNJ BIXI-1 (Oxford Spectroscopy, Inc., of Ke, Wuhan) 300MHz, BRUKER AVANCE III 400MHz, Bruker Avanceneo 400MHz, or JEOL 400MHz NMR instrument. The determination of liquid chromatography-mass spectrometry (LC-MS) was performed using Waters H-classUPLC-SQD2, Agilent 1260/6120, or Agilent 1100. The solvent for NMR measurement is deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS).

In addition, all operations involving easily oxidizable or hydrolyzable raw materials were carried out under nitrogen protection. Unless otherwise indicated, the starting materials used herein are all commercially available starting materials and can be used without further purification.

Preparation examples

5-chloro-2-methyl-3-nitrobenzol

5-chloro-2-methyl-3-nitrobenzoic acid (4.6g,21.0mmol) was dissolved in anhydrous tetrahydrofuran (50mL), the reaction was cooled to 0 ℃ under nitrogen, then borane in tetrahydrofuran (27.4mL,27.4mmol) was slowly added dropwise, the reaction was slowly warmed to room temperature, and then stirred at room temperature overnight. The reaction was quenched slowly with 10% hydrochloric acid (28.2mL) at 0 deg.C, diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium bicarbonate and brine, respectively, and concentrated to remove the solvent to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 5/1-3/1, vol.) to give 3.7g of 5-chloro-2-methyl-3-nitrobenzol, 87% yield, as a white solid.¹H-NMR(400MHz,DMSO-d₆)：7.89(s,1H),7.72(s,1H),5.57(s,1H),4.58(s,2H),2.24(s,3H)。

1-bromomethyl-5-chloro-2-methyl-3-nitrobenzene

5-chloro-2-methyl-3-nitrobenzol (1.8g,9.0mmol) was dissolved in dichloromethane (20mL), the reaction cooled to 0 deg.C, triphenylphosphine (2.6g,9.9mmol) was added, and then carbon tetrabromide (3.3g,9.9mmol) in dichloromethane (5mL) was slowly added dropwise. Stir at room temperature overnight. The solvent was removed by concentration to give a crude product. The crude product is purified by silica gel column chromatography (petroleum ether/ethyl acetate: 20/1-10/1, volume ratio) to obtain 2.1g of 1-bromomethyl-5-chloro-2-methyl-3-nitrobenzene, the yield is 64%, and the white solid is obtained.¹H NMR(400MHz,DMSO-d₆)：8.01(s,1H),7.93(s,1H),4.83(s,2H),2.45(s,3H)。

Bromo (5-chloro-2-methyl-3-nitrobenzyl) triphenylphosphine

1-bromomethyl-5-chloro-2-methyl-3-nitrobenzene (265mg,1.0mmol) was dissolved in toluene (5mL), triphenylphosphine (289mg,1.1mmol) was added, and the mixture was stirred at 80 ℃ for 6 hours. The reaction solution is cooled to room temperature, and the precipitated solid is collected by filtration, washed by toluene and dried in vacuum. 481mg of bromo (5-chloro-2-methyl-3-nitrobenzyl) triphenylphosphine were obtained in 91% yield as a white solid. 1H NMR (400MHz, DMSO-d 6): 8.04(s,1H),7.98-7.69(m,15H),7.27(s,1H),5.30(d,2H),1.64(s, 3H).

Tert-butyl 4- (5-chloro-2-methyl-3-nitrobenzylidene) piperidine-1-carboxylic acid ester

After stirring a suspension of sodium hydride (44mg, 60% purity) in dimethylsulfoxide (5mL) at 80 ℃ for 1 hour, it was cooled to 5 ℃, bromine (5-chloro-2-methyl-3-nitrobenzyl) triphenylphosphine (527mg,1.0mmol) was added and stirred for 10 minutes, then tert-butyl 4-oxopiperidine-1-carboxylate (200mg,1.0mmol) was added and stirred at room temperature for 1 hour, and the reaction was slowly warmed to 80 ℃ and stirred overnight. The reaction was quenched slowly with water and extracted with ether. The organic layers are combined, washed with common salt water, dried over anhydrous sodium sulfate, filtered and concentrated, and a crude product is purified by silica gel column chromatography (petroleum ether/ethyl acetate: 20/1-5/1 by volume ratio) to obtain 218mg of tert-butyl 4- (5-chloro-2-methyl-3-nitrobenzylidene) piperidine-1-carboxylate, wherein the yield is 60%, and the crude product is a colorless oily substance.¹H-NMR(300MHz,CDCl₃)：7.70(s,1H),7.27(s,1H),6.24(s,1H),3.54(t,2H),3.39(t,2H),2.37(t,2H),2.35(s,3H),2.19(t,2H),1.48(s,9H)。

4- (5-chloro-2-methyl-3-nitrobenzylidene) piperidine hydrochloride

Tert-butyl 4- (5-chloro-2-methyl-3-nitrobenzylidene) piperidine-1-carboxylate (218mg,0.59mmol) was dissolved in hydrochloric acid/ethyl acetate (2mL), stirred overnight at room temperature, filtered, washed with ethyl acetate, and the solid dried in vacuo. 82mg of 4- (5-chloro-2-methyl-3-nitrobenzylidene) piperidine hydrochloride are obtained in 45% yield as a white solid.¹H NMR(300MHz,DMSO-d₆)9.16(s,2H),7.95(s,1H),7.54(s,1H),6.44(s,1H),3.18-3.13(m,2H),3.07-3.04(m,2H),3.60-3.56(m,2H),2.38-2.34(m,2H),2.26(s,3H)。

(4- (5-chloro-2-methyl-3-nitrobenzylidene) piperidin-1-yl) (cyclopentyl) methanone

To a suspension of 4- (5-chloro-2-methyl-3-nitrobenzylidene) piperidine hydrochloride (3.0g,9.8mmol) in methylene chloride (200mL) at 0 deg.C was slowly added dropwise cyclopentylchloride (1.4mL,11.8mmol) and triethylamine (4.1mL,29.4mmol), and the mixture was stirred at room temperature for 10 minutes. Adding water into the reaction solution, layering, extracting with dichloromethane, combining organic layers, washing with saturated salt water, drying with anhydrous sodium sulfate, and concentrating to remove the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 5/1 vol.) to give (4- (5-chloro-2-methyl-3-nitrobenzylidene) piperidin-1-yl) (cyclopentyl) methanone 3.4g, 96% yield, as a brown oil.¹H-NMR(300MHz,DMSO-d₆)：7.92(s,1H),7.46(s,1H),6.37(s,1H),3.58-3.45(m,4H),3.02(m,1H),2.39-2.08(m,4H),2.26(s,3H),1.78-1.54(m,8H)。

(4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone

(4- (5-chloro-2-methyl-3-nitrobenzylidene) piperidin-1-yl) (cyclopentyl) methanone (3.1g,8.5mmol) was dissolved in ethanol/water (80mL/40mL), and sodium acetate trihydrate (2.3g,17.1mmol), acetic acid (9mL), and iron powder (1.9g,34.2mmol) were added at room temperature, followed by warming to 85 ℃ and stirring for 1 hour. The reaction solution was cooled to 0 ℃, diluted with 1N hydrochloric acid, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and concentrated to remove the solvent to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol-50/1 vol.) to give (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone 2.3g, 81% yield as a yellow solid.¹H NMR(300MHz,DMSO-d₆)：7.06(s,1H),6.79(s,1H),6.31(s,1H),3.62-3.50(m,2H),3.49-3.37(m,2H),3.06-2.91(m,1H),2.37-2.00(m,4H),2.06(s,3H),1.82-1.41(m,8H)。

6-methylnicotinoyl chloride

6-Methylnicotinic acid (82mg,0.6mmol) was dissolved in thionyl chloride (3mL) under nitrogen, warmed to 50 ℃ and stirred for 1 hour. Cooled to room temperature and concentrated to obtain crude 6-methylnicotinoyl chloride which is directly used in the next step.

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-methylnicotinamide (Compound 1)

(4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (100mg,0.3mmol) and 6-methylnicotinoyl chloride (crude product obtained in the previous step) were dissolved in anhydrous N, N-dimethylformamide (2mL), and triethylamine (0.2mL,1.5mmol) was added. The reaction was stirred at room temperature for 1.5 hours under nitrogen. The reaction solution was poured into water and extracted with dichloromethane. The organic layers were combined and concentrated to give a crude product which was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-methylnicotinamide 21mg, yield 15%, as a white solid.¹HNMR(400MHz,DMSO-d₆)10.12(s,1H),9.01(d,1H),8.20(dd,1H),7.43(d,1H),7.38(dd,1H),7.06(d,1H),6.38(s,1H),3.55-3.61(m,2H),3.44-3.49(m,2H),3.00-3.04(m,1H),2.56(s,3H),2.28-2.37(m,2H),2.12-2.22(m,2H),2.10(s,3H),1.49-1.79(m, 8H). MS calculated: 451.2, MS found: 452.0([ M + H)]⁺)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-fluoro-6-methylnicotinamide (Compound 2)

5-fluoro-6-methylnicotinic acid (54mg,0.35 mmol)) 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (159mg,0.42mmol) and N, N-diisopropylethylamine (0.2mL,1.1mmol) were dissolved in N, N-dimethylformamide (8mL), and the mixture was stirred at room temperature for 30 minutes under nitrogen atmosphere. Then, (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (115mg, 0.35mmol) was added thereto, and the reaction mixture was heated to 50 ℃ and stirred overnight under nitrogen gas. Concentration gave a crude product which was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-fluoro-6-methylnicotinamide 20mg, yield 12%, as an off-white solid.¹H NMR(400MHz,DMSO-d₆)10.23(s,1H),8.89(s,1H),8.10(dd,1H),7.44(s,1H),6.99(s,1H),6.37(s,1H),3.61-3.55(m,2H),3.61-3.55(m,2H),3.07-2.95(m,1H),2.53(d,3H),2.38-2.10(m,4H),2.10(s,3H),1.82-1.49(m, 8H). MS calculated: 469.2, MS found: 470.2([ M + H)]⁺)。

N- (5-chloro-3 ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzamide (Compound 3)

3-Cyanobenzoic acid (104mg,0.71mmol) was dissolved in thionyl chloride (4mL) and the reaction was stirred at 50 ℃ for 6 hours under nitrogen. The solvent was removed by concentration. The concentrated residue was dissolved in N, N-dimethylformamide (8 mL). To this was then added (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (100mg,0.30mmol) and triethylamine (0.2mL,1.4 mmol). The reaction mixture was stirred at 25 ℃ for 1 hour under nitrogen protection. Concentration gave a crude product, which was purified by preparative high performance liquid chromatography to give N- (5-chloro-3 ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzamide 20mg, yield 14%, as a white solid.¹H NMR(400MHz,DMSO-d₆)10.22(s,1H),8.40(s,1H),8.26(d,1H),8.10(d,1H),7.77(t,1H),7.38(d,1H),7.07(d,1H),6.38(s,1H),3.60-3.57(m,2H),3.50-3.45(m,2H),3.05-2.98(m,1H),2.38-2.11(m,4H),2.11(s,3H),1.80-1.51(m, 8H). MS calcd 461.2, MS found: 462.2([ M + H)]⁺)。

2-methylisonicotinic acid acyl chloride

2-Methylisonicotinic acid (206mg,1.5mmol) was dissolved in thionyl chloride (2mL) and stirred at room temperature for 1 hour under nitrogen. The reaction solution is concentrated to obtain a crude product of the 2-methyl isonicotinic acid acyl chloride which is directly used for the next reaction.

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -2-methylisonicotinamide (Compound 4)

(4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (100mg,0.3mmol) and 2-methylisonicotinic acid chloride (crude) were dissolved in N, N-dimethylformamide (5mL), and triethylamine (243mg,2.4mmol) was added to the reaction solution. The reaction mixture was stirred at room temperature for 1 hour under nitrogen. The reaction was quenched with water, extracted with dichloromethane, the organic phases combined and concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -2-methylisonicotinamide 8mg, 95% purity, 6% yield, as an off-white solid.¹H NMR(400MHz,DMSO-d₆)10.24(s,1H), 8.65(d,1H),7.74(s,1H),7.66(d,1H),7.36(d,1H),7.08(d,1H),6.38(s,1H),3.61-3.56(m,2H),3.50-3.44(m,2H),3.03-2.97(m,1H),2.58(s,3H),2.38-2.12(m,4H),2.09(s,3H),1.81-1.51(m, 8H). Calculated MS 451.2, found MS 452.1([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyanonicotinamide (Compound 5)

Methyl 5-cyanonicotinate (50mg,0.31mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (103mg,0.31mmol) were dissolved in toluene (5mL),the reaction was cooled to 0 ℃ under nitrogen and stirred, then a solution of trimethylaluminum (0.31mL,0.62mmol) was added. The reaction mixture was stirred at 80 ℃ for 3 hours. The reaction was quenched with ammonium chloride solution and extracted with dichloromethane (20 mL. times.3). The organic phases were combined, concentrated and the residue concentrated and purified by preparative high performance liquid chromatography to give 72mg of N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyanonicotinamide as a white solid in 94% purity and 47% yield.¹H NMR(400MHz,DMSO-d₆)10.32(s,1H),9.33(s,1H),9.23(s,1H),8.79(s,1H),7.41(s,1H),7.06(s,1H),6.36(s,1H),3.59-3.46(m,4H),3.05-2.97(m,1H),2.38-2.12(m,4H),2.12(s,3H),1.76-1.53(m, 8H). MS calculated: 462.1, MS found: 463.3([ M + H)]⁺)。

1-methyl-6-oxo-1, 6-dihydropyridazine-4-carboxylic acid methyl ester

6-oxo-1, 6-dihydropyridazine-4-carboxylic acid (1.0g,7.1mmol) and potassium carbonate (4.9g,35.4mmol) were dissolved in N, N-dimethylformamide (30mL), and methyl iodide (5.2mL,71.1mmol) was added to the reaction mixture under nitrogen. The reaction mixture was stirred at 50 ℃ for 2 hours. The solvent, N-dimethylformamide, was removed by concentration. Water was added to the concentrated residue, which was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane/methanol 40/1 vol.) to give 1.0g of methyl 1-methyl-6-oxo-1, 6-dihydropyridazine-4-carboxylate in 83% yield as a yellow solid.¹H NMR(400MHz,CDCl₃)：8.20(s,1H),7.49(s,1H),3.96(s,3H),3.82(s,3H)。

1-methyl-6-oxo-1, 6-dihydropyridazine-4-carboxylic acid

Methyl 1-methyl-6-oxo-1, 6-dihydropyridazine-4-carboxylate (414mg,2.5mmol) was dissolved in methanol (20mL) and 40% sodium hydroxide solution (5mL) was added. The reaction mixture was stirred at room temperature for 1 hourWhen this is done, the pH is then adjusted to3 with 1N hydrochloric acid solution. After concentrating to remove methanol, water was added and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give 220mg of 1-methyl-6-oxo-1, 6-dihydropyridazine-4-carboxylic acid, yield 58%, as a pale yellow solid.¹H NMR(400MHz,DMSO-d₆)：14.14(br,1H),8.17(s,1H),7.28(s,1H),3.68(s,3H)。

N- (5-chloro-3 ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -1-methyl-6-oxo-1, 6-dihydropyridazine-4-carboxamide (Compound 6)

1-methyl-6-oxo-1, 6-dihydropyridazine-4-carboxylic acid (120mg,0.78mmol) and N, N-dimethylformamide (0.1mL) were dissolved in thionyl chloride (4mL), and the reaction was stirred at room temperature for 20 minutes under nitrogen. The mixture was concentrated to remove thionyl chloride, and the concentrated residue was dissolved in N, N-dimethylformamide (10 mL). Then (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (125mg,0.38mmol) and triethylamine (0.2mL) were added. The reaction mixture was stirred at 25 ℃ for 1 hour under nitrogen protection. Concentration gave a crude product, which was purified by preparative high performance liquid chromatography to give N- (5-chloro-3 ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -1-methyl-6-oxo-1, 6-dihydropyridazine-4-amide 30mg, yield 17%, as a white solid. 1H NMR (400MHz, DMSO-d6)10.33(s,1H),8.22(s,1H),7.45(d,1H),7.38(d,1H),7.08(d,1H),6.37(s,1H),3.71(s,3H),3.61-3.55(m,2H),3.48-3.42(m,2H),3.05-2.97(m,1H),2.37-2.12(m,4H),2.09(s,3H),1.79-1.51(m, 8H). MS calculated: 468.2, MS found: 469.0([ M + H)]⁺)。

4-Cyanobenzoyl chloride

4-Cyanobenzoic acid (132mg,0.9mmol) was dissolved in thionyl chloride (3mL) and one drop of anhydrous N, N-dimethylformamide was added. The reaction was stirred at room temperature for 2 hours under nitrogen. The reaction solution is concentrated to obtain a crude product of the 4-cyanobenzoyl chloride, which is not purified and is directly used for the next reaction.

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -4-cyanobenzamide (Compound 7)

(4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (100mg,0.3mmol), 4-cyanobenzoyl chloride (crude, 0.9mmol) was dissolved in anhydrous N, N-dimethylformamide (3mL), followed by triethylamine (0.5 mL). The reaction mixture was stirred overnight at 30 ℃ under nitrogen. The reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -4-cyanobenzamide 5mg, purity 95%, yield 4%, and white solid.¹H NMR(400MHz,DMSO-d₆)10.27(s,1H),8.12(d,2H),8.05(d,2H),7.38(d,1H),7.07(d,1H),6.38(s,1H),3.56-3.61(m,2H),3.44-3.50(m,2H),2.99-3.04(m,1H),2.13-2.37(m,4H),2.10(s,3H),1.49-1.79(m, 8H). MS calcd 461.2, MS found 462.0([ M-H ]]⁺)。

3-bromo-5-methoxybenzoic acid methyl ester

3-bromo-5-hydroxybenzoic acid (401mg,1.85mmol), methyl iodide (1.0mL,13.7mmol) and potassium carbonate (767mg,5.55mmol) were dissolved in N, N-dimethylformamide (15mL) and stirred under nitrogen at 50 ℃ overnight. The reaction mixture was concentrated, and the concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1, vol.) to give methyl 3-bromo-5-methoxybenzoate 385mg, yield 85%, colorless oil.¹H NMR(400MHz,CDCl₃)7.76(s,1H),7.49(s,1H),7.24(d,1H),3.92(s,3H),3.84(s,3H)。

3-cyano-5-methoxybenzoic acid methyl ester

Methyl 3-bromo-5-methoxybenzoate (380mg,1.55mmol), zinc cyanide (218mg,1.86mmol) and tetrakis (triphenylphosphine) palladium (179mg,0.155mmol) were dissolved in N, N-dimethylformamide (20mL) and stirred under nitrogen at 90 ℃ overnight. The reaction mixture was concentrated, and the concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1, vol.) to give methyl 3-cyano-5-methoxybenzoate (260 mg), yield 87%, and white solid.¹H NMR(400MHz,CDCl₃)7.91(s,1H),7.78(d,1H),7.33(d,1H),3.96(s,3H),3.89(s,3H)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyano-5-methoxybenzamide (Compound 8')

Methyl 3-cyano-5-methoxybenzoate (83mg,0.430mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (143mg,0.429mmol) were dissolved in toluene (10mL) and trimethylaluminum (0.4mL,0.800mmol) in toluene was added slowly at 0 ℃ under nitrogen. The reaction solution was stirred at 80 ℃ for 1 hour and then cooled to room temperature. The reaction was quenched by addition of 1mol/L hydrochloric acid at 0 ℃. Extracted twice with 10mL ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 3/1, vol.) to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyano-5-methoxybenzamide 121mg, yield 57%, as a white solid.¹H NMR(400MHz,DMSO-d₆)10.16(s,1H),7.96(s,1H),7.80(s,1H),7.70(s,1H),7.36(d,1H),7.07(d,1H),6.37(s,1H),3.90(s,3H),3.59-3.57(m,2H),3.49-3.46(m,2H),3.05-2.97(m,1H),2.39-2.36(m,1H),2.32-2.28(m,1H),2.24-2.20(m,1H),2.15-2.12(m,1H),2.10(s,3H),1.77-1.51(m, 8H). N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyano-5-hydroxybenzamide (Compound 8)

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyano-5-methoxybenzamide (40mg,0.0813mmol) and tetrabutylammonium iodide (33mg,0.0893mmol) were dissolved in dichloromethane (5mL) and boron tribromide dichloromethane solution (0.3mL,0.300mmol) was added slowly at-78 ℃ under nitrogen. The reaction solution was stirred at-78 ℃ for 1 hour, and then stirred at room temperature for 2 hours. The reaction was quenched by the addition of hydrochloric acid (4mL,1mol/L) at 0 ℃. Extracted twice with 10mL of dichloromethane each time. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 3/1, vol.) to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyano-5-hydroxybenzamide as a white solid in a yield of 10 mg.¹H NMR(400MHz,DMSO-d₆)10.61(s,1H),10.10(s,1H),7.83(s,1H),7.64(s,1H),7.36(d,2H),7.06(s,1H),6.37(s,1H),3.59-3.57(m,2H),3.49-3.46(m,2H),3.06-2.97(m,1H),2.39-2.12(m,4H),2.10(s,3H),1.77-1.53(m, 8H). MS calculated 477.2 and MS found 478.1([ M + H ]]⁺)。

6-oxo-1, 6-dihydropyridazine-4-carboxylic acid methyl ester

6-oxo-1, 6-dihydropyridazine-4-carboxylic acid (1.0g,7.1mmol) was dissolved in methanol (20mL), the reaction mixture was cooled to 0 ℃ and thionyl chloride (3mL) was added under nitrogen. The reaction mixture was stirred at 50 ℃ for 2 hours and then concentrated in vacuo. The concentrated residue was purified by silica gel column chromatography (dichloromethane/methanol 100/1 vol.) to give methyl 6-oxo-1, 6-dihydropyridazine-4-carboxylate 760mg, yield 69%, as a pale yellow solid.¹H NMR(400MHz,DMSO-d₆)：13.46(s,1H),8.15(d,1H),7.27(s,1H),3.88(s,3H)。

