HK1115752B

HK1115752B - BENZAZOLE DERIVATIVES, COMPOSITIONS, AND METHODS OF USE AS β-SECRETASE INHIBITORS

Info

Publication number: HK1115752B
Application number: HK08105884.0A
Authority: HK
Inventors: 阿德南．M．M．米亚里; 大卫．琼斯; 黛维．雷迪．戈穆库拉; 黄国响; 杰弗．朱; 莫汉．饶; 罗伯特．C．安德鲁斯; 任坦
Original assignee: High Point Pharmaceuticals, Llc
Priority date: 2005-03-14
Filing date: 2006-03-14
Publication date: 2013-03-22

Description

Indole derivatives, compositions and methods of use as beta-secretase inhibitors

Statement of related application

This application claims the benefit of priority from U.S. provisional application No.60/661,349, filed 3/14/2005.

Technical Field

The present invention relates to indole derivatives useful as inhibitors of beta-secretase, beta-amyloid precursor protein cleaving enzyme (BACE).

Background

Alzheimer's disease is characterized by abnormal deposition of beta-amyloid (A β) in the brain, in the form of extracellular plaques and intracellular neurofibrillary tangles. The rate of amyloid accumulation is a combination of the rates of a β formation, aggregation and outflow to the brain. It is generally accepted that the major component of amyloid plaques is the 4kD amyloid protein (β a4, also known as a β, β -protein and β AP), which is a proteolytic product of a precursor protein of much larger size.

Amyloid Precursor Protein (APP) is a 695-DEG-S770 amino acid glycoprotein, expressed in neurons and glial cells in peripheral tissues. APP has a receptor-like structure that includes a large extracellular domain, a transmembrane region, and a short cytoplasmic tail. A β is a 39-42 amino acid peptide that forms part of the extracellular domain of APP and extends partially to the transmembrane region of APP.

There are at least two secretory mechanisms that release APP from the membrane and produce a soluble truncated form of APP (sAPP). Proteases that release APP and its fragments from the membrane are called "secretases". Most sAPP is released by putative α -secretase, which cleaves within the a β protein, releasing sAPP α and preventing release of intact a β. A small fraction of sAPP is released by the beta-secretase enzyme, which is in the vicinity of the NH of APP₂Terminal cleavage, yielding COOH-terminal fragments (CTFs) comprising the entire A β domain.

Thus, the activity of β -secretase or β -amyloid precursor protein-cleaving enzyme ("BACE") leads to abnormal cleavage of APP, production of A β and accumulation of β -amyloid plaques in the brain, which is characteristic of Alzheimer's disease. Furthermore, the processing of APP by β -secretase is considered to be a rate determining step in the production of a β. Thus, therapeutic agents that can inhibit BACE may be useful for the treatment of Alzheimer's disease.

The compounds of the present invention are useful in the treatment of Alzheimer's disease by inhibiting the activity of BACE, thereby preventing or reducing the rate of insoluble A β formation.

Summary of The Invention

The present invention relates to indole compounds that inhibit beta-amyloid precursor protein cleaving enzyme (BACE) and are useful for treating or preventing BACE-associated diseases, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such BACE related diseases.

In one aspect, the invention provides compounds of formula (I) shown below. In another aspect, the invention provides a process for preparing a compound of formula (I).

In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I). In one embodiment, the pharmaceutical composition comprises a compound of formula (I) and a pharmaceutically acceptable carrier, excipient, diluent, or mixture thereof. In another aspect, the invention provides a method of preparing a pharmaceutical composition comprising a compound of formula (I).

In another aspect, the invention provides a method of treatment or prevention comprising administering to a subject having a BACE-related disease or disorder a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I).

In another aspect, the invention provides a method of treatment or prophylaxis comprising administering to a subject having, or at risk of having, a disease or condition a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I), wherein the disease or condition is selected from: alzheimer's disease, mild cognitive impairment, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type Alzheimer's disease or central or peripheral amyloid diseases.

Other features of the invention are described below.

Detailed Description

In a first aspect, the present invention provides certain substituted indole compounds. These compounds are useful for reducing the proteolytic activity of BACE, as will be discussed in more detail below.

In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof:

(I)

wherein the content of the first and second substances,

a is-O-, -S-or-N (R)₅)-，

Wherein R is₅Selected from:

a) -hydrogen;

b) -an alkyl group;

c) -an aryl group;

d) -a heteroaryl group;

e) -a cycloalkyl group;

f) -a heterocyclic group;

g) -alkylene-aryl;

h) -alkylene-heteroaryl;

i) -alkylene-cycloalkyl; and

j) -alkylene-heterocyclyl;

L₁，L₆and L₇Each independently selected from:

a direct bond, -CH₂-，-O-，-N(R₆)-，-C(O)-，-CON(R₆)-，-N(R₆)C(O)-，-N(R₆)CON(R₇)-，-N(R₆)C(O)O-，-OC(O)N(R₆)-，-N(R₆)SO₂-，-SO₂N(R₆)-，-C(O)-O-，-O-C(O)-，-S-，-S(O)-，-S(O)₂-and-N (R)₆)SO₂N(R₇)-，

Wherein R is₆And R₇Independently selected from: -hydrogen, -alkyl, -aryl and-alkylene-aryl;

Q₁and Q₆Independently selected from the group consisting of a direct bond, alkylene, alkenylene, and alkynylene;

G₁selected from: heterocyclylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, fused arylcycloalkylene, fused cycloalkylarylene, fused cycloalkylheteroarylene, fused heterocyclylarylene, and fused heterocyclylheteroarylene, wherein G₁May be optionally substituted 1 to 7 times, wherein the substituents are independently selected from:

a) -a halogen;

b) -a cyano group;

c) -a nitro group;

d) -perhaloalkyl;

e)-R₈；

f)-L₂-R₈；

g)-L₂-Q₂-R₈(ii) a And

h)-Q₂-L₂-R₈；

wherein the content of the first and second substances,

R₈selected from the group consisting of hydrogen, -alkyl, -aryl and alkylene-aryl;

Q₂selected from the group consisting of a direct bond, alkylene, alkenylene, and alkynylene;

L₂selected from the group consisting of a direct bond, -CH₂-，-O-，-N(R₉)-，-C(O)-，-CON(R₉)-，-N(R₉)C(O)-，-N(R₉)CON(R₁₀)-，-N(R₉)C(O)O-，-OC(O)N(R₉)-，-N(R₉)SO₂-，-SO₂N(R₉)-，-C(O)-O-，-O-C(O)-，-S-，-S(O)-，-S(O)₂-and-N (R)₉)SO₂N(R₁₀)-，

Wherein R is₉And R₁₀Independently selected from: -hydrogen, -alkyl, -aryl and-alkylene-aryl; or R₉And R₁₀Together with the atoms to which they are attached form a 5-7 membered heterocyclic ring containing 0-2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur;

G₆selected from: hydrogen, heterocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, fused arylcycloalkyl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl and fused heterocyclylheteroaryl, wherein G ₆Optionally substituted 1-7 times, wherein the substituents are independently selected from

a) -a halogen;

b) -a cyano group;

c) -a nitro group;

d) -perhaloalkyl;

e)-R₁₀₈；

f)-L₁₀₂-R₁₀₈；

g)-L₁₀₂-Q₁₀₂-R₁₀₈(ii) a And

h)-Q₁₀₂-L₁₀₂-R₁₀₈；

wherein the content of the first and second substances,

R₁₀₈selected from the group consisting of hydrogen, -alkyl, -aryl and alkylene-aryl;

Q₁₀₂selected from the group consisting of a direct bond, alkylene, alkenylene, and alkynylene;

L₁₀₂selected from the group consisting of a direct bond, -CH₂-，-O-，-N(R₁₀₉)-，-C(O)-，-CON(R₁₀₉)-，-N(R₁₀₉)C(O)-，-N(R₁₀₉)CON(R₁₁₀)-，-N(R₁₀₉)C(O)O-，-OC(O)N(R₁₀₉)-，-N(R₁₀₉)SO₂-，-SO₂N(R₁₀₉)-，-C(O)-O-，-O-C(O)-，-S-，-S(O)-，-S(O)₂-and-N (R)₁₀₉)SO₂N(R₁₁₀)-，

Wherein R is₁₀₉And R₁₁₀Independently selected from: -hydrogen, -alkyl, -aryl and-alkylene-aryl; or R₁₀₉And R₁₁₀Together with the atoms to which they are attached form a 5-7 membered heterocyclic ring containing another 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

R₁，R₂，R₃and R₄Independently selected from:

a)-H；

b)-NH₂；

c) -a carboxyl group;

d) -a cyano group;

e) -a halogen;

f) -a nitro group;

g)-OH

h) -an alkyl group;

i) -an aryl group;

j) -alkylene-aryl;

k) -K-alkyl;

l) -K-aryl;

m) -K-alkylene-aryl;

n)-L₃-G₂-G₃(ii) a And

o)-L₈-Q₈-L₉-G₈-L₁₈-Q₁₈-L₁₉-G₁₈；

wherein R is₁，R₂，R₃And R₄At least one of which is not hydrogen; and wherein the one or more of the one,

k is selected from: -C (O) -O-, -O-C (O) -, -C (O) -NH-, -NH-C (O) -, -SO₂-，-SO₂-NH-，-NH-SO₂-and-c (o) -;

Q₈and Q₁₈Independently selected from the group consisting of a direct bond, alkylene, alkenylene, and alkynylene;

L₃，L₈，L₉，L₁₈and L₁₉Independently selected from: a direct bond, -CH₂-，-O-，-N(R₂₆)-，-C(O)-，-CON(R₂₆)-，-N(R₂₆)C(O)-，-N(R₂₆)CON(R₂₇)-，-N(R₂₆)C(O)O-，-OC(O)N(R₂₆)-，-N(R₂₆)SO₂-，-SO₂N(R₂₆)-，-C(O)-O-，-O-C(O)-，-S-，-S(O)-，-S(O)₂-，-N(R₂₆)SO₂N(R₂₇)-，-C(O)-N(R₂₆)-C(＝NH)-N(R₂₇) -and-C (O) -N (R)₂₆)-N(R₂₇)-，

Wherein R is₂₆And R₂₇Independently selected from: hydrogen, -alkyl, -aryl, -alkylene-aryl, or R ₂₆And R₂₇Together with the atoms to which they are attached form a 5-7 membered heterocyclic ring containing another 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur;

G₂selected from: a direct bond, alkylene, alkenylene, alkynylene and

wherein the content of the first and second substances,

L₁₀selected from the group consisting of alkylidene, cycloalkylidene, heteroarylidene, arylidene and heterocyclylidene;

L₁₂selected from-O-, -C (O) -N (R)₁₁) -, -C (O) -O-, -C (O) -and-N (R)₁₁)-CO-N(R₁₂) -, wherein R₁₁And R₁₂Independently comprise hydrogen, -aryl, -alkyl and-alkylene-aryl;

L₁₁selected from the group consisting of hydrogen, -alkyl, -alkenyl, alkynyl, -aryl, -alkylene-heteroaryl, alkylene-O-alkylene-aryl, -alkylene-S-alkylene-aryl, -alkylene-O-alkyl, -alkylene-S-alkyl, -alkylene-NH₂-alkylene-OH, -alkylene-SH, -alkylene-C (O) -OR₁₃-alkylene-C (O) -NR₁₃R₁₄-alkylene-NR₁₃R₁₄-alkylene-N (R)₁₃)-C(O)-R₁₄-alkylene-N (R)₁₃)-S(O)₂-R₁₄And natural or unnatural amino acid side chains, wherein

R₁₃And R₁₄Independently comprise hydrogen, -aryl, -alkyl and-alkylene-aryl; or

R₁₃And R₁₄Can be combined to form₁₃And R₁₄The nitrogen atom to which is bonded having the formula- (CH)₂)_q-Y-(CH₂)_r-wherein q and r are independently 1, 2, 3 or 4; y is-CH₂-、-C(O)-、-O-、-N(H)-、-S-、-S(O)-、-SO₂-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO₂-、-SO₂N(H)-、-(O)CO-、-NHSO₂NH-、-OC(O)-、-N(R₁₅)-、-N(C(O)R₁₅)-、-N(C(O)NHR₁₅)-、-N(SO₂NHR₁₅)-、-N(SO₂R₁₅) and-N (C (O) OR)₁₅) -, wherein R₁₅Selected from hydrogen, -alkyl, -aryl and-alkylene-aryl; or

R₁₃And R₁₄May form a heterocyclic or heteroaromatic ring together with the nitrogen atom to which it is attached; and is

G₃And G₁₈Independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, fused arylcycloalkyl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl and fused heterocyclylheteroaryl, wherein G is₃And G₁₈May be optionally substituted 1-7 times, wherein the substituents are independently selected from:

a) -a halogen;

b)-NH₂；

c) -a carboxyl group;

d) -a cyano group;

e) -a nitro group;

f)-OH；

g) -a haloalkyl group;

h) -perhaloalkyl;

i)-R₁₆；

j)-L₄-R₁₆；

k)-L₄-Q₄-R₁₆(ii) a And

l)-Q₄-L₄-R₁₆；

wherein the content of the first and second substances,

R₁₆selected from the group consisting of hydrogen, -alkyl, -cycloalkyl, -aryl, -heterocyclyl, -heteroaryl, and-alkylene-aryl;

Q₄selected from the group consisting of a direct bond, alkylene, alkenylene, and alkynylene;

L₄selected from the group consisting of a direct bond, -CH₂-，-O-，-N(R₁₈)-，-C(O)-，-CON(R₁₈)-，-N(R₁₈)C(O)-，-N(R₁₈)CON(R₁₉)-，-N(R₁₈)C(O)O-，-OC(O)N(R₁₈)-， -N(R₁₈)SO₂-，-SO₂N(R₁₈)-，-C(O)-O-，-O-C(O)-，-S-，-S(O)-，-S(O)₂-and-N (R)₁₈)SO₂N(R₁₉)-；

Wherein the content of the first and second substances,

R₁₈and R₁₉Independently selected from: -hydrogen, -alkyl, -aryl and-alkylene-aryl;

G₈selected from the group consisting of alkylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, fused arylcycloalkylene, fused cycloalkylarylene, fused cycloalkylheteroarylene, fused heterocyclylarylene, and fused heterocyclylheteroarylene, wherein G₈May be optionally substituted 1-7 times, wherein the substituents are independently selected from:

a) -a halogen;

b)-NH₂；

c) -a carboxyl group;

d) -a cyano group;

e) -a nitro group;

f)-OH；

g) -a haloalkyl group;

h) -perhaloalkyl;

i)-R₁₁₆；

j)-L₁₁₄-R₁₁₆；

k)-L₁₁₄-Q₁₁₄-R₁₁₆(ii) a And

l)-Q₁₁₄-L₁₁₄-R₁₁₆；

wherein the content of the first and second substances,

R₁₁₆selected from the group consisting of hydrogen, -alkyl, -cycloalkyl, -aryl, -heterocyclyl, -heteroaryl, and-alkylene-aryl;

Q₁₁₄selected from the group consisting of a direct bond, alkylene, alkenylene, and alkynylene;

L₁₁₄selected from the group consisting of a direct bond, -CH₂-，-O-，-N(R₁₁₈)-，-C(O)-，-CON(R₁₁₈)-，-N(R₁₁₈)C(O)-，-N(R₁₁₈)CON(R₁₁₉)-，-N(R₁₁₈)C(O)O-，-OC(O)N(R₁₁₈)-，-N(R₁₁₈)SO₂-，-SO₂N(R₁₁₈)-，-C(O)-O-，-O-C(O)-，-S-，-S(O)-，-S(O)₂-and-N (R)₁₁₈)SO₂N(R₁₁₉) -; wherein the content of the first and second substances,

R₁₁₈and R₁₁₉Independently selected from: hydrogen, -alkyl, -aryl and-alkylene-aryl;

wherein R is₁To R₁₁₉、L₁To L₁₁₄、G₁To G₁₈And Q₁To Q₁₁₄The alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, fused arylcycloalkyl group, fused cycloalkylaryl group, fused cycloalkylheteroaryl group, fused heterocyclylaryl group and fused hetero group in (1)The cyclyl heteroaryl group may be selected from:

a)-H；

b) -a halogen;

c) -a hydroxyl group;

d) -an amino group;

e) -a cyano group;

f) -a carbamoyl group;

g) -a carboxyl group;

h) -Z-alkyl;

i) -Z-haloalkyl;

j) -Z-perhaloalkyl;

k) -Z-aryl;

l) -Z-alkylene-aryl;

m) -Z-cycloalkyl;

n) -Z-alkylene-cycloalkyl;

o) -Z-heterocyclyl;

p) -Z-alkylene-heterocyclyl;

q) -Z-heteroaryl; and

r) -Z-alkylene-heteroaryl; is optionally substituted 1 to 4 times,

wherein Z is selected from the group consisting of a direct bond, -CH ₂-，-O-，-N(H)，-S-，SO₂-，-CON(H)-，-NHC(O)-，-NHCON(H)-，-NHSO₂-，-SO₂N(H)-，-C(O)-O-，-NHSO₂NH-and-O-CO-.

In one embodiment of the compounds of formula (I), A is-N (R)₅)-。

In another embodiment of the compounds of formula (I), A is-N (R)₅) -, and Q₁、G₁、L₆、Q₆、L₇And G₆Combine to form a compound selected from: isoquinolin-3-yl and (phenylethynyl) -pyridin-2-yl groups.

In another embodiment of the compounds of formula (I), A is-N (R)₅) -, and R₁Or R₄Is an imidazol-2-ylcarbamoyl group. In another embodiment of the compounds of formula (I), A is-N (R)₅) -, and R₁Or R₄Is imidazol-2-ylcarbamoyl, R₂And R₃Is hydrogen.

In another embodiment of the compounds of formula (I),

L₁is-NH-C (O) -, -NH-C (O) -, -NH-or a direct bond;

Q₁is a direct bond;

G₁is phenyl, indole, isoquinoline, pyridine, pyrimidine, benzofuran, benzothiophene, benzimidazole, furan, imidazole, 1-oxo-1, 2-dihydroisoquinoline, 1, 2, 3, 4-tetrahydroisoquinoline, cinnoline, quinoxaline, [1, 8 ] quinoline]-naphthyridine, 2, 3-dihydro- [1, 4]-dioxa- [2, 3-g]-isoquinoline, 1, 3-dioxacyclopenteno- [4, 5-g]-isoquinoline, 1, 3, 4, 9-tetrahydro- β -carboline, thieno- [2, 3-c]-pyridine, imidazole- [1, 2-a]-pyridine, imidazole- [2, 1-b ]A thiazole, wherein G₁Substituted or unsubstituted.

In another embodiment of the compounds of formula (I),

L₁is-NH-C (O) -, -NH-C (O) -, -NH-or a direct bond;

Q₁is a direct bond;

G₁is phenyl, indole, isoquinoline, pyridine, pyrimidine, benzofuran, benzothiophene, benzimidazole, furan, imidazole, 1-oxo-1, 2-dihydroisoquinoline, 1, 2, 3, 4-tetrahydroisoquinoline, cinnoline, quinoxaline, [1, 8 ] quinoline]-naphthyridine, 2, 3-dihydro- [1, 4]-dioxa- [2, 3-g]-isoquinoline, 1, 3-dioxacyclopenteno-, [2 ]4，5-g]-isoquinoline, 1, 3, 4, 9-tetrahydro- β -carboline, thieno- [2, 3-c]-pyridine, imidazole- [1, 2-a]-pyridine, imidazole- [2, 1-b]A thiazole, wherein G₁Substituted or unsubstituted;

L₆，Q₆，L₇is a direct bond, and

G₆is hydrogen.

In another embodiment of the compounds of formula (I),

L₁is-NH-C (O) -, -NH-C (O) -, -NH-or a direct bond;

Q₁is a direct bond;

G₁is phenyl, indol-2-yl, indol-3-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-5-yl, isoquinolin-6-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, benzimidazol-2-yl, 1-oxo-1, 2-dihydroisoquinolin-3-yl, 1, 2, 3, 4-tetrahydroisoquinolin-1-yl, 1, 2, 3, 4-tetrahydroisoquinolin-3-yl, 1, 2, 3, 4-tetrahydroisoquinolin-5-yl, 1, 2, 3, 4-tetrahydroisoquinolin-6-yl, cinnolin-3-yl, quinoxalin-2-yl, [1, 8 ]-naphthyridin-2-yl, 2, 3-dihydro [1, 4 ]]Dioxa [2, 3-g]-isoquinolin-8-yl, 1, 3-dioxacyclopenteno [4, 5-g]-isoquinolin-7-yl, 1, 3, 4, 9-tetrahydro-beta-carbolin-3-yl, thieno- [2, 3-c]-pyridin-5-yl, thieno- [2, 3-c]-pyridin-6-yl, imidazole- [1, 2-a]-pyridin-2-yl, imidazole- [1, 2-a]-pyridin-3-yl or imidazole- [2, 1-b]-thiazol-6-yl, wherein G₁Substituted or unsubstituted;

L₆，Q₆，L₇is a direct bond; and is

G₆Is hydrogen.

In another embodiment of the compounds of formula (I),

L₁is-NH-C (O) -, -NH-C (O) -, -NH-or a direct bond;

Q₁is a direct bond;

G₁is phenyl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-5-yl, isoquinolin-6-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl or pyrimidin-4-yl, wherein G₁Substituted or unsubstituted;

L₆，Q₆，L₇is a direct bond; and is

G₆Is hydrogen.

In another embodiment of the compounds of formula (I),

L₁is-NH-C (O) -, -NH-C (O) -, -NH-or a direct bond;

Q₁is a direct bond;

G₁is phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, wherein G₁Substituted or unsubstituted;

L₆is a direct bond, -CH₂-or-O-;

Q₆is a direct bond, lower alkylene or-C ≡ C-;

L₇Is a direct bond, -CH₂-or-O-; and is

G₆Is phenyl, furan, pyridine, thiophene, cyclopropyl, cyclopentyl, cyclohexyl, imidazole, pyrazole or isoxazole, wherein G₆Substituted or unsubstituted.

In another embodiment of the compounds of formula (I), L₁is-N (H) -C (O) -, and Q₁、G₁、L₆、Q₆、L₇And G₆Taken together to form a group selected from: [1,3]Dioxacyclopenteno [4, 5-g]Isoquinolin-7-yl, 1, 2, 3, 4-tetrahydro-isoquinolin-6-yl, 1, 2, 3, 4-tetrahydro-isoquinolin-3-yl, 1- (2-alkylsulfanyl-ethyl)-yl) -isoquinolin-3-yl, 1- (2-alkylsulfonyl-ethyl) -isoquinolin-3-yl, 1- (tetrahydro-pyran-4-yl) -isoquinolin-3-yl, 1-alkyl-6-haloalkoxy-isoquinolin-3-yl, 1-alkyl-7-haloalkoxy-isoquinolin-3-yl, 1-alkyl-isoquinolin-3-yl, 1-cycloalkylmethyl-7-alkoxy-isoquinolin-3-yl, 2, 3-dihydro- [1, 4-dihydro-isoquinolin-3-yl]Dioxa [2, 3-g]Isoquinolin-8-yl, 4-alkoxy-quinolin-2-yl, 5, 8-dialkoxy-isoquinolin-3-yl, 6, 7-di- (alkoxy-ethoxy) -isoquinolin-3-yl, 6, 7-alkoxy-isoquinolin-1-yl, 7-alkoxy-1-alkyl-isoquinolin-3-yl, 7-alkoxy-isoquinolin-1-yl, 7-alkylsulfonyl-1-alkyl-isoquinolin-3-yl, 7-halo-8-alkoxy-isoquinolin-3-yl, 7-hydroxy-1-alkyl-isoquinolin-3-yl, di-and tri-alkyl-isoquinolin-3-yl, 7-methanesulfonylamino-isoquinolin-3-yl, alkoxy-isoquinolin-3-yl, alkyl-isoquinolin-3-yl, benzyloxy-isoquinolin-3-yl, cycloalkoxy-isoquinolin-3-yl, 1-oxo-1, 2-dihydro-isoquinolin-3-yl, isoquinolin-5-yl and nitro-isoquinolin-3-yl.

In another embodiment of the compounds of formula (I), L₁is-N (H) -C (O) -, and Q₁、G₁、L₆、Q₆、L₇And G₆Taken together to form a group selected from: 2- (alkoxycarbonyl) -1, 2, 3, 4-tetrahydro-isoquinolin-6-yl, 2- (alkoxycarbonyl) -1, 2, 3, 4-tetrahydro-isoquinolin-3-yl, 2- (alkoxycarbonyl) -6, 7-dialkoxy-1, 2, 3, 4-tetrahydroisoquinolin-1-yl, 2-alkyl-1, 2, 3, 4-tetrahydro-isoquinolin-3-yl, 2-alkylsulfonyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl, 2-alkylsulfonyl-1, 2, 3, 4-tetrahydro-isoquinolin-3-yl, 2-benzenesulfonyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl and 2-benzyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl.

In another embodiment of the compounds of formula (I), L₁is-N (H) -C (O) -, and Q₁、G₁、L₆、Q₆、L₇And G₆Taken together to form a group selected from: ((alkoxyphenyl) -ethynyl) -pyridin-2-yl, ((alkylphenyl) -ethynyl) -pyridin-2-yl, ((alkyl phenyl) -ethynyl) ((R) pyridine(halophenyl) -ethynyl) -pyridin-2-yl, ((thiophen-3-yl) -ethynyl) -pyridin-2-yl, (1-phenyl-ethoxy) -pyridin-3-yl, (3-cycloalkyl-prop-1-ynyl) -pyridin-2-yl, (3-hydroxy-3-methyl-but-1-ynyl) -pyridin-2-yl, (alkoxy) -pyridin-3-yl, (alkoxy-phenyl) -pyridin-3-yl, (alkoxy-phenylethynyl) -pyridin-2-yl, (alkyl-phenylethynyl) -pyridin-2-yl, (alkylsulfonyl-phenyl) -pyridin-2-yl, (alkylsulfonyl-phenylethynyl) -pyridin-2-yl, (alkynyl) -pyridin-3-yl, (aminomethyl-phenyl) -pyridin-2-yl, (benzyloxy) -pyridin-3-yl, (carbamoyl-phenyl) -pyridin-2-yl, (cyanomethyl-phenyl) -pyridin-2-yl, (cyano-phenyl) -pyridin-3-yl, (cyano-phenyl) -pyridin-4-yl, (cycloalkoxy) -pyridin-3-yl, (cycloalkyl-alkoxy) -pyridin-2-yl, (cycloalkyl-alkoxy) -pyridin-3-yl, (cycloalkyl ethynyl) -pyridin-2-yl, (cycloalkyl ethynyl) -pyridin-3-yl, (dialkylamino-phenylethynyl) -pyridin-2-yl, (dihalo-phenyl) -pyridin-3-yl, (haloalkoxy-phenyl) -pyridin-2-yl, (haloalkoxy-phenyl) -pyridin-3-yl, (haloalkyl-phenyl) -pyridin-2-yl, (halo-phenyl) -pyridin-2-yl, (halo-phenyl) -pyridin-3-yl, (halo-phenylethynyl) -pyridin-2-yl, (phenylalkoxy) -pyridin-2-yl, (phenyl-alkyl) -pyridin-3-yl, (phenylethynyl) -pyridin-2-yl, (phenylethynyl) -pyridin-3-yl, (phenylethynyl) -pyridin-4-yl, (pyridin-3-ylethynyl) -pyridin-2-yl, (thiophen-2-yl) -pyridin-2-yl, [2, 3' ]Dipyridyl-6-yl, [2, 4']Bipyridin-6-yl, 2- (cyano-phenyl) -pyridin-4-yl, 2- (halo-phenoxy) -pyridin-3-yl, 2- (phenoxy) -pyridin-3-yl, phenethyl-pyridin-2-yl, 3-halo-6- (alk-1-ynyl) -pyridin-2-yl, 5- (phenoxy) -pyridin-3-yl, 6- (3-cyano-phenyl) -pyridin-2-yl, cyano-pyridin-3-yl, cyano-pyridin-4-yl, ethynyl-pyridin-2-yl, ethynyl-pyridin-3-yl, ethynyl-pyridin-4-yl, halo-pyridin-2-yl, halo-pyridin-3-yl, phenyl-pyridin-2-yl, phenyl-pyridin-3-yl and phenyl-pyridin-4-yl.

In the compounds of formula (I)In another embodiment of (1), L₁is-N (H) -C (O) -, and Q₁、G₁、L₆、Q₆、L₇And G₆Taken together to form a group selected from: cinnolin-3-yl, quinoxalin-2-yl, [1, 8]Naphthyridin-2-yl, cyano-phenyl, (cyano-phenyl) -phenyl, (pyridin-3-yl) -phenyl, (pyridin-4-yl) -phenyl, (haloalkyl-pyridin-2-yl) -phenyl, (haloalkyl-phenoxy) -phenyl, 2- (alkoxycarbonyl) -2, 3, 4, 9-tetrahydro-1H- β -carbolin-3-yl, 1-phenyl-2- (alkoxycarbonyl) -2, 3, 4, 9-tetrahydro-1H- β -carbolin-3-yl, 6- (phenyl) -pyrimidin-4-yl, 6- (halophenyl) -pyrimidin-4-yl, 2, 6-dialkoxy-pyrimidin-4-yl, thieno [2, 3-c) ]Pyridin-5-yl, thieno [3, 2-c)]Pyridin-6-yl, 2-alkyl-imidazo [1, 2-a ]]Pyridin-3-yl, imidazo [1, 2-a ]]Pyridin-2-yl, 5-alkyl-imidazo [1, 2-a ]]Pyridin-2-yl, imidazo [2, 1-b ]]Thiazol-6-yl and 8-alkyl-imidazo [1, 2-a ]]Pyridin-2-yl.

In another embodiment of the compounds of formula (I), A is-N (R)₅) -, and R₁Or R₄is-L₈-Q₈-L₉-G₈-L₁₈-Q₁₈-L₁₉-G₁₈Wherein

L₈Is a direct bond, -CH₂-、-C(O)-O-、-C(O)-N(R₂₆) -or-N (R)₂₆)-C(O)-，

Q₈Is a direct bond or an alkylene group,

L₉is a straight key, and the key is a straight key,

G₈is imidazole, 4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridine, imidazopyridine, piperidine, 1, 2, 3, 4-tetrahydroisoquinoline, phenyl, cycloalkyl, purine, isoquinoline, benzimidazole, oxazole, pyrazole, pyrimidine, 4, 5, 6, 7-tetrahydro-1H-benzimidazole, or furan, wherein G is₈Substituted or unsubstituted.

L₁₈Is a straight key、-SO₂-, -O-or-C (O) -,

Q₁₈is a direct bond or an alkylene group,

L₁₉is a direct bond, and

G₁₈is hydrogen, phenyl, quinoline, isoquinoline, cycloalkyl, pyridine, furan, alkyl, pyrrole, thiazole, imidazole, thiophene or pyrrolidine, wherein G₁₈Substituted or unsubstituted.

In another embodiment of the compounds of formula (I), A is-N (R)₅) -, and R₁Or R₄is-L₈-Q₈-L₉-G₈-L₁₈-Q₁₈-L₁₉-G₁₈Wherein L is ₉、G₈、L₁₈、Q₁₈、L₁₉And G₁₈Combine to form a group selected from piperidin-4-yl and 1- (alkoxycarbonyl) -piperidin-4-yl.

In another embodiment of the compounds of formula (I), A is-N (R)₅) -, and R₁Or R₄is-L₈-Q₈-L₉-G₈-L₁₈-Q₁₈-L₁₉-G₁₈Wherein L is₉、G₈、L₁₈、Q₁₈、L₁₉And G₁₈Taken together to form a group selected from: 1H-pyrazol-3-yl, imidazol-2-yl, imidazol-1-yl, 4, 5-dialkyl-imidazol-2-yl, 4-phenyl-1H-imidazol-2-yl, 4- (halo-phenyl) -1H-imidazol-2-yl, 5-adamantan-1-yl-1H-imidazol-2-yl, 5-alkyl-1H-imidazol-2-yl, 5-benzyl-1H-imidazol-2-yl, 4-alkyl-oxazol-2-yl, and furan-2-ylmethyl.

In another embodiment of the compounds of formula (I), A is-N (R)₅) -, and R₁Or R₄is-L₈-Q₈-L₉-G₈-L₁₈-Q₁₈-L₁₉-G₁₈Wherein L is₉、G₈、L₁₈、Q₁₈、L₁₉And G₁₈Taken together to form a group selected from: cycloalkyl, alkyl, 2-alkylsulfanyl-ethyl, (alkoxy-phenyl) -methyl, 2- (alkoxyphenyl) -ethyl, 2- (phenoxy-phenyl) -ethyl, 1- (alkylsulfonyl-phenyl) -ethyl, benzyl, cyano-benzyl, alkoxy-benzyl, alkyl-benzyl, alkylsulfonyl-benzyl, dihalo-benzyl, haloalkyl-halo-benzyl, haloalkoxy-benzyl, halo-benzyl, sulfamoyl-benzyl, alkoxyphenyl, halo-phenyl, and alkylsulfonyl-phenyl.

In another embodiment of the compounds of formula (I), A is-N (R)₅) -, and R₁Or R₄is-L₈-Q₈-L₉-G₈-L₁₈-Q₁₈-L₁₉-G₁₈Wherein L is₉、G₈、L₁₈、Q₁₈、L₁₉And G₁₈Taken together to form a group selected from: benzimidazol-2-yl, benzimidazol-5-yl, benzimidazol-6-yl, isoquinolin-3-yl, isoquinolin-6-yl, 4, 5, 6, 7-tetrahydro-benzimidazol-2-yl, 4, 5, 6, 7-tetrahydro-benzothiazol-2-yl, 5-dialkyl-7-oxo-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl, 6- (alkyl) -4, 5, 6, 7-tetrahydro-benzothiazol-2-yl, 1, 2, 3, 4-tetrahydro-isoquinolin-6-yl, 2- (alkoxycarbonyl) -1, 2, 3, 4-tetrahydro-isoquinolin-6-yl, 7H-purin-8-yl and 2-amino-pyrimidin-4-yl.

In another embodiment of the compounds of formula (I), A is-N (R)₅) -, and R₁Or R₄is-L₈-Q₈-L₉-G₈-L₁₈-Q₁₈-L₁₉-G₁₈Wherein Q is₈、L₉、G₈、L₁₈、Q₁₈、L₁₉And G₁₈Taken together to form a group selected from: (piperidin-3R-yl) methyl, (piperidin-3S-yl) methyl, (piperidin-4-yl) -methyl, (1- (alkoxycarbonyl) -piperidin-3-yl) -methyl, (1- (cycloalkylmethyl)) -piperidin-3-yl) methyl, (1- (cycloalkylmethyl) -piperidin-4-yl) methyl, (piperidin-4-yl) -methyl, (1- (alkoxycarbonyl) -piperidin-4-yl) -methyl, [1- (carboxylic acid methyl ester) -piperidin-3R-yl ]Methyl, [1- (carboxylic acid methyl ester) -piperidin-3S-yl]Methyl, [1- (cycloalkylmethyl) -piperidin-3S-yl]Methyl, [1- (cycloalkylmethyl) -piperidin-3R-yl]Methyl, 1- (1-alkyl-1H-imidazol-2-ylmethyl) -piperidin-3-ylmethyl, 1- (1-alkyl-1H-imidazol-4-ylmethyl) -piperidin-3-ylmethyl, 1- (1H-imidazol-2-ylmethyl) -piperidin-3-ylmethyl, [1- (cycloalkylmethyl) -piperidin-3R-yl]Methyl, 1- [1- (alkoxycarbonyl) -pyrrolidin-2R-ylmethyl]-piperidin-3-ylmethyl, 1- [1- (alkoxycarbonyl) -pyrrolidin-2S-ylmethyl]-piperidin-3-ylmethyl, 2- (piperidin-3-yl) -ethyl, 2- (piperidin-4-yl) -ethyl, 2- [1- (alkoxycarbonyl) -piperidin-3-yl]-ethyl and 2- [1- (alkoxycarbonyl) -piperidin-4-yl]-ethyl.

In another embodiment of the compounds of formula (I), A is-N (R)₅) -, and R₁Or R₄is-L₈-Q₈-L₉-G₈-L₁₈-Q₁₈-L₁₉-G₁₈Wherein Q is₈、L₉、G₈、L₁₈、Q₁₈、L₁₉And G₁₈Combine to form a group selected from: 4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 3H-imidazo [4, 5-c]Pyridin-2-yl, 3H-imidazo [4, 5-c]Pyridin-2-yl, [5- (2, 4-dialkoxy-benzyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, (5-alkyl-3H-imidazol-4-ylmethyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ]Pyridin-2-yl, 5- [1- (alkoxycarbonyl) -pyrrolidin-2S-ylmethyl]-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5- [1- (alkoxycarbonyl) -pyrrolidin-2R-ylmethyl]-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5- (1-alkyl-1H-imidazol-2-ylmethyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5- (1-alkyl-1H-pyrrol-2-ylmethyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5- (3-alkylsulfanyl-propyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5- (3-alkylsulfinyl-propyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5- (3-alkylsulfonyl-propyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5- (3H-imidazol-4-ylmethyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5- (alkoxy-benzyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5- (alkylsulfonyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5- (alkoxycarbonyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5- (cycloalkylmethyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5- (halo-benzyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ]Pyridin-2-yl, 5- (imidazol-2-ylmethyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5- (quinolin-3-ylmethyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5-alkyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5-alkylcarbamoyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5-alkylsulfonyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5-benzoyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5-benzyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5-cycloalkylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Ppyridin-2-yl, 5-furan-3-ylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5-phenethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5-pyridin-3-ylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5-pyrrolidin-2S-ylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5-thiazol-2-ylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl, 5-thiophen-2-ylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl and 5-thiophen-3-ylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ]Pyridin-2-yl.

In another embodiment, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt, ester or prodrug thereof:

(Ia)

wherein the content of the first and second substances,

L₁selected from: straight bond, -CH₂-、-O-、-N(R₆)-、-C(O)-、-CON(R₆)-、-N(R₆)C(O)-、-N(R₆)CON(R₇)-、-N(R₆)C(O)O-、-OC(O)N(R₆)-、-N(R₆)SO₂-、-SO₂N(R₆)-、-C(O)-O-、-O-C(O)-、-S-、-S(O)-、-S(O)₂-and-N (R)₆)SO₂N(R₇)-，

Wherein R is₆And R₇Independently selected from: hydrogen, -alkyl, -aryl and-alkylene-aryl;

Q₁selected from the group consisting of direct bonds and alkylene;

G₁selected from: aryl, heteroaryl, fused arylcycloalkyl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl and fused heterocyclylheteroaryl, and G₁Optionally substituted 1-7 times, wherein the substituents are independently selected from:

a) -a halogen;

b) -a cyano group;

c) -a nitro group;

d) -perhaloalkyl;

e)-R₈；

f)-L₂-R₈；

g)-L₂-Q₂-R₈(ii) a And

h)-Q₂-L₂-R₈；

wherein the content of the first and second substances,

Q₂selected from the group consisting of alkylene, alkenylene, and alkynylene;

L₂is selected from-CH₂-、-O-、-N(R₉)-、-C(O)-、-CON(R₉)-、-N(R₉)C(O)-、-N(R₉)CON(R₁₉)-、-N(R₉)C(O)O-、-OC(O)N(R₉)-、-N(R₉)SO₂-、-SO₂N(R₉)-、-C(O)-O-、-O-C(O)-、-S-、-S(O)-、-S(O)₂-and-N (R)₉)SO₂N(R₁₀)-，

Wherein R is₉And R₁₀Independently selected from: hydrogen, -alkyl, -aryl and-alkylene-aryl;

R₁，R₂，R₃and R₄Is independently selected from

a)-H；

b) -an alkyl group;

c) -an aryl group;

d) -alkylene-aryl;

e) -K-alkyl;

f) -K-aryl;

g) -K-alkylene-aryl; and

h)-L₃-G₂-G₃；

wherein the content of the first and second substances,

L₃Selected from: straight bond, -CH₂-、-O-、-N(R₂₆)-、-C(O)-、-CON(R₂₆)-、-N(R₂₆)C(O)-、-N(R₂₆)CON(R₂₇)-、-N(R₂₆)C(O)O-、-OC(O)N(R₂₆)-、-N(R₂₆)SO₂-、-SO₂N(R₂₆)-、-C(O)-O-、-O-C(O)-、-S-、-S(O)-、-S(O)₂-and-N (R)₂₆)SO₂N(R₂₇)-，

Wherein R is₂₆And R₂₇Independently selected from: -hydrogen, -alkyl, -aryl and-alkylene-aryl;

G₂selected from: straight bond and

wherein the content of the first and second substances,

L₁₁selected from the group consisting of hydrogen, -alkyl, -alkenyl, -alkynyl, -aryl, -alkylene-heteroaryl, alkylene-O-alkylene-aryl, -alkylene-S-alkylene-aryl, -alkylene-O-alkyl, -alkylene-S-alkyl, -alkylene-NH₂-alkylene-OH, -alkylene-SH, -alkylene-C (O) -OR₁₃-alkylene-C (O) -NR₁₃R₁₄-alkylene-NR₁₃R₁₄-alkylene-N (R)₁₃)-C(O)-R₁₄-alkylene-N (R)₁₃)-S(O)₂-R₁₄And natural or unnatural amino acid side chains, wherein

G₃Selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, fused arylcycloalkyl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, and fused heterocyclylheteroaryl, wherein,

G₃optionally substituted 1-7 times, wherein the substituents are independently selected from:

a) -a halogen;

b) -a cyano group;

c) -a nitro group;

d) -perhaloalkyl;

e)-R₁₆；

f)-L₄-R₁₆；

g)-L₄-Q₄-R₁₆(ii) a And

h)-Q₄-L₄-R₁₆；

wherein the content of the first and second substances,

R₁₆selected from the group consisting of hydrogen, -alkyl, -aryl and-alkylene-aryl;

Q₄selected from the group consisting of alkylene, alkenylene, and alkynylene;

L₄is selected from-CH₂-、-O-、-N(R₁₈)-、-C(O)-、-CON(R₁₈)-、-N(R₁₈)C(O)-、-N(R₁₈)CON(R₁₉)-、-N(R₁₈)C(O)O-、-OC(O)N(R₁₈)-、-N(R₁₈)SO₂-、-SO₂N(R₁₈)-、-C(O)-O-、-O-C(O)-、-S-、-S(O)-、-S(O)₂-and-N (R)₁₈)SO₂N(R₁₉)-；

Wherein the content of the first and second substances,

R₁₈and R₁₉Independently selected from: -hydrogen, -alkyl, -aryl and-alkylene-aryl; and is

Wherein R is₁-R₄At least one of which is-L₃-G₂-G₃(ii) a And is

R₅Selected from:

a) -hydrogen; and

b) -an alkyl group; and is

Wherein R is₁To R₂₇，L₁To L₁₂，G₁To G₃The aryl and/or alkyl groups in (a) may be selected from:

a)-H；

b) -a halogen;

c) -a hydroxyl group;

d) -a cyano group;

e) -a carbamoyl group;

f) -a carboxyl group;

g) -Z-alkyl;

h) -Z-aryl;

i) -Z-alkylene-aryl; is optionally substituted 1 to 4 times,

wherein Z is selected from-CH₂-、-O-、-N(H)、-S-、SO₂-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO₂-、-SO₂N(H)-、-C(O)-O-、-NHSO₂NH-and-O-CO-.

In embodiments of the compounds of formula (Ia),

L₁is-NH-C (O) -, -NH-or a direct bond;

Q₁is a direct bond;

G₁is phenyl, biphenyl, naphthyl, indole, isoquinolinyl, pyridine or pyrimidine; and wherein the one or more of the one,

R₁-R₄at least one of which is-L₃-G₂-G₃Wherein

L₃Selected from a) -CO₂-; b) -C (O) NH-; and c) -NH-;

G₂is a direct bond or alkylene; and is

G₃Selected from alkyl, phenyl, naphthyl, biphenyl, alkylene-phenyl, pyrrole (pyrole), thiophene, indole, imidazole, tetrazolyl, thiazole, 1, 3, 4-thiadiazole, pyrimidine, pyridine, benzimidazole and benzothiazole, wherein G₃Is selected from:

a) -a halogen;

b) -a cyano group;

c) -a nitro group;

d) -perhaloalkyl;

e)-R₁₆；

f)-L₄-R₁₆；

g)-L₄-Q₄-R₁₆(ii) a And

h)-Q₂-L₄-R₁₆(ii) a Is optionally substituted 1 to 7 times,

wherein

Q₄selected from the group consisting of-alkylene, -alkenylene, and-alkynylene;

L₄is selected from-CH₂-，-O-，-N(R₁₈)-，-C(O)-，-CON(R₁₈)-，-N(R₁₈)C(O)-，-N(R₁₈)CON(R₁₉)-，-N(R₁₈)C(O)O-，-OC(O)N(R₁₈)-，-N(R₁₈)SO₂-，-SO₂N(R₁₈)-，-C(O)-O-，-O-C(O)-，-S-，-S(O)-，-S(O)₂-and-N (R)₁₈)SO₂N(R₁₉) -; wherein the content of the first and second substances,

R₁₈and R₁₉Independently selected from: hydrogen, -alkyl, -aryl and-alkylene-aryl.

In another embodiment of the compounds of formula (Ia),

L₁is a direct bond, -NH-C (O) -or-NH-;

Q₁is a direct bond;

G₁is phenyl, biphenyl, isoquinolinyl, pyridine or pyrimidine; and is

R₁-R₄In which at least one is a group-L ₃-G₂-G₃Wherein

L₃is-C (O) -NH-;

G₂is that

Wherein

L₁₀In accordance with the definition set forth above,

L₁₁in accordance with the definition above, and

L₁₂is-C (O) -NH-; and is

G₃Selected from alkyl, phenyl, naphthyl, biphenyl, alkylene-phenyl, pyrrole (pyrole), imidazole, tetrazolyl, thiazole, 1, 3, 4-thiadiazole, pyrimidine, pyridine, benzimidazole and benzothiazole, wherein G₃Is selected from

a) -a halogen;

b) -a cyano group;

c) -a nitro group;

d) -perhaloalkyl;

e)-R₁₆；

f)-L₄-R₁₆；

g)-L₄-Q₄-R₁₆(ii) a And

h)-Q₂-L₄-R₁₆(ii) a Is optionally substituted 1 to 7 times,

wherein the content of the first and second substances,

Q₄selected from the group consisting of alkylene, alkenylene, and alkynylene;

L₄is selected from-CH₂-，-O-，-N(R₁₈)-，-C(O)-，-CON(R₁₈)-，-N(R₁₈)C(O)-，-N(R₁₈)CON(R₁₉)-，-N(R₁₈)C(O)O-，-OC(O)N(R₁₈)-，-N(R₁₈)SO₂-，-SO₂N(R₁₈)-，-C(O)-O-，-O-C(O)-，-S-，-S(O)-，-S(O)₂-and-N (R)₁₈)SO₂N(R₁₉)-；

Wherein the content of the first and second substances,

In another embodiment of the compounds of formula (Ia), G₃Is imidazole or benzimidazole.