1-Ethyl-6-oxo-1, 6-dihydropyridazine-4-carboxylic acid methyl ester

Methyl 6-oxo-1, 6-dihydropyridazine-4-carboxylate (97mg,0.63mmol), iodoethane (0.1mL,1.2mmol) and potassium carbonate (174mg,1.3mmol) were dissolved in N, N-dimethylformamide (10mL) and the reaction was stirred overnight at 50 ℃ under a blanket of liquid nitrogen. The reaction mixture was concentrated to remove the solvent, and the concentrated residue was purified by silica gel column chromatography (dichloromethane/methanol 100/1, vol.) to give 71mg of methyl 1-ethyl-6-oxo-1, 6-dihydropyridazine-4-carboxylate, yield 62%, as a pale yellow solid.¹H NMR(400MHz,CDCl₃)：8.21(d,1H),7.46(d,1H),4.24(q,2H),3.96(s,3H),1.39(t,2H)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl-2-tolyl) -1-ethyl-6-oxo-1, 6-dihydropyridazine-4-carboxamide (Compound 9)

Methyl 1-ethyl-6-oxo-1, 6-dihydropyridazin-4-carboxylate (70mg,0.39mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (128mg,0.38mmol) were dissolved in toluene (10mL), the reaction was cooled to 0 deg.C, and trimethylaluminum (0.4mL,0.80mmol) was slowly added under nitrogen. The reaction mixture was stirred at 80 ℃ for 2 hours. The reaction mixture was diluted with 10mL of water, and 1N hydrochloric acid (3mL) was added thereto. The mixture was extracted with ethyl acetate (10 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl-2-tolyl) -1-ethyl-6-oxo-1, 6-dihydropyridazine-4-carboxamide, 30mg, purity 95%, yield 16%, as a white solid.¹H NMR(400MHz,DMSO-d₆)10.29(s,1H),8.24(d,1H),7.43(s,1H),7.38(s,1H),7.07(d,1H),6.36(s,1H),4.14(q,2H),3.58(m,2H),3.47(m,2H),3.03-2.97(m,1H),2.37-2.08(m,4H),2.10(s,3H),1.77-1.53(m,8H),1.29(t, 3H). MS calculated: 482.2, MS found: 483.3([ M + H)]⁺)。

1-cyclopropyl-6-oxo-1, 6-dihydropyridazine-4-carboxylic acid methyl ester

Methyl 6-oxo-1, 6-dihydropyridazine-4-carboxylate (167mg,1.1mmol), cyclopropylboronic acid (209mg,2.4mmol), copper acetate (197mg,1.1mmol), bipyridine (169mg,1.1mmol) and sodium carbonate (260mg,2.5mmol) were dissolved in 1, 2-dichloroethane (15mL) and the reaction was stirred overnight at 70 ℃ under a blanket of liquid nitrogen. The reaction mixture was concentrated to remove the solvent, and the concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 50/1, vol.) to give 110mg of methyl 1-cyclopropyl-6-oxo-1, 6-dihydropyridazine-4-carboxylate, 52% yield, as a pale yellow solid.¹H NMR(400MHz,CDCl₃)：8.16(d,1H),7.46(d,1H),4.19(m,1H),3.95(s,3H),1.19-1.15(m,2H),1.07-1.02(m,2H)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -1-cyclopropyl-6-oxo-1, 6-dihydropyridazine-4-carboxamide (Compound 10)

Methyl 1-cyclopropyl-6-oxo-1, 6-dihydropyridazin-4-carboxylate (70mg,0.36mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (120mg,0.36mmol) were dissolved in toluene, (10mL) the reaction was cooled to 0 deg.C and trimethylaluminum (0.4mL,0.80mmol) was slowly added under nitrogen. The reaction mixture was stirred at 80 ℃ for 2 hours. The reaction solution was diluted with 5mL of water, and then 3mL of 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate (10 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl-2-tolyl) -1-cyclopropyl-6-oxo-1, 6-dihydropyridazine-4-carboxamide 40mg, purity 95%, yield 22%, as a white solid.¹H NMR(400MHz,DMSO-d₆)10.28(s,1H),8.19(s,1H),7.42(s,1H),7.38(s,1H),7.07(s,1H),6.36(s,1H),4.09-4.08(m,1H),3.58(m,2H),3.46(m,2H),3.05-2.97(m,1H),2.37-2.09(m,4H),2.09(s,3H),1.77-1.53(m,8H),1.03-1.01(m, 4H). MS calculated: 494.2, MS found: 495.2([ M + H)]⁺)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) imidazo [1,2-a ] pyridine-7-carboxamide (Compound 11)

Imidazole [1,2-a ]]Pyridine-7-carboxylic acid methyl ester (50mg,0.28mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (95mg,0.28mmol) were dissolved in toluene (5mL), the reaction stirred at 0 ℃ under liquid nitrogen atmosphere, and trimethylaluminum (0.29mL,0.56mmol) was added. The reaction mixture was stirred at 80 ℃ for 3 hours. After completion of the reaction, the reaction was quenched with ammonium chloride solution and ethyl acetate (20 mL. times.3). Combining the organic phases, concentrating, and purifying the concentrated residue by preparative high performance liquid chromatography to obtain N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -imidazo [1,2-a]Pyridine-7-carboxamide 24mg, purity 94%, yield 17%, white solid.¹H NMR(400MHz,DMSO-d₆)10.50(s,1H),8.96(d,1H),8.47(s,1H),8.41(s,1H),8.22(s,1H),7.81(d,1H),7.41(s,1H),7.10(s,1H),6.39(s,1H),3.59-3.48(m,4H),3.03-2.96(m,1H),2.38-2.13(m,4H),2.13(s,3H),1.77-1.53(m, 8H). MS calculated: 476.2, MS found: 477.0([ M + H ]]⁺)。

[1,2,4] triazolo [1,5-a ] pyridine-7-carboxylic acid methyl ester

7-bromo- [1,2,4]Triazole [1,5-a ]]Pyridine (200mg,1.0mmol) was dissolved in methanol (10mL) and [1,1' -bis (diphenylphosphino) ferrocene was added]Palladium dichloride (82mg,0.10mmol) and triethylamine (0.42mL,3.0 mmol). The reaction mixture was stirred overnight at 100 ℃ under nitrogen. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (petroleum ether/ethyl acetate: 3/1, vol.) to give [1,2,4]Triazole [1,5-a ]]Pyridine-7-carboxylic acid methyl ester 150mg, yield 85%, white solid.¹H NMR(400MHz,DMSO-d₆)：9.10(d,1H),8.70(s,1H),8.38(s,1H),7.60(dd,1H),3.95(s,3H)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) - [1,2,4] triazolo [1,5-a ] pyridine-7-carboxamide (Compound 12)

[1,2,4]Triazole [1,5-a ]]Pyridine-7-carboxylic acid methyl ester (50mg,0.28mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (94mg,0.28mmol) were dissolved in toluene (5mL), stirred at 0 ℃ under nitrogen, and trimethylaluminum (0.28mL,0.56mmol) was added. The reaction mixture was stirred at 80 ℃ for 3 hours. The reaction was quenched with ammonium chloride solution and extracted with dichloromethane (20 mL. times.3). Combining the organic phases and purifying by preparative high performance liquid chromatography to obtain N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) - [1,2, 4%]Triazole [1,5-a ]]Pyridine-7-carboxamide 73.8mg, purity 95%, yield 55%, white solid.¹H NMR(400MHz,DMSO-d₆)10.34(s,1H),9.11(d,1H),8.67(s,1H),8.49(s,1H),7.65(d,1H),7.42(s,1H),7.09(s,1H),6.39(s,1H),3.59-3.47(m,4H),3.05-2.98(m,1H),2.38-2.09(m,4H),2.14(s,3H),1.77-1.53(m, 8H). MS calculated: 477.1, MS found: 478.0([ M + H)]⁺)。

2-Cyclopropylpyrimidine-5-carboxylic acid ethyl ester

2-Chloropyrimidine-5-carboxylic acid ethyl ester (300mg,1.6mmol), cyclopropylboronic acid (690mg,8.0mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (130mg,0.16mmol) and potassium carbonate (662mg,4.8mmol) were dissolved in 1, 4-dioxane (20mL) and stirred at 90 ℃ for 14 h under the protection of liquid nitrogen. After the reaction was completed, filtration was performed. The filtrate was diluted with water and extracted with ethyl acetate (50 mL. times.3). The organic phases were combined, concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1 vol.) to give ethyl 2-cyclopropylpyrimidine-5-carboxylate 50mg as a yellow oil in 16% yield.¹H NMR(400MHz,DMSO-d₆)9.05(s,2H),4.35(q,2H),2.34-2.28(m,1H),1.33(t,3H),1.18-1.15(m,2H),1.12-1.09(m, 2H). N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -2-cyclo-phenylPropylpyrimidine-5-carboxamide (Compound 13)

Ethyl 2-cyclopropylpyrimidine-5-carboxylate (50mg,0.26mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (86mg,0.26mmol) were dissolved in toluene (5mL), cooled to 0 ℃ under a blanket of reaction liquid nitrogen, stirred, and then a solution of trimethylaluminum (0.26mL,0.52mmol) was added. The reaction mixture was stirred at 80 ℃ for 3 hours. The reaction was quenched with ammonium chloride solution and extracted with dichloromethane (20 mL. times.3). The organic phases were combined, concentrated and purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -2-cyclopropylpyrimidine-5-carboxamide, 21.8mg, purity 95%, yield 17%, as a white solid.¹H NMR(400MHz,DMSO-d₆)10.18(s,1H),9.09(s,2H),7.40(s,1H),7.06(s,1H),6.37(s,1H),3.58-3.46(m,4H),3.03-2.99(m,1H),2.37-2.10(m,5H),2.10(s,3H),1.75-1.52(m,8H),1.23-1.09(m, 4H). MS calculated: 478.2, MS found: 479.0([ M + H)]⁺)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-2-fluorobenzamide (compound 14)

(4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (100mg,0.30mmol) and methyl 5-cyano-2-fluorobenzoate (65mg,0.40mmol) were dissolved in anhydrous toluene (5mL), cooled to 0 ℃ and a trimethylaluminum toluene solution (0.3mL,0.60mmol) was added to the reaction solution. The reaction mixture was stirred at 80 ℃ for 4 hours under nitrogen, then cooled to 0 ℃, quenched with water, and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give 39mg of N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-2-fluorobenzamide in 95% purity, 27% yield and as a white solid.¹H NMR(400MHz,DMSO-d₆)10.22(s,1H),8.29(d,1H),8.15-8.11(m,1H),7.64(t,1H),7.49(d,1H),7.06(d,1H),6.37(s,1H),3.61-3.57(m,2H),3.50-3.44(m,2H),3.03-2.99(m,1H),2.38-2.13(m,4H),2.13(s,3H),1.78-1.48(m, 8H). MS calculated: 479.2, MS found: 480.3([ M + H)]⁺)。

3-cyano-2-fluorobenzoic acid methyl ester

3-bromo-2-fluorobenzonitrile (2.0g,10.0mmol) was dissolved in methanol (100mL), the reaction solution was placed in a 300mL sealed pressure bottle, and [1,1' -bis (diphenylphosphino) ferrocene was added]Palladium dichloride (82mg,0.10mmol) and triethylamine (2.8mL,20.0 mmol). The reaction mixture was pressurized with carbon monoxide (60psi) and stirred at 100 ℃ overnight. The reaction was cooled and purified by silica gel column chromatography (petroleum ether/ethyl acetate 40/1 vol.) to give methyl 3-cyano-2-fluorobenzoate 1.6g in 89% yield as a white solid.¹H NMR(300MHz,DMSO-d₆)8.23-8.17(m,2H),7.53(t,1H),3.88(s,3H)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyano-2-fluorobenzamide (Compound 15)

Methyl 3-cyano-2-fluorobenzoate (50mg,0.28mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone were dissolved in toluene (5mL) and stirred at 0 ℃ under nitrogen, and then a trimethylaluminum toluene solution (0.28mL,0.56mmol) was added to the reaction solution. The reaction mixture was stirred at 80 ℃ for 3 hours. The saturated ammonium chloride solution was quenched and extracted with dichloromethane (20 mL. times.3). The organic phases were combined, concentrated and the residue concentrated and purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyano-2-fluorobenzamide 15mg, purity 99%, yield 11%, as a white solid.¹H NMR(400MHz,DMSO-d₆)10.22(s,1H),8.15-8.07(m,2H),7.57(t,1H),7.51(s,1H),7.07(s,1H),6.37(s,1H),3.60-3.55(m,2H),3.50-3.44(m,2H),3.05-2.97(m,1H),2.37-2.13(m,4H),2.14(s,3H),1.79-1.50(m, 8H). MS calculated: 479.1, MS found: 480.2([ M + H)]⁺)。

3- (methylsulfonyl) benzoyl chloride

3- (Methylsulfonyl) benzoic acid (300mg,1.5mmol) was dissolved in thionyl chloride (3mL) and the reaction stirred at room temperature for 1 hour under a blanket of liquid nitrogen. The reaction solution was concentrated to give crude 3- (methylsulfonyl) benzoyl chloride, which was used in the next step without further purification.

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3- (methylsulfonyl) benzamide (compound 16)

(4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (100mg,0.30mmol), 3- (methylsulfonyl) benzoyl chloride (crude obtained in the previous step) were dissolved in anhydrous N, N-dimethylformamide (5mL), and triethylamine (243mg,2.4mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour under nitrogen. The reaction solution was diluted with water and extracted with dichloromethane. The organic phases were combined, concentrated and the residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3- (methylsulfonyl) benzamide 27mg as an off-white solid with a purity of 95% in 18% yield as an off-white solid.¹H NMR(400MHz,DMSO-d₆)10.34(s,1H),8.49(s,1H),8.30(d,1H),8.16(d,1H),7.84(t,1H),7.36(s,1H),7.08(d,1H),6.38(s,1H),3.60-3.50(m,2H),3.49-3.44(m,2H),3.30(s,3H),3.03-2.99(m,1H),2.37-2.11(m,4H),2.11(s,3H),1.78-1.51(m, 8H). MS calculated: 514.2, MS found: 515.0([ M + H)]⁺)。

6-methoxypyridazine-4-carboxylic acid

Sodium hydride (480mg,12.0mmol) was dissolved in 10mL of methanol and added slowly under nitrogen to a solution of methyl 6-chloropyridazine-4-carboxylate (345mg,2.00mmol) in methanol (10mL) at 0 ℃. The reaction mixture was stirred at 50 ℃ for three hours. Then, it was cooled to room temperature. The pH was adjusted to3 with 1mol/L hydrochloric acid. The reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give 80mg of 6-methoxypyridazine-4-carboxylic acid in 24% yield as an off-white solid.¹H NMR(400MHz,DMSO-d₆)14.15(br,1H),9.20(d,1H),7.50(d,1H),4.09(s,3H)。

6-methoxypyridazine-4-carboxylic acid

6-Methoxypyridazine-4-carboxylic acid (80mg,0.52mmol) was dissolved in 7mL of a methanol/tetrahydrofuran solution (volume ratio: 1/6), and trimethylsilyldiazomethane (0.5mL,1.00mmol) was added to the reaction mixture at 0 ℃ under nitrogen. The reaction mixture was stirred at 0 ℃ for 2 hours and concentrated. The residue was concentrated and used in the next reaction without further purification.

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-methoxypyridazine-4-carboxamide (Compound 17)

Methyl 6-methoxypyridazine-4-carboxylate (crude from the previous step, 0.519mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (150mg,0.450mmol) were dissolved in 10mL of toluene and a solution of trimethylaluminum (0.6mL,1.20mmol) in toluene was slowly added dropwise thereto at 0 ℃ under nitrogen. The reaction mixture was stirred at 80 ℃ for 2 hours. After diluting the reaction mixture with 10mL of water, 3mL of 1mol/L hydrochloric acid was added. The mixture was extracted with ethyl acetate (10 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Preparative high performance liquid phase for concentrating remainderChromatographic purification gave 80mg of N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-methoxypyridazine-4-carboxamide, 95% purity, 40% yield, as an off-white solid.¹H NMR(400MHz,DMSO-d₆)10.38(s,1H),9.28(d,1H),7.64(d,1H),7.41(d,1H),7.08(d,1H),6.37(s,1H),4.10(s,3H),3.58-3.57(m,2H),3.48-3.46(m,2H),3.03-2.97(m,1H),2.39-2.10(m,4H),2.11(s,3H),1.77-1.51(m, 8H). Calculated MS 468.2, found MS 469.2([ M + H ]]⁺)。

3, 5-dichloro-1-methylpyrazin-2 (1H) -one

2- (methylamino) -acetonitrile (10g,93.9mmol) was dissolved in chlorobenzene (80mL), oxalyl chloride (27mL,320mmol) was added dropwise at room temperature, and the reaction mixture was slowly warmed to90 deg.C and stirred for 5 hours. The solvent was removed by concentration, and the concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 10/1, vol.) to give 12.7g of 3, 5-dichloro-1-methylpyrazin-2 (1H) -one as a crude product, yield 75%, dark brown oil.

5-chloro-3- (diethylamino) -1-methylpyrazin-2 (1H) -one

3, 5-dichloro-1-methylpyrazin-2 (1H) -one (800mg,4.5mmol) was dissolved in 1, 4-dioxane (5mL), and diethylamine (1mL,9.0mmol) was added to the reaction solution. The reaction mixture was stirred at 50 ℃ for 2 hours. After the reaction was completed, the solvent was removed by concentration, and the residue obtained by concentration was dissolved in methylene chloride and washed with water. The organic layer was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate 7/1 vol.) to give 560mg of 5-chloro-3- (diethylamino) -1-methylpyrazin-2 (1H) -one in 58% yield as a yellow solid.¹H NMR(400MHz,DMSO-d₆)7.06(s,1H),3.66(q,4H),3.31(s,3H),1.13(t,6H)。

6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxylic acid methyl ester

5-chloro-3- (diethylamino) -1-methylpyrazin-2 (1H) -one (300mg,1.4mmol) and methyl acrylate (0.4mL,4.2mmol) were dissolved in 15mL of toluene and the reaction was stirred overnight at 80 ℃ under a protective atmosphere of liquid nitrogen. After the completion of the reaction, the solvent was removed by concentration, and the concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 3/1, volume ratio) to give 110mg of methyl 6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxylate, yield 41%, as a white solid.¹H NMR(400MHz,DMSO-d₆)7.35(d,1H),7.20(d,1H),3.87(s,3H),3.57(s,3H)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 18)

Methyl 6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxylate (50mg,0.26mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (87mg,0.26mmol) were dissolved in toluene (5mL), stirred at 0 ℃ under nitrogen, and then a solution of trimethylaluminum (0.26mL,0.52mmol) in toluene was added. The reaction mixture was stirred at 80 ℃ for 3 hours. The reaction was quenched with ammonium chloride solution and extracted with dichloromethane (20 mL. times.3). The organic phases were combined, concentrated and the residue concentrated and purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide, 56mg, 95% purity, 44% yield and white solid.¹H NMR(400MHz,DMSO-d₆)10.28(s,1H),7.40(s,1H),7.35(s,1H),7.32(s,1H),7.08(s,1H),6.37(s,1H),3.59(s,3H),3.59-3.41(m,4H),3.04-2.97(m,1H),2.40-2.04(m,4H),2.07(s,3H),1.75-1.52(m, 8H). Calculated MS value 492.2, found MS value 493.2([ M + H ]]⁺)。

2-Cyclopropylthiazole-5-carboxylic acid methyl ester

Methyl 2-chlorothiazole-5-carboxylate (500mg,2.8mmol), cyclopropanecarboxylic acid (1.2g,14mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (228mg,0.28mmol) and potassium carbonate (1.16g,8.4mmol) were dissolved in 1, 4-dioxane (30mL) and stirred at 90 ℃ for 14 h under nitrogen. The solvent was removed by concentration, diluted with water and extracted with dichloromethane (20 mL. times.3). The organic phases were combined, concentrated, and the concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 3/1 vol.) to give methyl 2-cyclopropylthiazole-5-carboxylate 180mg in 35% yield as a yellow oil.¹H NMR(400MHz,DMSO-d₆)8.23(s,1H),3.82(s,3H),2.51(m,1H),1.22-1.06(m,4H)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -2-cyclopropylthiazole-5-carboxamide (Compound 19)

Methyl 2-cyclopropylthiazole-5-carboxylate (60mg,0.33mmol), (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (109mg,0.33mmol) was dissolved in 5mL of anhydrous toluene, stirred at 0 ℃ under nitrogen protection, and a solution of trimethylaluminum (0.33mL,0.66mmol) in toluene was added to the reaction mixture. The reaction mixture was stirred at 80 ℃ for 3 hours. The ammonium chloride solution was quenched and extracted with dichloromethane (20 mL. times.3). After combining the organic layers, concentration was performed, and the residue was concentrated and purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -2-cyclopropylthiazole-5-carboxamide as 35mg, purity 95%, yield 22%, and white solid.¹H NMR(400MHz,DMSO-d₆)10.09(s,1H),8.35(s,1H),7.31(s,1H),7.05(s,1H),6.36(s,1H),3.59-3.55(m,2H),3.47-3.45(m,2H),3.01-2.97(m,1H),2.40-2.08(m,5H),2.07(s,3H),1.76-1.53(m,8H),1.21-1.16(m,2H),1.06-1.02(m, 2H). Calculated MS 483.1, found MS 484.2([ M + H ]]⁺)。

1-cyclopropyl-1-hydro-pyrazole-4-carboxylic acid methyl ester

Methyl 1-hydro-pyrazole-4-carboxylate (252mg,2.00mmol), cyclopropyl acid (378mg,4.40mmol), copper acetate (363mg,2.00mmol), 2, 2' -bipyridine (312mg,2.00mmol) and sodium carbonate (488mg,4.60mmol) were dissolved in dichloroethane (20mL), and the reaction was stirred overnight at 70 ℃ under a protective atmosphere of liquid nitrogen. The solvent was removed by concentration, and the concentrated residue was purified by silica gel column chromatography (dichloromethane/methanol 100/1, vol.) to give 1-cyclopropyl-1 h-pyrazole-4-carboxylic acid methyl ester 100mg, yield 36%, as a colorless oil.¹H NMR(400MHz,CDCl₃)7.94(s,1H),7.87(s,1H),3.82(s,3H),3.63(m,1H),1.17-1.12(m,2H),1.10-1.04(m,2H)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -1-cyclopropyl-1H-pyrazole-4-carboxamide (Compound 20)

Methyl 1-cyclopropyl-1H-pyrazole-4-carboxylate (60mg,0.361mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (120mg,0.360mmol) were dissolved in 10mL of toluene and trimethylaluminum (0.4mL,0.800mmol) was slowly added to the reaction solution at 0 ℃ under nitrogen. The reaction mixture was stirred at 80 ℃ for 2 hours. The reaction mixture was diluted with 10mL of water, and 3mL of 1mol/L hydrochloric acid was added. Extraction with ethyl acetate (10 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -1-cyclopropyl-1H-pyrazole-4-carboxamide 12mg in 95% purity, 7% yield and as a white solid.¹H NMR(400MHz,DMSO-d₆)9.53(s,1H),8.38(s,1H),7.96(s,1H),7.32(s,1H),7.02(s,1H),6.36(s,1H),3.84-3.78(m,1H),3.61-3.55(m,2H),3.50-3.42(m,2H),3.05-2.97(m,1H),2.40-2.10(m,4H),2.08(s,3H),1.77-1.53(m,8H),1.09-1.05(m,2H),1.03-0.98(m, 2H). Calculated MS 466.2, found MS 467.2([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-methoxybenzamide (Compound 21)

Methyl 3-methoxybenzoate (50mg,0.3mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (79mg,0.237mmol) were dissolved in toluene (10mL), stirred at 0 ℃ under nitrogen, and a toluene solution of trimethylaluminum (0.3mL,0.6mmol) was slowly added to the reaction solution. The reaction mixture was stirred at 80 ℃ for 3 hours. The reaction was quenched with ammonium chloride solution and extracted with dichloromethane (20 mL. times.3). The organic phases were combined, concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-methoxybenzamide 11mg, purity 95%, yield 8%, as a white solid.¹H NMR(400MHz,DMSO-d₆)9.96(s,1H),7.56(d,1H),7.50(d,1H),7.46-7.42(m,1H),7.34(d,1H),7.18-7.15(m,1H),7.05(s,1H),6.37(s,1H),3.83(s,3H),3.58-3.55(m,2H),3.48-3.44(m,2H),3.03-2.99(m,1H),2.37-2.09(m,4H),2.08(s,3H),1.76-1.51(m, 8H). Calculated MS 466.2, found MS 467.0([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-methoxycyclobutylamide (Compound 22)

3-methoxycyclobutylformic acid (101mg,0.78mmol) was dissolved in thionyl chloride (4mL) and the reaction was stirred at 50 ℃ for 2 hours under nitrogen. The thionyl chloride was removed by concentration, and the residue was dissolved in 6mL of N, N-dimethylformamide. Then (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (129mg,0.39mmol) and triethylamine (0.2mL,1.43mmol) were added. The reaction mixture was stirred at 25 ℃ for 1 hour under nitrogen protection. Concentrating to obtain crude product, and purifying by preparative high performance liquid chromatography to obtain N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-methoxybutaneamide 20mg with purity of 95%, yield of 12%, and white solidAnd (3) a body.¹H NMR(400MHz,DMSO-d₆)9.37(s,1H),7.39(s,1H),6.94(d,1H),6.33(s,1H),3.79(p,1H),3.60-3.54(m,2H),3.46-3.40(m,2H),3.13(s,3H),3.04-2.94(m,1H),2.85-2.76(m,1H),2.43-2.34(m,3H),2.28-2.26(t,1H),2.18(t,1H),2.14-1.98(m,6H),1.78-1.46(m, 8H). MS calculated: 444.2, MS found: 445.2([ M + H)]⁺)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-phenylpropanamide (Compound 23)

3-Phenylpropionic acid (100mg,0.67mmol) was dissolved in thionyl chloride (4mL), and the reaction solution was stirred at 50 ℃ for 2 hours. Concentrating to remove solvent, and vacuum drying. The residue was dissolved in N, N-dimethylformamide (8mL), followed by addition of (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (100mg,0.30mmol) and triethylamine (0.13mL,0.90 mmol). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was removed by concentration, and the residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3 ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-phenylpropanamide 14mg, purity 95%, yield 10%, as a white solid.¹H NMR(400MHz,DMSO-d₆)9.39(s,1H),7.35-7.24(m,5H),7.21-7.17(m,1H),6.93(s,1H),6.31(s,1H),3.54-3.58(m,2H),3.41-3.47(m,2H),2.98-3.03(m,1H),2.92(t,2H),2.67(t,2H),2.09-2.34(m,4H),1.96(s,3H),1.79-1.71(m,2H),1.67-1.23(m, 6H). MS calculated: 464.2, MS found: 465.2([ M + H)]⁺)。

Tert-butyl 4- (3-amino-5-chloro-2-methylbenzylidene) piperidine-1-carboxylic acid ester

Tert-butyl 4- (-5-chloro-2-methyl-3-nitrobenzylidene) piperidine-1-carboxylate (900mg,2.5mmol), sodium acetate (407mg,5.0mmol) and acetic acid (2mL) were dissolved in ethanol/water (40mL/20mL), and iron powder (556mg,9.9mmol) was added to the reaction solution. The reaction mixture is stirred for 1 hour at 80 DEG CThen (c) is performed. The reaction solution was poured into water, and extracted with ethyl acetate. The organic phases were combined, concentrated, and the concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 8/1, vol.) to give 650mg of tert-butyl 4- (3-amino-5-chloro-2-methylbenzylidene) piperidine-1-carboxylate in 78% yield as a yellow oil.¹H NMR(400MHz,DMSO-d₆)：6.56(d,1H),6.26(d,1H),6.25(s,1H),5.14(s,2H),3.41(t,2H),3.28(t,2H),2.25(t,2H),2.09(t,2H),1.89(s,3H),1.40(s,9H)。

4- (5-chloro-3- (3-cyanobenzamide) -2-methylbenzylidene) piperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- (3-amino-5-chloro-2-methylbenzylidene) piperidine-1-carboxylate (100mg,0.30mmol) and methyl 3-cyanobenzoate (48mg,0.30mmol) were dissolved in anhydrous toluene (2mL), the temperature was reduced to 0 ℃ and a solution of trimethylaluminum (0.3mL,2M,0.60mmol) in toluene was added to the reaction mixture under nitrogen. The reaction mixture was stirred at 80 ℃ for 3 hours under nitrogen protection. Saturated ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic phases were combined, concentrated, and the concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2/1, vol.) to give 140mg of tert-butyl 4- (5-chloro-3- (3-cyanobenzamide) -2-methylbenzylidene) piperidine-1-carboxylate in 100% yield as a white solid.¹H NMR(400MHz,DMSO-d₆)10.21(s,1H),8.40(s,1H),8.26(d,1H),8.09(d,1H),7.77(t,1H),7.37(d,1H),7.06(d,1H),6.37(s,1H),3.44(t,2H),3.33(t,2H),2.31(t,2H),2.17(d,2H),2.10(s,3H),1.41(s,9H)。

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -3-cyanobenzamide hydrochloride

4- (5-chloro-3- (3-cyanobenzamide) -2-methylbenzylidene) piperidine-1-carboxylic acid ester (140mg,0.30mmol) was dissolved in ethyl acetate (2mL), and ethyl acetate/hydrochloric acid solution (2mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -3-cyanobenzamide hydrochloride, which was used in the next reaction without further purification.

N- (5-chloro-2-methyl-3- ((1- (tetrahydro-2H-pyran-4-carbonyl) piperidin-4-ylidene) methyl) phenyl) 3-cyanobenzamide (Compound 24)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -3-cyanobenzamide hydrochloride (0.30mmol), tetrahydro-2H-pyran-4-carboxylic acid (39mg,0.30mmol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (114mg,0.3mmol) were dissolved in N, N-dimethylformamide (3mL), and triethylamine (0.3mL) was added to the reaction solution. The reaction mixture was stirred at 40 ℃ for 2 hours under nitrogen protection. The reaction solution was concentrated, and the residue was concentrated to give 27mg of N- (5-chloro-2-methyl-3- ((1- (tetrahydro-2H-pyran-4-carbonyl) piperidin-4-ylidene) methyl) phenyl) 3-cyanobenzamide by preparative liquid chromatography with a purity of 95%, a yield of 20%, and a white solid.¹H NMR(400MHz,DMSO-d₆)10.24(s,1H),8.41(s,1H),8.27(d,1H),8.16(d,1H),7.78(t,1H),7.39(d,1H),7.08(d,1H),6.39(s,1H),3.84-3.86(m,2H),3.36-3.62(m,6H),2.90-2.95(m,1H), 2.14-2.40(m,4H),2.12(s,3H),1.53-1.66(m, 4H). MS calculated: 477.2, MS found: 478.2([ M + H)]⁺)。

N- (5-chloro-3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzamide (Compound 25)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -3-cyanobenzamide hydrochloride (0.22mmol), cyclopropylacetic acid (0.5mL,0.55mmol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (92mg,0.24mmol) were dissolved in N, N-dimethylformamide (3mL), and triethylamine (0.3mL) was added to the reaction solution. Stirring the reaction mixed liquid at 40 ℃ under the protection of nitrogenStirring for 2 hours. The reaction solution was concentrated, and the residue was concentrated to give 21mg of N- (5-chloro-3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzamide by preparative liquid chromatography with a purity of 95%, yield of 21%, and white solid.¹H NMR(400MHz,DMSO-d₆)10.21(s,1H),8.40(s,1H),8.26(d,1H),8.09(d,1H),7.77(t,1H),7.38(d,1H),7.07(d,1H),6.38(s,1H),3.51-3.58(m,2H),3.40-3.47(m,2H),2.13-2.39(m,6H),2.10(s,3H),0.96(m,1H),0.43-0.47(m,2H),0.12(t, 2H). MS calculated: 447.2, MS found: 448.0([ M + H)]⁺)。

N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzamide (compound 26)

Dissolving N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl-3-cyanobenzamide (50mg,0.14mmol), 3-difluorocyclopentylcarboxylic acid (42mg,0.28mmol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (53mg,0.14mmol) in N, N-dimethylformamide (3mL), adding triethylamine (0.1mL) to the reaction solution, stirring at room temperature for 2 hours under nitrogen protection to concentrate the reaction solution, purifying the concentrated residue by preparative high performance liquid chromatography to obtain 20mg of N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzamide, purity 95%, yield 29%, white solid.¹H NMR(400MHz,DMSO-d₆)10.22(s,1H),8.40(s,1H),8.26(d,1H),8.09(d,1H),7.77(t,1H),7.38(s,1H),7.06(s,1H),6.39(s,1H),3.48-3.60(m,4H),3.31-3.40(m,1H),2.01-2.39(m,9H),2.11(s,3H),1.80(m, 1H). MS calculated: 497.2, MS found: 498.0([ M + H)]⁺)。

N- (3- ((1- (bicyclo [3.1.0] hexane-3-carbonyl) piperidin-4-ylidene) methyl) -5-chloro-2-tolyl-3-cyanobenzamide (compound 27)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -3-cyanobenzamide (50mg,0.14mmol), bicyclo [3.1.0]Hexane-3-carboxylic acid (35mg,0.28mmol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (53mg,0.14mmol) were dissolved in N, N-dimethylformamide (3mL), and triethylamine (0.1mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours under nitrogen. Concentrating the reaction solution, purifying the concentrated residue by preparative high performance liquid chromatography to obtain white solid N- (3- ((1- (bicyclo [3.1.0]]Hexane-3-carbonyl) piperidin-4-ylidene) methyl) -5-chloro-2-tolyl-3-cyanobenzamide 20mg, purity 95%, yield 30%.¹H NMR(400MHz,DMSO-d₆)10.19(s,1H),8.40(s,1H),8.26(d,1H),8.09(d,1H),7.77(t,1H),7.38(s,1H),7.06(s,1H),6.37(s,1H),3.52(s,2H),3.41(s,2H),3.29-3.31(m,1H),2.10-2.36(m,6H),2.10(s,3H),1.89(d,2H),1.23(s,2H),0.21-0.33(m, 2H). MS calculated: 473.2, MS found: 474.0([ M + H)]⁺)。

N- (5-chloro-3- ((1- (3, 3-difluorocyclobutylcarbonyl) piperidin-4-ylidene) methyl-2-tolyl) -3-cyanobenzamide (Compound 28)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -3-cyanobenzamide (70mg,0.19mmol), 3-difluorocyclobutylcarboxylic acid (51mg,0.38mmol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (80mg,0.21mmol) were dissolved in N, N-dimethylformamide (3mL), and triethylamine (0.1mL) was added to the reaction solution. The reaction mixture was stirred at 40 ℃ for 1 hour under nitrogen protection. The reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give 35mg of N- (5-chloro-3- ((1- (3, 3-difluorocyclobutylcarbonyl) piperidin-4-ylidene) methyl-2-tolyl) -3-cyanobenzamide with a purity of 95%, yield of 38%, and white solid.¹H NMR(400MHz,DMSO-d₆)10.19(s,1H),8.40(s,1H),8.26(d,1H),8.08(d,1H),7.77(t,1H),7.38(s,1H),7.06(s,1H),6.39(s,1H),3.26-3.59(m,5H),2.75-2.85(m,4H),2.17-2.36(m,4H),2.11(s, 3H). MS calculated: 483.2, MS found: 484.2([ M + H)]⁺)。

N- (3- ((1- (2- (bicyclo [1.1.1] pentan-1-yl) acetyl) piperidin-4-ylidene) methyl) -5-chloro-2-tolyl) -3-cyanobenzamide (compound 29)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -3-cyanobenzamide (60mg,0.16mmol), 2- (bicyclo [ 1.1.1)]Pentane-1-yl) acetic acid (40mg,0.32mmol) and triethylamine (0.1mL) were dissolved in N, N-dimethylformamide (3mL), and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (61mg,0.16mmol) was added to the reaction solution. The reaction mixture was stirred at 50 ℃ for 1.5 hours under nitrogen. Concentrating the reaction solution, purifying the concentrated residue by preparative high performance liquid chromatography to obtain N- (3- ((1- (2- (bicyclo [ 1.1.1)]Pentan-1-yl) acetyl) piperidin-4-ylidene) methyl) -5-chloro-2-tolyl) -3-cyanobenzamide 30mg, purity 95%, yield 39%, white solid.¹HNMR(400MHz,DMSO-d₆)10.19(s,1H),8.40(s,1H),8.26(d,1H),8.09(d,1H),7.77(t,1H),7.38(d,1H),7.07(s,1H),6.38(s,1H),3.57-3.53(m,2H),3.46-3.42(m,2H),2.56(d,2H),2.46(d,1H),2.38-2.12(m,4H),2.11(s,3H),1.74(d, 6H). Calculated MS 473.2, found MS 474.1([ M + H ]]⁺)。

4- (5-chloro-3- (6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-amide) -2-methylbenzylidene) piperidine-1-carboxylic acid tert-butyl ester

Methyl 6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxylate (300mg,1.56mmol) and tert-butyl 4- (3-amino-5-chloro-2-methylbenzylidene) piperidine-1-carboxylate (525mg,1.56mmol) were dissolved in toluene (10mL) and stirred at 0 ℃ under nitrogen. Then trimethylaluminum in toluene (1.56mL,3.12mmol) was added. The reaction mixture was stirred at 80 ℃ for 3 hours. The reaction was quenched with ammonium chloride solution and extracted with dichloromethane (20 mL. times.5). Combining the organic phases, concentrating, and purifying the concentrated residue by silica gel column chromatography (2/1 (vol/vol))Tert-butyl 5-chloro-3- (6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-amide) -2-methylbenzylidene) piperidine-1-carboxylate 620mg, 80% yield as a white solid.¹H NMR(400MHz,DMSO-d₆)10.27(s,1H),7.40(d,1H),7.34(d,1H),7.32(s,1H),7.07(s,1H),6.35(s,1H),3.60(s,3H),3.43-3.41(m,2H),3.34-3.32(m,2H),3.32-3.29(m,2H),3.16-3.13(m,2H),2.07(s,3H),1.41(s,9H)。

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide

Tert-butyl 4- (5-chloro-3- (6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide) -2-methylbenzylidene) piperidine-1-carboxylate (620mg,1.25mmol) was dissolved in dichloromethane (4mL) and trifluoroacetic acid (6mL) was added to the reaction. The reaction mixture was stirred at room temperature overnight. The solvent was removed by concentration, and the concentrated residue was diluted with water, neutralized with sodium bicarbonate solution, and extracted with dichloromethane (20 mL. times.5). The combined organic phases were concentrated and dried in vacuo to give crude N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide as 600mg of a yellow solid.¹H NMR(400MHz,DMSO-d₆)10.27(s,1H),7.48(s,1H),7.41(s,1H),7.31(s,1H),6.90(s,1H),6.20(s,1H),3.58(s,3H),3.41-3.39(m,1H),3.28-3.26(m,1H),2.77-2.75(m,1H),2.67-2.64(m,1H),2.25-2.16(m,2H),2.08-2.03(m,2H),2.06(s,3H)。

N- (3- ((1- (2- (bicyclo [1.1.1] pentan-1-yl) acetyl) piperidin-4-ylidene) methyl) -5-chloro-2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 30)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (100mg,0.27mmol), 2- (bicyclo [ 1.1.1)]Pentane-1-yl) acetic acid (60mg,0.54mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylUrea-based hexafluorophosphate (308mg,0.81mmol) and triethylamine (0.22mL,0.81mmol) were dissolved in N, N-dimethylformamide (3mL) and stirred at room temperature overnight. After the reaction is finished, the reaction solution is purified by preparative high performance liquid chromatography to obtain N- (3- ((1- (2- (bicyclo [ 1.1.1)]Pentan-1-yl) acetyl) piperidin-4-ylidene) methyl) -5-chloro-2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (36mg, 95% purity, 26% yield, white solid.¹H NMR(400MHz,DMSO-d₆)10.25(s,1H),7.39(d,1H),7.35(d,1H),7.32(d,1H),7.08-7.06(s,1H),6.36(s,1H),3.59(s,3H),3.56-3.54(m,1H),3.52-3.49(m,1H),3.45-3.42(m,1H),3.40-3.36(m,1H),2.55(d,2H),2.46(d,1H),2.37-2.35(m,1H),2.30-2.27(m,1H),2.21-2.18(m,1H),2.13-2.10(m,1H),2.07(s,3H),1.74-1.72(m, 6H). MS calculated value 504.2, MS found value 505.0([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (4, 4-difluorocyclohexylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 31)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (50mg,0.135mmol),4, 4-difluorocyclohexanecarboxylic acid (44mg,0.27mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (154mg,0.40mmol) and triethylamine (0.11mL,0.40mmol) were dissolved in N, N-dimethylformamide (3mL) and stirred at room temperature overnight. After the completion of the reaction, the reaction solution was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (4, 4-difluorocyclohexylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide, 5mg in purity of 94%, yield of 7%, and white solid.¹H NMR(400MHz,DMSO-d₆)10.26(s,1H),7.39(s,1H),7.35(s,1H),7.32(s,1H),7.09(d,1H),6.37(s,1H),3.64-3.44(m,4H),3.60(s,3H),2.86-2.79(m,1H),2.40-2.12(m,4H),2.06(s,3H),2.04-2.02(m,2H),1.95-1.83(m,2H),1.76-1.73(m,2H),1.63-1.54(m, 2H). Calculated MS 542.2 and found MS 543.0([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (4, 4-difluorocyclohexylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzamide (Compound 32)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -3-cyanobenzamide (60mg,0.16mmol), 4, 4-difluorocyclohexanecarboxylic acid (53mg,0.32mmol) and triethylamine (0.1mL) were dissolved in N, N-dimethylformamide (3mL), and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (61mg,0.16mmol) was added to the reaction mixture. The reaction mixture was stirred at 50 ℃ for 1 hour under protection of liquid nitrogen. The reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give 20mg of N- (5-chloro-3- ((1- (4, 4-difluorocyclohexylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzamide having a purity of 95%, a yield of 24%, and a white solid.¹H NMR(400MHz,DMSO-d₆)10.21(s,1H),8.40(s,1H),8.26(d,1H),8.09(d,1H),7.77(t,1H),7.38(s,1H),7.08(d,1H),6.39(s,1H),3.63-3.47(m,4H),2.82-2.89(m,1H),2.41-2.16(m,4H),2.11(s,3H),2.00-2.06(m,2H),1.83-1.95(m,2H),1.73-1.76(m,2H),1.57-1.64(m, 2H). Calculated MS 511.2, found MS 512.1([ M + H ]]⁺)。

N- (5-chloro-2-methyl-3- ((1- (thiophene-2-carbonyl) piperidin-4-ylidene) methyl) phenyl) -3-cyanobenzamide (Compound 33)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -3-cyanobenzamide (150mg,0.41mmol), potassium carbonate (171mg,1.23mmol) were dissolved in acetonitrile (12mL), and thiophene-2-carbonyl chloride (180mg,1.23mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight under nitrogen. Water was added to the reaction solution, followed by extraction with ethyl acetate. Combining the organic phases, concentrating, purifying the concentrated residue by preparative high performance liquid chromatography to obtain N- (5-chloro-2-methyl-3- ((1- (thiophene-2-carbonyl) piperidin-4-ylidene) methyl) phenyl) -3-cyanobenzamide 80mg with purity of 95%, yield of 39%, whiteA colored solid.¹H NMR(400MHz,DMSO-d₆)10.20(s,1H),8.40(s,1H),8.26(d,1H),8.09(dt,1H),7.75-7.79(m,2H),7.44(dd,1H),7.39(d,1H),7.12-7.14(m,1H),7.09(d,1H),6.42(s,1H),3.74(t,2H),3.63(t,2H),2.45(t,2H),2.30(t,2H),2.12(s, 3H). Calculated MS 475.1, found MS 476.0([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (2-cyclobutylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 34)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (110mg,0.27mmol), 2-cyclobutylacetic acid (0.03mL,0.33mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (188mg,0.50mmol) and triethylamine (0.12mL,0.81mmol) were dissolved in N, N-dimethylformamide (3mL) and stirred at room temperature overnight. After the reaction was completed, the reaction solution was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (2-cyclobutylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide 12mg, purity 95%, yield 9%, white solid.¹H NMR(400MHz,DMSO-d₆)10.25(s,1H),7.39(d,1H),7.34(d,1H),7.32(d,1H),7.06(d,1H),6.35(s,1H),3.59(s,3H),3.54-3.50(m,2H),3.44-3.36(m,2H),2.66-2.56(m,1H),2.46-2.45(m,2H),2.36-2.08(m,4H),2.07(s,3H),2.05-1.97(m,2H),1.85-1.77(m,2H),1.67-1.61(m, 2H). Calculated MS 492.2, found MS 493.0([ M + H ]]⁺)。

4- (5-chloro-3- (5-cyanonicotinamide) -2-methylbenzylidene) piperidine-1-carboxylic acid tert-butyl ester

Methyl 5-cyanonicotinate (100mg,0.62mmol) and tert-butyl 4- (3-amino-5-chloro-2-methylbenzylidene) piperidine-1-carboxylate (207mg,0.62mmol) were dissolved in 10mL of toluene, stirred at 0 ℃ under nitrogen, and then a solution of trimethylaluminum (0.62mL,1.24mmol) in toluene was added. The reaction mixture was stirred at 80 ℃ for 3 hours. The reaction was quenched with ammonium chloride solution and extracted with dichloromethane (20 mL. times.3). The organic phases were combined and concentrated, and the concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2/1 vol.) to give 4- (5-chloro-3- (5-c cyanonicotinamide) -2-methylbenzylidene) piperidine-1-carboxylic acid tert-butyl ester 120mg, 42% yield, as a white solid.