In another embodiment of the compounds of formula (Ia), G₁Is isoquinoline.

In another embodiment of the compounds of formula (Ia), the compounds of formula (Ia) have the formula:

wherein the content of the first and second substances,

G₁is unsubstituted 2-isoquinolin-3-yl or pyridin-2-yl; and is

G₂And G₃Together form a radical selected from phenyl, isobutyl, n-butyl, 1H-imidazol-2-yl, [1, 3, 4 ]Groups of-thiadiazol-2-yl, thiazol-2-yl, 1H-imidazol-2-yl, benzothiazol-2-yl, pyridin-3-yl and 4-phenyl-1H-imidazol-2-yl.

wherein the content of the first and second substances,

L₁₁is 2, 2-dimethylpropyl, 2-chloro-benzyl, 2-fluorobenzyl, 2-phenyl-ethyl, 3, 4, 5-trifluorobenzyl, 3, 5-difluoro-benzyl, 3-chlorobenzyl, 3-fluorobenzyl, 3-fluoro-phenyl, 3-methoxyphenyl, 3-trifluoromethylbenzyl, 4-chlorobenzylA group, 4-fluorobenzyl, 4-methoxyphenyl, 4-methylbenzyl, 4-phenyl-benzyl, butyl-2-yl, isobutyl, isopropyl, cyclopropyl or phenyl,

n is 0 or 1, and

G₃is 1H-benzimidazol-2-yl, 1H-imidazol-2-yl, pyridin-2-yl or thiazol-2-yl.

wherein the content of the first and second substances,

L₁₁is benzyl or 3, 5-difluorobenzyl, and

G₃is methyl, isobutyl, 1H-imidazol-2-yl, thiazol-2-yl, benzothiazol-2-yl, 1H-benzimidazol-2-yl, 2-methyl-piperidine-1-carboxylic acid tert-butyl ester or 3-methyl-piperidine-1-carboxylic acid tert-butyl ester.

Wherein the content of the first and second substances,

G₁is unsubstituted 2-isoquinolin-3-yl, 5-bromopyridin-2-yl, phenyl or pyridin-2-yl;

G₂and G₃Together form a compound selected from (benzothiazol-2-yl) methyl, 1H-imidazol-2-yl, 2, 4-dichlorobenzyl, 2, 5-dichlorophenyl, 3-hydroxypropyl, 3-tert-butylphenyl, 4' -biphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methyl-benzylRadicals of the general formula I, 4-phenoxyphenyl, 4-phenylthiazol-2-yl, 4-phenyl-thiazol-2-yl, 4-tert-butyl-benzyl, benzo 1H-imidazol-2-yl, benzothiazol-6-yl, benzothiazol-2-yl, benzyl, methyl, phenyl, pyridin-2-yl and thiazol-2-yl.

wherein the content of the first and second substances,

G₁is 1, 5-dimethyl-indol-2-yl, 1-benzyl-indol-2-yl, 1H-imidazol-2-yl, 1H-indazole (indoline) -3-yl, 1H-indol-2-yl, 1-methyl-indoline (indoline) -3-yl, 1-methyl-indol-2-yl, 1-n-propyl-indol-2-yl, 2, 4-difluorophenyl, 2-chloro-phenyl, 2-fluoro-phenyl, 2-isoquinolin-3-yl, 3, 4-dimethoxyphenyl, 3-chloro-phenyl, 3-fluoro-phenyl, 3-methoxy-4-fluoro-phenyl, 4' -biphenyl, 4-fluorobenzyl, 4-fluorophenyl, 4-isopropyl-phenyl, 4-methoxy-phenyl, 4-nitro-phenyl, 4-phenoxyphenyl, 4-tert-butyl-phenyl, 4-trifluoromethylphenyl, 5-chloro-benzofuran-2-yl, 5-methyl-indol-2-yl, 5-phenoxy-pyridin-2-yl, 6, 7-dimethoxy-2-isoquinolin-3-yl, benzofuran-2-yl, benzothien-2-yl, furan-3-yl, naphthalene-2-yl, phenyl, quinolin-2-yl or quinolin-3-yl; and is

G₂And G₃Together form a compound selected from (1-methylbenzimidazol-2-yl) methyl, (1R) -phenylethyl, (1S) -phenylethyl, (5-methylfuran-2-yl) -methyl, (benzothien-2-yl) methyl, (benzothiazol-2-yl) methyl, (thien-2-yl) ethyl, (thien-2-yl) methyl, {1, 3, 4} -thiadiazol-2-yl, 1H-benzimidazol-2-ylmethyl, 1H-imidazol-2-yl, 1H-indazol-5-yl, 2- (1H-Benzimidazol-2-yl) -ethyl, 2, 3, 4, 9-tetrahydro-1H-beta-carbolin-2-yl, 2-phenoxy-phenyl, 3-phenoxy-phenyl, 4-phenyl-1H-imidazol-2-yl, benzothiazol-2-yl, benzyl, ethyl, furan-2-ylmethyl, phenethyl, phenyl, pyridin-2-yl, pyridin-3-yl, quinolin-3-yl, tert-butyl, thiazol-2-yl and thiazol-2-yl-methyl.

wherein the content of the first and second substances,

G₂and G₃Together form a group selected from isopropyl, isobutyl and phenyl.

wherein R is₁，R₂，R₃，R₅，G₁，G₂And G ₃Are as defined above for the compounds of formula (Ia).

wherein R is₁，R₂，R₃，R₅，G₁，G₂And G₃In combination with the above definition of formula (Ia)The definition of things is consistent.

wherein R is₁，R₃，R₅，G₁，G₂And G₃Are as defined above for the compounds of formula (Ia).

In another embodiment, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt, ester or prodrug thereof:

(Ib)

wherein the content of the first and second substances,

L₁is-N (R)₆) -, wherein R₆Selected from: hydrogen, -alkyl, -aryl and-alkylene-aryl;

Q₁is a direct bond;

G₁is hydrogen;

R₁，R₂，R₃and R₄Is independently selected from

a)-H；

b) -an alkyl group;

c) -an aryl group;

d) -alkylene-aryl;

e) -K-alkyl;

f) -K-aryl;

g) -K-alkylene-aryl; and

h)-L₃-G₂-G₃；

wherein R is₁-R₄At least one of which is not hydrogen; and is

Wherein the content of the first and second substances,

G₂selected from: straight bond and

Wherein the content of the first and second substances,

L₁₂selected from-O-, -C (O) -N (R)₁₁) -, -C (O) -O-, -C (O) -and-N (R)₁₁)-CO-N(R₁₂) -, wherein R₁₁And R₁₂Independently include hydrogen, -aryl, -alkyl, and-alkylene-aryl;

L₁₁selected from the group consisting of hydrogen, -alkyl, -alkenyl, -alkynyl, -aryl, -alkylene-aryl,Alkylene-heteroaryl, alkylene-O-alkylene-aryl, -alkylene-S-alkylene-aryl, -alkylene-O-alkyl, -alkylene-S-alkyl, -alkylene-NH₂-alkylene-OH, -alkylene-SH, -alkylene-C (O) -OR₁₃-alkylene-C (O) -NR₁₃R₁₄-alkylene-NR₁₃R₁₄-alkylene-N (R)₁₃)-C(O)-R₁₄-alkylene-N (R)₁₃)-S(O)₂-R₁₄And a natural or unnatural amino acid side chain, wherein,

R₁₃and R₁₄Independently comprise hydrogen, -aryl, -alkyl and-alkylene-aryl; or this

R₁₃And R₁₄Can be combined to form₁₃And R₁₄To which the nitrogen atom is bonded and having the formula- (CH)₂)_q-Y-(CH₂)_r-wherein q and r are independently 1, 2, 3 or 4; y is-CH₂-、-C(O)-、-O-、-N(H)-、-S-、-S(O)-、-SO₂-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO₂-、-SO₂N(H)-、-(O)CO-、-NHSO₂NH-、-OC(O)-、-N(R₁₅)-、-N(C(O)R₁₅)-、-N(C(O)NHR₁₅)-、-N(SO₂NHR₁₅)-、-N(SO₂R₁₅) and-N (C (O) OR)₁₅) -, wherein R₁₅Selected from hydrogen, -alkyl, -aryl and-alkylene-aryl; or a

G₃Selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, fused arylcycloalkyl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl and fused heterocyclylheteroaryl, wherein G ₃Optionally substituted 1-7 times, wherein the substituents are independently selected from:

a) -a halogen;

b) -a cyano group;

c) -a nitro group;

d) -perhaloalkyl;

e)-R₁₆；

f)-L₄-R₁₆；

g)-L₄-Q₄-R₁₆(ii) a And

h)-Q₄-L₄-R₁₆；

wherein the content of the first and second substances,

Q₄selected from the group consisting of alkylene, alkenylene, and alkynylene;

Wherein

R₅Selected from:

a) -hydrogen; and

b) -an alkyl group; and is

Wherein R is₁To R₁₉，L₁To L₁₂，G₂And G₃The aryl and/or alkyl groups in (a) may be selected from:

a)-H；

b) -a halogen;

c) -a hydroxyl group;

d) -a cyano group;

e) -a carbamoyl group;

f) -a carboxyl group;

g) -Z-alkyl;

h) -Z-aryl;

i) -Z-alkylene-aryl; is optionally substituted 1 to 4 times,

In embodiments of the compounds of formula (Ib),

L₁is-NH-C (O) -, -NH-or a direct bond; and is

R₁-R₄In which at least one is a group-L₃-G₂-G₃Wherein, in the step (A),

L₃selected from:

a) a direct bond;

b)-CO₂-；

c) -C (O) NH-; and

d)-NH-

G₂is a direct bond or alkylene; and is

G₃Selected from alkyl, phenyl, naphthyl, biphenyl, alkylene-phenyl, pyrrole (pyrole), thiophene, indole, imidazole, tetrazolyl, thiazole, 1, 3, 4-thiadiazole, pyrimidine, pyridine, benzimidazole and benzothiazole, wherein G ₃Is selected from:

a) -a halogen;

b) -a cyano group;

c) -a nitro group;

d) -perhaloalkyl;

e)-R₁₆；

f)-L₄-R₁₆；

g)-L₄-Q₄-R₁₆(ii) a And

h)-Q₂-L₄-R₁₆(ii) a Is optionally substituted 1 to 7 times,

wherein

Wherein the content of the first and second substances,

In the compounds of formula (I), the different functional groups are understood to be the points of attachment on the functional group with hyphen. In other words at-C_1-10In the case of alkylene-aryl, it is understood that the point of attachment is alkylene; such as benzyl. In groups, e.g. -C (O) -NH-C_1-10In the case of alkylene-aryl, the point of attachment is the carbonyl carbon.

The term "BACE inhibitor" is used to indicate a compound having the structure described herein, which is capable of interacting with BACE and inhibiting its enzymatic activity. Inhibiting BACE enzymatic activity means reducing the ability of BACE to cleave a peptide or protein. The peptide or protein may be APP and the BACE inhibitor may reduce the NH proximity of BACE to APP₂The ability to terminally cleave APP and generate COOH-terminal fragments (CTFs) that include the entire A β domain. In various embodiments, this reduction in BACE activity is at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In various embodiments, the concentration of BACE inhibitor required to reduce BACE enzymatic activity is less than about 30 μ M, less than about 10 μ M, or less than about 1 μ M.

Also included within the scope of the present invention are the individual enantiomers of the compounds of formula (I) above and any fully or partially racemic mixtures thereof. The invention also includes mixtures of individual enantiomers of the compounds of formula (I) above and diastereomers thereof in which one or more stereocenters are inverted. Unless otherwise indicated, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except for replacing hydrogen atoms by deuterium or tritium, or by¹³C-or¹⁴Compounds having this structure in place of a carbon atom with a C-rich carbon are within the scope of the present invention.

In another aspect, the invention provides a pharmaceutically acceptable salt, solvate, or prodrug of a compound of formula (I). In one embodiment, the prodrug comprises a biohydrolyzable ester or biohydrolyzable amide of the compound of formula (I).

Examples of compounds of formula (I) of the present invention having potentially useful biological activity are listed below by name in table 1. The ability of compounds of formula (I) to inhibit the proteolytic activity of BACE was determined by representative compounds of formula (I) listed in table 1 using the enzyme assay described in the examples section. Compounds of formula (I) in Table 1 inhibit IC of BACE in enzymatic assays ₅₀Less than or equal to 30 μ M.

Examples of compounds of formula (I) of the present invention are given in table 1 below and in the examples section.

In the chemical structures listed in Table 1, the unused valences of heteroatoms such as oxygen and nitrogen are each assumed to be used up with hydrogen atoms.

The compounds having basic or acidic groups in table 1 are described and named as free bases or acids. Depending on the reaction conditions and purification conditions, the different compounds having basic groups in table 1 are isolated in the form of the free base, or as a salt (e.g. HCl salt), or both.

In another aspect, the invention includes a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, excipient, diluent, or mixture thereof.

The term "lower" as used herein refers to a group containing 1 to 6 carbons.

The term "alkyl" as used herein refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, silyloxy optionally substituted with alkoxy or alkyl or aryl, silyl optionally substituted with alkoxy or alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, optionally substituted with alkyl, and allowed to be substituted multiple times. Such "alkyl" may contain one or more of O, S (O) or S (O) ₂An atom. Examples of "alkyl" as used herein include, but are not limited to, methyl, n-butyl, t-butyl, n-pentyl, isobutyl, and isopropyl, and the like.

The term "alkylene" as used herein refers to a straight or branched chain divalent hydrocarbon radical containing from 1 to 10 carbon atoms, selected from: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, silyloxy optionally substituted with alkoxy or alkyl or aryl, silyl optionally substituted with alkoxy or alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, optionally substituted with alkyl, and allowed to be substituted multiple times.Such "alkylene" may comprise one or more of O, S (O) or S (O)₂An atom. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, and the like.

The term "alkenyl" as used herein refers to a hydrocarbon group containing 2 to 10 carbons and at least 1 carbon-carbon double bond, selected from the group consisting of: lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, silyloxy optionally substituted with alkoxy or alkyl or aryl, silyl optionally substituted with alkoxy or alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, and is allowed to be substituted multiple times. Such "alkenyl" groups may contain one or more of O, S (O) or S (O) ₂An atom.

The term "alkenylene" as used herein refers to a straight or branched chain divalent hydrocarbon radical containing from 2 to 10 carbon atoms and one or more carbon-carbon double bonds, selected from: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, silyloxy optionally substituted with alkoxy or alkyl or aryl, silyl optionally substituted with alkoxy or alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, optionally substituted with alkyl, and allowed to be substituted multiple times. Such "alkenylene" may contain one or more of O, S (O) or S (O)₂An atom. Examples of "alkenylene" as used herein include, but are not limited to, ethylene-1, 2-diyl, propylene-1, 3-diyl, methylene-1, 1-diyl, and the like.

The term "alkynyl" as used herein refers to a hydrocarbon group containing 2 to 10 carbons and at least 1 carbon-carbon triple bond, selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl Lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, silyloxy optionally substituted with alkoxy or alkyl or aryl, silyl optionally substituted with alkoxy or alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, and allows multiple substitutions. Such "alkynyl" groups may contain one or more of O, S (O) or S (O)₂An atom.

The term "alkynylene" as used herein refers to a straight or branched chain divalent hydrocarbon radical containing from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds, selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, silyloxy optionally substituted with alkoxy or alkyl or aryl, silyl optionally substituted with alkoxy or alkyl or aryl, nitro, cyano, halogen or lower perfluoroalkyl, optionally substituted with alkyl, and allowed to be substituted multiple times. Such "alkynylene" may comprise one or more of O, S (O) or S (O) ₂An atom. Examples of "alkynylene" as used herein include, but are not limited to, acetylene-1, 2-diyl, propyne-1, 3-diyl, and the like.

The terms "haloaliphatic", "haloalkyl", "haloalkenyl" and "haloalkoxy" as used herein, refer to an aliphatic group, alkyl, alkenyl or alkoxy, which may be substituted as the case may be with one or more halogen atoms.

"cycloalkyl" as used herein refers to any alicyclic hydrocarbon group having one or more degrees of unsaturation and containing from 3 to 12 carbon atoms, selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, nitro, cyano, halogen, or a substituent of lower perfluoroalkyl, and is allowed to be substituted multiple times. "cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, as well as bicyclic and tricyclic structures, such as adamantane.

The term "cycloalkylene" as used herein refers to a non-aromatic divalent alicyclic hydrocarbon group containing from 3 to 12 carbon atoms and optionally having one or more degrees of unsaturation, selected from: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, nitro, cyano, halogen, or a substituent of lower perfluoroalkyl, and is allowed to be substituted multiple times. Examples of "cycloalkylene" as used herein include, but are not limited to, cyclopropyl-1, 1-diyl, cyclopropyl-1, 2-diyl, cyclobutyl-1, 2-diyl, cyclopentyl-1, 3-diyl, cyclohexyl-1, 4-diyl, cycloheptyl-1, 4-diyl or cyclooctyl-1, 5-diyl, as well as bicyclic and tricyclic structures.

The term "heterocycle" or the term "heterocyclyl" as used herein means optionally having one or more unsaturations and comprising one or more substituents selected from S, SO₂A non-aromatic 3-12 membered heterocycle of a substituted heteroatom of O or N selected from: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, nitro, cyano, halogen, or a substituent of lower perfluoroalkyl, and allows multiple substitutions. Such rings may be optionally fused to 1-3 benzene rings or 1-3 other "heterocyclic" or cycloalkyl rings. Examples of "heterocyclic" include, but are not limited to, tetrahydrofuran, 1, 4-dioxane, 1, 3-dioxane, piperidine, pyrrolidine, morpholine, piperazine and the like.

The term "heterocyclylene" as used herein means optionally having one or more unsaturations and comprising one or more substituents selected from S, SO₂3-12 membered heterocyclic diradical of a heteroatom selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, nitro, cyano, halogen, or a substituent of lower perfluoroalkyl, and is allowed to be substituted multiple times. Such rings may be optionally fused to 1-3 benzene rings or 1-3 other "heterocyclic" or cycloalkyl rings. Examples of "heterocyclylene" include, but are not limited to, tetrahydrofuran-2, 5-diyl, morpholine-2, 3-diyl, pyran-2, 4-diyl, 1, 4-dioxan-2, 3-diyl, 1, 3-dioxan-2, 4-diyl, piperidine-1, 4-diyl, pyrrolidine-1, 3-diyl, morpholine-2, 4-diyl, piperazine-1, 4-diyl, and the like.

The term "aryl" as used herein refers to a benzene ring or an optionally substituted benzene ring system fused to 1 to 3 optionally substituted benzene rings, selected from the group consisting of: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, di (lower alkyl) aminoalkyl, oxygen, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acylamino, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, siloxy optionally substituted by alkoxy or alkyl or aryl, silyl optionally substituted by alkoxy or alkyl or aryl, nitro, cyano, halogen or a substituent of lower perfluoroalkyl, and allows multiple substitutions. Examples of aryl groups include, but are not limited to, phenyl, 2-naphthyl, 1-anthracenyl, and the like.

The term "arylene" as used herein refers to a phenyl ring diradical or a phenyl ring system diradical fused to 1-3 optionally substituted phenyl rings, selected from: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, di (lower alkyl) aminoalkyl, oxygen, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acylamino, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, siloxy optionally substituted by alkoxy or alkyl or aryl, silyl optionally substituted by alkoxy or alkyl or aryl, nitro, cyano, halogen or a substituent of lower perfluoroalkyl, and allows multiple substitutions. Examples of "arylene" include, but are not limited to, benzene-1, 4-diyl, naphthalene-1, 8-diyl, and the like.

The term "heteroaryl" as used herein refers to a 5-7 membered aromatic or polycyclic aromatic ring (up to 3 rings) containing one or more nitrogen, oxygen or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible aromatic ring substitutes selected from: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, siloxy optionally substituted with alkoxy or alkyl or aryl, silyl optionally substituted with alkoxy or alkyl or aryl, nitro, cyano, halogen or a substituent of lower perfluoroalkyl, optionally substituted multiple times. For polycyclic aromatic ring systems, one or more of the rings may contain one or more heteroatoms. Examples of "heteroaryl" as used herein are furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, quinazoline, benzofuran, benzothiophene, indole, indazole, and the like.

The term "heteroarylene" as used herein refers to a 5-7 membered aromatic or polycyclic aromatic ring diradical (up to 3 rings) containing one or more nitrogen, oxygen or sulfur heteroatoms, wherein the N-oxides and sulfur monoxides and sulfur dioxides are permissible aromatic ring substitutes selected from: halogen, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, oxygen, hydroxy, mercapto, amino optionally substituted with alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted with alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, siloxy optionally substituted with alkoxy or alkyl or aryl, silyl optionally substituted with alkoxy or alkyl or aryl, nitro, cyano, halogen or a substituent of lower perfluoroalkyl, optionally substituted multiple times. For a diradical of a polycyclic aromatic ring system, one or more of the rings may contain one or more heteroatoms. Examples of "heteroarylene" as used herein are furan-2, 5-diyl, thiophene-2, 4-diyl, 1, 3, 4-oxadiazole-2, 5-diyl, 1, 3, 4-thiadiazole-2, 5-diyl, 1, 3-thiazole-2, 4-diyl, 1, 3-thiazole-2, 5-diyl, pyridine-2, 4-diyl, pyridine-2, 3-diyl, pyridine-2, 5-diyl, pyrimidine-2, 4-diyl, quinoline-2, 3-diyl, and the like.

The term "fused cycloalkylaryl" as used herein means a cycloalkyl fused to an aryl, both cycloalkyl and aryl moieties sharing two atoms, and wherein the aryl is the position where substitution occurs. Examples of "fused cycloalkylaryl" as used herein include 5-indanyl, 5, 6, 7, 8-tetrahydro-2-naphthyl,and the like.

The term "fused cycloalkylarylene" as used herein refers to fused cycloalkylaryl groups in which the aryl group is divalent. Examples includeAnd the like.

The term "fused arylcycloalkyl" as used herein means an aryl fused to a cycloalkyl, the two moieties aryl and cycloalkyl sharing two atoms, and wherein the cycloalkyl is the position at which substitution occurs. Examples of "fused arylcycloalkyl" as used herein include 1-indanyl, 2-indanyl, 1- (1, 2, 3, 4-tetrahydronaphthyl),

and the like.

The term "fused arylcycloalkylene" as used herein refers to a fused arylcycloalkyl group, wherein the cycloalkyl group is divalent. Examples include

And the like.

The term "fused heterocyclylaryl" as used herein means that a heterocyclyl is fused to an aryl, and that the two moieties of the heterocyclyl and aryl share two atoms, and wherein the aryl is the position where substitution occurs. Examples of "fused heterocyclylaryl" as used herein include 3, 4-methylenedioxy-1-phenyl, And the like.

The term "fused heterocyclylarylene" as used herein refers to a fused heterocyclylaryl group in which the aryl group is divalent. Examples includeAnd the like.