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -5-cyanonicotinamide

Tert-butyl 4- (5-chloro-3- (5-cyanonicotinamide) -2-methylbenzylidene) piperidine-1-carboxylate (120mg,0.258mmol) was dissolved in dichloromethane (8mL) and trifluoroacetic acid (2mL) was added slowly. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated. The residue was concentrated and used for the next reaction without purification.

N- (5-chloro-3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyanonicotinamide (Compound 35)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -5-cyanonicotinamide (110mg,0.237mmol), 2-cyclopropylacetic acid (24mg,0.240mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (108mg,0.284mmol) and N, N-diisopropylethylamine (0.2mL) were dissolved in N, N-dimethylformamide (6mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated. The residue was concentrated, and water (10mL) was added to the residue, followed by extraction with ethyl acetate (20 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give 16mg of N- (5-chloro-3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyanonicotinamide with a purity of 95%, yield of 15%, and white solid.¹H NMR(400MHz,DMSO-d₆)10.33(s,1H),9.33(d,1H),9.23(d,1H),8.79(t,1H),7.41(d,1H),7.07(d,1H),6.38(s,1H),3.59-3.51(m2H),3.47-3.40(m,2H),2.38-2.11(m,6H),2.12(s,3H),0.97(m,1H),0.46-0.43(m,2H),0.13-0.11(m, 2H). Calculated MS 428.2 and found MS 449.0([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 36)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (80mg crude, 0.2mmol), 2-cyclopropylacetic acid (24mg,0.24mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (137mg,0.36mmol) and triethylamine (0.1mL,0.6mmol) were dissolved in N, N-dimethylformamide (2mL), and the reaction solution was stirred overnight at room temperature. After completion of the reaction, the mixture was purified by preparative high performance liquid chromatography to give 2mg of N- (5-chloro-3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide, purity 90%, yield 2.3%, white solid.¹H NMR(400MHz,DMSO-d₆)10.25(s,1H),7.39(s,1H),7.35(s,1H),7.31(s,1H),7.06(s,1H),6.36(s,1H),3.61(s,3H),3.59-3.51(m,2H),3.44-3.40(m,2H),2.38-2.11(m,6H),2.07(s,3H),0.97(m,1H),0.46-0.43(m,2H),0.13-0.09(m, 2H). Calculated MS value 478.2, found MS value 479.0.

4- (5-chloro-3- (5-chloro-6-methylnicotinamide) -2-methylbenzylidene) piperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- (3-amino-5-chloro-2-methylbenzylidene) piperidine-1-carboxylate (100mg,0.3mmol), methyl 5-chloro-6-methylnicotinate (61mg,0.33mmol) in dry toluene (10mL) was added to the reaction mixture under nitrogen at 0 deg.C in a toluene solution of trimethylaluminum (0.3mL,2M,0.6 mmol). The reaction mixture was stirred at 80 ℃ for 3 hours under nitrogen protection. After quenching the reaction with ammonium chloride solution, extraction was performed with ethyl acetate. Is combined withThe organic phase was concentrated, and the concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2/1, vol.) to give tert-butyl 4- (5-chloro-3- (5-chloro-6-methylnicotinamide) -2-methylbenzylidene) piperidine-1-carboxylate 100mg, 69% yield, as a colorless oil. Calculated MS 489.2, found MS 490.1([ M + H ]]⁺)。

5-chloro-N- (5-chloro-2-methylamino-3- (piperidin-4-ylidenemethyl) phenyl) -6-methylnicotinamide hydrochloride

Tert-butyl 4- (5-chloro-3- (5-chloro-6-methylnicotinamide) -2-methylbenzylidene) piperidine-1-carboxylate (100mg,0.2mmol) was dissolved in ethyl acetate (4mL), and ethyl acetate hydrochloride gas solution (2mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 30 minutes. The reaction was concentrated to give 5-chloro-N- (5-chloro-2-methylamino-3- (piperidin-4-ylidenemethyl) phenyl) -6-methylnicotinamide hydrochloride as a white solid which was used in the next reaction without further purification.

5-chloro-N- (5-chloro-3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-methylnicotinamide (Compound 37)

5-chloro-N- (5-chloro-2-methylamino-3- (piperidin-4-ylidenemethyl) phenyl) -6-methylnicotinamide hydrochloride (crude, 0.21mmol), 2-cyclopropylacetic acid (0.05mL,0.525mmol), triethylamine (0.3mL) were dissolved in N, N-dimethylformamide (3mL), and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (88mg,0.23mmol) was added to the reaction mixture. The reaction mixture was stirred at 40 ℃ for 3 hours under nitrogen protection. The reaction solution was concentrated, and the concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 1/2, volume ratio) to give 90mg of 5-chloro-N- (5-chloro-3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-methylnicotinamide with a purity of 93%, yield of 87%, and white solid.¹HNMR(400MHz,DMSO-d₆)10.20(s,1H),8.95(d,1H),8.35(d,1H),7.37(d,1H),7.06(d,1H) 6.37(s,1H),3.51-3.58(m,2H),3.40-3.47(m,2H),2.64(s,3H),2.36-2.13(m,6H),2.10(s,3H),0.90-1.10(m,1H),0.42-0.48(m,2H),0.12(t, 2H). Calculated MS 471.2 and found MS 472.0([ M + H ]]⁺)。

N- (5-chloro-2-methyl-3- ((1- (3,3, 3-trifluoropropionyl) piperidin-4-ylidene) methyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 38)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide hydrochloride (100mg,0.25mmol), 3,3, 3-trifluoropropionic acid (64mg,0.5mmol), triethylamine (0.3mL) dissolved in N, N-dimethylformamide (3mL), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (96mg,0.25mmol) was added at 0 ℃. The reaction solution was stirred for 1.5 hours at room temperature. The reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-2-methyl-3- ((1- (3,3, 3-trifluoropropionyl) piperidin-4-ylidene) methyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide 60mg, purity 95%, yield 47%, and white solid.¹H NMR(400MHz,DMSO-d₆)10.29(s,1H),7.40(s,1H),7.35(s,1H),7.33(s,1H),7.08(s,1H),6.38(s,1H),3.64-3.76(m,2H),3.60(s,3H),3.60-3.44(m,4H),2.41-2.14(m,4H),2.08(s, 3H). MS calculated value 506.1, MS found value 507.2([ M + H ]]⁺)。

N- (5-chloro-2-methyl-3- ((1- (tetrahydrofuran-3-carbonyl) piperidin-4-ylidene) methyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 39)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide hydrochloride (100mg,0.25mmol), tetrahydrofuran-3-carboxylic acid (58mg,0.5mmol), triethylamine (0.2mL) dissolved in N, N-dimethylformamide (3mL) was added 2- (7-azobenzoTriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (96mg,0.25 mmol). The reaction solution was stirred for 1.5 hours at room temperature. The reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-2-methyl-3- ((1- (tetrahydrofuran-3-carbonyl) piperidin-4-ylidene) methyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide 55mg, purity 95%, yield 44%, and white solid.¹HNMR(400MHz,DMSO-d₆)10.29(s,1H),7.40(s,1H),7.35(s,1H),7.32(s,1H),7.08(m,1H),6.37(s,1H),3.86-3.93(m,1H),3.66-3.73(m,3H),3.60(s,3H),3.55-3.60(m,2H),3.46-3.50(m,2H),3.58-3.43(m,1H),2.36-2.12(m,4H),2.08(s,3H),2.00-2.04(m, 2H). Calculated MS value of 494.2 and found MS value of 495.2([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (3, 3-dimethylcyclobutylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 40)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide hydrochloride (100mg,0.25mmol), 3, 3-dimethylbutylcyclobutyric acid (32mg,0.25mmol) and triethylamine (77mg,0.76mmol) were dissolved in N, N-dimethylformamide (5mL) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (144mg,0.38mmol) was added at 0 ℃. The reaction mixture was stirred at room temperature overnight. Quenching the reaction with water, and extracting with ethyl acetate. The organic phases were combined and concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give 61mg of N- (5-chloro-3- ((1- (3, 3-dimethylcyclobutylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide, purity 95%, yield 48%, white solid.¹H NMR(400MHz,DMSO-d₆)10.26(s,1H),7.39(s,1H),7.34(s,1H),7.32(s,1H),7.06(s,1H),6.35(s,1H),3.59(s,3H),3.55-3.53(m,1H),3.44-3.39(m,2H),3.30-3.27(m,2H),2.32-2.27(m,2H),2.17-2.12(m,2H),2.09(s,3H),1.98-1.93(m,2H),1.91-1.86(m,2H),1.15(d,3H),1.01(s, 3H). MS calculated value 506.2, MS found value 507.3([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (1-fluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 41)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide hydrochloride (100mg,0.25mmol), 1-fluorocyclopentylcarbamic acid (33mg,0.25mmol,1eq) and triethylamine (77mg,0.76mmol) were dissolved in N, N-dimethylformamide (5mL) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (144mg,0.38mmol,1.5eq) was added at 0 ℃. The reaction mixture was stirred at room temperature overnight. Quenching the reaction with water, and extracting with ethyl acetate. The organic phases were combined and concentrated, and the residue was concentrated and purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (1-fluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide as 58mg in 95% purity, 45% yield and as a white solid.¹H NMR(400MHz,DMSO-d₆)10.26(s,1H),7.39(s,1H),7.35(s,1H),7.32(s,1H),7.068(s,1H),6.37(s,1H),3.79-3.66(m,1H),3.64-3.54(m,5H),3.53-3.43(m,1H),2.43-2.33(m,2H),2.32-2.14(m,4H),2.08(s,3H),2.05-1.93(m,2H),1.78-1.61(m, 4H). Calculated MS 510.2, found MS 511.2([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 42)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide hydrochloride (100mg,0.25mmol), 3, 3-difluorocyclopentylcarboxylic acid (38mg,0.25mmol,1eq) and triethylamine (77mg,0.76mmol) were dissolved in N, N-dimethylformamide (5mL) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyl was added at 0 deg.CUrea hexafluorophosphate (144mg,0.38 mmol). The reaction mixture was stirred at room temperature overnight. Quenching the reaction with water, and extracting with ethyl acetate. The organic phases were combined and concentrated, and the residue was concentrated and purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide as 55mg in 95% purity, 42% yield and as a white solid.¹H NMR(400MHz,DMSO-d₆)10.26(s,1H),7.39(s,1H),7.35(s,1H),7.32(s,1H),7.08(s,1H),6.37(s,1H),3.59-3.58(m,5H),3.52-3.43(m,2H),3.42-3.35(m,1H),2.45-2.35(m,2H),2.34-2.25(m,2H),2.25-2.19(m,1H),2.17-2.09(m,2H),2.08(s,3H),2.05-1.94(m,2H),1.86-1.72(m, 1H). Calculated MS 528.2, found MS 529.1([ M + H ]]⁺)。

(R) -N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 43)

(R) -3, 3-Difluorocyclopentylcarbamic acid (125mg,0.83mmol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (315mg,0.83mmol) were dissolved in dichloromethane (5mL), triethylamine (209mg,2.07mmol) was added and stirred for 10 minutes. Then N- (5-chloro-2-methyl-3- (4-piperidine-methylene) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide hydrochloride (300mg,0.69mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give (R) -N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide 201mg, purity 95%, yield 55%, white solid. 1H NMR (400MHz, DMSO-d6)10.27(s,1H),7.40(d,1H),7.35(d,1H),7.32(s,1H),7.07(t,1H),6.37(s,1H),3.60(s,3H),3.59-3.60(m,2H),3.47(s,1H),3.35-3.42(m,1H),2.36-2.42(m,2H),2.26-2.31(m,2H),2.22-2.23(m,1H),2.13-2.18(m,2H),1.99-2.06(m,2H),1.80-1.82(m, 1H). Calculated MS 528.2, found MS 529.2([ M + H ] +)

(S) -N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 44)

(S) -3, 3-Difluorocyclopentylcarbamic acid (125mg,0.83mmol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (315mg,0.83mmol) were dissolved in dichloromethane (5mL), and triethylamine (209mg,2.07mmol) was added thereto and stirred at room temperature for 10 minutes. N- (5-chloro-2-methyl-3- (4-piperidine-methylene) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide hydrochloride (300mg,0.69mmol) was then added. The reaction solution was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give (S) -N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide 237mg, purity 95%, yield 65%, white solid. 1H NMR (400MHz, DMSO-d6)10.27(s,1H),7.40(d,1H),7.35(d,1H),7.32(s,1H),7.08(t,1H),6.37(s,1H),3.60(s,3H),3.56-3.59(m,2H),3.47(s,1H),3.35-3.42(m,1H),2.36-2.42(m,2H),2.26-2.31(m,2H),2.22-2.23(m,1H),2.13-2.18(m,2H),1.97-2.05(m,2H),1.75-1.84(m, 1H). Calculated MS 528.2, found MS 529.2([ M + H ] +)

N- (5-chloro-2-methyl-3- ((1- (tetrahydrofuran-2-carbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 45)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide hydrochloride (100mg,0.25mmol), tetrahydrofuran-2-carboxylic acid (29mg,0.25 mmol)l) and triethylamine (77mg,0.76mmol) were dissolved in N, N-dimethylformamide (5mL), and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (144mg,0.38mmol) was added at 0 ℃. The reaction mixture was stirred at room temperature overnight. Quenching the reaction with water, and extracting with ethyl acetate. The organic phases were combined and concentrated, and the residue was concentrated and purified by preparative high performance liquid chromatography to give N- (5-chloro-2-methyl-3- ((1- (tetrahydrofuran-2-carbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide 50mg, purity 95%, yield 40%, white solid.¹H NMR(400MHz,DMSO-d₆)10.26(s,1H),7.39(s,1H),7.35(s,1H),7.32(s,1H),7.07(s,1H),6.36(s,1H),4.73-4.65(m,1H),3.82-3.69(m,2H),3.65-3.55(m,4H),3.54-3.45(m,2H),2.44-3.35(m,1H),2.41-2.35(m,1H),2.34-2.27(m,1H),2.26-2.18(s,1H),2.17-2.10(m,1H), 2.07(s,3H),2.05-1.93(m,2H),1.91-1.75(m, 2H). Calculated MS value of 494.2 and found MS value of 495.2([ M + H ]]⁺)。

N- (5-chloro-3- ((1-isobutyrylpiperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 46)

N- (5-chloro-2-methyl-3- (piperidine-4-methylene) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide hydrochloride (100mg,0.25mmol), triethylamine (0.1mL) was dissolved in dichloromethane (5mL), isobutyryl chloride (0.03mL,0.3mmol) was added at 0 ℃. The reaction solution was stirred at 0 ℃ for half an hour. The reaction mixture was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1-isobutyrylpiperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide 35mg, purity 95%, yield 30%, and white solid.¹H NMR(400MHz,DMSO-d₆)10.26(s,1H),7.39(d,1H),7.35(d,1H),7.32(d,1H),7.08(s,1H),6.37(s,1H),3.60(s,3H),3.56-3.60(m,2H),3.44-3.48(m,2H),2.87-2.93(m,1H),2.12-2.39(m,4H),2.08(s,3H),1.01(d, 6H). Calculated MS 466.2, found MS 467.2([ M + H ]]⁺)。

N- (5-chloro-2-methyl-3- ((1- (3-methylbutyryl) piperidine-4-methylene) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 47)

N- (5-chloro-2-methyl-3- (piperidine-4-methylene) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide hydrochloride (100mg,0.25mmol), potassium carbonate (173mg,1.25mmol) in acetonitrile (5mL) and 3-methylbutyryl chloride (60mg,0.5mmol) at 0 ℃. The reaction solution was stirred at 0 ℃ for half an hour. The reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give 60mg of N- (5-chloro-2-methyl-3- ((1- (3-methylbutyryl) piperidine-4-methylene) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide, purity 95%, yield 50%, and white solid.¹H NMR(400MHz,DMSO-d₆)10.25(s,1H),7.39(d,1H),7.35(d,1H),7.32(s,1H),7.07(s,1H),6.36(s,1H),3.60(s,3H),3.55-3.56(m,2H),3.43-3.45(m,2H),2.35-2.37(m,1H),2.28-2.27(m,1H),2.20-2.25(m,3H),2.11-2.13(m,1H),2.08(s,3H),1.96-2.04(m,1H),0.91(t, 6H). Calculated MS 480.2, found MS 481.2([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (2-fluoro-2-methylpropanoyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 48)

2-fluoro-2-methylpropanoic acid (30mg,0.28mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (106mg,0.28mmol) and triethylamine (70mg,0.69mmol) were dissolved in dichloromethane (2mL) and stirred at room temperature for 10 minutes. N- (5-chloro-2-methyl-3- (piperidine-4-methylene) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide hydrochloride (100mg,0.23mmol) was then added and stirred at room temperature for one hour. The reaction mixture was poured into water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Concentrating the residue by preparative high performance liquid chromatographyPurification yielded N- (5-chloro-3- ((1- (2-fluoro-2-methylpropanoyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide 17mg, purity 95%, yield 15%, white solid.¹H NMR (400MHz, DMSO-d6)10.25(s,1H),7.39(d,1H),7.35(d,1H),7.32(s,1H),7.08(d,1H),6.37(s,1H),3.71-3.77(m,2H),3.60(s,3H),3.42-3.60(m,2H),2.39(s,2H),2.22(s,2H),2.08(s,3H),1.59(s,3H),1.53(s, 3H). Calculated MS 484.2, found MS 485.2([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (cyclobutylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 49)

N- (5-chloro-2-methyl-3- (piperidine-4-methylene) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide hydrochloride (100mg,0.25mmol), cyclobutylcarboxylic acid (25mg,0.25mmol), triethylamine (0.14mL,1mmol) dissolved in dichloromethane (5mL) was added 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (95mg,0.25mmol) at 0 ℃. The mixed reaction solution was stirred for one hour at room temperature. The reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give 88mg of N- (5-chloro-3- ((1- (cyclobutylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide, purity 95%, yield 73%, white solid.¹H NMR(400MHz,DMSO-d₆)10.25(s,1H),7.39(s,1H),7.35(s,1H),7.32(s,1H),7.06(s,1H),6.35(s,1H),3.60(s,3H),3.54-3.56(m,1H),3.28-3.41(m,4H),2.29-2.32(m,2H),2.07-2.16(m,6H),2.07(s,3H),1.85-1.96(m,1H),1.74-1.76(m, 1H). Calculated MS 478.2, found MS 479.3([ M + H ]]⁺)。

5-cyano-2-hydroxy-6-methylnicotinic acid ethyl ester

(E) -3-amino-2-enenitrile (8.2g,100mmol) and diethyl 2- (ethoxymethylene) malonate (21.6g,100mmol) were placed in a round-bottomed flask, stirred at 150 ℃ for 2 hours, and left to stand at room temperature overnight. The reaction solution was filtered. The filtered precipitate was washed with iced methanol to give 6.4g of ethyl 5-cyano-2-hydroxy-6-methylnicotinate in 31% yield as a yellow solid.

2-chloro-5-cyano-6-methylnicotinic acid ethyl ester

Ethyl 5-cyano-2-hydroxy-6-methylnicotinate (2g,9.7mmol) was dissolved in phosphorus oxychloride (15mL) and stirred at 106 ℃ overnight. After completion of the reaction, the reaction mixture was concentrated to remove phosphorus oxychloride, and the concentrated residue was diluted with water and extracted with dichloromethane (20 mL. times.4). The combined organic phases were concentrated and dried in vacuo to give the crude ethyl 2-chloro-5-cyano-6-methylnicotinate as a red oil.

5-cyano-6-methylnicotinic acid ethyl ester

Ethyl 2-chloro-5-cyano-6-methylnicotinate (2.79g,12.5mmol) was dissolved in methanol (50mL), and ammonium formate (12g,18.8mmol) and Pd/C (1g) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated. The concentrated residue was diluted with water and extracted with dichloromethane (50 mL. times.3). The organic phases were combined and concentrated, and the concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 5/1 vol.) to give 2g of ethyl 5-cyano-6-methylnicotinate in 84% yield as a white solid. 4- (5-chloro-3- (5-cyano-6-methylnicotinamide) -2-methylbenzylidene) piperidine-1-carboxylic acid tert-butyl ester

4- (3-amino-5-chloro-2-methylbenzylidene) piperidine-1-carboxylic acid tert-butyl ester (780mg,2.32mmol), ethyl 5-cyano-6-methylnicotinate (485mg,2.55mmol) were dissolved in anhydrous toluene (20mL) and trimethylaluminum (2.3mL, 2M/tolumene, 4.64mmol) was added at 0 ℃ under nitrogen. Reaction mixtureStirred at 80 ℃ for 3 hours. The reaction was quenched with ammonium chloride solution and extracted with ethyl acetate (20 mL. times.3). The organic phases were combined and concentrated, and the concentrated residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 2/1 vol.) to give 4- (5-chloro-3- (5-cyano-6-methylnicotinamide) -2-methylbenzylidene) piperidine-1-carboxylic acid tert-butyl ester 580mg, 53% yield, as a white solid. Calculated MS 480.2, found MS 481.2([ M + H ]]⁺)。

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -5-cyano-6-methylnicotinamide

Tert-butyl 4- (5-chloro-3- (5-cyano-6-methylnicotinamide) -2-methylbenzylidene) piperidine-1-carboxylate (580mg,1.21mmol) was dissolved in dichloromethane (6mL) and trifluoroacetic acid (3mL) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the concentrated residue was dissolved in water. After the pH of the sodium carbonate solution was adjusted to a value of more than 9, extraction was carried out with ethyl acetate. The organic phases were combined and concentrated to give N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -5-cyano-6-methylnicotinamide 440mg, 96% yield, as a white solid.

N- (5-chloro-3- ((1- (1-fluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -5-cyano-6-methylnicotinamide (compound 50)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -5-cyano-6-methylnicotinamide (38mg,0.29mmol), 1-fluorocyclopentylcarboxylic acid (38mg,0.29mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109mg,0.29mmol) was dissolved in N, N-dimethylformamide (3mL), and triethylamine (0.1mL,0.78mmol) was added at 0 ℃. The reaction solution was stirred for 2.5 hours at room temperature. Adding water to quench the reaction, and extracting with ethyl acetate. Combining the organic phases, concentrating, purifying the concentrated residue by silica gel column chromatography (petroleum ether/ethyl acetate: 1/1, volume ratio) to obtain N- (5-chloro-3- ((1- (1-fluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -30mg of 5-cyano-6-methylnicotinamide, 95% purity, 23% yield, white solid.¹H NMR(400MHz,DMSO-d₆)10.25(s,1H),9.20(s,1H),8.72(s,1H),7.40(s,1H),7.08(s,1H),6.39(s,1H),3.70-3.60(m,4H),2.77(s,3H),2.39(s,2H),2.17-2.30(m,4H),2.12(s,3H),1.98-2.07(m,2H),1.65-1.73(m, 4H). Calculated MS value of 494.2 and found MS value of 495.2([ M + H ]]⁺)。

(R) -N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-6-methylnicotinamide (Compound 51)

N- (5-chloro-2-methyl-3- (piperidine-4-methylene) phenyl) -5-cyano-6-methylnicotinamide (200mg,0.53mmol),3, 3-difluorocyclopentylcarboxylic acid (80mg,0.53mmol), triethylamine (0.2mL,1.59mmol) was dissolved in N, N-dimethylformamide (3mL), and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (200mg,0.53mmol) was added at 0 ℃. The reaction solution was stirred for 1.5 hours at room temperature. The reaction solution was concentrated, and the concentrated residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 1/1, vol.) to give a white solid. Chiral resolution of a white solid (column: AD-H-Hex (250 mm. times.4.6 mm 5 um); mobile phase: EtOH/DEA. times. 50/50 (v/v); flow rate: 1 mL/min; detection wavelength: UV 230 nm; column temperature: 30 ℃ C.) gave ((R) -N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-6-methylnicotinamide 23mg, purity 95%, yield 8%, as a white solid.¹H NMR(400MHz,DMSO-d₆)10.30(s,1H),9.20(d,1H),8.72(d,1H),7.40(d,1H),7.06(d,1H),6.39(s,1H),3.59(s,2H),3.48(s,2H),3.33-3.42(m,1H),2.77(s,3H),2.20-2.43(m,5H),2.13-2.16(m,2H),2.12(s,3H),1.99-2.08(m,2H),1.76-1.85(m, 1H). Calculated MS 512.2, found MS 513.2([ M + H ]]⁺)。

(S) -N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-6-methylnicotinamide (compound 52)

The procedure is as in example KLS1228 and chiral resolution gives 33mg of (S) -N- (5-chloro-3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-6-methylnicotinamide in 95% purity, 12% yield and as a white solid.¹H NMR(400MHz,DMSO-d₆)10.33(s,1H),9.21(d,1H),8.72(d,1H),7.41(d,1H),7.05(d,1H),6.38(s,1H),3.59(s,2H),3.48(s,2H),3.33-3.42(m,1H),2.77(s,3H),2.20-2.43(m,5H),2.13-2.16(m,2H),2.11(s,3H),1.99-2.08(m,2H),1.75-1.85(m, 1H). Calculated MS 512.2, found MS 513.2([ M + H ]]⁺)。

N- (5-chloro-3- ((1-isobutyrylpiperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-6-methylnicotinamide (Compound 53)

N- (5-chloro-2-methyl-3- (piperidin-4-methylene) phenyl) -5-cyano-6-methylnicotinamide (100mg,0.26mmol), triethylamine (0.1mL) was dissolved in dichloromethane (5mL) and isobutyryl chloride (0.03mL,0.31mmol) was added at 0 ℃. The reaction solution was stirred at 0 ℃ for half an hour. The reaction mixture was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1-isobutyrylpiperidin-4-ylidene) methyl) -2-tolyl) -5-cyano-6-methylnicotinamide 39mg, purity 95%, yield 33%, and white solid.¹H NMR(400MHz,DMSO-d₆)10.26(s,1H),9.20(d,1H),8.72(d,1H),7.40(d,1H),7.07(s,1H),6.38(s,1H),3.58(s,2H),3.47(s,2H),2.88-2.94(m,1H),2.77(s,3H),2.11-2.40(m,4H),2.12(s,3H),1.02(d, 6H). MS calculated value 450.2, MS found value 451.2([ M + H ]]⁺)。

N- (5-chloro-3- (1- (4, 4-difluoropiperidine-1-carbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 54)

4, 4-Difluoropiperidine hydrochloride (88mg,0.56mmol) was dissolved in dichloro-benzeneMethane (1mL) was added triethylamine (70mg,0.70 mmol). Triphosgene (166mg,0.56mmol) was added under nitrogen at 0 deg.C and stirred for 20 min. N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide hydrochloride (120mg,0.28mmol) was then dissolved in dichloromethane (1mL) and triethylamine (71mg,0.70mmol) was added. This mixture was then added dropwise to the previous reaction at 0 ℃ and stirred at room temperature for 3 hours. The reaction was quenched with water and extracted with dichloromethane (10 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- (1- (4, 4-difluoropiperidine-1-carbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide, 12mg, purity 95%, yield 8%, as a white solid.¹H NMR(400MHz,DMSO-d₆)10.25(s,1H),7.39(d,1H),7.34(d,1H),7.32(s,1H),7.06(d,1H),6.34(s,1H),3.60(s,3H),3.25-3.28(m,5H),3.18(t,2H),2.36(t,2H),2.20(t,2H),2.07(s,3H),1.94-2.01(m, 5H). Calculated MS value 543.2, found MS value 544.2([ M + H ]]⁺)

N- (5-chloro-3- ((1- (3, 3-difluoropyrrole-1-carbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzamide (Compound 55)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -3-cyanobenzamide hydrochloride (100mg,0.249mmol) and triphosgene (37mg,0.125mmol) were dissolved in methylene chloride (12mL) and triethylamine (0.2mL,1.42mmol) was slowly added to the reaction solution at 0 ℃ under nitrogen protection, followed by stirring for 30 minutes. Then, 3-difluoropyrrole hydrochloride (36mg,0.251mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (3, 3-difluoropyrrole-1-carbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzamide 25mg, purity 95%, yield 20%, and white solid.¹H NMR(400MHz,DMSO-d₆)10.20(s,1H),8.40(s,1H),8.26(d,1H),8.09(d,1H),7.77(t,1H),7.38(d,1H),7.06(d,1H),6.36(s,1H),3.71(t,2H),3.54(t,2H),332-3.30(m,2H),3.21-3.18(m,2H),2.38-2.32(m,4H),2.22(t,2H),2.11(s, 3H). MS calculated value of 498.2 and MS found value of 498.9([ M + H ]]⁺)。

N- (5-chloro-2-methyl-3- ((1- (tetrahydropyrrole-1-carbonyl) piperidin-4-ylidene) methyl) phenyl) -3-cyanobenzamide (compound 56)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -3-cyanobenzamide (60mg,0.16mmol) and tetrahydropyrrole-1-yl chloride (43mg,0.32mmol) were dissolved in anhydrous N, N-dimethylformamide (3mL), and triethylamine (0.1mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour under nitrogen. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic phases were combined, concentrated and the residue concentrated was purified by column chromatography on silica gel to give N- (5-chloro-2-methyl-3- ((1- (tetrahydropyrrole-1-carbonyl) piperidin-4-ylidene) methyl) phenyl) -3-cyanobenzamide 25mg, 95% purity, 34% yield and white solid.¹H NMR(400MHz,DMSO-d₆)10.19(s,1H),8.40(s,1H),8.26(d,1H),8.09(d,1H),7.77(t,1H),7.37(s,1H),7.06(s,1H),6.34(s,1H),3.28-3.31(m,6H),3.16(s,2H),2.36(s,2H),2.21(s,2H),2.11(s,3H),1.75(s, 4H). MS calculated: 462.2, MS found: 463.2([ M + H)]⁺)。

4- (5-chloro-3- (3-cyanobenzamide) -2-methylbenzylidene) piperidine-1-carboxylic acid isopropyl ester (Compound 57)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -3-cyanobenzamide (60mg,0.16mmol) and isopropoxycarbonyl chloride (39mg,0.32mmol) were dissolved in anhydrous N, N-dimethylformamide (3mL), and triethylamine (0.1mL) was added to the reaction mixture. The reaction mixture was stirred at 0 ℃ for 1 hour under nitrogen protection. Concentrating the reaction solution, purifying the concentrated residue by preparative high performance liquid chromatography to obtain 30mg of isopropyl 4- (5-chloro-3- (3-cyanobenzamide) -2-methylbenzylidene) piperidine-1-carboxylate with purity of 95%, yield of 42%, and whiteA colored solid.¹H NMR(400MHz,DMSO-d₆)10.19(s,1H),8.40(s,1H),8.26(d,1H),8.08(d,1H),7.77(t,1H),7.37(s,1H),7.06(s,1H),6.37(s,1H),4.79(m,1H),3.48(s,2H),3.36(s,2H),2.33(s,2H),2.18(s,2H),2.10(s,3H),1.20(d, 6H). MS calculated: 451.2, MS found: 452.0([ M + H)]⁺)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzenesulfonamide (compound 58)

3-Cyanobenzenesulfonyl chloride (73mg,0.362mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (73mg,0.219mmol) were dissolved in pyridine (6mL) and stirred at room temperature under nitrogen overnight. Washed twice with hydrochloric acid (10mL,1 mol/L). The organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give 31mg of N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3-cyanobenzenesulfonamide in 95% purity, 28% yield and as a white solid.¹H NMR(400MHz,DMSO-d₆)10.09(s,1H),8.18(d,1H),8.02(s,1H),7.95(s,1H),7.84-7.80(m,1H),7.03(s,1H),6.89(s,1H),6.23(s,1H),3.58-3.55(m,2H),3.45-3.42(m,2H),3.06-2.95(m,1H),2.32-2.21(m,2H),2.08-1.98(m,2H),1.78(s,3H),1.77-1.53(m, 8H). Calculated MS value is 497.2, and found MS value is 498.1([ M + H ]]⁺)。

1- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3- (pyridin-2-yl) urea (compound 59)

(4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (99mg,0.297mmol) and triethylamine (0.3mL,2.13mmol) were dissolved in dichloromethane (6mL), and triphosgene (44mg,0.148mmol) was added to the reaction solution. The reaction mixture was stirred for 30 minutes at 0 ℃ under nitrogen. Then pyridin-2-amine (28mg,0.298mmol) was added and the reaction was stirred for an additional 2 hours at 0 ℃. Reaction ofThe solution was concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give 25mg of 1- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -3- (pyridin-2-yl) urea in 95% purity, 19% yield and as an off-white solid.¹H NMR(400MHz,DMSO-d₆)11.23(br,1H),9.92(s,1H),8.28(d,1H),8.12(s,1H),7.78(t,1H),7.27(d,1H),7.03(t,1H),6.83(s,1H),6.37(s,1H),3.60-3.57(m,2H),3.49-3.46(m,2H),3.05-2.96(m,1H),2.37-2.07(m,4H),2.21(s,3H),1.77-1.52(m, 8H). Calculated MS 452.2, found MS 453.1([ M + H ]]⁺)。

6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxylic acid methyl ester

Methyl 6-cyano-2-oxo-1, 2-dihydropyridine-4-carboxylate (1.0g,5.65mmol), iodoethane (2.5mL,31.2mmol) and potassium carbonate (2.3g,16.6mmol) were dissolved in N, N-dimethylformamide (30mL) and stirred overnight at 50 ℃ under nitrogen. The reaction solution was concentrated. The concentrated residue was dissolved in aqueous ethanol (20mL, volume ratio 1: 1). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 mL. times.2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 50/1-10/1, vol.) to give methyl 6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxylate 200mg, 17% yield, as an off-white solid.¹H NMR(400MHz,DMSO-d₆):7.38(d,1H),7.21(d,1H),4.11(q,2H),3.87(s,3H),1.27(t,3H)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 60)

(4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (98mg,0.294mmol) was dissolved in toluene (10mL) and a solution of trimethylaluminum (0.4mL,0.800mmol) in toluene was added slowly at 0 ℃ under nitrogen. However, the device is not suitable for use in a kitchenThen methyl 6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxylate (60mg,0.293mmol) was added. The reaction solution was stirred at 80 ℃ for 4 hours and then cooled to room temperature. The reaction was quenched by the addition of hydrochloric acid (10mL,1 mol/L). Extraction was performed with ethyl acetate (10 mL. times.2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxamide 60mg, purity 95%, yield 40%, as a white solid.¹H NMR(400MHz,DMSO-d₆)10.26 (d,1H),7.43(d,1H),7.35(d,1H),7.32(d,1H),7.07(dd,1H),6.36(s,1H),4.13(q,2H),3.59-3.53(m,2H),3.48-3.44(m,2H),3.05-2.97(m,1H),2.38-2.10(m,4H),2.08(s,3H),1.77-1.51(m,8H),1.29(t, 3H). MS calculated value 506.2, MS found value 507.2([ M + H ]]⁺)。

4- (5-chloro-3- (6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxamide) -2-methylbenzylidene) piperidine-1-carboxylic acid tert-butyl ester

Methyl 6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxylate (366mg,1.78mmol) was dissolved in toluene (20mL) and trimethylaluminum (2.4mL,4.80mmol) was added slowly at 0 deg.C under nitrogen. Tert-butyl 4- (3-amino-5-chloro-2-methylbenzylidene) piperidine-1-carboxylic acid tert-butyl ester (598mg,1.78mmol) was then added, the reaction mixture was stirred at 80 ℃ for 4 hours, then cooled to room temperature, and the reaction was quenched by addition of hydrochloric acid (15mL,1 mol/L). Extraction was performed with ethyl acetate (20 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 3/1, vol.) to give 347mg of tert-butyl 4- (5-chloro-3- (6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxamide) -2-methylbenzylidene) piperidine-1-carboxylate in 38% yield as a white solid.¹H NMR(400MHz,DMSO-d₆):10.24(s,1H),7.42(d,1H),7.35(d,1H),7.32(d,1H),7.07(d,1H),6.35(s,1H),4.13(q,2H),3.46-3.40(m,2H),3.34-3.31(m,2H),2.35-2.28(m,2H),2.16-2.13(m,2H),2.07(s,3H),1.41(s,9H),1.29(t,3H)。

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -1-ethyl-6-oxo-1, 6-dihydropyridazine-4-carboxamide

Tert-butyl 4- (5-chloro-3- (6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxamide) -2-methylbenzylidene) piperidine-1-carboxylate (347mg,0.682mmol) was dissolved in trifluoroacetic acid dichloromethane (20mL, volume ratio: 1/4) and stirred at room temperature for 3 hours. The reaction solution was concentrated, and the concentrated residue was used directly in the next reaction.

N- (5-chloro-3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 61)

2-Cyclopropylacetic acid (22mg,0.220mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (100mg,0.263mmol) and N, N-diisopropylethylamine (0.2mL,1.11mmol) were dissolved in N, N-dimethylformamide (6mL), and the reaction was stirred at room temperature for 30 minutes under a liquid nitrogen atmosphere. Then N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (crude, 0.216mmol) was added and the reaction mixture was stirred at 50 ℃ for 2 hours. The reaction mixture was concentrated, and the concentrated residue was dissolved in an aqueous ethanol solution (20mL, volume ratio 1: 1). The organic phase was separated, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxamide 40mg, purity 95%, yield 38%, white solid.¹H NMR(400MHz,d6-DMSO):10.24(s,1H),7.42(s,1H),7.35(d,1H),7.32(d,1H),7.07(s,1H),6.36(s,1H),4.13(q,2H),3.56-3.52(m,2H),3.45-3.41(m,2H),2.38-2.34(m,1H),2.32-2.26(m,3H),2.24-2.18(m,1H),2.14-2.10(m,1H),2.08(s,3H),1.29(t,3H),0.98-0.96(m,1H),0.46-0.43(m,2H)0.13-0.11(m, 2H). Calculated MS 492.2, found MS 493.0([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (2-cyclobutylacetyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 62)

2-cyclobutyl acetic acid (105mg,0.920mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (409mg,1.08mmol) and N, N-diisopropylethylamine (0.7mL,3.97mmol dissolved in N, N-dimethylformamide (8mL) were stirred at room temperature under the protection of liquid nitrogen for 30 minutes, then N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (crude product, 0.444mmol) was added, the reaction mixture was stirred at 50 ℃ for 2 hours, the reaction mixture was concentrated, the concentrated residue was dissolved in an aqueous ethanol solution, the organic phase was separated, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (2-cyclobutylacetyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -6-cyano-1-ethyl-2-oxo-1, 2-dihydropyridine-4-carboxamide 70mg, purity 95%, yield 31%, white solid.¹H NMR(400MHz,DMSO-d₆)10.24(s,1H), 7.43(d,1H),7.35(d,1H),7.32(d,1H),7.07(d,1H),6.36(s,1H),4.13(q,2H),3.53-3.51(m,2H),3.44-3.39(m,2H),2.65-2.55(m,1H),2.46(d,2H),2.40-2.35(m,1H),2.30-2.25(m,1H),2.26-2.18(m,1H),2.13-2.08(m,1H),2.07(s,3H),2.08-2.02(m,2H),1.85-1.75(m,2H),1.70-1.60(m,2H),1.29(t, 3H). MS calculated value 506.2, MS found value 507.0([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -5-cyano-6-methylnicotinamide (Compound 63)

5-cyano-6-methylnicotinic acid ethyl ester (68mg,0.36mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (120mg,0.36mmol) was dissolved in toluene (5mL) and stirred at 0 ℃ under nitrogen. Then trimethylaluminum (0.40mL,0.72mmol) was added. The reaction mixture was stirred at 80 ℃ for 3 hours. The reaction was quenched with ammonium chloride solution and extracted with ethyl acetate (20 mL. times.3). The organic phases were combined and concentrated, and the concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -5-cyano-6-methylnicotinamide 103mg, purity 95%, yield 60%, as a yellow solid.¹H NMR(400MHz,DMSO-d₆)10.28(s,1H), 9.20(s,1H),8.73(s,1H),7.40(s,1H),7.08(d,1H),6.38(s,1H),3.59-3.57(m,2H),3.48-3.45(m,2H),3.05-2.97(m,1H),2.77(s,3H),2.38-2.10(m,4H),2.07(s,3H),1.76-1.51(m, 8H). MS calculated 476.2 and MS found 477.0([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (2-cyclopropaneacetyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -5-cyano-6-methylnicotinamide (Compound 64)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -5-cyano-6-methylnicotinamide (100mg,0.26mmol), 2-cyclopropylacetic acid (52mg,0.52mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109mg,0.286mmol) was dissolved in N, N-dimethylformamide (3mL), and triethylamine (0.1mL) was added to the reaction solution. The reaction mixture was stirred at 50 ℃ for 1 hour under nitrogen protection. The reaction solution was concentrated, and the concentrated residue was purified by silica gel column chromatography (100% ethyl acetate) to give N- (5-chloro-3- ((1- (2-cyclopropaneacetyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -5-cyano-6-methylnicotinamide 80mg, purity 95%, yield 66%, and white solid.¹H NMR(400MHz,DMSO-d₆)10.27(s,1H), 9.20(d,1H),8.72(d,1H),7.40(d,1H),7.07(s,1H),6.38(s,1H),3.53-3.57(m,2H),3.41-3.46(m,2H),2.77(s,3H),3.36-3.38(m,1H),2.72-2.32(m,2H),2.72-2.32(m,1H),2.21-2.23(m,1H),2.13-2.15(m,1H),2.11(s,3H),0.94-0.97(m,1H),0.44-0.47(m,2H),0.12(t, 2H). MS calculated 462.2, MS found 463.2([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (2-cyclobutylacetyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -5-cyano-6-methylnicotinamide (Compound 65)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -5-cyano-6-methylnicotinamide (100mg,0.26mmol), 2-cyclobutylacetic acid (59mg,0.52mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109mg,0.286mmol) was dissolved in N, N-dimethylformamide (3mL), and triethylamine (0.1mL) was added to the reaction solution. The reaction mixture was stirred at 50 ℃ for 1 hour under nitrogen protection. The reaction solution was concentrated, and the concentrated residue was purified by silica gel column chromatography (100% ethyl acetate) to give N- (5-chloro-3- ((1- (2-cyclobutylacetyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -5-cyano-6-methylnicotinamide 70mg, purity 95%, yield 56%, and white solid.¹H NMR(400MHz,DMSO-d₆)10.27(s,1H), 9.20(s,1H),8.72(s,1H),7.40(s,1H),7.07(s,1H),6.37(s,1H),3.50-3.56(m,2H),3.39-3.40(m,2H),2.77(s,3H),2.57-2.62(m,1H),2.45-2.50(m,2H),2.36-2.34(m,1H),2.26-2.29(m,1H),2.21-2.23(m,1H),2.11-2.15(m,1H),2.11(s,3H),2.02-2.05(m,2H),1.77-1.83(m,2H),1.62-1.68(m, 2H). MS calculated 476.2 and MS found 477.2([ M + H ]]⁺)。