The term "fused arylheterocyclyl" as used herein means an aryl group fused to a heterocyclyl group, the two moieties aryl and heterocyclyl sharing the sameTwo atoms, and wherein heterocyclyl is the position at which substitution occurs. Examples of "fused arylheterocyclyl" as used herein include 2- (1, 3-benzodioxolyl),and the like.

The term "fused arylheterocyclylene" as used herein refers to a fused arylheterocyclyl group, wherein the heterocyclyl group is divalent. Examples includeAnd the like.

The term "fused cycloalkylheteroaryl" as used herein refers to a cycloalkyl group fused to a heteroaryl group, the two moieties of which share two atoms, and wherein the heteroaryl group is the position where substitution occurs. Examples of "fused cycloalkylheteroaryl" as used herein include 5-aza-6-indanyl,and the like.

The term "fused cycloalkylheteroarylene" as used herein refers to a fused cycloalkylheteroaryl group in which the heteroaryl group is divalent, examples of which includeAnd the like.

The term "fused heteroarylcycloalkyl" as used herein means that a heteroaryl is fused to a cycloalkyl, the two moieties heteroaryl and cycloalkyl sharing two atoms, and wherein the cycloalkyl is the position where substitution occurs. Examples of "fused heteroarylcycloalkyl" as used herein include 5-aza-1-indanyl, And the like.

The term "fused heteroarylcycloalkylene" as used herein refers to a fused heteroarylcycloalkyl group,wherein the cycloalkyl group is divalent. Examples includeAnd the like.

The term "fused heterocyclylheteroaryl" as used herein means that a heterocyclyl group is fused to a heteroaryl group, and that the two moieties of the heterocyclyl and heteroaryl group share two atoms, and wherein the heteroaryl group is the position where substitution occurs. Examples of "fused heterocyclylheteroaryl" as used herein include 1, 2, 3, 4-tetrahydro-beta-carbolin-8-yl,and the like.

The term "fused heterocyclylheteroarylene" as used herein refers to a fused heterocyclylheteroaryl group, wherein the heteroaryl group is divalent. Examples includeAnd the like.

The term "fused heteroarylheterocyclyl" as used herein means that the heteroaryl is fused to a heterocyclyl, both parts of which share two atoms, and wherein the heterocyclyl is the position where substitution occurs. Examples of "fused heteroarylheterocyclyl" as used herein include 5-aza-2, 3-dihydrobenzofuran-2-yl,and the like.

The term "fused heteroarylheterocyclylene" as used herein refers to a fused heteroarylheterocyclyl wherein the heterocyclyl is divalent. Examples include And the like.

The term "direct bond" as used herein as part of the specification of a variable structure refers to the variable (preceding and following) directly attached to the side of a substituent, referred to as a "direct bond". When two or more consecutive variables are specified as being "direct bonds", then the substituents flanking (preceding and following) the two or more consecutive specified "direct bonds" are directly connected.

The term "alkoxy" as used herein refers to the group R_aO-, wherein R_aIs an alkyl group.

The term "alkenyloxy" as used herein refers to the group R_aO-, wherein R_aIs an alkenyl group. The term "alkynyloxy" as used herein refers to the group R_aO-, wherein R_aIs an alkynyl group.

The term "alkylsulfanyl" as used herein refers to the group R_aS-, wherein R_aIs an alkyl group.

The term "alkenylsulfanyl" as used herein refers to the group R_aS-, wherein R_aIs an alkenyl group.

The term "alkynylsulfanyl" as used herein refers to the group R_aS-, wherein R_aIs an alkynyl group.

The term "alkylsulfinyl" as used herein refers to the group R_aS (O) -, wherein R_aIs an alkyl group.

The term "alkenylsulfinyl" as used herein refers to the group R_aS (O) -, wherein R_aIs an alkenyl group.

The term "alkynylsulfinyl" as used herein refers to the group R _aS (O) -, wherein R_aIs an alkynyl group.

The term "alkylsulfonyl" as used herein refers to the group R_aSO₂-, wherein R_aIs an alkyl group.

The term "alkenylsulfonyl" as used herein refers to the group R_aSO₂-, wherein R_aIs an alkenyl group.

The term "alkynylsulfonyl" as used herein refers to the group R_aSO₂-, wherein R_aIs an alkynyl group.

The term "acyl" as used herein refers to the group R_aC (O) -, wherein R_aIs alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or heterocyclyl.

The term "aroyl" as used herein refers to the group R_aC (O) -, wherein R_aIs an aryl group.

The term "heteroaroyl" as used herein refers to the group R_aC (O) -, wherein R_aIs a heteroaryl group.

The term "alkoxycarbonyl" as used herein refers to the group R_aOC (O) -, wherein R_aIs an alkyl group.

The term "acyloxy", as used herein, refers to the group R_aC (O) O-, wherein R_aIs alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or heterocyclyl.

The term "aroyloxy" as used herein refers to the group R_aC (O) O-, wherein R_aIs an aryl group.

The term "heteroaroyloxy" as used herein refers to the group R_aC (O) O-, wherein R_aIs a heteroaryl group.

The term "optionally" is used herein to indicate that the subsequently described event may or may not occur, and includes both occurring and non-occurring events.

The term "substituted" as used herein means substituted with the indicated substituent or substituents, and, unless otherwise indicated, multiple substitutions are permissible only if the substitution results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one that has a substantially unchanged chemical structure when stored at a temperature of about-80 ℃ to about +40 ℃ for at least one week in the absence of moisture or other chemical reaction conditions, or that retains its integrity for a length of time sufficient for therapeutic or prophylactic administration to a patient. The phrase "one or more substituents" as used herein means that the number of substituents is equal to the maximum number of substituents possible based on the number of available bonding points, provided that the conditions of stability and chemical feasibility described above are met.

The term "comprising" or "containing" as used herein may mean O, S, SO₂Any one or more of N or N-alkyl groups may be insertionally substituted at any position within the alkyl, alkenyl, alkynyl or cycloalkyl substituents defined hereinbefore, including, for example, -CH₂-O-CH₂-，-CH₂-SO₂-CH₂-，-CH₂-NH-CH₃And the like.

The term "solvate" as used herein is a complex of variable stoichiometry formed by a solute (in the present invention, a compound of formula (I)) and a solvent. Such solvents, which meet the object of the present invention, do not substantially affect the biological activity of the solute. The solvent may be, for example, water, ethanol or acetic acid.

The term "biohydrolyzable ester" as used herein is an ester of a drug substance (in the present invention, a compound of formula (I)) which either a) does not affect the biological activity of the parent substance but confers on the substance advantageous in vivo properties, such as duration of action, time of onset, etc., or b) is biologically inactive but is readily converted in vivo in a subject to the biologically active ingredient. Advantageously, the biohydrolyzable ester is absorbed from the intestinal tract after oral administration and converted to formula (I) in plasma, for example. Many examples of such esters are well known in the art and include, for example, lower alkyl esters (e.g., C)₁-C₄) Lower acyloxyalkyl esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkylamidoalkyl esters and choline esters.

The term "biohydrolyzable amide" as used herein is an amide of a drug substance (in the present invention, a compound of formula (I)) which either a) does not affect the biological activity of the parent substance but confers on the substance advantageous in vivo properties, such as duration of action, time of onset, etc., or b) is biologically inactive but is readily converted in vivo in a subject to a biologically active ingredient. Advantageously, for example, the biohydrolyzable amide is absorbed from the intestinal tract after oral administration and converted to formula (I) in plasma. Many examples of such amides are well known in the art and include, for example, lower alkyl amides, alpha-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

The term "prodrug" as used herein is a) a biohydrolyzable amide or biohydrolyzable ester, and includes a compound wherein the biohydrolyzable functionality in such prodrug is included in the compound of formula (I), or b) a compound that is biologically oxidizable or reducible at a specific functional group to produce the drug substance of formula (I). Examples of such functional groups include, but are not limited to, 1, 4-dihydropyridine, N-alkylcarbonyl-1, 4-dihydropyridine, 1, 4-cyclohexadiene, t-butyl, and the like.

When the term "alkyl" or "aryl" or any of their prefixes appears in the name of a substituent (e.g., arylalkoxyaryloxy), it should be construed to include those limitations given above for "alkyl" and "aryl". Specified number of carbon atoms (e.g., C)_1-10) Shall independently refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group or cycloalkyl moiety, or to the number of carbon atoms in an alkyl moiety of a bulky substituent in which the term "alkyl" appears as its prefix.

The term "oxygen" as used herein shall mean the substituent ═ O.

The term "halogen" or "halo" as used herein shall include iodine, bromine, chlorine and fluorine.

As used herein, the term "mercapto" shall refer to the substituent-SH.

The term "carboxy" as used herein shall mean the substituent-COOH.

The term "cyano" as used herein shall mean the substituent-CN.

The term "aminosulfonyl" as used herein shall mean the substituent-SO₂NH₂。

As used herein, the term "carbamoyl" shall mean the substituent-C (O) NH₂。

The term "thioalkyl" as used herein shall mean the substituent-S-.

The term "sulfinyl", as used herein, shall mean the substituent-S (O) -.

The term "sulfonyl", as used herein, shall mean the substituent-S (O)₂-。

The compounds may be prepared according to the following reaction schemes (in which the variables are in accordance with or defined below) using readily available starting materials, reagents and conventional synthetic methods. In these reactions, it is likewise possible to use variables which are known to the person skilled in the art themselves, but are not mentioned in greater detail here.

The invention also provides processes for the preparation of compounds of formula (I), and processes for the synthesis of compounds useful as intermediates in the preparation of compounds of formula (I).

The general steps in the process for the preparation of the compounds of formula (I) according to the invention are described hereinafter, wherein the definitions of the variable groups are the same as described for the compounds of formula (I).

As shown in scheme I, diaminomethylbenzoate (1) is treated with a carboxylic acid in the presence of a coupling agent such as, but not limited to HBTU, to form amide (2). Amide (2) is then refluxed in a solvent such as, but not limited to, AcOH to form benzimidazole (3). The methyl ester of benzimidazole (3) is hydrolyzed with a base such as, but not limited to, LiOH to give the free carboxylic acid, which is then coupled with an amine in the presence of a coupling agent such as, but not limited to, HBTU to form amide (4).

Flow chart I

As shown in scheme II, the methyl ester of benzimidazole (3) is hydrolyzed with a base such as, but not limited to, LiOH to give the free carboxylic acid, which is then coupled with compound (5) in the presence of a coupling agent such as, but not limited to, HBTU to form amide (6). Compound (5) is prepared by first coupling an amino protected amino acid, such as a BOC protected amino acid, with an amine and then removing the amino protecting group to give compound (5).

Scheme II

As shown in scheme III, the diaminomethylbenzoate (1) is reacted with the isothiocyanate (7) by refluxing in a solvent such as, but not limited to, THF to afford intermediate (8). Isothiocyanate (7) is either commercially available or prepared by reacting the corresponding amine with 1, 1' -thiocarbonyldiimidazole in a solvent such as, but not limited to, THF. Intermediate (8) is treated with a coupling agent such as, but not limited to, DCC to form benzimidazole (9). Hydrolysis of the methyl ester of benzimidazole (9) with a base such as, but not limited to, LiOH gives the free carboxylic acid, which is then coupled with an amine in the presence of a coupling agent such as, but not limited to, HBTU, gives the amide (10).

Scheme III

As shown in scheme IV, in a mixed solvent such as, but not limited to, EtOH: H₂Diaminomethylbenzoate (1) is treated with cyanogen bromide in O to form 2-aminobenzimidazole (11). The amine of benzimidazole (11) is coupled with a carboxylic acid in the presence of a coupling agent such as, but not limited to, HBTU to form amide (12). Hydrolysis of the methyl ester of amide (12) with a base such as, but not limited to, LiOH, to give the free carboxylic acid, which is then reacted with an amine in a coupling agent such as, but not limited to, LiOHCoupling in the presence of HBTU to form amide (13) is not limited.

Flow chart IV

Scheme V shows another general method for preparing amide (13). As shown in scheme V, nitro-aminobenzoic acid (14) is coupled with an amine in the presence of a coupling agent such as, but not limited to HBTU to form an amide, which is then reduced under conditions such as, but not limited to, Pd/C under a hydrogen atmosphere to provide diamine (15). The resulting diamine (15) is reacted with cyanogen bromide in a mixed solvent such as, but not limited to, EtOH: H₂Reaction in O to form 2-aminobenzimidazole (16). The amino group of benzimidazole (16) is coupled with a carboxylic acid in the presence of a coupling agent such as, but not limited to, HBTU to afford amide (13).

Flow chart V

As shown in scheme VI, with a nitrating agent such as, but not limited to, KNO ₃/H₂SO₄Compound (11a) is treated to provide benzimidazole (17). The amine of benzimidazole (17) is coupled with a carboxylic acid in the presence of a coupling agent such as, but not limited to, HBTU to form amide (18). Hydrolysis of the methyl ester of amide (18) with a base such as, but not limited to, LiOH provides the free carboxylic acid which is then coupled with an amine in the presence of a coupling agent such as, but not limited to, HBTU to form amide (19). The nitro group of amide (19) is reduced under conditions such as, but not limited to, Pd/C under hydrogen atmosphere, and the resulting amide is then reacted with an acid chloride in the presence of a base such as, but not limited to, pyridine to provide compound (20).

Flow chart VI

As shown in scheme VII, Compound (12) is reacted with cyanogen bromide in a mixed solvent such as, but not limited to, EtOH-H₂And O to form 2-aminobenzimidazole (22). The amino group of benzimidazole (22) is coupled with a carboxylic acid in the presence of a coupling agent such as, but not limited to, HBTU to form an amide, followed by reduction of the nitro group under conditions such as, but not limited to, Pd/C under a hydrogen atmosphere to give amine (23). Amine (23) is then reacted with sulfonyl chloride in the presence of a base such as, but not limited to, pyridine to provide compound (24). In scheme VII, the variable R is a group such as, but not limited to, aryl, arylalkylene, heteroarylalkylene, or heteroaryl, or an optionally substituted form thereof.

Flow chart VII

As shown in scheme VIII, amine (23) can also be reacted with a coupling agent such as CDI, followed by reaction with an alkyl or aryl amine to provide urea (25). In scheme VIII, the variable R is a group such as, but not limited to, aryl, arylalkylene, heteroarylalkylene, or heteroaryl, or an optionally substituted form thereof.

Flow chart VIII

As shown in scheme IX, compound (26) is reacted with bromine in a solvent such as, but not limited to, AcOH to provide aryl bromide (27). Aryl bromide (27) is then coupled with a boronic acid in the presence of a palladium reagent such as, but not limited to, tetrakis (triphenylphosphine) palladium to form aryl compound (28), and aryl compound (28) is then subjected to the sequential reactions shown in scheme V to afford benzimidazole (29). Aryl bromide (27) may also be coupled with an aryl and alkenyl tin reagent to provide an aryl compound, which may then be subjected to the sequential reactions shown in scheme V to provide benzimidazole (29). In scheme IX, the variable R is a group such as, but not limited to, aryl, heterocyclyl, arylalkenylene, alkenyl, heteroarylalkenylene, or optionally substituted versions thereof.

Flow diagram IX

As shown in scheme X, with a nitrating agent such as, but not limited to, HNO ₃/H₂SO₄Compound (30) is treated to give nitro compound (31). Treatment of nitro compound (31) with ammonium carbonate in a solvent such as DMF affords aminonitro compound (32), which is followed by treatment of aminonitro compound (32) with sodium alkoxide or sodium aryloxide to afford aryl ether (33). Aryl ether (33) is then subjected to the sequential reaction shown in scheme V to afford benzimidazole (34). In scheme X, the variable R is a group such as, but not limited to, aryl, heteroaryl, arylalkylene, alkyl, heteroarylalkylene, or optionally substituted versions thereof.

Flow diagram X

As shown in scheme XI, compound (32) is reacted with sodium mercaptide (sodium thiolate) in the presence or absence of a base such as triethylamine to provide compound (35), which is then subjected to the sequential reactions shown in scheme V to provide benzimidazole (36). Benzimidazole (36) is then treated with an oxidizing agent such as a peroxide, including but not limited to MCPBA, to give sulfone (37). In scheme XI, the variable R is a group such as, but not limited to, aryl, heteroaryl, arylalkylene, alkyl, heteroarylalkylene, or optionally substituted forms thereof.

Flow chart XI

As shown in scheme XII, the acid input compounds used in the above schemes can be prepared using bromo carboxylic acid (38) by reaction with an alkenyl or aryl boronic acid in the presence of a palladium reagent such as, but not limited to, tetrakis (triphenylphosphine) palladium to form aryl compound (39). In scheme XII, the variable R is a group such as, but not limited to, aryl, heteroaryl, arylalkenylene, alkenyl, heteroarylalkenylene, or optionally substituted forms thereof. The variable X in scheme XII can be a group such as, but not limited to, N or CH, or an optionally substituted form thereof.

Scheme XII

The acid input compounds used in the above schemes can also be prepared as shown in scheme XIII by reacting acetylene with bromo acid (40) (where X is a group such as, but not limited to, CH or N) in the presence of a palladium reagent such as, but not limited to, dichlorobis (triphenylphosphine) palladium (II) to give acetylene (41). In scheme XIII, the variable R is a group such as, but not limited to, aryl, heteroaryl, alkyl, cycloalkyl, or optionally substituted forms thereof.

Scheme XIII

The term "amino protecting group" as used herein refers to a substituent of an amino group that is typically used to block or protect the amino functionality when other functional groups of the compound are reacted. Examples of such amino-protecting groups include formyl, trityl, phthalimidyl, trichloroacetyl, chloroacetyl, bromoacetyl and iodoacetyl groups, urethane-based protecting groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2, 4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanophenoxy-carbonyl, 2- (4-biphenyl) isopropoxycarbonyl, 1, 1-diphenyleth-1-yloxycarbonyl, 1, 1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2- (p-toluyl) prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentyloxycarbonyl, cyclohexyloxycarbonyl, 1-methylcyclohexyloxycarbonyl, 2- (4-toluoylsulfonyl) ethoxycarbonyl, 2- (methylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphino) ethoxycarbonyl, 9-fluorenylmethoxycarbonyl ("FMOC"), tert-butoxycarbonyl ("BOC"), 2- (trimethylsilyl) ethoxycarbonyl, allyloxycarbonyl, 1- (trimethylsilylmethyl) prop-1-enyloxycarbonyl, 5-benzisoxazolyl (benzisoxalyl) methoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4- (decyloxy) benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidinyloxycarbonyl and the like; amino protecting groups such as benzoylmethylsulfonyl, 2- (nitro) phenylsulfinyl, diphenylphosphineoxide, and the like. The type of amino protecting group used is not critical as long as the derivatized amino group is stable under the conditions of subsequent reactions occurring at other positions of the compound of formula (I) and can be removed at the desired point without cleaving the remainder of the molecule. Commonly used amino protecting groups are allyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl and trityl. Similar amino protecting groups used in the cephalosporin, penicillin and peptide arts are also encompassed by the above terms. The related term "protected amino" refers to an amino group substituted with an amino protecting group as discussed above.

Other examples of proradicals (progroup) to which the above terms refer are described In J.W.Barton, "Protective Groups In Organic Chemistry," J.G.W.McOmie, Ed., Plenum Press, New York, N.Y., 1973 and T.W.Greene, "Protective Groups In Organic Synthesis," John Wiley and Sons, New York, N.Y., 1981.

The present invention further provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof. The term "pharmaceutical composition" as used herein refers to a composition which may be administered to a mammalian host, for example, orally, topically, parenterally, by inhalation spray, or rectally, in the form of unit dose formulations including conventional non-toxic carriers, diluents, adjuvants, vehicles, and the like. The term "parenteral" as used herein includes subcutaneous injections, intravenous, intramuscular, intracisternal injection, or by infusion techniques.

The term "therapeutically effective amount" as used herein refers to the amount of a drug or pharmaceutical agent that will elicit the therapeutic response in the subject sought. In embodiments, a therapeutically effective amount is an amount that inhibits the interaction of BACE with its physiological ligand, such as, but not limited to, Amyloid Precursor Protein (APP).

As used herein, the phrase "subject" or "subject in need of treatment" includes mammalian subjects, e.g., humans, suffering from, or at risk of, one or more of the aforementioned diseases or conditions, but may also include other mammals, e.g., dogs, cats, mice, rats, cows, horses, sheep, rabbits, monkeys, orangutans, or other apes or primates. In one embodiment, the subject is an individual who wishes to inhibit beta-secretase activity or treat the above-mentioned conditions. Thus, in the context of the treatment methods of the present invention, the methods also include methods of treating a mammalian subject prophylactically, or prior to the onset of such diseases or disease states. Factors that may influence the formulation of an effective amount will depend on the size and weight of the subject, the biodegradability of the therapeutic agent, the activity of the therapeutic agent and its bioavailability.

Pharmaceutical compositions containing the compounds of the present invention may be in a form suitable for oral use, for example, as tablets, buccal tablets, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any known method and such compositions may contain one or more ingredients selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may comprise the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. It may also be coated by these techniques to form a controlled release therapeutic osmotic tablet.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions may include the active compound in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example Heptadecaethyl-ethyleneoxycetanol (heptadecethyl-eneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids with hexitol, for example polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids with hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also include one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may include a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant, such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soybean oil, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also include a demulcent (demulcent), a preservative and fragrance and coloring agents. The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated in accordance with known procedures using suitable dispersing or wetting agents and suspending agents, as described above. The sterile injectable preparation may likewise be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable media and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils (fixed oils) are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil employing synthetic mono-or diglycerides may be employed. In addition, fatty acids, such as oleic acid find use in the preparation of injectables.

The compositions may also be in the form of suppositories for rectal administration of the compounds of the invention. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, for example, cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions, suspensions, etc., containing the compounds of the present invention are all possible. For the purposes of this application, topical application shall include mouth washes and throat rinses.

The compounds of the invention may also be administered in the form of liposomal delivery systems, such as small unilamellar liposomes, large unilamellar liposomes and multilamellar liposomes. Liposomes can be composed of a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The invention also provides prodrugs of the invention.

Pharmaceutically acceptable salts of the compounds of the present invention having basic or acidic groups in the structure are also included within the scope of the present invention. The term "pharmaceutically acceptable salt" refers to non-toxic salts of the compounds of the present invention, which are typically prepared by reacting the free base with a suitable organic or inorganic acid, or by reacting an acid with a suitable organic or inorganic base. Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, laurylsulfate, ethylsulfonate, fumarate, gluceptate (gluceptate), gluconate, glutamate, glycollylarate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, naphthalenesulfonate, nitrate, N-methylglucamine, oxalate, pamoate, palmitate, pantothenate, phosphoric acid/diphosphate, polygalacturonate, potassium salt, salicylate, sodium salt, stearate, subacetate, succinate, tannate, tartrate, theachlorate, tosylate, triethyliodide, trimethylammonium salt, and valerate. When an acidic substituent such as-COOH is present, ammonium, morpholine, sodium, potassium, barium, calcium salts and the like may be formed for use as dosage forms. When a basic group, such as amino or a basic heteroaryl group, such as pyridyl, is present, acidic salts include, for example, hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartrate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate, ethanesulfonate, picrate, and the like, and include acids associated with the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2(1977) p.1-19.

In one embodiment, the compounds of formula (I) having one or more basic groups may be used and/or formulated in the form of HCl salts.

Other non-pharmaceutically acceptable salts may be used in the preparation of the compounds of the invention and these form a further aspect of the invention.

In addition, some compounds of formula (I) may form solvates with water or common organic solvents. Such solvates are also included within the scope of the present invention.

Accordingly, another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent or mixture thereof.

Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein said therapeutically effective amount of a compound of formula (I) preferably inhibits the interaction of BACE with its physiological ligand compared to the interaction of other secretases, such as α -secretase, with its physiological ligand, and a pharmaceutically acceptable carrier, excipient, diluent or mixture thereof.

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier, excipient, diluent or mixture thereof, and further comprising one or more therapeutic agents.

The compounds of formula (I) may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of a disease or condition for which the compounds of the invention are effective. In one embodiment, the drugs combined together are safer or more effective than each drug alone. In addition, the compounds of formula (I) may be used in combination with one or more other drugs that treat, prevent, control, alleviate or reduce the risk of side effects or toxicity of the compounds of the present invention. These other drugs may be administered by a route and in their usual amounts, simultaneously or sequentially with the compound of formula (I).

Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients in addition to the compound of formula (I). The compositions may be administered as part of a unit dosage form combination product, or as a kit or treatment regimen in which one or more other drugs are administered in separate dosage forms as part of a treatment regimen.

Examples of combinations of a compound of the invention with other drugs in unit dose or kit form include combinations with: anti-Alzheimer's disease agents, other beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, non-steroidal anti-inflammatory drugs (NSAID's), including ibuprofen, naproxen, diclofenac, N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine, cholinesterase inhibitors, such as galantamine, rivastigmine, donepezil and tacrine, vitamin E, CB-1 receptor antagonists or CB-1 receptor inverse agonists, antibiotics, such as doxycycline and rifampin, agents that bind to or induce binding to a β, anti-a β antibodies, a β vaccines, RAGE/RAGE ligand interaction antagonists, and other compositions of drugs that affect receptors or enzymes, or increase the effectiveness, safety, convenience, or reduce the deleterious side effects or toxicity of the compounds of the invention.

The foregoing list of combinations is illustrative only and is not intended to be limiting in any way.

In another embodiment, the present invention provides a method comprising: administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof.

In another embodiment, the present invention provides a method of inhibiting the interaction of BACE with its physiological ligand comprising: administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof. Examples of physiological ligands for BACE include, but are not limited to, Amyloid Precursor Protein (APP).

In another embodiment, the present invention provides a method of increasing the α -secretory pathway in a subject, comprising: administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof.

In another embodiment, the invention provides a method of treating or preventing a BACE mediated disease comprising: administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, or prodrug thereof.

In another embodiment, the present invention provides a method of treating a disorder or disease selected from alzheimer's disease, mild cognitive impairment, down's syndrome, hereditary cerebral hemorrhage with amyloidosis of the dutch type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type alzheimer's disease or central or peripheral amyloid disease, comprising administering to a subject an amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester or prodrug thereof, effective in treating the disorder or disease.

In another embodiment, the invention provides a method of treating a disorder or disease wherein the disorder or disease being treated is dementia of the alzheimer's type and is selected from the group consisting of early-onset simple dementia of the alzheimer's type, early-onset dementia of the alzheimer's type with delusions, early-onset dementia of the alzheimer's type with depressed mood, late-onset simple dementia of the alzheimer's type, late-onset dementia of the alzheimer's type with delusions and late-onset dementia of the alzheimer's type with depressed mood, comprising administering to said mammal an amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester or prodrug thereof, effective in treating said disorder or disease.

In another embodiment, the present invention provides a method of treating one or more disorders associated with plaque accumulation comprising administering to a subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester or prodrug thereof. In one embodiment, administration of the compound of formula (I) reduces the rate of neurofibrillary tangle formation in the subject. In another embodiment, administration of the compound of formula (I) reduces the rate of plaque accumulation in the subject.

In the methods of the invention, the compounds of formula (I) may be administered alone or in combination with a compound selected from anti-Alzheimer's disease agents, other beta secretase inhibitors, gamma secretase inhibitors, HMG-CoA reductase inhibitors, non-steroidal anti-inflammatory drugs (NSAID's), including ibuprofen, naproxen, diclofenac, N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine, cholinesterase inhibitors, such as galantamine, rivastigmine, donepezil and tacrine, vitamin E, CB-1 receptor antagonists or CB-1 receptor inverse agonists, antibiotics, such as doxycycline and rifampin, agents that bind to or induce antibodies that bind to A β, anti-A β antibodies, A β vaccines, RAGE/RAGE ligand interaction antagonists and other influencing receptors or enzymes, or a drug that increases the effectiveness, safety, convenience, or reduces the harmful side effects or toxicity of the compounds of the invention.

The compounds of formula (I) of the present invention may be administered at dosage levels of about 0.01 to 1000mg/kg body weight of the subject being treated. In another embodiment, the compounds of formula (I) of the present invention may be administered in a dosage range of 0.01 to 100 mg/kg. In another embodiment, the compounds of formula (I) of the present invention may be administered in a dosage range of 0.5 to 10mg/kg body weight/day. The amount of active ingredient that is combined with the carrier materials to produce a single dose will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain 1mg to 2g of a compound of formula (I) and an appropriate amount of carrier material, which may vary from about 5% to 95% of the total composition. Dosage unit forms typically contain from about 5mg to about 500mg of the active ingredient. Such dosages may be considered individually by the clinician depending on the particular clinical condition of the subject being treated. It will be understood, therefore, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

Examples

The invention may be further understood by reference to the following non-limiting examples. Examples of compounds of the invention and methods useful for making and identifying useful compounds of the invention are described below.

Abbreviations used in the examples are as follows:

AcOH ═ acetic acid

Boc ═ tert-butoxycarbonyl

CDI ═ carbonyldiimidazole

DCC ═ N, N-dicyclohexylcarbodiimide

DCE ═ 1, 2-dichloroethane

DCM ═ dichloromethane

DDQ ═ 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinoline

DIAD (diisopropyl azodicarboxylate)

DIEA is diisopropylethylamine

DME ═ dimethoxyethane

DMF ═ N, N-dimethylformamide

DMSO ═ dimethyl sulfoxide

EDCI ═ 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride

EDTA-EDTA

Et₂Ethyl ether (O ═ ethyl ether)

EtOAc ═ ethyl acetate

h is hour

HBTU ═ O-benzotriazol-1-yl-N, N' -tetramethyluronium hexafluorophosphate

m-CPBA ═ m-chloroperbenzoic acid

N-methylpyrrolidine and NMP

r.t. room temperature

TEA ═ triethylamine

THF ═ tetrahydrofuran

In 4 Waters 1525 binary HPLC pumps were run and equipped with parallel MUX with Mux-UV 2488 multichannel UV-Vis detector (recorded at 215 and 254 nM) and Leap technologies HTS PAL autosampler ^TMSystematically, elution was performed with a waters Xterra MS C18 column (4.6X 50mm) gradient, giving LC-MS data. A three minute gradient was run from 25% B (97.5% acetonitrile, 2.5% water, 0.05% TFA) and 75% a (97.5% water, 2.5% acetonitrile, 0.05% TFA) to 100% B. The system was connected to a waters micromass ZQ mass spectrometer using electrospray ionization. All MS data were obtained in positive ion mode unless otherwise stated. Obtained on a Varian 400 MHz spectrometer¹H NMR data.

General procedure a: formation of amides

To a solution of carboxylic acid (1.0mmol) in dry DMF (2.5mL) was added HBTU (1.2mmol) in one portion, the reaction mixture was stirred at room temperature for 10min, then amine (1.0mmol) and DIEA (0.8mL) were added sequentially. The resulting reaction mixture was stirred at room temperature for 12 hours, or in some cases at 70 ℃ for 1-3 hours. The reaction mixture was diluted with water (50mL) to precipitate the product. The product was either isolated by filtration, followed by washing with water and ethyl acetate, or by silica gel column chromatography.

General procedure B: hydrolysis of methyl benzoate

To a suspension of methyl ester (1.0mmol) in methanol (5mL) was added lithium hydroxide monohydrate (5.0mmol), water (5mL) and THF (5 mL). The reaction mixture was refluxed for 2 h. After cooling to room temperature, the reaction mixture was neutralized with AcOH (3 mL). After removal of the organic solvent under vacuum, the crude product was suspended in water (50mL) and collected by filtration. The solid was further washed with water and dried under high vacuum to give the corresponding acid.

General procedure C: reduction of nitro groups to amines

10.0mmol of nitro compound was dissolved in 20mL of CH₃OH and 5mL acetic acid. To the stirred solution was added 100mg of 10% Pd/C and the resulting mixture was in H at 42psi₂Hydrogenation at room temperature for 3.0 h. The reaction mixture was filtered and the solid was washed with portions of methanol. And combining the filtrate and the washing liquid, and evaporating to dryness to obtain the corresponding amine. The product was used directly in the subsequent reaction without further purification.

Example 1

Synthesis of 2, 3-diamino-benzoic acid methyl ester from 2-amino-3-nitro-benzoic acid methyl ester (2.0g, 10.2mmol) as described in general procedure C. 1.7g (10.0mmol) of isoquinoline-3-carboxylic acid and 4.6g (12.0mmol) of HBTU are reacted with 1.7g (10.2mmol) of the diamine synthesized above as described in general procedure A to give 2-amino-3- [ (isoquinoline-3-carbonyl) -amino ] -amino]-benzoic acid methyl ester. LCMS: 322(M +1)⁺.

To the crude 2-amino-3- [ (isoquinoline-3-carbonyl) -amino group]-methyl benzoate in AcOH (25mL) solution AcONH was added₄(16g) In that respect The reaction mixture was refluxed for 3 h. After removal of the AcOH under vacuum, the reaction mixture was washed with water (150 mL). The crude solid product, 2-isoquinolin-3-yl-1H-benzimidazole-4-carboxylic acid methyl ester, was collected after filtration. LCMS: 304(M +1) ⁺. This product was hydrolyzed according to general procedure C to give 2-isoquinolin-3-yl-1H-benzimidazole-4-carboxylic acid (1.6g, 55% overall yield from the three-step reaction). LCMS: 290(M+1)⁺。

To a solution of 2.0g (10mmol) of 2-bromoacetophenone in DMF (30mL) was added 3.0g (29mmol) of 1-acetylguanidine in one portion and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with EtOAc (250mL) and saturated NH₄Aqueous CI (50 mL). Organic phase over MgSO₄Dried and concentrated under vacuum. The residue was purified by flash column chromatography eluting with EtOAc to give N- (4-phenyl-1H-imidazol-2-yl) -acetamide (0.5g, 24%). LCMS: 203(M +1)⁺.

To a solution of the above 0.5g (2.4mmol) N- (4-phenyl-1H-imidazol-2-yl) -acetamide in MeOH (20mL) was added water (20mL) and concentrated H₂8O₄(1 mL). The mixture was refluxed under nitrogen for 2 days. After cooling to room temperature, the organic solvent was removed under vacuum. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate (50mL) and extracted with ethyl acetate (150 mL). The organic layer was dried and concentrated. The residue was purified by flash column chromatography eluting with EtOAc followed by EtOAc/MeOH 7: 1 to give 4-phenyl-1H-imidazol-2-ylamine (160mg, 41%). LCMS: 160(M +1)⁺.

Following general procedure A, 120mg (0.4mmol) of 2-isoquinolin-3-yl-1H-benzimidazole-4-carboxylic acid were reacted with 400mg (1.1mmol) of HBTU and 160mg (1.0mmol) of 4-phenyl-1H-imidazol-2-ylamine (160mg, 1 mmol). The residue was purified by flash column chromatography (EtOAc) to give 2-isoquinolin-3-yl-1H-benzimidazole-4-carboxylic acid (4-phenyl-1H-imidazol-2-yl) -amide (30mg, 17.5%). LCMS: 431(M +1) ⁺.

The compounds of examples 2-7 were prepared using procedures analogous to those used to prepare the compound of example 1.

Examples	Amide position	W	Ar₁	LCMS (M+1)⁺
					2	5	Isobutyl radical	2-isoquinolin-3-yl	355
3	5	1H-benzimidazol-2-yl	Pyridin-2-yl	355
					4	5	1H-benzimidazol-2-yl	2-naphthalen-2-yl	404
5	4	Isobutyl radical	2-isoquinolin-3-yl	345
					6	4	Phenyl radical	2-isoquinolin-3-yl	365
7	4	N-butyl	2-isoquinolin-3-yl	345

Example 8

1.6g of 2-isoquinolin-3-yl-1H-benzimidazole-5-carboxylic acid were prepared according to the method for the synthesis of 2-isoquinolin-3-yl-1H-benzimidazole-4-carboxylic acid described in example 1, starting with 1.7g (10mmol) of methyl 3, 4-diaminobenzoate.

203mg (1.0mmol) of 3-tert-butoxycarbonylamino-3-cyclopropyl-propionic acid (0.23g, 1mmol) were reacted with 380mg (1.0mmol) of HBTU and 130mg (1.0mmol) of 2-aminoimidazole sulfate as described in general procedure A. The target amide product was isolated by column chromatography (EtOAc/silica gel) and directly subjected to the next step. The BOC compound in DCM (3mL) was treated with 4.0M HCl/dioxane (15mL) for about 1 h. Solid 3-amino-3-cyclopropyl-N- (1H-imidazol-2-yl) -propionamide (180mg, 100%) was collected by filtration and used directly in the next step.

289mg (1mmol) of 2-isoquinolin-3-yl-1H-benzene are reacted as described in general method ABenzimidazole-5-carboxylic acid (289mg, 1mmol) was reacted with 380mg (1mmol) HBTU and 3-amino-3-cyclopropyl-N- (1H-imidazol-2-yl) -propionamide (230mg, 1 mmol). Precipitating the solid from the solution, collecting the solid by filtration, and purifying with H₂O and Et₂O washing to obtain 2-isoquinoline-3-yl-1H-benzimidazole-5-carboxylic acid [ 1-cyclopropyl-2- (1H-imidazole-2-ylcarbamoyl) -ethyl]Amide (20mg, 4%). LCMS: 466(M +1)⁺.¹H NMR(DMSO-d₆，400MHz)：δ9.20(s，1H)，8.56(s，1H)，8.09-7.34(m，9H)，6.39(s，2H)，3.71(t，1H)，2.44(m，2H)，0.81(m，1H)，0.10(m，4H)ppm.

Example 9

229mg (1.0mmol) of 1-tert-butoxycarbonylamino-cyclopentanecarboxylic acid (0.23g, 1mmol) were reacted with 420mg (1.2mmol) of HBTU and 200mg (1.5mmol) of 2-aminoimidazole sulfate as described in general method A. The BOC compound in DCM (3mL) was treated with 4.0M HCl/dioxane (15mL) for about 1 h. The solid 1-amino-cyclopentanecarboxylic acid (1H-imidazol-2-yl) -amide HCl salt (230mg, 100%) was collected by filtration and used directly in the next step.

145mg (0.5mmol) of 2-isoquinolin-3-yl-1H-benzimidazole-5-carboxylic acid (synthesized in example 1, step 3) were reacted with 280mg (0.75mmol) of HBTU and 1-amino-cyclopenta-rboxylic acid (1H-imidazol-2-yl) -amide HCl salt (120mg, 0.5mmol) as described in general procedure A. Precipitating the solid from the solution, collecting the solid by filtration, and purifying with H ₂O and EtOAc washes to give 2-isoquinolin-3-yl-1H-benzimidazole-5-carboxylic acid [1- (1H-imidazol-2-ylcarbamoyl) -cyclopentyl]Amide (24mg, 10%). LCMS: 466(M +1)⁺.

The compounds of examples 10-36 were prepared using procedures analogous to those used to prepare the compound of example 9.

Examples	X	Stereochemistry	B	N	LCMS (M+1)⁺
						10	2-fluorobenzyl	S	1H-imidazol-2-yl	0	520
11	Benzyl radical	S	1H-imidazol-2-yl	0	502
						12	2-chlorobenzyl	S	1H-imidazol-2-yl	0	536
13	2-fluorophenyl group	Despin	1H-imidazol-2-yl	1	520
						14	Biphenyl radical	Despin	1H-imidazol-2-yl	1	578
15	3, 5-difluoro-benzyl	S	1H-imidazol-2-yl	0	538
						16	2-phenyl-ethyl	R	1H-imidazol-2-yl	1	530
17	4-phenyl-benzyl	Despin	1H-imidazol-2-yl	1	592
						18	3-fluorobenzyl	S	1H-imidazol-2-yl	0	520
19	4-methoxyphenyl radical	Despin	1H-imidazol-2-yl	1	532
						20	Phenyl radical	Despin	1H-imidazol-2-yl	1	502
21	4-chlorobenzyl	S	1H-imidazol-2-yl	0	536
						22	4-methylbenzyl radical	S	1H-imidazol-2-yl	0	516
23	Benzyl radical	S	Thiazol-2-yl	0	519
						24	Benzyl radical	S	Pyridin-2-yl	0	513
25	3, 4, 5-trifluorobenzyl	S	1H-imidazol-2-yl	0	556
						26	3-methoxyphenyl radical	Despin	1H-imidazol-2-yl	1	532
27	3-trifluoromethylbenzyl group	S	1H-imidazol-2-yl	0	570
						28	2, 2-Dimethylpropyl	S	1H-imidazol-2-yl	0	482
29	Benzyl radical	S	1H-benzimidazol-2-yl	0	552
						30	4-fluorobenzyl	S	1H-imidazol-2-yl	0	520
31	4-phenyl-benzyl	Despin	1H-imidazol-2-yl	0	578
						32	Isobutyl radical	S	1H-imidazol-2-yl	0	468
33	3-fluorophenyl group	Despin	1H-imidazol-2-yl	1	520
						34	But-2-yl	S	1H-imidazol-2-yl	0	468
35	Isopropyl group	S	1H-imidazol-2-yl	0	454
						36	3-chlorobenzyl	S	1H-imidazol-2-yl	0	536

Example 37

1.05g (5.0mmol) 2-amino-3- (3, 5-difluoro-phenyl) -propionic acid (1.05g, 5mmol) was dissolved in 30.0mL MeOH, then 1.0mL thionyl chloride was added dropwise. The mixture was refluxed overnight. The solvent was evaporated to dryness to afford 2-amino-3- (3, 5-difluoro-phenyl) -propionic acid methyl ester HCl salt as a solid (1.26g, 100%) and used directly in the next step.

145mg (0.5mmol) of 2-isoquinolin-3-yl-1H-benzimidazole-4-carboxylic acid (synthesized in example 1, step 3) are reacted with 280mg (0.75mmol) of HBTU and 2-amino-3- (3, 5-difluoro-phenyl) -propionic acid methyl ester HCl salt (126mg, 0.5mmol) as described in general procedure A. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL). The organic phase was washed with 1% aqueous NaOH solution and then Na ₂SO₄Dried and concentrated under vacuum. The residue is purified by flash column chromatography (eluting first with DCM/EtOAc 1: 1 and then DCM/EtOAc/MeOH 15: 1) to give 3- (3, 5-difluoro-phenyl) -2- [ (2-isoquinolin-3-yl-1H-benzimidazole-4-carbonyl) -amino ] -2- [ (2-oxo-3-yl ] -1H-benzimidazole-4-carbonyl ] -amino ] -amide]Methyl propionate (120mg, 50%). LCMS: 487(M +1)⁺.

Example 38

100mg (0.2mmol) of (3- (3, 5-difluoro-phenyl) -2- [ (2-isoquinolin-3-yl-1H-benzimidazole-4-carbonyl) -amino-e-nz-e-a-mine-B-as described in general method B]-methyl propionate waterHydrolysis to give 3- (3, 5-difluoro-phenyl) -2- [ (2-isoquinolin-3-yl-1H-benzimidazole-4-carbonyl) -amino]Propionic acid (97mg, 100%). LCMS: 473(M +1)⁺.

Example 39

602mg (2.0mmol) 2-tert-butoxycarbonylamino-3- (3, 5-difluoro-phenyl) -propionic acid (0.60g, 2mmol) were reacted with 1140mg (3.0mmol) HBTU and 400mg (3.0mmol) 2-aminoimidazole sulfate as described in general procedure A. The BOC compound was treated with 4.0M HCl/dioxane (15mL) in DCM (3mL) for about 1 h. Solid 2-amino-3- (3, 5-difluoro-phenyl) -N- (1H-imidazol-2-yl) -propionamide HCl salt (303mg, 50%) was collected by filtration and used directly in the next step.

145mg (0.5mmol) of 2-isoquinolin-3-yl-1H-benzimidazole-4-carboxylic acid are reacted with 280mg (0.75mmol) of HBTU and 2-amino-3- (3, 5-difluoro-phenyl) -N- (1H-imidazol-2-yl) -propionamide HCl salt (152mg, 0.5mmol) as described in general procedure A. Precipitating the solid from the solution, collecting the solid by filtration, and purifying with H ₂O and EtOAc washes to give 2-isoquinolin-3-yl-1H-benzimidazole-4-carboxylic acid [2- (3, 5-difluoro-phenyl) -1- (1H-imidazol-2-ylcarbamoyl) -ethyl]Amide (60mg, 22%). LCMS: 538(M +1)⁺.

The compounds of examples 40-46 were prepared using procedures analogous to those used to prepare the compound of example 39.

Examples	X	B	LCMS (M+1)⁺
				40	Benzyl radical	1H-benzimidazol-2-yl	552
41	3, 5-difluorobenzyl	Methyl radical	486
				42	Benzyl radical	2-methyl-piperidine-1-carboxylic acid tert-butyl ester	633
43	Benzyl radical	Thiazol-2-yl	519
				44	Benzyl radical	Isobutyl radical	492
45	Benzyl radical	3-methyl-piperidine-1-carboxylic acid tert-butyl ester	633
				46	Benzyl radical	Benzothiazol-2-yl	569

Example 47

To a stirred solution of 0.86g (6.0mmol) isoquinolin-3-ylamine in dry THF (30mL) was added 1.25g (7.0mmol) of bis-imidazol-1-yl-thione. The reaction mixture was refluxed for 30 min. After cooling to room temperature, a solution of 1.7g (10mmol) of 2, 3-diamino-benzoic acid methyl ester (synthesis see example 1) in TBDF (40mL) and DIEA (2mL) were added in succession. The reaction mixture was stirred at room temperature for 1h and diluted with hexane (40 mL). The resulting precipitate was filtered. The solid was washed with water and diethyl ether and dried under vacuum to give methyl 2-amino-3- (3-isoquinolin-3-yl-thioureido) -benzoate as a solid.

To a solution of the above thiourea (6.0mmol) in DCE (50mL) were added polymer supported DCC (6.0g, 7.8mmol) and DMF (25 mL). The reaction mixture was stirred at 85 ℃ for 1 h. The hot reaction mixture was filtered and the solid resin on the filter paper was further washed with hot DMF (25 mL). The combined organic solutions were concentrated in vacuo to give methyl 2- (isoquinolin-3-ylamino) -3H-benzimidazole-4-carboxylate. This methyl ester was hydrolyzed according to general procedure C to give 2- (isoquinolin-3-ylamino) -3H-benzimidazole-4-carboxylic acid (1.3g, 71% overall yield from the 3-step reaction). LCMS: 305(M +1)⁺.