N- (5-chloro-3- ((1- (4, 4-difluorocyclohexylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -5-cyano-6-methylnicotinamide (Compound 66)

N- (5-chloro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) -5-cyano-6-methylnicotinamide (100mg,0.26mmol), 4, 4-difluorocyclohexanecarboxylic acid (85mg,0.52mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (296mg,0.78mmol) was dissolved in N, N-dimethylformamide (2mL), and triethylamine (0.1mL,0.78mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. Concentrating the reaction solution, purifying the concentrated residue by preparative high performance liquid chromatography to obtain N- (5-chloro-3- ((1- (4, 4-difluorocyclohexylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) -5-cyano-6-methylnicotinamide 60mg, purity 95%, yield 44%, white solid.¹H NMR(400MHz,DMSO-d₆)10.27(s,1H), 9.20(s,1H),8.72(s,1H),7.40(s,1H),7.09(d,1H),6.39(s,1H),3.64-3.60(m,1H),3.60-3.54(m,1H),3.54-3.50(m,1H),3.48-3.42(m,1H),2.89-2.80(m,1H),2.77(s,3H),2.41-2.39(m,1H),2.32-2.30(m,1H),2.25-2.24(m,1H),2.15-2.13(m,1H),2.11(s,3H),2.08-1.70(m,6H),1.63-1.54(m, 2H). Calculated MS 526.1 and found MS 527.2([ M + H ]]⁺)。

2-chloro-6-methoxyisonicotinic acid

2, 6-Dichloroisonicotinic acid (2.0g,10.4mmol) was dissolved in methanol (20mL) and 33% strength sodium hydroxide solution (9.0g,75.0mmol) was added slowly at 0 ℃. The reaction solution was stirred at 70 ℃ for 3 hours and then cooled to room temperature. The pH was adjusted to3 with hydrochloric acid (1 mol/L). The precipitate was filtered off, washed with hydrochloric acid (1mol/L), and dried to give 1.7g of 2-chloro-6-methoxyisonicotinic acid in 81% yield as a white solid.¹HNMR(400MHz,DMSO-d₆):13.86(br s,1H),7.40(d,1H),7.19(d,1H),3.90(s,3H)。

2-chloro-6-methoxyisonicotinic acid methyl ester

2-chloro-6-methoxyisonicotinic acid (1.7g,9.09mmol) was dissolved in methanol (20mL) and thionyl chloride (4.0mL,55.0mmol) was added slowly at 0 ℃. The reaction was stirred at 50 ℃ for 4 hours under the protection of liquid nitrogen and then concentrated. The concentrated residue was purified by silica gel column chromatography (dichloromethane/methanol 100/1 vol.) to give methyl 2-chloro-6-methoxyisonicotinate 1.3g in 72% yield as a white solid.¹HNMR(400MHz,DMSO-d₆):7.43(s,1H),7.21(s,1H),3.91(s,3H),3.86(s,3H)。

6-chloro-2-oxo-1, 2-dihydropyridine-4-carboxylic acid methyl ester

Methyl 2-chloro-6-methoxyisonicotinate (209mg,1.04mmol) and sodium iodide (476mg,3.18mmol) were dissolved in thionyl chloride (8mL) and trimethylchlorosilane (0.4mL,3.16mmol) was added dropwise to the reaction at 0 ℃ under nitrogen. The reaction mixture was stirred at 80 ℃ for 4 hours and then cooled to room temperature. The reaction was quenched with 10mL of water. The organic phase was washed with saturated sodium thiosulfate, dried over anhydrous sodium sulfate, and concentrated. The concentrated residue was purified by silica gel column chromatography (dichloromethane/methanol 100/1 vol.) to give methyl 6-chloro-2-oxo-1, 2-dihydropyridine-4-carboxylate 150mg in 77% yield as a white solid.¹HNMR(400MHz,DMSO-d₆):12.07(s,1H),7.29(s,1H),7.03(s,1H),3.87(s,3H)。

6-chloro-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxylic acid methyl ester

Methyl 6-chloro-2-oxo-1, 2-dihydropyridine-4-carboxylate (140mg,0.749mmol), sodium iodide (0.2mL,2.73mmol) and potassium carbonate (310mg,2.24mmol) were dissolved in N, N-dimethylformamide (10mL) and stirred overnight at 50 ℃ under nitrogen. The reaction solution was concentrated. The concentrated residue was purified by silica gel column chromatography (dichloromethane/methanol 100/1 vol.) to give methyl 6-chloro-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxylate 64mg in 43% yield as a white solid.

6-chloro-N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 67)

Methyl 6-chloro-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxylate (57mg,0.284mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (94mg,0.282mmol) were dissolved in toluene (10mL) and trimethylaluminum (0.3mL,0.600mmol) was slowly added to the reaction under nitrogen at 0 ℃. Reaction solution 80Stir overnight at rt, then cool to room temperature. The reaction was quenched with hydrochloric acid (1mol/L,5 mL). Extraction was performed with ethyl acetate (10 mL. times.2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give 6-chloro-N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide, 50mg, purity 95%, yield 35%, as a white solid.¹HNMR(400MHz,DMSO-d₆)10.19 (d,1H),7.33(d,1H),7.07(d,1H),6.98(d,1H),6.84(d,1H),6.36(s,1H),3.61(s,3H),3.58-3.56(m,2H),3.48-3.44(m,2H),3.05-2.95(m,1H),2.38-2.11(m,4H),2.07(s,3H),1.77-1.51(m, 8H). MS calculated 501.2 and MS found 502.2([ M + H ]]⁺)。

6-oxo-1, 6-dihydropyridazine-4-carboxylic acid methyl ester

6-oxo-1, 6-dihydropyridazine-4-carboxylic acid (209mg,1.49mmol) was dissolved in methanol (10mL) and thionyl chloride (2.0mL) was added slowly at 0 ℃. The reaction was stirred at 50 ℃ for 5 hours under a blanket of liquid nitrogen and then concentrated. The concentrated residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 10/1 vol.) to give 172mg of methyl 6-oxo-1, 6-dihydropyridazine-4-carboxylate in 75% yield as an off-white solid.¹HNMR(400MHz,DMSO-d₆):13.47(brs,1H),8.16-8.15(m,1H),7.27(d,1H),3.88(s,3H)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-oxo-1, 6-dihydropyridazine-4-carboxamide (Compound 68)

Methyl 6-oxo-1, 6-dihydropyridazine-4-carboxylate (45mg,0.292mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (98mg,0.294mmol) were dissolved in toluene (10mL) and, under nitrogen, a trimethylaluminum toluene solution (0.3mL,0.600mmol) was added slowly at 0 ℃. The reaction mixture was stirred at 80 ℃ for 4 hours and then cooled to room temperature. Quenching with hydrochloric acid (1mol/L,4mL)The reaction was quenched and extracted with ethyl acetate (10 mL. times.2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give 15mg of N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-oxo-1, 6-dihydropyridazine-4-carboxamide, purity 95%, yield 11%, as a white solid.¹HNMR(400MHz,DMSO-d₆) 13.35(brs,1H),10.29(brs,1H),8.18(d,1H),7.39(d,1H),7.37(d,1H),7.10(d,1H),6.36(s,1H),3.61(s,3H),3.59-3.57(m,2H),3.48-3.44(m,2H),3.05-2.97(m,1H),2.38-2.11(m,4H),2.10(s,3H),1.77-1.51(m, 8H). Calculated MS 454.2, found MS 455.2([ M + H ]]⁺)。

2-cyano-6-methoxyisonicotinic acid methyl ester

Methyl 2-chloro-6-methoxyisonicotinate (8.5g,42.3mmol), zinc cyanide (6.0g,51.1mmol) and tetrakis (triphenylphosphine) palladium (4.9g,4.24mmol) were dissolved in N, N-dimethylformamide (200mL) and stirred under nitrogen at 90 ℃ overnight. The reaction solution was concentrated, and the concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 50/1, vol.) to give methyl 2-cyano-6-methoxyisonicotinate 6.0g in 74% yield as a white solid.¹HNMR(400MHz,CDCl₃):7.99(s,1H),7.55(s,1H),3.96(s,3H),3.91(s,3H)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -2-cyano-6-methoxyisonicotinamide (compound 69)

Methyl 2-cyano-6-methoxyisonicotinate (50mg, 0.262mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (87mg,0.261mmol) were dissolved in toluene (5mL) and a solution of trimethylaluminum in toluene (0.2mL,0.400mmol) was added slowly at 0 ℃ under nitrogen. The reaction mixture was stirred at 80 ℃ for 3 hours and then cooled to room temperature. The reaction was quenched with hydrochloric acid (1mol/L,3mL) and extracted with ethyl acetate (10 mL. times.2).The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -2-cyano-6-methoxyisonicotinamide 40mg, purity 95%, yield 31%, as a white solid.¹HNMR(400MHz,DMSO-d₆) 10.35(s,1H),8.07(s,1H),7.65(s,1H),7.39(d,1H),7.09(d,1H),6.37(s,1H),3.98(s,3H),3.60-3.56(m,2H),3.48-3.44(m,2H),3.05-2.97(m,1H),2.38-2.11(m,4H),2.10(s,3H),1.77-1.51(m, 8H). Calculated MS 492.2, found MS 493.0([ M + H ]]⁺)。

6-cyano-2-oxo-1, 2-dihydropyridine-4-carboxylic acid methyl ester

Methyl 2-cyano-6-methoxyisonicotinate (4.9g,25.6mmol) and sodium iodide (12.0g,80.0mmol) were dissolved in acetonitrile (100mL) and trimethylchlorosilane (10mL,78.9mmol) was added slowly at 0 ℃ under nitrogen. The reaction mixture was stirred at 80 ℃ for 4 hours and then cooled to room temperature. Water (100mL) was added, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated residue was purified by silica gel column chromatography (dichloromethane/methanol 100/1 vol.) to give methyl 6-cyano-2-oxo-1, 2-dihydropyridine-4-carboxylate 3.0g in 67% yield as a white solid.¹HNMR(400MHz,DMSO-d₆):12.42(brs,1H),7.80(s,1H),7.34(s,1H),3.90(s,3H)。

N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 70)

Methyl 6-cyano-2-oxo-1, 2-dihydropyridine-4-carboxylate (42mg,0.237mmol) and (4- (3-amino-5-chloro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (79mg,0.237mmol) were dissolved in toluene (10mL) and trimethylaluminum in toluene (0.2mL,0.400mmol) was added slowly at 0 ℃ under nitrogen. The reaction mixture was stirred at 80 ℃ for 3 hours and then cooled to room temperatureAnd (4) warming. The reaction was quenched with hydrochloric acid (1mol/L,3mL) and extracted with ethyl acetate (10 mL. times.2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give N- (5-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-tolyl) -6-cyano-2-oxo-1, 2-dihydropyridine-4-carboxamide, 10mg, purity 95%, yield 9%, as a white solid.¹HNMR(400MHz,DMSO-d₆)10.26 (brs,1H),7.78(s,1H),7.37(s,2H),7.08(d,1H),6.37(s,1H),3.60-3.57(m,2H),3.47-3.42(m,2H),3.05-2.97(m,1H),2.38-2.11(m,4H),2.09(s,3H),1.77-1.51(m, 8H). Calculated MS 478.2, found MS 479.2([ M + H ]]⁺)。

4- (Bromomethylene) piperidine-1-carboxylic acid tert-butyl ester

Lithium hexamethyldisilazane (1M,11mL) was added dropwise to a suspension of bromomethyltriphenylphosphine bromide (4.8g,11mmol) in tetrahydrofuran (11mL) at-15 ℃ under argon. After stirring for 15 min, 4-oxopiperidine-1-carboxylic acid tert-butyl ester (1.99g,10mmol) was added at-15 ℃. The reaction mixture was stirred at room temperature for 2 hours, quenched with water, extracted with ethyl acetate (30mL × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:50 to 1:10) gave 1.6g of tert-butyl 4- (bromomethylene) piperidine-1-carboxylate as a colorless oil in 59% yield.¹H NMR(400MHz,CDCl₃)5.99(t,1H),3.46-3.36(m,4H),2.41-2.35(m,2H),2.27-2.19(m,2H),1.46(s,9H)。

5-fluoro-2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline

To a solution of 3-bromo-5-fluoro-2-methylaniline (1g,4.9mmol), pinacol diboron (1.5g,6mmol) and potassium acetate (735mg,7.5mmol) in dioxane (30mL) under argon atmosphere was added [1,1' -bis (hydroxymethyl) aniline(diphenylphosphino) ferrocene]Palladium dichloride (220mg,0.3 mmol). The reaction solution was stirred at 100 ℃ overnight, and then solid impurities were filtered off, followed by purification by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:20 → 1:5) to give 1.07g of 5-fluoro-2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline as a yellow solid with a yield of 87%. LC-MS 252.0[ M + H ]⁺]

4- (3-amino-5-fluoro-2-methylbenzylidene) piperidine-1-carboxylic acid tert-butyl ester

To a solution of 5-fluoro-2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (126mg,0.5mmol), tert-butyl 4- (bromomethylene) piperidine-1-carboxylate (165mg,0.6mmol) and saturated sodium carbonate solution (100 μ L) in dioxane (10mL) under argon was added [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (37mg,0.05 mmol). The reaction mixture was stirred at 90 ℃ overnight, solid impurities were filtered off, and the reaction mixture was concentrated under reduced pressure. The resultant mixture was purified by preparative thin layer chromatography (ethyl acetate: petroleum ether ═ 1:4) to give tert-butyl 4- (3-amino-5-fluoro-2-methylbenzylidene) piperidine-1-carboxylate as a colorless oil 80mg in 50% yield. LC-MS 265.1[ M-^tBu+H⁺]

4- (3- (3-Cyanobenzoylamino) -5-fluoro-2-methylbenzylidene) piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4- (3-amino-5-fluoro-2-methylbenzylidene) piperidine-1-carboxylate (80mg,0.25mmol), 3-cyanobenzoic acid (44mg,0.3mmol) and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (143mg,0.375mmol) in dichloromethane (4mL) was added diisopropylethylamine (124. mu.L, 0.75 mmol). The reaction mixture was stirred at room temperature overnight and then directly concentrated under reduced pressure and purified by preparative thin layer chromatography (ethyl acetate: petroleum ether ═ 1:4) to give 99mg of tert-butyl 4- (3- (3-cyanobenzoylamino) -5-fluoro-2-methylbenzylidene) piperidine-1-carboxylate as a white solid in 88% yield.LC-MS:394.2[M-^tBu+H⁺]3-cyano-N- (5-fluoro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) benzamide trifluoroacetate salt

Trifluoroacetic acid (1mL) was added to a solution of tert-butyl 4- (3- (3-cyanobenzoylamino) -5-fluoro-2-methylbenzylidene) piperidine-1-carboxylate in dichloromethane (5mL) and stirred at room temperature for 4 hours. The mixture was directly concentrated under reduced pressure to give a crude product of 3-cyano-N- (5-fluoro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) benzamide trifluoroacetate as a colorless oil (100 mg). LC-MS 350.2[ M + H ]⁺]

3-cyano-N- (3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -5-fluoro-2-methylphenyl) benzamide (compound 71)

Cyclopentylcarbonyl chloride (63. mu.L, 0.52mmol) was added to a solution of 3-cyano-N- (5-fluoro-2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) benzamide trifluoroacetate (100mg) and triethylamine (109. mu.L, 0.78mmol) in dichloromethane (5 mL). The reaction solution was stirred at room temperature for 2 hours, then directly concentrated and purified by preparative thin layer chromatography (ethyl acetate: petroleum ether ═ 1:2) to give 35.1mg of 3-cyano-N- (3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -5-fluoro-2-methylphenyl) benzamide as a pale yellow solid with a yield of 30%.¹H NMR(400MHz,CD₃OD)8.32(s,1H),8.25(d,1H),7.96(d,1H),7.73(t,1H),7.11(dd,1H),6.88-6.80(m,1H),6.42(s,1H),3.70(dd,2H),3.57(dd,J＝11.3,5.3Hz,2H),3.16-3.03(m,1H),2.49-2.23(m,4H),2.16(s,3H),1.91-1.57(m,8H)。LC-MS:446.2[M+H⁺]

3-bromo-2-chloro-aniline

1-bromo-2-chloro-3-nitrobenzene (1g,4.23mmol), iron powder (1.2g,21.5 mmol) were addedl) and ammonium chloride (228mg,4.3mmol) were added to ethanol and water (3mL/1.5 mL). The mixture was stirred at 60 ℃ for 2 hours. The reaction solution was filtered to remove solids, and the residue was concentrated under reduced pressure and dissolved in ethyl acetate, washed with water and brine, respectively, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give 0.824g of 3-bromo-2-chloro-aniline as a brown oil in 93% yield. LC-MS 205.9[ M + H ]⁺]

2-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline

To a solution of 3-bromo-2-chloroaniline (0.5g,2.4mmol), pinacol diboron (0.62g,2.4mmol) and potassium acetate (470mg,4.8mmol) in dioxane (10mL) under argon atmosphere was added [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (88mg,0.12 mmol). The reaction solution was stirred at 100 ℃ overnight, and then solid impurities were filtered off, and purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:20 → 1:5) to obtain 0.48g of 2-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline as a white solid in a yield of 79%. LC-MS 254.1[ M + H ]⁺]

4- (3-amino-2-chlorobenzylidene) piperidine-1-carboxylic acid tert-butyl ester

To a solution of 2-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (202mg,0.8mmol), 4- (bromomethylene) piperidine-1-carboxylic acid tert-butyl ester (264mg,0.96mmol) and saturated potassium carbonate solution (150. mu.L) in dioxane (10mL) under argon was added [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (59mg,0.08 mmol). The reaction mixture was stirred at 90 ℃ overnight, solid impurities were filtered off, and the reaction mixture was concentrated under reduced pressure. The resultant mixture was purified by preparative thin layer chromatography (ethyl acetate: petroleum ether ═ 1:4) to give 150mg of tert-butyl 4- (3-amino-2-chlorobenzylidene) piperidine-1-carboxylate as a white solid in 58% yield. LC-MS 267.1[ M-^tBu+H⁺]

4- (2-chloro-3- (3-cyanobenzoylamino) benzylidene) piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4- (3-amino-2-chlorobenzylidene) piperidine-1-carboxylate (150mg,0.47mmol), 3-cyanobenzoic acid (82mg,0.56mmol) and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (268mg,0.71mmol) in dichloromethane (8mL) was added diisopropylethylamine (233. mu.L, 1.41 mmol). The reaction mixture was stirred at room temperature overnight and then directly concentrated under reduced pressure and purified by preparative thin layer chromatography (ethyl acetate: petroleum ether ═ 1:4) to give 91mg of tert-butyl 4- (2-chloro-3- (3-cyanobenzoylamino) benzylidene) piperidine-1-carboxylate as a white solid in 43% yield. LC-MS 396.1[ M-^tBu+H⁺]

N- (2-chloro-3- (piperidin-4-ylidenemethyl) phenyl) -3-cyanobenzamide trifluoroacetate salt

Trifluoroacetic acid (1mL) was added to a solution of tert-butyl 4- (2-chloro-3- (3-cyanobenzoylamino) benzylidene) piperidine-1-carboxylate in dichloromethane (5mL) and stirred at room temperature for 4 hours. The mixture was directly concentrated under reduced pressure to give 93mg of a crude colorless oily N- (2-chloro-3- (piperidin-4-ylidenemethyl) phenyl) -3-cyanobenzamide trifluoroacetate salt. LC-MS 352.1[ M + H ]⁺]

N- (2-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) phenyl) -3-cyanobenzamide (Compound 72)

Cyclopentylcarbonyl chloride (73. mu.L, 0.6mmol) was added to a solution of N- (2-chloro-3- (piperidin-4-ylidenemethyl) phenyl) -3-cyanobenzamide trifluoroacetate (93mg) and diisopropylethylamine (100mg,0.78mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 2 hours and then directly concentrated to prepare a thin layer colorPurification by chromatography (ethyl acetate: petroleum ether ═ 1:2) afforded N- (2-chloro-3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) phenyl) -3-cyanobenzamide as a pale yellow solid, 24mg in 27% yield.¹H NMR(400MHz,CD₃OD)8.34-8.22(m,2H),7.95(d,1H),7.71(t,1H),7.63(d,1H),7.32(t,1H),7.19(d,1H),6.43(s,1H),3.73-3.63(m,2H),3.55(d,2H),3.14-3.00(m,1H),2.38(tt,4H),1.95-1.53(m,8H)。LC-MS:448.2[M+H⁺]

2-methyl-3-nitrobenzyl alcohol

To a solution of methyl 2-methyl-3-nitrobenzoate (1.95g,10mmol) in tetrahydrofuran (10mL) was added sodium borohydride (1.52g,40mmol) at room temperature. The mixture was refluxed for 3 hours, then methanol (5mL) was added and the mixture was refluxed for 4 hours and stirred at room temperature overnight. Quenched by addition of water (20mL), extracted with ethyl acetate (30 mL. times.3), washed with saturated brine and concentrated to give 2-methyl-3-nitrobenzyl alcohol 1.4g as a yellow solid in 84% yield.