Following general procedure A, 100mg (0.33mmol) of the above carboxylic acid were reacted with 200mg (0.53mmol) HBTU and 200mg (1.2mmol) 2-aminoimidazole sulfateShould be used. The crude product was purified by flash column chromatography (eluting with EtOAc followed by EtOAc/MeOH 10: 1) to give 2- (isoquinolin-3-ylamino) -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (20mg, 15%). LCMS: 370(M +1)⁺.¹H NMR(DMSO-d₆，400MHz)：δ6.82(s，1H)，6.89(s，1H)，7.20(dd，1H)，7.47(dd，1H)，7.71(m，2H)，7.84(dd，1H)，8.04(s，1H)，8.08(d，1H)，8.18(d，1H)，9.21(s，1H)，11.14(s，1H)，11.84(s，1H)，12.11(s，1H)，12.60(s，1H)ppm.

The compounds of examples 48-57 were prepared using procedures analogous to those used to prepare the compound of example 47.

Examples	Amide position	G₁	G₂	LCMS (M+1)⁺
					48	5	1H-imidazol-2-yl	2-Isoquinolin-3-yl	370
49	4	4-fluorophenyl group	2-isoquinolin-3-yl	398
					50	4	Phenyl radical	2-isoquinolin-3-yl	380
51	5	1H-imidazol-2-yl	Pyridin-2-yl	320
					52	4	4-chlorophenyl group	2-isoquinolin-3-yl	414
53	4	4-methoxyphenyl radical	2-isoquinolin-3-yl	410
					54	4	Benzyl radical	2-isoquinolin-3-yl	394
55	5	Benzo 1H-imidazol-2-yl	Pyridin-2-yl	370
					56	4	3-hydroxypropyl radical	2-isoquinolin-3-yl	362
57	4	Methyl radical	2-isoquinolin-3-yl	318

Intermediate A-2-amino-3H-benzimidazole-4-carboxylic acid methyl ester

Methyl 2, 3-diamino-benzoate was synthesized in some yield (1.7g) from methyl 2-amino-3-nitro-benzoate (2.0g, 8.8mmol) as described in general procedure C.

1.7g (10.2mmol) of the above methyl ester were dissolved in 20mL of ethanol and 10mL of H₂And O in a mixture. To this stirred solution was added 1.6g (15.3mmol) BrCN in one portion and the resulting mixture was refluxed for 1.0 h. The reaction mixture was cooled to room temperature and concentrated to 10mL, washed with ethyl acetate (20 mL). The EtOAc layer was extracted with water (20 mL). With saturated NaHCO₃The combined aqueous extracts were neutralized to pH about 8 and the resulting suspension was extracted with EtOAc (50 mL). The organic layer was washed with water and brine solution and dried (Na)₂SO₄) And evaporated to dryness to give 1.7g (90%) of the title compound. LCMS: 192(M +1) ⁺.

Intermediate B-2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide

5.0g (27.4mmol) 2-amino-3-nitro-benzoic acid, 12.48g (32.9mmol) HBTU were suspended in 20mL DMF. To this suspension 10mL DIEA was added and the resulting mixture was stirred for 10min to form a paste. To the paste was added 10mL of DMF followed by 9g (68.2mmol) of 2-aminoimidazole sulfate. The resulting mixture was heated at 75 ℃ for 3.0 h. The reaction mixture was cooled to room temperature, 5mL of 2N NaOH was added, followed by 200mL of brine solution. The solid precipitated from solution, and the solid was collected by filtration, washed with water (300ml), ethyl acetate (100ml) and dried under vacuum to give 5.3g (75%) of 2-amino-N- (1H-imidazol-2-yl) -3-nitro-benzamide as a yellow solid. This product was hydrogenated according to general procedure C to give 2, 3-diamino-N- (1H-imidazol-2-yl) -benzamide (4.5 g).

4.5g (21.2mmol) of the above solid were dissolved in 40mL of ethanol and 8mL of H₂And O in a mixture. To the stirred solution was added 3.3g (31.8mmol) BrCN and the resulting mixture was refluxed for 1.0 h. The reaction mixture is cooled to room temperature, the solvent is evaporated off and taken up with NH₄The pH of the aqueous OH solution was adjusted to about 8.0. What is needed isThe solid obtained is filtered. The solid was further washed with water (100mL), ethyl acetate (50mL) and dried under vacuum to give 2.5g (50%) of 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide. LCMS: 243(M +1) ⁺.

Example 58

Synthesis of 2.6g (75%) of 2- [ (isoquinoline-3-carbonyl) -amino ] -4-carboxylic acid from isoquinoline-3-carboxylic acid (1.7g, 10mmol), HBTU (4.6g, 12mmol) and methyl 2-amino-3H-benzimidazole-4-carboxylate (1.9g, 10mmol) synthesized above as described in general procedure A]-1H-benzimidazole-4-carboxylic acid methyl ester. The ester was then hydrolyzed according to general procedure B to give 2.2g (88%) of acid. LCMS: 333(M +1)⁺.

332mg (1.0mmol) of the above-mentioned 2- [ (isoquinoline-3-carbonyl) -amino group are reacted as described in general method A]-1H-benzimidazole-4-carboxylic acid (0.33g, 1.0mmol) was reacted with 800mg (2.0mmol) HBTU and 2-aminoimidazole sulfate (400mg, 3.0mmol) in 3.0mL DMF and 1.0mL DIEA. After cooling to room temperature, the reaction mixture was diluted with 0.6mL of 5N aqueous NaOH solution and 4.0mL of brine. The solid was collected by filtration, washed with 2N aqueous NaOH (3.0mL) and then H₂O and EtOAc (3X each) washes to provide 224.0mg of crude compound. The crude product was heated in 3.0mL of DMF at 80 ℃ for 20 min. The filter cake was washed with another 1.0mL of hot DMF. The combined filtrates were reheated to a clear solution, then cooled, 2.0mL EtOAc added, then 4.0mL H added₂And O. The mixture was stirred and the solid gradually dissolved in EtOAc and DMF/H ₂And the O layer is formed between the O layers. Filtering to collect solid, and using H₂O, EtOAc and MeOH (3 times each) and then dried to give isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]Amide (83.0mg, 21%). LCMS: 398.0(M +1)⁺.¹H NMR(DMSO-d₆，400MHz)：δ12.29(s，1H)，11.86(s，1H)，9.52(s，1H)，8.81(s，1H)，8.31(t，2H)，7.80-7.95(m，4H)，7.32(t，1H)，6.88(s，1H)，6.77(s，1H)ppm.

Example 59

70mg (0.45mmol) 4-chloro-benzoic acid, 170mg (0.45mmol) HBTU were reacted in a mixture of 3mL DMF and 1mL DIEA with 100mg (0.4mmol) of the 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide synthesized above and 2- (4-chloro-benzoylamino) -1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide isolated (30mg, 17.24%) as described in general procedure A. LCMS: 382(M +1)⁺.¹H NMR(DMSO-d₆，400MHz)：δ11.99(d，1H)，8.16(d，2H)，7.94(d，1H)，7.70(dd，3H)，7.30(t，1H)，6.81(d，2H)ppm.

The compounds of examples 60-127 were prepared using procedures analogous to those used to prepare example 59.

Examples	Amide position	W	Ar₁	LCMS (M+1)⁺
					60	4	1H-benzimidazol-2-yl	Isoquinolin-3-yl	448
61	4	Benzothiazol-2-yl	Isoquinolin-3-yl	465
					62	4	{1, 3, 4} -thiadiazol-2-yl radical	Isoquinolin-3-yl	416
63	4	Pyridin-2-yl	Isoquinolin-3-yl	409
					64	4	Pyridin-3-yl	Isoquinolin-3-yl	409
65	4	1H-benzimidazol-2-yl	1H-indol-2-yl	435
					66	5	1H-benzimidazol-2-yl	Isoquinolin-3-yl	448
67	4	1H-indazol-5-yl	Isoquinolin-3-yl	448
					68	4	Quinolin-3-yl	Isoquinolin-3-yl	459
69	5	Benzothiazol-2-yl	Isoquinolin-3-yl	465
					70	5	Thiazol-2-yl	Isoquinolin-3-yl	415
71	4	1H-imidazol-2-yl	Phenyl radical	347
					72	4	Furan-2-ylmethyl	Isoquinolin-3-yl	412
73	4	2-phenoxy-phenyl	Isoquinolin-3-yl	500
					74	4	3-phenoxy-phenyl	Isoquinolin-3-yl	500
75	4	4-phenoxy-phenyl	Isoquinolin-3-yl	500
					76	4	(1S) -1-Phenylethyl	Isoquinolin-3-yl	436
77	4	(1R) -1-phenylethyl group	Isoquinolin-3-yl	436
					78	4	1H-imidazol-2-yl	Benzothiophen-2-yl	403
79	4	1H-imidazol-2-yl	Naphthalen-2-yl	397
					80	4	1H-imidazol-2-yl	4' -Biphenyl radical	423
81	4	1H-imidazol-2-yl	1H-indol-2-yl	386
					82	4	1H-imidazol-2-yl	3, 5-difluorophenyl	383
83	4	1H-imidazol-2-yl	4-fluorophenyl group	365
					84	4	(Thien-2-yl) ethyl	Isoquinolin-3-yl	442
85	5	Phenyl radical	Isoquinolin-3-yl	408
					86	4	(5-Methylfuran-2-yl) -methyl	Isoquinolin-3-yl	426
87	4	Benzyl radical	Isoquinolin-3-yl	422
					88	4	(Thien-2-yl) methyl	Isoquinolin-3-yl	428
89	4	Phenylethyl group	Isoquinolin-3-yl	436
					90	4	Ethyl radical	Isoquinolin-3-yl	360
91	4	Tert-butyl radical	Isoquinolin-3-yl	388
					92	4	1H-imidazol-2-yl	Benzofuran-2-yl	387
93	4	2, 3, 4, 9-tetrahydro-1H-beta-carbolin-2-yl	Isoquinolin-3-yl	487
					94	4	(Benzothien-2-yl) methyl	Isoquinolin-3-yl	478
95	4	(benzothiazol-2-yl) methyl	Isoquinolin-3-yl	479
					96	4	(1-methylbenzimidazol-2-yl) methyl	Isoquinolin-3-yl	476
97	4	2- (1H-benzimidazol-2-yl) ethyl	Isoquinolin-3-yl	476
					98	4	1H-imidazol-2-yl	4-fluorobenzyl	379
99	4	1H-imidazol-2-yl	3-methoxy-4-fluoro-phenyl	395
					100	4	1H-imidazol-2-yl	3, 4-Dimethoxyphenyl	407
101	4	Thiazol-2-yl-methyl	Isoquinolin-3-yl	429
					102	4	1H-benzimidazol-2-ylmethyl	Isoquinolin-3-yl	462
103	4	1H-imidazol-2-yl	4-trifluoromethylphenyl group	415
					104	4	1H-imidazol-2-yl	4-phenoxyphenyl	439
105	4	1H-imidazol-2-yl	Quinolin-3-yl	398
					106	4	1H-imidazol-2-yl	Quinolin-2-yl	398
107	4	1H-imidazol-2-yl	Furan-3-yl	334
					108	4	1H-imidazol-2-yl	4-tert-butyl-phenyl	403
109	4	1H-imidazol-2-yl	4-Nitro-phenyl	392
					110	4	1H-imidazol-2-yl	4-methoxy-phenyl	377
111	4	1H-imidazol-2-yl	1H-imidazol-2-yl	337
					112	4	1H-imidazol-2-yl	4-isopropyl-phenyl	389
113	4	1H-imidazol-2-yl	3-fluoro-phenyl	365
					114	4	1H-imidazol-2-yl	2-fluoro-phenyl	365
115	4	1H-imidazol-2-yl	5-chloro-benzofuran-2-yl	421
					116	4	1H-imidazol-2-yl	6, 7-dimethoxy-2-isoquinolin-3-yl	458
117	4	1H-imidazol-2-yl	3-chloro-phenyl	381
					118	4	1H-imidazol-2-yl	2-chloro-phenyl	381
119	4	1H-imidazol-2-yl	1H-indazol-3-yl	387
					120	4	1H-imidazol-2-yl	1-methyl-indol-2-yl	400
121	4	1H-imidazol-2-yl	1-methyl-indazol-3-yl	401
					122	4	4-phenyl-1H-imidazol-2-yl	Isoquinolin-3-yl	474
123	4	1H-imidazol-2-yl	5-methyl-indol-2-yl	400
					124	4	1H-imidazol-2-yl	5-phenoxy-pyridin-2-yl	440
125	4	1H-imidazol-2-yl	1-benzyl-indol-2-yl	476
					126	4	1H-imidazol-2-yl	1-n-propyl-indol-2-yl	428
127	4	1H-imidazol-2-yl	1, 5-dimethyl-indol-2-yl	414

Example 128

1.0g (5.2mmol) of methyl 2-amino-3H-benzimidazole-4-carboxylate are suspended in 10mL of concentrated H at-15 ℃₂SO₄And (4) cooling to-30 ℃. Potassium nitrate (0.58g, 5.72mmol), dissolved in 10mL of sulphuric acid and cooled to 0 ℃, was then added dropwise to the reaction mixture. The reaction mixture was stirred at-30 ℃ for 15min and then heated to-10 ℃ within 30 min. The mixture was then poured into a beaker containing ice and neutralized with a concentrated aqueous ammonia solution (pH about 8). The resulting solid was filtered. The resulting solid was washed with cold water and ether and dried under vacuum to give 0.85g (70%) of methyl 2-amino-6-nitro-1H-benzimidazole-4-carboxylate as a solid. LCMS: 239(M +1)⁺.

As described in general procedure A, 0.5g (2.12mmol) methyl 2-amino-6-nitro-1H-benzimidazole-4-carboxylate were reacted with 0.37g (2.12mmol) isoquinoline-3-carboxylic acid and 0.89g (2.33 mmol) HBTU to give 0.67g (80%) 2- [ (isoquinoline-3-carbonyl) -amino ] -b-enz-e]-6-nitro-1H-benzimidazole-4-carboxylic acid methyl ester. LCMS: 392(M +1)⁺. The ester was dissolved in dry DMF (5mL) and 0.22g (5.1mmol) LiCl was added in one portion. The resulting mixture was stirred at 120 ℃ for 12h, diluted with water and the solid collected by filtration. The solid was washed with water (20mL), diethyl ether (10mL) and dried under vacuum to give 0.6g (93%) of 2- [ (isoquinoline-3-carbonyl) -amino group ]-6-nitro-1H-benzimidazole-4-carboxylic acid. LCMS: 378(M +1)⁺.

0.5g (1.3mmol) of the above-mentioned acid (example 128) are reacted with 0.6g (1.6mmol) of HBTU and 0.35g (1.3mmol) of 2-aminoimidazole as described in general method A. After completion of the reaction, the reaction mixture was diluted with water 20(mL), 3.0mL of 2N NaOH and stirred for 15 min. The resulting solid was filtered, washed with water, diethyl ether and dried under vacuum to give 0.1g (17.2%) of isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -6-nitro-1H-benzimidazol-2-yl]-an amide. LCMS: 443(M +1)⁺.

Example 129

0.1g (0.2mmol) of isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -6-nitro-1H-benzimidazol-2-yl]The amide (example 129) was suspended in a mixture of 2mL DMF and 5mL acetic acid. To the stirred solution was added about 20mg of 10% Pd/C and the resulting mixture was in H at 42psi₂Hydrogenation at room temperature for 3.0 h. The reaction mixture was filtered and the solid was washed with 5ml of dmf. The filtrate and washings were combined, evaporated to reduce the volume to 10mL, and then saturated NaHCO was used₃Diluted (10mL) and extracted with ethyl acetate. The organic layer was washed with water and brine and evaporated to dryness to give 85mg (91%) of isoquinoline-3-carboxylic acid [ 6-amino-4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ]-an amide. LCMS: 413(M +1)⁺.

Example 130

20mg (0.04mmol) of isoquinoline-3-carboxylic acid [ 6-amino-4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]The amide (example 129) was dissolved in pyridine (2 mL). To this stirred solution was added 5.6mg (0.053mmol) of isobutyryl chloride in one portion at 0 ℃. The reaction mixture was stirred at 0 ℃ for 10min and warmed to room temperature. The pyridine was evaporated to dryness and water (5mL) was added to the reaction mixture. The mixture was stirred for 10min, the resulting solid was filtered, washed with water (2mL) and diethyl ether (5mL), and dried to give 15.5mg (66.5%) of isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -6-isobutyramido-1H-benzimidazol-2-yl]-an amide. LCMS: 483(M +1)⁺.¹HNMR(CD₃OD，400MHz)：δ9.43(s，1H)，8.77(s，1H)，8.06-8.31(m，5H)，7.80-7.93(m，3H)，7.08(s，2H)，2.45(m，1H)，1.1(d，6H)ppm.

The compound of example 131-133 was prepared in a similar manner to the compound used to prepare example 130.

Examples	R	LCMS(M+1)⁺
			131	Phenyl radical	517
132	Isobutyl radical	497
			133	Benzyl radical	531

Example 134

To a solution of 0.1g (0.52mmol) of methyl 2-amino-1H-benzimidazole-4-carboxylate (intermediate A) in DMSO (1mL) was added 0.089g (0.52mmol) of benzyl bromide and the reaction mixture was stirred at room temperature for 3H. The progress of the conversion was monitored by LCMS. After conventional work-up, the residue was purified by column chromatography eluting with DCM/methanol (v/v ═ 10: 1) to give 0.08g (55%) of methyl 2-amino-1-benzyl-1H-benzimidazole-4-carboxylate. LCMS: 281(M +1) ⁺；¹H NMR(DMSO-d₆，400MHz)：δ7.49(dd，1H)，7.29(t，2H)，7.25(m，2H)，7.16(m，2H)，7.05(bs，2H)，6.85(t，1H)，5.28(s，2H)，3.79(s，3H)ppm.

To a solution of 0.031g (0.18mmol) isoquinoline-3-carboxylic acid in DMF (1mL) are added 0.085g (0.22mmol) HBTU and 0.1mL DIEA. The mixture was stirred for 5min, then 0.04g (0.18mmol) of 2-amino-1-benzyl-1H-benzimidazole-4-carboxylic acid methyl ester was added in one portion. The reaction mixture was stirred for 1 h. After customary work-up, purification is carried out by column chromatography eluting with DCM/methanol (v/v from 15: 1 to 10: 1) and 45mg (73%) of 1-benzyl-2- [ (isoquinoline-3-carbonyl) -amino ] -are isolated]-1H-benzimidazole-4-carboxylic acid methyl ester. LCMS: 437(M +1)⁺；¹H NMR(DMSO-d₆，400MHz)：δ12.8(s，1H)，9.41(s，1H)，8.92(s，1H)，8.20(d，1H)，8.14(d，1H)，7.84(t，1H)，7.77(m，3H)，7.51(d，2H)，7.32(m，4H)，5.63(s，2H)，3.99(s，3H)ppm.

Example 135

To a solution of 45mg (0.12mmol) (1-benzyl-2- [ (isoquinoline-3-carbonyl) -amino)]To a solution of-1H-benzimidazole-4-carboxylic acid methyl ester (example 134) in THF (1mL) were added methanol (1mL) and a 1N solution of LiOH (1 mL). The reaction was heated at 65 ℃ for 45min and the progress of the conversion was monitored by TLC. After cooling to room temperature, the solvent was removed under reduced pressure and the reaction residue was acidified by addition of 1N HCl solution (pH 2). The solid product was collected by filtration and further dried to yield 43mg (100%) of 1-benzyl-2- [ (isoquinoline-3-carbonyl) -amino]-1H-benzimidazole-4-carboxylic acid. LCMS: 423(M +1)⁺.

To a solution of 43mg (0.12mmol) of the above crude acid in DMF (0.7mL) was added 75mg (0.2mmol) HBTU and DIEA (0.1 mL). The mixture was stirred for 5min, then 40mg (0.3mmol) of 2-aminoimidazole sulfate were added in one portion. The reaction mixture was heated at 80 ℃ for 1 h. After routine inspection, 25mg (50%) of isoquinoline-3-carboxylic acid [ 1-benzyl-4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ] -is isolated as described in general procedure A, eluting with DCM/methanol (v/v from 15: 1 to 7: 1) via column chromatography ]-an amide. LCMS: 488(M +1)⁺.

Example 136

15mg of isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1-methyl-1H-benzimidazol-2-yl ] was synthesized in the same manner as described in example 135, except that methyl iodide was used instead of benzyl bromide]-an amide. LCMS: 412(M +1)⁺.

Example 137

Except that methyl iodide is used instead of benzyl bromide and benzylamine is used instead of 2-aminoimidazole sulfate, according to20mg of isoquinoline-3-carboxylic acid (4-benzylcarbamoyl-1-methyl-1H-benzimidazol-2-yl) -amide is synthesized in the same manner as described in example 135. LCMS: 436(M +1)⁺.

Example 138

To a solution of 48.4mg (0.2mmol) 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B) in dry DMF (1.0mL) was added 49mg (0.3mmol) bis-imidazol-1-yl-methanone in one portion. The mixture was heated at 50 ℃ for 30min, cooled to room temperature and 23mg (0.16mmol) of isoquinolin-3-ylamine were added to the reaction mixture. The reaction mixture was stirred at 45 ℃ for 45 min. After cooling to room temperature, the organic solvent was removed under reduced pressure. The residue is purified by column chromatography eluting with DCM/methanol (v/v ═ 10: 1 to 8: 1) to give 17mg (20%) of 2- (3-isoquinolin-3-yl-ureido) -1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide. LCMS: 413(M +1) ⁺.

Example 139

To a solution of 150mg (0.95mmol) isoquinoline-3-carbaldehyde in dry DCE (1mL) are added 60mg (0.25mmol) 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B) and Ti (OiPr)₄(3 mL). The mixture was sonicated for 30min and then stirred at room temperature for 6 h. Adding NaBH₄(0.5g), the mixture was stirred for 12 h. Methanol (2mL) was added to terminate the reaction. After customary work-up, the residue is purified by column chromatography, eluting first with DCM and then with EtOAc/methanol (v/v. RTM.100: 5) to give 7mg (7%) of 2- [ (isoquinolin-3-ylmethyl) -amino ] -amino]-1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide. LCMS: 384(M +1)⁺.¹HNMR(DMSO-d₆，400MHz)：δ12.58(s，1H)，11.8(s，1H)，11.6(s，1H)，9.07(s，1H)，8.69(s，1H)，8.22(t，1H)，7.96(d，1H)，7.91(d，1H)，7.67(m，2H)，7.53(t，1H)，7.36(d，1H)，7.02(t，1H)，6.90(s，1H)，6.85(s，1H)，4.78(d，2H)ppm.

Example 140

3.4g (20.5mmol) methyl 3, 4-diaminobenzoate were dissolved in 50mL ethanol and 10mL H₂And O in a mixture. To this stirred solution was added 2.6g (24.5mmol) BrCN in one portion and the resulting mixture was heated under reflux for 1.0 h. The reaction mixture was cooled to room temperature, concentrated to 10mL, and washed with ethyl acetate (20 mL). The EtOAc layer was extracted with water (20 mL). The combined aqueous extracts were washed with saturated NaHCO₃The solution was neutralized to a pH of about 8 and the resulting suspension was extracted with EtOAc (50 mL). The organic layer was washed with water and brine solution, and Na was added₂SO₄Dried and evaporated to dryness to give methyl 2-amino-1H-benzimidazole-5-carboxylate, which was used in the next step without further purification.

Methyl 2- [ (isoquinoline-3-carbonyl) -amino ] -1H-benzimidazole-5-carboxylate was prepared as described in general procedure A using 1.9g (10mmol) of isoquinoline-3-carboxylic acid monohydrate, 4.6g (12mmol) of HBTU and 1.9g (10mmol) of methyl 2-amino-1H-benzimidazole-5-carboxylate. 0.35g (1.0mmol) of methyl 2- [ (isoquinoline-3-carbonyl) -amino ] -1H-benzimidazole-5-carboxylate are subsequently hydrolyzed according to general method B to give 2- [ (isoquinoline-3-carbonyl) -amino ] -1H-benzimidazole-5-carboxylic acid as a pale yellow solid, which is used directly in the final coupling step without further purification.