2-methyl-3-nitrobenzyl bromide

A solution of phosphorus tribromide (1.88mL,20mmol) in dichloromethane (20mL) was added dropwise to a solution of 2-methyl-3-nitrobenzyl alcohol (1.4g,8.38mmol) in dichloromethane (15mL) at 0 ℃. The reaction solution was returned to room temperature and stirred for 3 hours, and then the reaction was quenched with water at 0 ℃, extracted with dichloromethane (30mL × 3), washed with saturated potassium carbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.6g of 2-methyl-3-nitrobenzyl bromide as a yellow oil in 83% yield.

(2-methyl-3-nitrobenzyl) triphenylphosphonium bromide

2-methyl-3-nitrobenzyl bromide (900mg,3.9mmol) and triphenylphosphine under argon(1g,3.9mmol) was dissolved in toluene (15 mL). The mixture was stirred at 110 ℃ for 4 hours, then cooled to 0 ℃ and filtered to obtain 1.7g of (2-methyl-3-nitrobenzyl) triphenylphosphonium bromide as a white solid with a yield of 89%. LC-MS 412.2[ M + H ]⁺]

4- (2-methyl-3-nitrobenzylidene) piperidine-1-carboxylic acid tert-butyl ester

Lithium hexamethyldisilazane (1M,1.1mL) was added to (2-methyl-3-nitrobenzyl) triphenylphosphonium bromide (491mg,1mmol) in tetrahydrofuran (3mL) at-15 ℃ under argon. After stirring for 15 minutes, a tetrahydrofuran solution of tert-butyl 4-oxopiperidine-1-carboxylate (199mg,1mmol) was added to the reaction mixture at-15 ℃ under argon protection, the mixture was allowed to return to room temperature and stirred for 2 hours, the reaction was quenched with water, extracted with ethyl acetate (30 mL. times.3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:50 → 1:10) to give 70mg of tert-butyl 4- (2-methyl-3-nitrobenzylidene) piperidine-1-carboxylate as a colorless oil in 21% yield. LC-MS 277.1[ M-^tBu+H⁺]

4- (2-methyl-3-aminobenzylidene) piperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- (2-methyl-3-nitrobenzylidene) piperidine-1-carboxylate (70mg,0.21mmol), iron powder (59mg,1.05mmol) and ammonium chloride (11mg,0.21mmol) were added to ethanol and water (3mL/0.5mL), followed by stirring at 60 ℃ for 4 hours. The reaction solution was filtered off to remove a solid, concentrated under reduced pressure, and purified by preparative thin layer chromatography (ethyl acetate: petroleum ether ═ 1:4) to give tert-butyl 4- (2-methyl-3-aminobenzylidene) piperidine-1-carboxylate as a yellow oil 50mg in 79% yield.

4- (3- (3-Cyanobenzoylamino) -2-methylbenzylidene) piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4- (2-methyl-3-aminobenzylidene) piperidine-1-carboxylate (50mg,0.17mmol), 3-cyanobenzoic acid (29mg,0.2mmol) and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (97mg,0.26mmol) in dichloromethane (4mL) was added diisopropylethylamine (84. mu.L, 0.51 mmol). The reaction mixture was stirred at room temperature overnight. The reaction solution was purified by preparative thin layer chromatography (ethyl acetate: petroleum ether ═ 1:2.5) to give 67mg of tert-butyl 4- (3- (3-cyanobenzoylamino) -2-methylbenzylidene) piperidine-1-carboxylate as a white solid in 91% yield. LC-MS 376.1[ M-^tBu+H⁺]

3-cyano-N- (2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) benzamide trifluoroacetate salt

To a solution of tert-butyl 4- (3- (3-cyanobenzoylamino) -2-methylbenzylidene) piperidine-1-carboxylate (67mg,0.16mmol) in dichloromethane (5mL) was added trifluoroacetic acid (1mL), and the reaction mixture was stirred at room temperature for 4 hours and then directly concentrated under reduced pressure to give 70mg of a crude 3-cyano-N- (2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) benzamide trifluoroacetate as a colorless oil. LC-MS 332.2[ M + H ]⁺]

3-cyano-N- (3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) benzamide (compound 73)

To a dichloromethane solution of 3-cyano-N- (2-methyl-3- (piperidin-4-ylidenemethyl) phenyl) benzamide trifluoroacetate and diisopropylethylamine was added cyclopentylcarbonyl chloride, the reaction solution was stirred at room temperature for 2 hours, concentrated under reduced pressure, and purified by preparative thin layer chromatography (ethyl acetate: petroleum ether ═ 1:2) to give 67mg of 3-cyano-N- (3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -2-methylphenyl) benzamide as a yellow solid in 39% yield.¹H NMR(400MHz,CD₃OD)8.37-8.22(m,2H),7.94(d,1H),7.71(t,1H),7.2-7.16(m,2H),7.07(d,1H),6.43(s,1H),3.61(ddd,4H),3.17-3.00(m,1H),2.49-2.22(m,4H),2.18(s,3H),1.89-1.57(m,-8H)。LC-MS:428.2[M+H⁺]

6-cyano-N- (3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -5-fluoro-2-methylphenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 74)

(4- (3-amino-5-fluoro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (100mg,0.32mmol) and methyl 6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxylate (62mg,0.32mmol) were dissolved in toluene (10mL) and trimethylaluminum (0.4mL,2M,0.62mmol) was added dropwise at 0 ℃. The reaction mixture was stirred at 80 ℃ for 2 hours. Then water was added at 0 ℃ and extracted with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give 91mg of 6-cyano-N- (3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -5-fluoro-2-methylphenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide, purity 95%, yield 60%, as a white solid.¹H NMR(400MHz,DMSO-d₆)10.25(s,1H),7.40 (s,1H),7.33(s,1H),7.14(dd,1H),6.91-6.87(m,1H),6.38(s,1H),3.60-3.57(m,5H),3.48-3.44(m,2H),3.03-2.97(m,1H),2.37-2.14(m,4H),2.33-2.32(s,1H),2.06(s,3H),1.79-1.53(m, 8H). MS calculated value 476.2, and MS found value 477.1([ M + H ]]⁺)。

6-cyano-N- (3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -5-fluoro-2-methylphenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 75)

1- (4- (3-amino-5-fluoro-2-methylbenzylidene) piperidin-1-yl) -2-cyclopropylethanone (100mg,0.33mmol) and methyl 6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxylate (64mg,0.33mmol) were dissolved in toluene (10mL) and tris (hydroxymethyl) phosphonium chloride was added dropwise at 0 deg.CMethylaluminum (0.4mL,2M,0.66 mmol). The reaction mixture was stirred at 80 ℃ for 2 hours. Then water was added at 0 ℃ and extracted with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give 46mg of 6-cyano-N- (3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -5-fluoro-2-methylphenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide, purity 95%, yield 30%, white solid.¹HNMR(400MHz,DMSO-d₆):10.25(s,1H),9.20(s,1H),7.40(s,1H),7.14(dd,1H),6.88(dd,1H),3.60-3.51(m,3H),3.46-3.41(m,2H),2.43(t,2H),2.36-2.15(m,3H),2.08(t,1H),2.06(t,3H),1.89(s,3H),0.97-0.96(m,1H),0.14-0.11(m,2H),0.01(t,2H)。¹⁹F NMR (376MHz, DMSO-d6) -117.3(d, 1F). MS calculated 462.2, MS found 463.1([ M + H ]]⁺)。

1- (4- (5-fluoro-2-methyl-3-nitrobenzylidene) piperidin-1-yl) -2-methylpropan-1-one

4- (5-fluoro-2-methyl-3-nitrobenzylidene) piperidine hydrochloride (500mg,1.75mmol) was dissolved in dichloromethane (10mL) and triethylamine (530mg,5.25mmol) was added. Isobutyryl chloride (223mg,2.1mmol) was then added dropwise at 0 ℃ under nitrogen. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, and the concentrated residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate: 3/2, vol.) to give 1- (4- (5-fluoro-2-methyl-3-nitrobenzylidene) piperidin-1-yl) -2-methylpropan-1-one 550mg, 98% yield, as a yellow oil. Calculated MS 320.2 and found MS 321.0([ M + H ]]⁺)。

1- (4- (3-amino-5-fluoro-2-methylbenzylidene) piperidin-1-yl) -2-methylpropan-1-one

1- (4- (5-fluoro-2-methyl-3-nitrobenzylidene) piperidin-1-yl) -2-methylpropan-1-one (550mg,1.72mmol) was dissolved in ethanol (10mL) and water (5mL), and sodium acetate (282mg,3.44mmol), vinegar was added thereto at room temperatureAcid (1mL) and iron powder (385mg,6.88 mmol). The reaction mixture was stirred at 85 ℃ for 1 hour. The reaction solution is cooled to 0 ℃, quenched by sodium carbonate solution and extracted by ethyl acetate. The combined organic phases were washed with brine and concentrated. The concentrated residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 1/1 vol.) to give 1- (4- (3-amino-5-fluoro-2-methylbenzylidene) piperidin-1-yl) -2-methylpropan-1-one 490mg in 98% yield as a yellow oil. MS calculated value 290.2, MS found value 291.1([ M + H ]]⁺)。

6-cyano-N- (5-fluoro-3- ((1-isobutyrylpiperidin-4-ylidene) methyl) -2-methylphenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 76)

1- (4- (3-amino-5-fluoro-2-methylbenzylidene) piperidin-1-yl) -2-methylpropan-1-one (100mg,0.34mmol) and 6-cyano-1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxylate (71mg,0.37mmol) were dissolved in toluene (2mL) and trimethylaluminum (0.34mL,2M in toluene,0.68mmol) was slowly added dropwise at 0 ℃ under nitrogen. The reaction mixture was stirred at 85 ℃ for 4 hours. Cooling the reaction liquid to zero degree, quenching the reaction by potassium sodium tartrate solution, and extracting by ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give 66mg of 6-cyano-N- (5-fluoro-3- ((1-isobutyrylpiperidin-4-ylidene) methyl) -2-methylphenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide, 95% purity, 43% yield, and white solid.¹H NMR (400MHz, DMSO-d6)10.25(s,1H),7.40(d,1H),7.32(d,1H),7.15(dd,1H),6.89(t,1H),6.38(s,1H),3.60(s,3H),3.58-3.60(m,2H),3.46(m,2H),2.87-2.95(m,1H),2.14-2.38(m,4H),2.07(s,3H),1.01(t, 6H). MS calculated value 450.2, MS found value 451.2([ M + H ]]⁺)。

(R) -6-cyano-N- (3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -5-fluoro-2-methylphenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide (Compound 77)

(R) -3, 3-Difluorocyclopentylcarboxylic acid (126mg,0.84mmol), triethylamine (212mg,2.1mmol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (319mg,0.84mmol) were dissolved in dichloromethane (4mL) and stirred at room temperature for 10 minutes. 6-cyano-N- (5-fluoro-2-methyl-3- (piperidine-4-methylene) phenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide hydrochloride (290mg,0.70mmol) was then added and the reaction was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give 189mg of (R) -6-cyano-N- (3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -5-fluoro-2-methylphenyl) -1-methyl-2-oxo-1, 2-dihydropyridine-4-carboxamide in 95% purity, 53% yield and as a white solid.¹H NMR(400MHz,DMSO-d6)7.40(s,1H),7.33(s,1H),7.15(dd,1H),6.89(t,1H),6.39(s,1H),3.60(s,3H),3.57-3.60(m,2H),3.47(t,2H),3.35-3.42(m,1H),2.36-2.42(m,2H),2.28-2.34(m,2H),2.21-2.26(m,2H),2.14-2.16(m,1H),2.06(s,3H),1.99-2.03(m,2H),1.80-1.82(m,1H)。¹⁹F NMR (376MHz, DMSO-d6) -89.26-88.52 (m,1F), -91.86-91.08 (m,1F), -117.39-117.25 (m, 1F). Calculated MS 512.2, found MS 513.2([ M + H ]]⁺)。

(5-fluoro-2-methyl-3-nitrophenyl) methanol

5-fluoro-2-methyl-3-nitrobenzoic acid (2.0g,10mmol) was dissolved in tetrahydrofuran (20mL) and borane tetrahydrofuran solution (13.0mL,13mmol) was added dropwise at 0 ℃ under nitrogen. The reaction mixture was stirred at room temperature overnight. The reaction was quenched by dropwise addition of methanol at 0 ℃. The mixture was then concentrated. The concentrated residue was diluted with water and extracted with dichloromethane. The organic phase was washed with sodium bicarbonate, saturated brine, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 5/1 to 1/1, volume ratio) to give (5-fluoro-2-methyl-3-nitrophenyl) methylAlcohol 0.8g, yield 45%, white solid.¹HNMR(300MHz,DMSO-d₆):7.72(dd,2H),7.55(dd,2H),5.58(t,1H),4.58(d,2H),2.22(s,3H)。

1- (bromomethyl) -5-fluoro-2-methyl-3-nitrobenzene

(5-fluoro-2-methyl-3-nitrophenyl) methanol (7.2g,38.9mmol) was dissolved in dichloromethane (100mL) and triphenylphosphine (16.3g,62.2mmol) was added at 0 ℃. A solution of carbon tetrabromide (20.6g,62.2mmol) in methylene chloride (50mL) was then added dropwise at 0 ℃. The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated, and the concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 100/1 to 50/1 by volume) to give 7.3g of 1- (bromomethyl) -5-fluoro-2-methyl-3-nitrobenzene in 71% yield as a brown oil.¹H NMR(400MHz,DMSO-d₆):7.50(dd,1H),7.32(dd,1H),4.49(s,2H),2.48(s,3H)

(5-fluoro-2-methyl-3-nitrobenzyl) bromotriphenylphosphine

1- (bromomethyl) -5-fluoro-2-methyl-3-nitrobenzene (600mg,2.4mmol) was dissolved in toluene (10mL) and triphenylphosphine (760mg,2.9mmol) was added at room temperature. The reaction mixture was stirred at 80 ℃ for 6 hours. And then cooled to room temperature. The precipitated solid was collected by filtration and washed with toluene. The filter cake was dried under reduced pressure to give (5-fluoro-2-methyl-3-nitrobenzyl) bromotriphenylphosphine 1.1g, 91% yield, as a white solid.¹H NMR(400MHz,DMSO-d₆):7.98-7.92(m,4H),7.80-7.69(m,12H),7.11(d,2H),5.32-5.27(m,2H),1.59(s,3H)。

4- (5-fluoro-2-methyl-3-nitrobenzylidene) piperidine-1-carboxylic acid tert-butyl ester

A suspension of sodium hydrogen (96mg,2.4mmol) and dimethyl sulfoxide (10mL) was heated to 80 deg.C and stirredFor 1 hour. The mixture was then cooled to 5 ℃ and (5-fluoro-2-methyl-3-nitrobenzyl) bromotriphenylphosphine (1.1g,2.2mmol) was added. Stirring was continued for 10 min, then tert-butyl 4-oxopiperidine-1-carboxylate (0.44g,2.2mmol) was added at 5 ℃. The reaction mixture was warmed to 80 ℃ and stirred overnight. Water was added at 0 ℃ and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1, vol.) to give 375mg of tert-butyl 4- (5-fluoro-2-methyl-3-nitrobenzylidene) piperidine-1-carboxylate in 49% yield as a colorless oil.¹H NMR(400MHz,DMSO-d₆):7.76(s,1H),7.32(s,1H),6.38(s,1H),3.44(t,2H),3.32(m,2H),3.32(t,2H),2.25(s,3H),2.14(t,2H),1.41(s,9H)。

4- (5-fluoro-2-methyl-3-nitrobenzylidene) piperidine hydrochloride

Tert-butyl 4- (5-fluoro-2-methyl-3-nitrobenzylidene) piperidine-1-carboxylate (375mg,1.1mmol) was dissolved in ethyl acetate hydrochloride solution (6mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated. The crude product was used in the next reaction without further purification.

2-cyclopropyl-1- (4- (5-fluoro-2-methyl-3-nitrobenzylidene) piperidin-1-yl) ethanone

2-Cyclopropylacetic acid (0.9mL,9.6mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (5.47g,14.4mmol) and triethylamine (7.6mL,14.4mL) were dissolved in N, N-dimethylformamide (30mL) and stirred at room temperature for 1 hour. 4- (5-fluoro-2-methyl-3-nitrobenzylidene) piperidine hydrochloride (1.38g,4.8mmol) was then added. The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated. The residue was diluted with water and extracted with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 10/1 to 3/1, vol.) to give 2-ringPropyl-1- (4- (5-fluoro-2-methyl-3-nitrobenzylidene) piperidin-1-yl) ethanone 1.52g, 96% yield, brown oil.¹H NMR(400MHz,CDCl₃):7.46(d,1H),7.04(d,1H),6.30(d,1H),3.74(t,1H),3.61-3.56(m,2H),3.43-3.38(t,1H),2.45-2.41(m,2H),2.36-2.30(m,5H),2.26-2.20(m,2H),1.18-1.01(m,1H),0.62-0.56(m,2H),0.22-0.16(m,2H)。

1- (4- (3-amino-5-fluoro-2-methylbenzylidene) piperidin-1-yl) -2-cyclopropylethanone

2-cyclopropyl-1- (4- (5-fluoro-2-methyl-3-nitrobenzylidene) piperidin-1-yl) ethanone (1.52g,1.0mmol), iron powder (1.03g,18.4mmol), sodium acetate (0.76g,9.2mmol) and acetic acid were dissolved in an aqueous ethanol solution (50mL, v/v. RTM. 2/1) and stirred at 80 ℃ for 2 hours. The resulting mixture was then filtered through celite. The filter cake was washed with methanol and dichloromethane. The filtrate was concentrated. The concentrated residue was diluted with water and extracted with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by silica gel column chromatography (dichloromethane/methanol 100/1 vol.) to give 1- (4- (3-amino-5-fluoro-2-methylbenzylidene) piperidin-1-yl) -2-cyclopropylethanone 1.36mg, yield 98%, brown oil.¹HNMR(400MHz,DMSO-d₆):6.35-6.29(m,2H),6.06(dd,1H),5.17(s,2H),3.57-3.49(m,2H),3.45-3.37(m,3H),2.34-2.27(m,4H),2.24-1.93(m,2H),1.91(d,3H),0.49-0.43(m,2H),0.14-0.10(m,2H)。

5-chloro-N- (3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -5-fluoro-2-methylphenyl) -6-methylnicotinamide (Compound 78)

1- (4- (3-amino-5-fluoro-2-methylbenzylidene) piperidin-1-yl) -2-cyclopropylethanone (100mg,0.33mmol) and methyl 5-chloro-6-methylnicotinate (62mg,0.33mmol) were dissolved in toluene (10mL) and trimethylaluminum (0.4mL,2M,0.66mmol) was added dropwise at 0 ℃. The reaction mixture was stirred at 80 ℃ for 2 hours. Adding water at 0 deg.CThe reaction was quenched and extracted with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give 75mg of 5-chloro-N- (3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -5-fluoro-2-methylphenyl) -6-methylnicotinamide in 95% purity, 50% yield and as a white solid.¹H NMR(400MHz,DMSO-d₆)10.20(s,1H), 8.95(s,1H),8.36(s,1H),7.17(dd,1H),6.87(dd,1H),6.39(s,1H),3.57-3.51(m,2H),3.47-3.40(m,2H),2.64(s,3H),2.37(t,1H),2.32-2.27(m,3H),2.23(t,1H),2.16(t,1H),2.09(s,3H),1.02-0.99(m,1H),0.46-0.44(m,2H),0.12(t, 2H). Calculated MS 455.2, found MS 456.1([ M + H ]]⁺)。

5-cyano-N- (3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -5-fluoro-2-methylphenyl) -6-methylnicotinamide (Compound 79)

(4- (3-amino-5-fluoro-2-methylbenzylidene) piperidin-1-yl) (cyclopentyl) methanone (100mg,0.32mmol) and methyl 5-cyano-6-methylnicotinate (61mg,0.32mmol) were dissolved in toluene (10mL) and trimethylaluminum (0.4mL,2M,0.62mmol) was added dropwise at 0 ℃. The reaction mixture was stirred at 80 ℃ for 2 hours. Then water was added at 0 ℃ and extracted with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give 43.8mg of 5-cyano-N- (3- ((1- (cyclopentylcarbonyl) piperidin-4-ylidene) methyl) -5-fluoro-2-methylphenyl) -6-methylnicotinamide in 95% purity, 30% yield and as a white solid.¹H NMR(400MHz,DMSO-d₆)10.25(s,1H),9.20(s,1H),8.72(s,1H), 7.20(dd,1H),6.91-6.87(m,1H),6.39(s,1H),3.60-3.56(m,2H),3.49-3.45(m,2H),3.06-2.97(m,1H),2.77(s,3H),2.37-2.36(m,1H),2.33-2.30(m,1H),2.30-2.23(m,1H),2.15-2.08(m,1H),1.77(s,3H),1.77-1.23(m, 8H). Calculated MS value 460.2, found MS value 461.3([ M + H ]]⁺)483.3([M+Na]⁺)。

5-cyano-N- (3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -5-fluoro-2-methylphenyl) -6-methylnicotinamide (Compound 80)

1- (4- (3-amino-5-fluoro-2-methylbenzylidene) piperidin-1-yl) -2-cyclopropylethanone (100mg,0.33mmol) and methyl 5-chloro-6-methylnicotinate (63mg,0.33mmol) were dissolved in toluene (10mL) and trimethylaluminum (0.4mL,2M,0.66mmol) was added dropwise at 0 ℃. The reaction mixture was stirred at 80 ℃ for 2 hours. Then water was added at 0 ℃ and extracted with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give 51mg of 5-cyano-N- (3- ((1- (2-cyclopropylacetyl) piperidin-4-ylidene) methyl) -5-fluoro-2-methylphenyl) -6-methylnicotinamide in 95% purity, 34% yield and as a white solid.¹H NMR(400MHz,DMSO-d₆)10.25(s,1H),9.20(s,1H),8.72(s,1H), 7.20(dd,1H),6.87(dd,1H),6.39(s,1H),3.57-3.51(m,2H),3.46-3.40(m,2H),2.77(s,3H),2.42(t,1H),2.37-2.33(m,3H),2.30-2.23(m,1H),2.17-1.91(m,1H),2.09(s,3H),0.97-0.95(m,1H),0.45-0.44(m,2H),0.13-0.01(m, 2H). Calculated MS 446.2 and found MS 447.2([ M + H ]]⁺)。