As described in general procedure A, 0.15g (0.45mmol) of 2- [ (isoquinoline-3-carbonyl) -amino ] -are reacted]-1H-benzimidazole-5-carboxylic acid was reacted with 0.26g (0.68mmol) HBTU and 0.06g (0.45mmol) 2-aminoimidazole sulfate in 3.0mL DMF and 1.0mL DIEA. After cooling to room temperature, the reaction mixture was diluted with water, the solid collected by filtration, dissolved in MeOH, evaporated onto silica gel and flash column chromatographed (500mL DCM/20mL NH)₃MeOH) to yield about 10mg of the desired product isoquinoline-3-carboxylic acid [5- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 398.0(M +1)⁺

Example 141

To a solution of 1.53g (10mmol) of 3-nitro-benzene-1, 2-diamine in ethanol (20mL) were added 1.3g (12.5mmol) of BrCN and water (5 mL). The mixture was refluxed for 1.0 h. After cooling to room temperature, the solvent was concentrated and the residue was dissolved in water and saturated NaHCO ₃The solution was adjusted to pH 8.0. The resulting solid was filtered, washed with water, and dried under vacuum to give 1.42g (80%) of 7-nitro-1H-benzimidazol-2-ylamine. LCMS: 179(M +1)⁺.

1.42g (8mmol) of the abovementioned 7-nitro-1H-benzimidazol-2-ylamine are reacted as described in general method A with 1.38g (8mmol) of isoquinoline-3-carboxylic acid, 3.4g (9mmol) of HBTU in 30.0mL of DMF and 5.0mL of DIEA. After cooling to room temperature, the reaction mixture was taken up with 60mL of saturated NaHCO₃And 100mL of water. The solid was collected by filtration, washed with water and dried under reduced pressure, then hydrogenated as described in general procedure C to give 1.0g (41%) of isoquinoline-3-carboxylic acid (7-amino-1H-benzoimidazol-2-yl) -amide. LCMS: 304(M +1)⁺

To a solution of 30mg (0.1mmol) of the above isoquinoline-3-carboxylic acid (7-amino-1H-benzimidazol-2-yl) -amide in dry DMF (1mL) is added 24mg (0.15mmol) of bi-imidazol-1-yl-methanone in one portion. The mixture was heated at 50 ℃ for 30 min. After cooling to room temperature, 16mg (0.15mmol) of 4-fluoro-phenylamine were added to the reaction. The reaction mixture was stirred at 45 ℃ for 45 min. After cooling to room temperature, the organic solvent was removed under reduced pressure and the residue was purified by column chromatography eluting with DCM/methanol (v/v ═ 10: 0.5 to 10: 1) to give 17mg (39%) of isoquinoline-3-carboxylic acid {7- [3- (4-fluoro-phenyl) -ureido ] -7-carboxylic acid ]-1H-benzimidazol-2-yl } -amide. LCMS: 441(M +1)⁺.

The following compounds were synthesized by analogous methods as used in the preparation of example 141 and the related schemes above.

Examples	Ar	LCMS(M+1)⁺
			142	4-Methoxyphenylethyl group	481
143	4-methoxybenzyl	467

Example 144

To a stirred solution of 200mg (0.92mmol)2, 3-diamino-N- (1H-imidazol-2-yl) -benzamide (synthesized as described for intermediate-B) in 2.0mL acetic acid was added 200mg (1.15mmol)2, 2, 2-trichloroacetamide and stirring continued at room temperature for 30 min. Then 0.5mL of 1% HCl in methanol was added and stirred at room temperature for an additional 45 min. The solvent was evaporated to dryness to afford the crude ester dissolved in 4: 1 THF and methanol (5mL), then 1.0mL of 2N LiOH was added at room temperature. The reaction mixture was stirred at room temperature for 30min, the pH was adjusted to 3.0, and then extracted 2 times with ethyl acetate (2X 25 mL). The combined organic solvents were dried and evaporated to dryness to give 100mg (40%) of 4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazole-2-carboxylic acid, which was used in the next step without further purification. LCMS: 272(M +1)⁺.

To a stirred solution of 100mg (0.36mmol) of the above acid in 2.0mL DMF was added 140mg (0.72mmol) EDCI. The reaction mixture was stirred for 10min, then 53mg (0.36mmol) of isoquinolin-3-ylamine were added. The reaction mixture was stirred for an additional 20h, cooled to room temperature, and 5.0mL water and 5.0mL saturated NaHCO were added ₃. The resulting solid was filtered, washed with water, diethyl ether and dried to give 20mg (13.6%) of 1H-benzimidazole-2, 4-dicarboxylic acid 4- [ (1H-imidazol-2-yl) -amide]2-isoquinolin-3-ylamide. LCMS: 398(M +1)⁺.

Example 145

To 0.33g (1.0mmol) - [ (isoquinoline-1-carbonyl) -amino ]]To a solution of-3H-benzimidazole-4-carboxylic acid (from example 58) in DMF (5mL) was added 0.47g (1.25mmol) HBTU and DIEA (0.5 mL). The mixture was stirred for 5min, then 0.22g (2.0mmol) of benzene-1, 2-diamine was added in one portion. The reaction mixture was heated at 50 ℃ for 1h, cooled to room temperature, and then saturated aqueous sodium carbonate (15mL) was added to precipitate the coupling product. The solid was filtered, washed with water and dried to give 0.35g (80%) of isoquinoline-1-carboxylic acid [7- (2-amino-phenylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 443(M +1)⁺.

To 169mg (0.4mmol) of isoquinoline-1-carboxylic acid [7- (2-amino-phenylcarbamoyl) -1H-benzimidazol-2-yl]-amide in AcOH (15mL) solution NH was added₄OAc (0.5 g). The mixture was heated at 130 ℃ for 30 min. After cooling to room temperature, the AcOH was removed under reduced pressure, extracted with EtOAc (50mL), washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and concentrated. The residue was dissolved in DCM (3mL) and 5mL of hexane was added. The resulting solid was filtered and dried to give 120mg (75%) of isoquinoline-1-carboxylic acid (1H, 3 'H- [2, 4' ]Bibenzimidazol-2' -yl) -amide. LCMS: 405(M +1)⁺.

The following compounds were synthesized by analogous methods as used in the preparation of example 145 and the related schemes above.

Examples	R	LCMS(M+1)⁺
			146	3H-imidazole [4, 5-c]Pyridin-2-yl	406
147	4-phenyl-1H-imidazol-2-yl	431
			148	1H-imidazol-2-yl	355
149	4- (4-chloro-phenyl) -1H-imidazol-2-yl	465

Example 150

To a solution of 61mg (0.2mmol) isoquinoline-3-carboxylic acid (4-amino-1H-benzimidazol-2-yl) -amide in AcOH (5mL) is added formaldehyde (0.7mL, 37% in water), 0.3mL glyoxal and NH₄OAc (0.5 g). The mixture was heated at 120 ℃ for 1 h. After cooling to rt and completion of the usual work-up, the residue is purified by column chromatography eluting with EtOAc/methanol (v/v ═ 10: 1) to give 13mg (18%) of isoquinoline-3-carboxylic acid (4-imidazol-1-yl-1H-benzoimidazol-2-yl) -amide LCMS: 355(M +1)⁺.

Example 151

To 0.17g (0.5mmol) of 2- [ (isoquinoline-3-carbonyl) -amino group]To a solution of (E) -1H-benzimidazole-4-carboxylic acid (from example 58) in DMF (3mL) was added 0.13g (1mmol) of 1-chloro-3, 3-dimethyl-butan-2-one and DIEA (1 mL). The mixture was stirred at room temperature for 1h, extracted with ethyl acetate, washed with water and brine. The organic layer was dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 0.17g (85%) of ketoester, which was dissolved in AcOH (5mL) and 0.5g NH was added ₄OAc, the mixture was stirred under microwave (150W, 250psi) at 100 ℃ for 1 h. The solvent was evaporated to dryness and the residue was purified by column chromatography eluting with DCM/EtOAc (v/v ═ 1: 1) to give 90mg (73%) of isoquinoline-3-carboxylic acid [4- (4-tert-butyl-oxazol-2-yl) -1H-benzimidazol-2-yl ] -3-carboxylic acid]-an amide. LCMS: 412(M +1)⁺.

Example 152

To a stirred mixture of 1.0g (5.2mmol) of methyl 2-amino-3H-benzimidazole-4-carboxylate (intermediate A) and 0.86g (5.2mmol) of CDI in 3.0mL of DMF was added 0.75g (5.2mmol) of isoquinolin-3-ylamine. The reaction mixture was heated at 60 ℃ for 30min, then cooled to room temperature and 5.0mL of water was added. The resulting solid was filtered, washed with water (10mL) and diethyl ether (10mL) and dried to give methyl 2- (3-isoquinolin-3-yl-ureido) -1H-benzimidazole-4-carboxylate as a solid, which was hydrolyzed as described in general procedure B to give 0.75g (40%) of 2- (3-isoquinolin-3-yl-ureaYl) -1H-benzimidazole-4-carboxylic acid. LCMS: 348(M +1)⁺.

0.2g (0.57mmol) of the above acid are reacted with 0.24g (0.63mmol) of HBTU and 0.083g (0.57) of 1H-pyrazole-1-carboxamdine, as described in general method A. After completion of the reaction, the reaction mixture was diluted with water (5.0mL) and saturated NaHCO was added₃And stirring for 15 min. The resulting solid was filtered, washed with water, diethyl ether and dried under vacuum to give 0.15g (62.5%) of isoquinoline-3-carboxylic acid {4- [ (imino-pyrazol-1-yl-methyl) -carbamoyl group as a solid ]-1H-benzimidazol-2-yl } -amide. LCMS: 425(M +1)⁺.

To a stirred solution of 0.05g (0.12mmoL) of the above amide and 0.088g (1.12mmoL) of 3-amino-propan-1-ol in DCM (5.0mL) was added 0.077g (0.68mmoL) of DIEA. The reaction mixture was stirred at room temperature overnight. 5.0mL of water was added, the resulting solid was filtered, washed with water and diethyl ether, and dried to give 0.03g (57.6%) of 1- {4- [ N' - (3-hydroxy-propyl) -guanidinocarbonyl]-1H-benzimidazol-2-yl } -3-isoquinolin-3-yl-urea. LCMS: 447(M +1)⁺.

The following compounds were synthesized by analogous methods as used in the preparative example 152 and the related schemes described above.

Examples	R	LCMS(M+1)⁺
			153	N-propyl radical	431
154	4-hydroxy-butyl	461

Example 155

As described in general method A, 100mg (0.3mmol) of 2- [ (isoquinoline-3-carbonyl) -amino]-1H-benzimidazole-4-carboxylic acid (from example 58) was reacted with 130mg (0.33mmol) HBTU and 55mg (0.3mmol) 4-methanesulfonyl-benzylamine in 3.0mL DMF and 1.0mL DI EA. After conventional work-up, 50mg (33%) of isoquinoline-3-carboxylic acid [4- (4-methanesulfonyl-benzylcarbamoyl) -1H-benzimidazol-2-yl ] -are isolated as described in general procedure A]-an amide. LCMS: 500(M +1)⁺.

Example 156

To a solution of 5g (38mmol) 2-chloro-cyclohexanone in MeCN (150mL) was added 7g (69mmol) N-acetyl-guanidine. The mixture was refluxed for 24 h. After removal of all solvents, the residue was taken up with saturated Na ₂CO₃The aqueous solution (50mL) was stirred for 5min, filtered and the solid dried to yield 1g (14%) of N- (4, 5, 6, 7-tetrahydro-1H-benzimidazol-2-yl) -acetamide. LCMS: 180(M +1)⁺. ¹H NMR(DMSO-d₆，400MHz)：δ2.38(m，4H)，2.00(s，3H)，1.65(m，4H)ppm.

To a solution of 150mg (0.83mmol) N- (4, 5, 6, 7-tetrahydro-1H-benzimidazol-2-yl) -acetamide in methanol (3mL) was added water (3mL) and concentrated H₂SO₄(0.3 mL). The mixture was heated at 100 ℃ for 1h under microwave (150w, 250 psi). After removal of all solvents, the residue was taken up with saturated Na₂CO₃The aqueous solution was neutralized and then diluted with methanol (50 mL). After removal of the inorganic salts by filtration, the organic phase is concentrated and dried under vacuum to yield 100mg (86%) of 4, 5, 6, 7-tetrahydro-1H-benzimidazol-2-ylamine, which is used directly in the next step without further purification.

To 70mg (0.2mmol) of 2- [ (isoquinoline-3-carbonyl) -amino group]To a solution of (E) -3H-benzimidazole-4-carboxylic acid in DMF (2mL) was added 100mg (0.26mmol) of HBTU and DIEA (0.3 mL). The mixture was stirred for 5min, then 100mg (0.7mmol) of 4, 5, 6, 7-tetrahydro-1H-benzimidazol-2-ylamine was added. The resulting reaction mixture was heated at 80 ℃ for 1.5 h. After conventional work-up, the residue was purified by column chromatography eluting with DCM/EtOAc (v/v ═ 1: 1) to give 12mg (13%) of isoquinoline-3-carboxylic acid [4- (4, 5, 6, 7-tetrahydro-1H-benzimidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ] -3-carboxylic acid ]-an amide. LCMS: 452(M +1)⁺.

Example 157

A mixture of 4.9g (29.4mmol) (1H-imidazol-4-yl) -acetic acid hydrochloride, 4N HCl in dioxane (22.5mL) and methanol (70mL) was refluxed overnight. The solvent was evaporated to dryness to give (1H-imidazol-4-yl) -acetic acid methyl ester hydrochloride. LCMS: 141(M +1)⁺.

An aqueous solution (5.1mL) of sodium nitrite (4.5mmol, 311mg) was cooled in an ice bath and added to a mixture of 694mg (4.5mmol) of methyl 4-amino-benzoate in 2.36N aqueous HCl (7.5mL) at 0 ℃. The mixture was stirred at 0 ℃ for 30min and the reaction mixture was added to a mixture of 795mg (4.5mmol) (1H-imidazol-4-yl) -acetic acid methyl ester hydrochloride in saturated aqueous sodium tetraborate (150 mL). The mixture was stirred at 0 ℃ for 1.5h and slowly warmed to room temperature. After filtration and washing with water, the yield of quantitative 4- (4-methoxycarbonylmethyl-1H-imidazol-2-ylazo) -benzoic acid methyl ester was obtained. LCMS: 303(M +1)⁺.

The above components are combinedThe resulting mixture of methyl 4- (4-methoxycarbonylmethyl-1H-imidazol-2-ylazo) -benzoate (2mmol, 604mg), platinum (IV) oxide (60mg) and methanol (50mL) was hydrogenated (60psi) for two days (another portion of PtO)₂Added after one day). Trifluoroacetic acid (TFA) (2mmol, 0.15mL) was added to the reaction mixture, which was filtered. The filtrate was concentrated, diluted with water and washed with diethyl ether (2X 50 mL). The water in the aqueous solution was evaporated to dryness to give the TFA salt of (2-amino-1H-imidazol-4-yl) -acetic acid methyl ester (273.8mg, 51%). LCMS: 156(M +1) ⁺.

Following general method A, with 339mg (1.02mmol) of 2- [ (isoquinoline-3-carbonyl) -amino group]Synthesis of 2- ({2- [ (isoquinoline-3-carbonyl) -amino ] -2-carboxylic acid, 1.02mmol of (2-amino-1H-imidazol-4-yl) -acetic acid methyl ester trifluoro-acetic acid, 387mg (1.02mmol) of HBTU, 3mL of DMF and 0.704mL (4mmol) of DIEA by heating at 80 ℃ for 2H]-1H-benzimidazole-4-carbonyl } -amino) -3H-imidazol-4-yl]-methyl acetate. Purification by column chromatography gave 234mg (0.50mmol, yield 49%) of the title compound. LCMS: 470(M +1)⁺.

Example 158

Following general method B, starting from 225mg (0.479mmol)2- ({2- [ (isoquinoline-3-carbonyl) -amino)]-1H-benzimidazole-4-carbonyl } -amino) -3H-imidazol-4-yl]Synthesis of [2- ({2- [ (isoquinoline-3-carbonyl) -amino ] -2- ({2- [ (isoquinoline-3-carbonyl) -amino) -by stirring (methyl acetate), 0.5mL of a 2N aqueous LiOH solution, 2mL of THF and 0.5mL of methanol at room temperature for 3h]-1H-benzimidazole-4-carbonyl } -amino) -3H-imidazol-4-yl]-acetic acid. 116.9mg (54%) of product are obtained. LCMS: 456(M +1)⁺.

Example 159

Following general method A, 109mg (0.239mmol) of 2- ({2- [ (isoquinoline-3-carbonyl) -amino)]-1H-benzimidazole-4-carbonyl } -amino) -3H-imidazol-4-yl]Synthesis of isoquinoline-3-carboxylic acid (4- {5- [ (methoxy-) -carboxylic acid, 50mg (0.5mmol) of O, N-dimethyl-hydroxylamine hydrochloride, 91mg (0.24mmol) of HBTU, 0.176mL (1mmol) of DIEA and 1mL of DMF by stirring at room temperature for 1 hour Methyl-carbamoyl) -methyl]-1H-imidazol-2-ylcarbamoyl } -1H-benzimidazol-2-yl) -amide. 64.4mg (54%) of product are obtained. LCMS: 499(M +1)⁺.

The following compounds were synthesized by analogous methods as used in preparation example 155-159 and the related schemes described above.

Examples	W	LCMS(M+1)⁺
			160	5-isopropyl-1H-imidazol-2-yl	440
161	4-fluoro-phenyl	426
			162	1- (4-Methylsulfonyl-phenyl) -ethyl	514
163	3-methanesulfonyl-phenyl	486
			164	4-trifluoromethoxy-benzyl	506
165	4-methoxy-benzyl	452
			166	4-methyl-benzyl	436
167	4-fluoro-benzyl	440
			168	4-chloro-benzyl	456
169	3-trifluoromethyl-benzyl	490
			170	3-fluoro-4-trifluoromethyl-benzyl	508
171	3, 5-difluoro-benzyl	458
			172	4-cyano-benzyl	447
173	N' (4, 5-dihydro-1H-imidazol-2-yl) -hydrazino	415
			174	3-methoxy-benzyl	452
175	4-methoxy-phenyl	438
			176	2- (4-methoxy-phenyl) -ethyl	466
177	3-fluoro-benzyl	440
			178	4-sulfamoyl-benzyl	501
179	2-methoxy-benzyl	452
			180	2-ethoxy-benzyl	466
181	2, 2-dioxo-1, 3-dihydrobenzo [ c ]]Thien-5-yl	498
			182	2- (4-phenoxy-phenyl) -ethyl	528
183	Butyl radical	388
			184	3H-imidazole [4, 5-c]Pyridin-2-yl	449
185	7H-purin-8-yl	450
			186	Isoquinolin-6-yl	459
187	2-methylsulfanyl-ethyl	406
			188	5, 5-dimethyl-7-oxo-4, 5, 6, 7-tetrahydro-benzothiazole-2-yl	511
189	1H-benzimidazol-5-yl	448
			190	1-pyrazol-3-yl	398
191	2-amino-pyrimidin-4-yl	425
			192	4-tert-butyl-1H-imidazol-2-yl	454
193	4, 5-dimethyl-1H-imidazol-2-yl	426
			194	5-Ethyl-1H-imidazol-2-yl	426
195	5-adamantan-1-yl-1H-imidazol-2-yl	532
			196	5-benzyl-1H-imidazol-2-yl	488

Example 197

To a solution of 4g (20mmol) of tert-butyl 4-oxo-piperidine-1-carboxylate in THF (60mL) was added 10g (20mmol) of pyrrolidone hydrobromide tribromide. The reaction mixture was refluxed for 5min, cooled to room temperature, filtered to remove the solid (pyrrolidone HBr salt), and the organic layer was concentrated and used in the next step without further purification.

The above crude material was dissolved in ethanol (50mL) and 2.2g (30mmol) of thiourea was added. The mixture was refluxed for 3h and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (50mL) and a solution of 4M HCl in 1, 4-dioxane (24mL) was added. The mixture was refluxed for 5 min. After removing all solvents, the residue was dissolved in DCM (20mL) and hexane (20mL) was added. The resulting solid was filtered and dried to give 4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ] ]Pyridin-2-ylamine HCl salt, which was then dissolved in dioxane (25mL) and sodium carbonate solution (1M, 25 mL). To the stirred solution was added 2.2g (10mmol) of di-tert-butyl dicarbonate. The reaction mixture was then stirred at room temperature for 2h, extracted with ethyl acetate, washed with water and brine. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography eluting with hexane/ethyl acetate (v/v first 1: 1, then 1: 2) to give 1.2g (24%, 3 steps of reaction) of 2-amino-6, 7-dihydro-4H-thiazolo [5, 4-c ] -a]Pyridine-5-carboxylic acid tert-butyl ester.¹H NMR(DMSO-d₆，400MHz)：δ6.82(bs，2H)，4.29(s，2H)，3.58(t，2H)，2.41(t，2H)，1.41(s，9H)ppm.

To 0.25g (0.75mmol) of 2- [ (isoquinoline-3-carbonyl) -amino group]-3H-benzimidazole-4-carboxylic acidTo a solution of the acid in DMF (4mL) was added 0.4g (1.05mmol) HBTU and DIEA (1 mL). The mixture was stirred for 5min, then 0.18g (0.7mmol) 2-amino-6, 7-dihydro-4H-thiazolo [5, 4-c ] was added]Pyridine-5-carboxylic acid tert-butyl ester. The resulting reaction mixture was heated at 80 ℃ for 2 h. After customary work-up, the residue is purified by column chromatography to give 0.2g (55%) of 2- ({2- [ (isoquinoline-3-carbonyl) -amino ] -amino]-3H-benzimidazole-4-carbonyl } -amino) -6, 7-dihydro-4H-thiazolo [5, 4-c]Pyridine-5-carboxylic acid tert-butyl ester. LCMS: 570(M +1)⁺.¹H NMR(DMSO-d₆，400MHz)：δ9.56(s，1H)，8.84(s，1H)，8.35(m，2H)，7.96(m，4H)，7.84(d，1H)，7.35(t，1H)，4.58(bs，2H)，3.70(t，2H)，2.73(t，2H)，1.44(s，9H)ppm.

Example 198

To 0.2g (0.35mmol) of 2- ({2- [ (isoquinoline-3-carbonyl) -amino) ]-3H-benzimidazole-4-carbonyl } -amino) -6, 7-dihydro-4H-thiazolo [5, 4-c]Pyridine-5-carboxylic acid tert-butyl ester to a solution in methanol (1mL) was added HCl solution (5mL, 4M HCl in 1, 4-dioxane). The mixture was stirred at room temperature for 30 min. The conversion process was checked by LCMS. After removal of the organic phase, the residue was diluted with DCM (50mL) and the organic phase was saturated with Na₂CO₃Washed with aqueous solution, water, brine, over Na₂SO₄Dried on top and concentrated to yield 160mg (100%) of isoquinoline-3-carboxylic acid [7- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ]]Pyridin-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 470(M +1)⁺.