5-cyano-N- (5-fluoro-3- ((1-isobutyrylpiperidin-4-ylidene) methyl) -2-methylphenyl) -6-methylnicotinamide (compound 81)

- (4- (3-amino-5-fluoro-2-methylbenzylidene) piperidin-1-yl) -2-methylpropan-1-one (100mg,0.34mmol) and ethyl 5-cyano-6-methylnicotinate (70mg,0.37mmol) were dissolved in toluene (2mL) and trimethylaluminum (0.34mL,2M in tolumen, 0.68mmol) was slowly added dropwise at 0 ℃ under nitrogen. The reaction mixture was stirred at 80 ℃ for 4 hours. Cooling the reaction liquid to zero degree, quenching the reaction by potassium sodium tartrate solution, and extracting by ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purifying the concentrated residue with preparative high performance liquid chromatography to obtain 111mg of 5-cyano-N- (5-fluoro-3- ((1-isobutyrylpiperidin-4-ylidene) methyl) -2-methylphenyl) -6-methylnicotinamide with purity of 95% and yield of 74%, and white solid。¹H NMR (400MHz, DMSO-d6)10.21(s,1H),9.20(d,1H),8.73(d,1H),7.20(dd,1H),6.88(t,1H),6.39(s,1H),3.58(s,2H),3.47(s,2H),2.83-2.97(m,1H),2.77(s,3H),2.15-2.39(m,4H),2.10(s,3H),1.01(t, 6H). Calculated MS 434.2, found MS 435.2([ M + H ]]⁺)。

(R) -5-cyano-N- (3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -5-fluoro-2-methylphenyl) -6-methylnicotinamide (Compound 82)

(R) -3, 3-Difluorocyclopentylcarboxylic acid (90mg,0.6mmol), triethylamine (152mg,1.5mmol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (228mg,0.6mmol) were dissolved in dichloromethane (4mL) and stirred at room temperature for 10 minutes. 5-cyano-N- (5-fluoro-2-methyl-3- (piperidin-4-ylidene) phenyl) -6-methylnicotinamide hydrochloride (200mg,0.5mmol) was then added. The reaction solution was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was purified by preparative high performance liquid chromatography to give 118mg of (R) -5-cyano-N- (3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -5-fluoro-2-methylphenyl) -6-methylnicotinamide in 95% purity and 48% yield as a white solid.¹H NMR (400MHz, DMSO-d6)10.23(d,1H),9.20(d,1H),8.72(d,1H),7.18-7.22(m,1H),6.86-6.90(m,1H),6.40(s,1H),3.59(t,2H),3.48(t,2H),3.33-3.42(m,1H),2.77(s,3H),2.38-2.44(m,2H),2.30-2.37(m,2H),2.21-2.28(m,2H),2.15-2.18(m,1H),2.10(s,3H),1.97-2.06(m,2H),1.75-1.85(m, 1H). Calculated MS value 496.2, found MS value 497.2([ M + H ]]⁺)。

Test examples

Example 1 human ROR γ t (hROR γ t) radioligand binding assay

The activity of ROR γ t inverse agonists in cell-free systems was assessed by determining the competition between the test compound and [26,27-3H ] 25-hydroxy-cholesterol (Perkin ElmerNET674250UC) at the ligand binding site on recombinant human ROR γ t-LBD protein. The protein used in this radioligand competitive binding assay was N-6XHis-GST-ROR γ t-LBD (GenBank accession No. P51449, amino acids 265) -518.

The experimental method comprises the following steps:

the assay was carried out in the presence of 150mM NaCl, 5mM MgCl ₂10% glycerol, 2mM CHAPS, 0.5mM β -octyl glucopyranoside, 5mM DTT and 50mM HEPES buffer (pH 7.4). The compounds to be tested were dissolved in DMSO and a half log (3.162 x) serial dilution of the compounds was prepared with the same solvent. mu.L of DMSO solution was mixed with 28. mu.L of 8.6nM [26,27-3H ]]25-hydroxy-cholesterol was mixed with 50 μ L of 12nM ROR γ t LBD. The plate was shaken at 700rpm for 20 minutes and allowed to stand at room temperature for 10 minutes before 40. mu.L of Poly-Lys YSi SPA beads (polylysine YSi SPA, 50. mu.g per well, Perkinelmer) were added. The plates were incubated on a shaker for 20 minutes and then left without agitation for 10 minutes at room temperature, and the intensity of the SPA's tritium beta radiation was read on a microbeta (perkinelmer). Percent inhibition values were calculated using the high signal obtained with DMSO control and the lowest signal observed for ROR γ t at 10 μ MTO901317 (Sigma). IC was calculated from inflection point concentration fit on dose-response curves₅₀The value is obtained.

hROR gamma t protein binding activity of the compounds determined in Table 2

Compound numbering	IC₅₀(nM)	Compound numbering	IC₅₀(nM)
				1	6.9	2	4.9
3	3.2	4	8.0
				5	3.3	6	12.0
7	6.4	8	4.6
				9	3.4	10	5.5
11	5.6	12	4.0
				13	4.0	14	3.8
15	2.8	16	4.9
				17	10.6	18	12.8
19	6.6	20	7.7
				21	3.3	22	28.9
23	2.3	24	16.3
				25	4.3	26	5.1
27	4.2	28	5.1
				29	3.1	30	11.4
31	30.6	32	9.0
				33	5.7	34	8.7
35	13.8	36	11.6
				37	7.5	38	43.9
39	43.1	40	6.0
				41	4.0	42	8.3
43	22.3	44	11.5
				45	60.4	46	22.9
47	15.5	48	11.1
				49	14.0	50	4.4
51	11.5	52	9.1
				53	8.2	54	22.9
55	7.1	56	7.2
				57	4.1	58	4.4
59	5.7	60	6.5
				61	15.5	62	7.2
63	4.8	64	9.8
				65	7.5	66	8.8
67	5.6	68	5.9
				69	2.6	70	9.4
71	7.0	72	5.5
				73	4.9	74	9.0
75	29.7	76	23.9
				77	15.5	78	21.4
79	5.2	80	15.6
				81	11.7	82	11.0

Example 2 activity assay in Jurkat cells:

the transcriptional activity of the human full-length ROR γ t protein was determined in Jurkat cells (ATCC) using secreted Nanoluc luciferase. Using KpnI and HindIII restriction sites, 5 repeats of ROR γ t response element (RORE) AAAGTAGGTCA were inserted into the promoterless plasmid pNL1.3[ secNluc ] (Promega). Expression plasmids for full-length ROR γ t in humans were purchased from Genecopoeia.

The experimental method comprises the following steps:

3000 million Jurkat cells were transfected with 10. mu.g ROR γ t plasmid and 25. mu.g reporter plasmid in OptiMEM medium using LTX lipofectamine and Plus reagents (Life Technologies). At 37 ℃ 5% CO₂After 5 hours of incubation in the chamber, transfected cells were collected and resuspended in phenol red-free RPMI medium containing 10% charcoal-treated FBS and distributed to 384-well tissue culture plates (30,000 cells per well). The compounds tested were dissolved in DMSO and a half log (3.162 x) serial dilution of the compound was prepared with the same solvent. The compounds to be tested were added to transfected cells (final concentration of DMSO 0.1%) in 384-well tissue culture plates, and the plates were placed in 5% CO at 37 ℃₂Incubate in incubator for 40-44 hours. The supernatant was taken to measure the luciferase activity of NanoGlo (Promega). Percent inhibition values were calculated based on complete inhibition (10 μ M TO317) and uninhibited (DMSO) controls, and values were regressed against test compound concentrations using a four-parameter nonlinear fitting model TO obtain IC₅₀The value is obtained.

TABLE 3 transcriptional Activity of Jurkat ROR gamma t protein of the compounds assayed in Jurkat cells

Example 3 in vitro differentiation inhibition assay of Th17 cells

The experimental method comprises the following steps:

1) isolation of naive CD4+ T cells and differentiation experiments of Th17 cells. Differentiation conditions of Th17 cells according to the prior art (Xu et al, J Biol chem.2011; 286(26):22707-10.2011), several wild-type C57BL/6 mice 6-10 weeks old were treated with CO₂The spleen and peripheral lymph node tissues of the mice were harvested by suffocation, placed in a sterile 1 × PBS solution containing 1% serum, single cell suspension prepared by filter paper cover milling, and then CD4 positive T cells were sorted by using magnetic bead sorting reagent of meinity. These enriched CD4 positive T cells were then surface-stained with flow fluorescent antibodies to CD62L, CD44, CD25 and sorted CD4 using flow cytometry⁺CD25^-CD62L^hiCD44^loThe naive T cells of (1). In vitro differentiation of Th17 cells was performed in 48-well plates, which were blocked by adding 200. mu.l of 1 XPBS solution containing anti-CD3(8ng/ml, 1 XPBS) and anti-CD28 antibody (8ng/ml, 1 XPBS) per well the day before culturing. The culture conditions of Th17 cells were 0.78ml of RPMI1640 complete cell culture medium containing 0.4X 10 cells, added to each well⁶One naive T cell, 1ng/ml TGF-beta, 10ng/ml IL-6, 6.25ng/ml IL-23, 10ng/ml IL-1 beta. The 48-well plates with the cells plated were then placed in CO at 37 ℃ in ice₂An incubator for 3-4 days, adding PMA (Phorbol 12-Myrristate 13-Acetate) (50ng/ml), INOMYCIN (500ng/ml), BD GlogiStop to the culture medium^TM(1:1000 dilution) of reagents, after 4-5 hours of continued stimulation at 37 ℃ then cells were harvested and expression of IL-17 and IL-17F was determined using BD Cytox/Cytoperm^TMThe Plus fixed staining kit was used for intracellular fluorescent antibody staining, and finally the staining results were analyzed using the LSRFortessa instrument and FlowJo software from BD.

2) Small molecule inhibition experiments: the small molecule compounds (i.e., compounds herein) were first dissolved in DMSO at a stock concentration of 50mM and frozen in a freezer at-80 ℃ in the dark. Before use, the cells were diluted with DMSO to a working solution concentration of 1000X, then diluted with RPMI1640 complete medium to a working solution concentration of 10X, and then one-tenth of the volume was added to the culture system of Th17 cells before the start of differentiation.

The formula of the RPMI1640 complete culture solution used in the experiment in the step is as follows: 500ml of RPMI1640 culture solution, 56ml of Fetal Bovine Serum (FBS), 5ml of penicillin-streptomycin double antibody solution (100X), 0.5ml of beta-mercaptoethanol. The 1 × PBS formulation used in the experiment of this step was diluted with sterile water with 10 × PBS (P1022) from solibao corporation, and the specific components of the 10 × PBS were: 1000ml of water contains: 8g NaCl, 0.2g KCl, 1.44g Na₂HPO₄And 0.24g KH₂PO₄，pH7.2-7.4。

Th17 cell in vitro differentiation inhibitory Activity of the Compounds determined in Table 4

Example 4 Experimental Autoimmune Encephalomyelitis (EAE) assay in mice:

the experimental method comprises the following steps:

animals: 7-9 weeks, 17-20g female C57BL/6 mice.

Animal immunization: on the first day of the experiment, MOG35-55 lyophilized powder was dissolved in physiological saline at a concentration of 2mg/ml, and then mixed with 4mg/ml Complete Freund's Adjuvant (CFA) in equal volume to obtain an emulsion. After inhalation anesthesia of experimental animals with a mixture of 2% -3% isoflurane and oxygen, after shaving the back, a total of 100 μ L of the emulsion was injected subcutaneously at 3 spots: one spot was placed in the middle of the two shoulders and the other two spots were placed on either side of the lower dorsal midline to induce Experimental Autoimmune Encephalomyelitis (EAE) in mice. After immunization (day 0) and 48 hours after immunization, mice were intraperitoneally injected with pertussis toxin (200 ng of pertussis toxin was dissolved in 200 μ LPBS).

Animal dosing and clinical observations: the day of animal immunization was considered day 0. Mice were clinically observed and scored daily for 25 consecutive days of gavage starting on day 1.

Clinical scores were according to the clinical symptoms scoring criteria of the Hooke Laboratories (Lawrence, MA, USA):

0 minute: normal mice, no apparent disease manifestation

1 minute: weakness of the tail or the hind limbs

And 2, dividing: weakness of the tail and weakness of the hind limbs

And 3, dividing: complete paralysis of hind limbs

And 4, dividing: complete paralysis of hind limbs and partial paralysis of fore limbs

And 5, dividing: an moribund state; experimental Autoimmune Encephalomyelitis (EAE) lethality in mice; humanitarian sacrifice

In a mouse Experimental Autoimmune Encephalomyelitis (EAE) study, compounds 18, 31, 46 and 64 were tested at doses of 10, 30 or 100mg/kg, administered twice daily (b.i.d). Experimental Autoimmune Encephalomyelitis (EAE) in mice results showed that compounds 18, 31, 46 and 64 were able to reduce clinical scores. The results of the experiments on compound 31 are shown in FIGS. 1-3.

Claims

1. A compound of formula (I)

Wherein

X is

R₁Is hydrogen, C1-C6 alkyl, C3-C7 alicyclic hydrocarbon group, C1-C6 halogenated alkyl, C1-C6 alkoxy, halogen or cyano; the C1-C6 alkyl group, the C3-C7 alicyclic hydrocarbon group, the C1-C6 halogenated alkyl group and the C1-C6 alkoxy group are respectively and independently optionally substituted by one or more groups selected from the group consisting of C1-C6 alkyl group, C1-C6 halogenated alkyl group, cyano group, C1-C6 alkoxy group, C1-C6 halogenated alkoxy group, C3-C7 alicyclic hydrocarbon group and 3-7-membered heterocyclic alkyl groupSubstitution;

each R is₂Independently is C1-C6 alkyl, C3-C7 alicyclic hydrocarbon, C1-C6 haloalkyl, C1-C6 alkoxy, halogen or cyano; the C1-C6 alkyl group, the C3-C7 alicyclic hydrocarbon group, the C1-C6 halogenated alkyl group are respectively and independently optionally substituted by one or more groups selected from the group consisting of C1-C6 alkyl, C1-C6 halogenated alkyl, cyano, C1-C6 alkoxy, C1-C6 halogenated alkoxy, C3-C7 alicyclic hydrocarbon group and 3-7-membered heterocyclic alkyl;

m is 0, 1 or 2;

p is 0 or 1;

2. A compound according to claim 1 or a stereoisomer, enantiomer or tautomer thereof or thereofA mixture, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein X is

3. A compound according to claim 1, or a stereoisomer, enantiomer or tautomer thereof or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R₁Is hydrogen, C1-C6 alkyl, C3-C7 alicyclic hydrocarbon, C1-C6 haloalkyl, C1-C6 alkoxy or halogen; preferably hydrogen, C1-C6 alkyl or halogen; more preferably methyl or Cl.

4. The compound of claim 1, or a stereoisomer, enantiomer or tautomer thereof, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each of said R₂Independently is C1-C6 alkyl, C3-C7 alicyclic hydrocarbon, C1-C6 haloalkyl, C1-C6 alkoxy or halogen; preferably halogen; more preferably F and Cl; preferably, when m is 1 or 2, at least one R₂At R₁And (4) contraposition.

5. A compound according to claim 1, or a stereoisomer, enantiomer or tautomer thereof or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R is₄Is C3-C7 alicyclic hydrocarbon group, 3-7 membered alicyclic hydrocarbon group containing hetero atom, C5-C10 aryl group or 5-10 membered heteroaryl group; the C3-C7 alicyclic hydrocarbon group, the 3-7 membered heteroatom-containing alicyclic hydrocarbon group, the C5-C10 aryl group or the 5-10 membered heteroaryl group are each independently optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, amino, cyano, acyl, carboxyl, hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, carbonyl, C3-C7 alicyclic hydrocarbon group, the 3-7 membered heteroatom-containing alicyclic hydrocarbon group and sulfonyl optionally substituted with C1-C3 alkyl.

6. A compound according to claim 5 orA stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R is₄Is a 3-7 membered heteroatom containing cycloaliphatic, C5-C10 aryl or 5-10 membered heteroaryl, said 3-7 membered heteroatom containing cycloaliphatic, C5-C10 aryl or 5-10 membered heteroaryl being optionally substituted by one or more groups selected from halogen, C1-C6 alkyl, cyano, C1-C6 alkoxy, carbonyl, C3-C7 cycloaliphatic and sulfonyl optionally substituted by C1-C3 alkyl.

7. A compound according to claim 5, or a stereoisomer, enantiomer or tautomer thereof or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R₄Is optionally substituted by one or more of F, Cl, C1-C3 alkyl and cyano

C5-C10 aryl or 5-10 membered heteroaryl; preferably R₄Is optionally substituted by one or more of F, Cl, C1-C3 alkyl and cyano

C5-C10 aryl or 5-10 membered heteroaryl.

8. A compound according to claim 5, or a stereoisomer, enantiomer or tautomer thereof or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R₄Is composed of

9. A compound according to claim 1 or a stereoisomer, enantiomer or tautomer thereof or mixture thereof, or a pharmaceutically acceptable salt thereofA pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R is₃Is C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, or 5-10 membered heteroaryl; the C1-C6 alkyl, C1-C6 alkoxy, C3-C7 alicyclic hydrocarbon, 3-7 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C1-C6 alkyl.

10. The compound of claim 9, or a stereoisomer, enantiomer or tautomer thereof, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is₃Is C1-C4 alkyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, or 5-6 membered heteroaryl; the C1-C4 alkyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted with fluoro, C1-C3 fluoroalkyl, C1-C6 alkoxy, C1-C3 fluoroalkoxy, or C1-C6 alkyl.

11. The compound of claim 9, or a stereoisomer, enantiomer or tautomer thereof, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R is₃Is composed of

12. A compound according to claim 1 or a stereoisomer, enantiomer or tautomer thereof or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein

R₁Is C1-C6 alkyl; r₂Is halogen; r₃Is C1-C6 alkyl or C3-C7 alicyclic hydrocarbon optionally substituted by halogen; x is

R₄Is optionally covered byC5-C10 aryl or 5-10 membered heteroaryl substituted with one or more of halogen, C1-C6 alkyl and cyano; m is 1; p is 0 or 1;

preferably, R₁Is methyl; r₂Is Cl or F; r₃Is isopropyl, cyclopropyl, cyclopentyl or cyclohexyl optionally substituted with one or more F; x is

R₄Is phenyl, pyridyl or substituted by one or more of F, methyl and cyano

m is 1; p is 0 or 1;

preferably, R₁Is methyl; r₂Is Cl or F; r₃Is isopropyl, cyclopropyl, cyclopentyl or cyclohexyl optionally substituted with one or two F; x is

R₄Is pyridyl optionally substituted by one F, methyl and cyano group or

m is 1; p is 0 or 1.

13. A compound, or a stereoisomer, enantiomer or tautomer thereof, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which compound is:

compound 1

Compound 2

Compound 3

Compound 4

Compound 5

Compound 6

Compound 7

Compound 8

Compound 9

Compound 10

Compound 11

Compound 12

Compound 13

Compound 14

Compound 15

Compound 16

Compound 17

Compound 18

Compound 19

Compound 20

Compound 21

Compound 22

Compound 23

Compound 24

Compound 25

Compound 26

Compound 27

Compound 28

Compound 29

Compound 30

Compound 31

Compound 32

Compound 33

Compound 34

Compound 35

Compound 36

Compound 37

Compound 38

Compound 39

Compound 40

Compound 41

Compound 42

Compound 43

Compound 44

Compound 45

Compound 46

Compound 47

Compound 48

Compound 49

Compound 50

Compound 51

Compound 52

Compound 53

Compound 54

Compound 55

Compound 56

Compound 57

Compound 58

Compound 59

Compound 60

Compound 61

Compound 62

Compound 63

Compound 64

Compound 65

Compound 66

Compound 67

Compound 68

Compound 69

Compound 70

Compound 71

Compound 72

Compound 73

Compound 74

Compound 75

Compound 76

Compound 77

Compound 78

Compound 79

Compound 80

Compound 81

Compound 82

(R) -5-cyano-N- (3- ((1- (3, 3-difluorocyclopentylcarbonyl) piperidin-4-ylidene) methyl) -5-fluoro-2-tolyl) -6-methylnicotinamide.

14. A pharmaceutical composition comprising a compound of any one of claims 1-13, or a stereoisomer, enantiomer or tautomer thereof, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable excipients and/or carriers.

15. Use of a compound of any one of claims 1-13, or a stereoisomer, enantiomer or tautomer thereof, or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of claim 14, for the preparation of an inhibitor of ROR γ t receptors.

16. Use of a compound of any one of claims 1-13, or a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of claim 14, for the manufacture of a medicament for the treatment of a disease associated with abnormal activation of the ROR γ t receptor.

17. The use of claim 16, wherein the diseases associated with abnormal activation of the roryt receptor include autoimmune diseases, allergic diseases and cancer;

preferably, the diseases associated with abnormal activation of ROR γ t receptor include psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, sjogren's syndrome, dry eye syndrome, graft-versus-host disease, inflammatory bowel disease, chronic obstructive pulmonary disease, asthma, autoimmune uveitis, autoimmune hepatitis, autoimmune thyroiditis, autoimmune nephritis, atopic dermatitis, prostatitis and prostate cancer.

18. Use of a compound of formula (I) as defined in any one of claims 1 to 13 or a stereoisomer, enantiomer or tautomer thereof or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition as defined in claim 14, for the inhibition of the ROR γ t receptor.