Example 199

To a solution of 20mg (0.042mmol) of isoquinoline-3-carboxylic acid [7- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ]]Pyridin-2-ylcarbamoyl) -1H-benzimidazol-2-yl]Amide (example above) to a solution of DCE (3mL) were added 0.2g (0.94mmol) of sodium triacetoxyborohydride and acetaldehyde (0.1 mL). The mixture was stirred at room temperature overnight. After LCMS indicated complete consumption of starting material, the reaction was stopped by addition of methanol (2mL)Should be used. After conventional treatment, the residue was dissolved in DCM (1 mL). Hexane was added to precipitate the desired product, and 12mg (57%) of isoquinoline-3-carboxylic acid [7- (5-ethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ] was collected by filtration ]Pyridin-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 498(M +1)⁺.

Example 200

To 25mg (0.05mmol) of isoquinoline-3-carboxylic acid [7- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ]]Pyridin-2-ylcarbamoyl) -1H-benzimidazol-2-yl]Amide (example 198) to a solution of pyridine (2mL) was added 21.3mg (0.15mmol) of 1-propanesulfonyl chloride. The mixture was stirred at room temperature for 12h, extracted with ethyl acetate, washed with 1N HCl, water and brine. The organic layer was dried over magnesium sulfate and evaporated to dryness under reduced pressure. The crude product was dissolved in DCM (0.5mL), hexane (4mL) was added, and the resulting precipitate was filtered and dried to give 12mg (57%) of isoquinoline-3-carboxylic acid [7- (5-propyl-1-sulfonyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ]]Pyridin-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 576(M +1)⁺.

Example 201

To a solution of 20mg (0.042mmol) of isoquinoline-3-carboxylic acid [7- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ]]Pyridin-2-ylcarbamoyl) -1H-benzimidazol-2-yl]To a solution of the amide (example 198) in THF (2mL) was added 0.1mL 2-isocyanato-2-methyl-propane and DIEA (0.2 mL). The mixture was stirred at room temperature for 30 min. LCMS showed complete consumption of starting material, reaction mixture was diluted with ethyl acetate (20 mL). Saturated Na for organic phase ₂CO₃Washing with aqueous solution in Na₂SO₄Dried and concentrated under reduced pressure. The crude product was dissolved in DCM (0.5mL), hexane (4mL) was added, and the resulting precipitate was filtered and dried to give 11mg (46%) of isoquinoline-3-carboxylic acid [4- (5-tert-butylcarbamoyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ]]Pyridin-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 569(M +1)⁺.

Example 202

To 30mg (0.063mmol) of isoquinoline-3-carboxylic acid [7- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ]]Pyridin-2-ylcarbamoyl) -1H-benzimidazol-2-yl]Amide (example 198) to a solution of DCM (2mL) was added pyridine (0.5mL) and benzoyl chloride (0.05 mL). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (20mL) and the organic phase was saturated Na₂CO₃Washing with aqueous solution in Na₂SO₄Dried and concentrated under reduced pressure. The crude product was dissolved in DCM (0.5mL), hexane (4mL) was added, and the resulting precipitate was filtered and dried to give 17mg (47%) of isoquinoline-3-carboxylic acid [4- (5-benzoyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ])]Pyridin-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 574(M +1)⁺.

Example 203

To a solution of 30mg (0.064mmol) of isoquinoline-3-carboxylic acid [7- (4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ] ]Pyridin-2-ylcarbamoyl) -1H-benzimidazol-2-yl]To a solution of the amide (example 198) in DCE (0.7mL) was added 3-methylsulfanyl-propionaldehyde (0.1mL), 0.2g (0.94mmol) sodium triacetoxyborohydride and the mixture was stirred at room temperature for 1 h. Methanol (0.5mL) was added to stop the reaction. After conventional work-up, the reaction was quenched by addition of methanol (2 mL). After conventional work-up, the residue was dissolved in DCM (1mL) and hexane was added to precipitate the desired product. After filtration 21mg (58%) of isoquinoline-3-carboxylic acid {4- [5- (3-methylsulfanyl-propyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ] are collected]Pyridin-2-ylcarbamoyl]-1H-benzimidazol-2-yl } -amide. LCMS: 558(M +1)⁺.

Example 204

To a solution of 20mg (0.037mmol) of thioether (example 203) in DCM (2.5mL) was added 25mg (0.14mmol) m-CPBA. ReactantsStirred at room temperature for 2 h. The solvent was evaporated under reduced pressure. The crude product was dissolved in DCM (0.5mL), hexane (4mL) was added, and the resulting precipitate was filtered and dried to give 11mg (47%) of isoquinoline-3-carboxylic acid {4- [5- (3-methanesulfonyl-propyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ]]Pyridin-2-ylcarbamoyl]-1H-benzimidazol-2-yl } -amide. LCMS: 590(M +1)⁺.

The following compounds were synthesized by analogous methods as used in preparation example 197-204 and the related schemes described above.

Examples	W	LCMS (M+1)⁺
			205	Piperidin-4-yl-1-carboxylic acid tert-butyl ester	515
206	Piperidin-4-yl radical	488
			207	Piperidin-4-yl-1-carboxylic acid isopropyl ester	501
208	5-methanesulfonyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ]]Pyridin-2-yl	548
			209	5-benzyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	560
210	4, 5, 6, 7-tetrahydro-benzothiazol-2-yl	469
			211	6-methyl-4, 5, 6, 7-tetrahydro-benzothiazol-2-yl	483
212	5-methyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	484
			213	5-Cyclopentylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	662
214	5-pyridin-3-ylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	707
			215	5-cyclohexylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	676
216	5-Furan-3-ylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ]]Pyridin-2-yl	660
			217	Piperidin-3-ylmethyl-1-carboxylic acid tert-butyl ester	529
218	Piperidin-4-ylmethyl-1-carboxylic acid tert-butyl ester	529
			219	Piperidin-3-ylmethyl radical	538
220	Piperidin-4-ylmethyl radical	538
			221	5- (1-methyl-1H-pyrrol-2-ylmethyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	563
222	5-propyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ]Pyridin-2-yl	621
			223	5- (2-ethyl-butyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	664
224	5-isobutyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	636
			225	1-cyclohexylmethyl-piperidin-3-ylmethyl radical	635
226	1-cyclohexylmethyl-piperidin-4-ylmethyl radical	635
			227	2-piperidin-3-yl-ethyl-1-carboxylic acid tert-butyl ester	543
228	2-piperidin-4-yl-ethyl-1-carboxylic acid tert-butyl ester	543
			229	2-piperidin-3-yl-ethyl	552
230	2-piperidin-4-yl-ethyl	552
			231	5- (2, 4-dimethoxy-benzyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	620
232	5- (4-chloro-benzyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	595
			233	5- (4-fluoro-benzyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	578
234	5- (4-isopropoxy-benzyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	618
			235	5- (2-methoxy-benzyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	590
236	5- (3-methoxy-benzyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	590
			237	5- (4-methoxy-benzyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	590
238	5-phenethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ]Pyridin-2-yl	574
			239	5-thiophen-2-ylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	566
240	5-thiophen-3-ylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	566
			241	5- (3-methyl-butyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	540
242	piperidin-3S-ylmethyl-1-carboxylic acid tert-butyl ester	529
			243	piperidin-3R-ylmethyl-1-carboxylic acid tert-butyl ester	529
244	piperidin-3S-ylmethyl	429
			245	piperidin-3R-ylmethyl	429
246	5- (3H-imidazol-4-ylmethyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	550
			247	5- (1-methyl-1H-imidazol-2-ylmethyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	564
248	5- (1H-imidazol-2-ylmethyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	550
			249	5-Cyclopropylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	524
250	5- (3, 3-dimethyl-butyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridine-2-radical	554
			251	1, 2, 3, 4-tetrahydro-isoquinolin-6-yl-2-carboxylic acid tert-butyl ester	563
252	1, 2, 3, 4-tetrahydro-isoquinolin-6-yl	572
			253	1-cyclohexylmethyl-piperidin-3S-ylmethyl radical	635
254	1-cyclohexylmethyl-piperidin-3R-ylmethyl	635
			255	5-thiazol-2-ylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c ]]Pyridin-2-yl	567
256	5- (5-methyl-3H-imidazol-4-ylmethyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	564
			257	5- (2-Ethyl-5-methyl-3H-imidazol-4-ylmethyl) -4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	592
258	2S- [ 2-amino-6, 7-dihydro-4H-thiazolo [5, 4-c ]]Pyridin-5-ylmethyl]-pyridinePyrrolidine-1-carboxylic acid tert-butyl ester	653
			259	5-quinolin-3-ylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	611
260	2S- {3- [ amino-methyl group]-piperidin-1-ylmethyl } -pyrrolidine-1-carboxylic acid tert-butyl ester	612
			261	2R- {3- [ amino-methyl]-piperidin-1-ylmethyl } -pyrrolidine-1-carboxylic acid tert-butyl ester	612
262	5-pyrrolidin-2S-ylmethyl-4, 5, 6, 7-tetrahydro-thiazolo [5, 4-c]Pyridin-2-yl	699
			263	1- (1H-imidazol-2-ylmethyl) -piperidin-3-ylmethyl	509
264	1- (1-methyl-1H-imidazol-2-ylmethyl) -piperidin-3-ylmethyl	523
			265	1- (1H-imidazol-4-ylmethyl) -piperidin-3-ylmethyl	509

Example 266

To 100mg (0.3mmol) of 2- [ (isoquinoline-3-carbonyl) -amino group]To a solution of-3H-benzimidazole-4-carboxylic acid (from example 58) in DMF (2mL) was added 200mg (0.53mmol) of HBTU and DIEA (0.5 mL). The mixture is stirred for 5min, then 140mg (1.0mmol) N- (4-fluoro-benzyl) -N-methyl-amine are added. The resulting reaction mixture was heated at 70 ℃ for 1 h. After customary work-up as described in general procedure a, the residue was purified by column chromatography eluting with DCM/EtOAc (v/v ═ 1: 1) to give 90mg (66%) of isoquinoline-3-carboxylic acid {7- [ (4-fluoro-benzyl) -methyl-carbamoyl ] -3-carboxylic acid ]-1H-benzimidazol-2-yl } -amide. LCMS: 454(M +1)⁺.

Example 267

Isoquinoline-3-carboxylic acid (4-dibenzylcarbamoyl-1H-benzimidazol-2-yl) -amide (40mg) is synthesized following the general procedure of Synthesis example 266, except that N, N-dibenzylamine is used instead of N- (4-fluorobenzyl) -N-methyl-amine. LCMS: 512(M +1)⁺.

Example 268

3.00g (10mmol) of tert-butoxycarbonylamino- (dimethoxy-phosphoryl) -acetic acid methyl ester are added at 0 ℃ to a solution containing 1.69g (10mmol) of 2-formyl-benzoic acid methyl ester in 50mL of dichloromethaneEster and 1.51mL (10mmol) of DBU. The reaction was slowly warmed to room temperature overnight, then diluted with dichloromethane (100mL), washed once with water (150mL), and dried over sodium sulfate. Purification by silica gel column chromatography gave 2.12g (70%) of the product as a white solid. LCMS: 304(M +1)⁺.

6mL of 4N HCl in dioxane (6mL) was added to the previous step solution of 1-oxo-1H-isoquinoline-2, 3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester and 10mL of dichloromethane and stirred overnight. The reaction mixture was concentrated in ethyl acetate (100mL) and saturated NaHCO₃The solutions (100mL) were partitioned between. The aqueous layer was separated and extracted again with ethyl acetate (100 mL). The combined organic layers were dried over sodium sulfate. The solvent was evaporated down in vacuo to afford 1.39g (98%) of methyl 1-oxo-1, 2-dihydro-isoquinoline-3-dicarboxylate as a white solid. LCMS: 204(M +1) ⁺.

663mg (81%) of 1-oxo-1, 2-dihydro-isoquinoline-3-dicarboxylic acid is synthesized according to general procedure B using 877mg (4.32mmol) of methyl 1-oxo-1, 2-dihydro-isoquinoline-3-dicarboxylate synthesized above, 4.3mL of 2N aqueous LiOH, 16mL of THF and 4mL of methanol stirred at room temperature overnight. LCMS: 190(M +1)⁺.

Following general procedure A, 76mg (0.4mmol) of 1-oxo-1, 2-dihydro-isoquinoline-3-dicarboxylic acid is reacted with 73mg (0.3mmol) of intermediate B (2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide), 152mg (0.4mmol) of HBTU, 0.176mL (1mmol) of DIEA and 1.2mL of DMF at 85 ℃ with stirring for 2H to give 54.5mg (0.132mmol, 44%) of 1-oxo-1, 2-dihydro-isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ] -3-carboxylic acid]-an amide. LCMS: 414(M +1)⁺.

Example 269

Following general procedure A, 798mg (2.82mmol) 2-tert-butyl 3, 4-dihydro-1H-isoquinoline-2, 6-dicarboxylate, 540mg (2.82mmol) intermediate A (methyl 2-amino-1H-benzimidazole-4-carboxylate), 1.28g (3.38mmol) HBTU, 0.992mL (5.64mmol) DIEA and 15mL DMF at room temperatureTert-butyl 6- (4-methoxycarbonyl-1H-benzimidazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinoline-2-carboxylate (114mg, 90%) was synthesized by stirring overnight. LCMS: 451(M +1) ⁺.

Example 270

109mg (0.242mmol) of tert-butyl 6- (4-methoxycarbonyl-1H-benzimidazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinoline-2-carboxylate are hydrolyzed as described in general method B with 1mL of 2N aqueous LiOH solution, 4mL of THF and 1mL of methanol at room temperature with stirring for one day. 76.5mg (72%) of 6- (4-carboxy-1H-benzimidazol-2-ylcarbamoyl) -3, 4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester product are obtained. LCMS: 437(M +1)⁺.

72.9mg (0.167mmol) of the above-mentioned acid were reacted with 47mg (0.35mmol) of 2-aminoimidazole sulfate, 95mg (0.25mmol) of HBTU, 0.176mL (1mmol) of DIEA and 1mL of DMF. The mixture was stirred at 80 ℃ for 18H according to general procedure A to give 54.7mg (65%) of 6- [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzoimidazol-2-ylcarbamoyl ] -1H-benzoimidazol-2-ylcarbamoyl]-3, 4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester. LCMS: 502(M +1)⁺.

Example 271

49.8mg (0.10mmol) of 6- [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzoimidazol-2-ylcarbamoyl) -in 2mL of 4N HCl in dioxane are stirred at room temperature]-3, 4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester for 2H. The solvent was evaporated under vacuum to afford a quantitative yield of 1, 2, 3, 4-tetrahydro-isoquinoline-6-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ]-an amide. LCMS: 402(M +1)⁺.

Example 272

25mg (0.049mmol) of 1, 2, 3, 4-tetrahydro-isoquinoline-6-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) in 0.5mL of DMF are stirred at room temperature1H-benzimidazol-2-yl radical]Amide, 0.01mL (0.07mmol) of benzenesulfonyl chloride and 0.07mL (0.5mmol) of triethylamine for 1 h. The reaction mixture was then treated with 0.024mL hydrazine hydrate and diluted with water. The precipitated solid was filtered and washed with water to give 2-benzenesulfonyl-1, 2, 3, 4-tetrahydro-isoquinoline-6-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]Amide (17.2mg, 65%). LCMS: 542(M +1)⁺.

Example 273

25mg (0.049mmol) of 1, 2, 3, 4-tetrahydro-isoquinoline-6-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]A mixture of amide, 0.0152mL (0.15mmol) of benzaldehyde and 0.6mL of DMF was stirred for 10 min. 67mg (0.3mmol) of sodium triacetoxyborohydride are added and the reaction mixture is stirred at room temperature for 24 h. The reaction mixture was partitioned between dichloromethane (10mL) and water (10 mL). The organic layer was separated and dried over sodium sulfate. Purification by silica gel column chromatography gave 11.7mg (49%) of 2-benzyl-1, 2, 3, 4-tetrahydro-isoquinoline-6-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ]-an amide. LCMS: 492(M +1)⁺.

Example 274

41mg (0.08mmol) of 1, 2, 3, 4-tetrahydro-isoquinoline-6-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ] in 0.6mL of DMF and 0.176mL (1mmol) of DIEA]The amide was treated with 0.024mL (0.3mmol) of methyl chloroformate and stirred at room temperature for 14 h. The reaction mixture was then treated with 0.15mL of 2N aqueous LiOH. Water was added to the reaction mixture. The precipitated solid was collected by filtration and washed with water to give 11.4mg (0.0248mmol, 31%) of 6- [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzoimidazol-2-ylcarbamoyl ] -1H-benzoimidazol-2-ylcarbamoyl]-3, 4-dihydro-1H-isoquinoline-2-carboxylic acid methyl ester. LCMS: 460(M +1)⁺.

The following compounds were synthesized by a similar method as used in preparation example 269-274 and the related scheme above.

Examples	W	LCMS (M+1)⁺
			275	2-methanesulfonyl-1, 2, 3, 4-tetrahydro-isoquinolin-6-yl	480
276	2-ethoxycarbonyl-3, 4-dihydro-1H-isoquinolin-6-yl	474
			277	2-propoxycarbonyl-3, 4-dihydro-1H-isoquinolin-6-yl	488
278	2-isobutoxycarbonyl-3, 4-dihydro-1H-isoquinolin-6-yl	502
			279	2-Isopropoxycarbonyl-3, 4-dihydro-1H-isoquinolin-6-yl	488
280	2-Butoxycarbonyl-3, 4-dihydro-1H-isoquinolin-6-yl	502
			281	(3S) -2-tert-butoxycarbonyl-3, 4-dihydro-1H-isoquinolin-3-yl	502
282	(3S) -1, 2, 3, 4-tetrahydro-isoquinolin-3-yl	511
			283	(3S) -2-methanesulfonyl-1, 2, 3, 4-tetrahydro-isoquinolin-3-yl	480
284	(3S) -2-Ethyl-1, 2, 3, 4-tetrahydro-isoquinolin-3-yl	539
			285	(3S) -2-tert-butoxycarbonyl-1, 3, 4, 9-tetrahydro-beta-carbolin-3-yl	541
286	(3S) -2-tert-butoxycarbonyl-1-phenyl-1, 3, 4, 9-tetrahydro-beta-carbolin-3-yl	617
			287	2, 3, 4, 9-tetrahydro-1H-beta-carbolin-3-yl	550

Example 288

To a stirred solution of 5.0g (27.5mmol)2- (3, 4-dimethoxy-phenyl) -ethylamine was added 3.7g (27.5mmol) ethyl oxalyl chloride at 0 ℃. The reaction mixture was warmed to room temperature, stirred for 1.0h, and 100mL DCM was added. The solvent was washed with 1.0N HCl, water and brine, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 7.76g (100%) of N- [2- (3, 4-dimethoxy-phenyl) -ethyl ] -N- [2- (3, 4-dimethoxy-phenyl ] -ethyl]-ethyl oxalate, which was used directly in the next step without further purification. LCMS: 282(M +1)⁺.

To a solution of 5.0g (17.7mmol) of the above oxamide in 100mL CH₃20mL of POCl was added to the refluxing solution in CN₃. After 12 hours of reflux, the reaction mixture was poured into ice and extracted 3 times with ether (3X 50 mL). The ether extracts were washed 2 times with 1N HCl. The combined aqueous extracts were washed with NaHCO₃The solid was adjusted to pH 8. The aqueous extract was then washed 5 times with EtOAc (5X 50 mL). The combined organic layers were dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 3.2g (69%) of ethyl 6, 7-dimethoxy-3, 4-dihydro-isoquinoline-1-carboxylate. LCMS: 264(M +1) ⁺.

A mixture of 0.26g (1.0mmol) of the above imine and 10% Pd-C in 5.0mL EtOH was stirred at room temperature under hydrogen (1 atm). After 5h, the reaction mixture was filtered and evaporated to dryness and the residue was dissolved in DCM (5.0mL) containing 0.2g (2.0mmol) triethylamine. To the solution stirred at room temperature was added 0.24g (1.1mmol) of di-tert-butyl dicarbonate and stirring was continued for 2 h. The reaction mixture was washed with DCM (10 m)L) extraction, washing with water, brine, drying over magnesium sulfate and evaporation to dryness gave 0.35g (97%) of 2-tert-butyl 6, 7-dimethoxy-3, 4-dihydro-1H-isoquinoline-1, 2-dicarboxylate 1-ethyl ester. LCMS: 366(M +1)⁺.

To a stirred solution of 0.35g (0.95mmol) of the above ester in a mixture of THF (10mL) and methanol (3.0mL) was added 3.0mL of 2N LiOH at room temperature. The reaction mixture was stirred at room temperature for 45min, neutralized with 2.0N HCl (pH 6.0), and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 0.3g (90%) of 2-tert-butyl 6, 7-dimethoxy-3, 4-dihydro-1H-isoquinoline-1, 2-dicarboxylate. LCMS: 338(M +1)⁺.

0.25g (0.74mmol) of the above acid, 0.30g (0.81mmol) of HBTU and 0.18g (0.74mmol) of 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B) in a mixture of 4.0mL of DMF and 0.5mL of DIEA were reacted as described in general procedure A. The reaction mixture was cooled to room temperature and 5.0mL water and 5.0mL saturated NaHCO were added ₃. The resulting solid was filtered, washed with water, diethyl ether and dried to give 0.2g (48%) of 1- [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-ylcarbamoyl]-6, 7-dimethoxy-3, 4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester. LCMS: 562(M +1)⁺.

Example 289

To a refluxing solution of 2.0g (8.0mmol) of ethyl 6, 7-dimethoxy-3, 4-dihydro-isoquinoline-1-carboxylate is added 2.0g of 10% Pd-C. After refluxing for 12h, the reaction mixture was cooled, filtered through celite, and evaporated to dryness under reduced pressure to give 2.0g (98%) of ethyl 6, 7-dimethoxy-isoquinoline-1-carboxylate. LCMS: 262(M +1)⁺.

To a stirred solution of 0.35g (1.3mmol) of the above ester in a mixture of THF (10mL) and methanol (3.0mL) was added 3.0mL of 2N LiOH at room temperature. The reaction mixture was stirred at room temperature for 45min, neutralized with 2.0N HCl (pH 6.0), and extracted with ethyl acetate. The organic layer is treated with water,Washed with brine, dried over magnesium sulfate and the solvent evaporated under reduced pressure to give 0.3g (96%) of 6, 7-dimethoxy-isoquinoline-1-carboxylic acid. LCMS: 234(M +1)⁺.

0.1g (0.43mmol) of the above acid, 0.17g (0.47mmol) of HBTU in a mixture of 2.0mL DMF and 0.24mL DIEA was reacted with 0.10g (0.43mmol) of 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B) as described in general procedure A. The reaction mixture was cooled to room temperature and 5.0mL of water, 5.0mL of saturated NaHCO, was added ₃The resulting solid was filtered, washed with water, diethyl ether and dried to give 0.005g (2.6%) of 6, 7-dimethoxy-isoquinoline-1-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 458(M +1)⁺.¹H NMR(DMSO-d₆，400MHz)：δ8.86(s，1H)，8.57(d，1H)，8.11(d，1H)，7.96(d，1H)，7.88(d，1H)，7.57(s，1H)，7.38(m，3H)，3.98(s，3H)，3.97(s，3H)ppm.

Example 290

To a solution of 2.1g (10mmol) of HCl salt of 1, 2, 3, 4-tetrahydro-isoquinoline-3-carboxylic acid (2.1g, 10mmol) in concentrated H at-10 deg.C₂SO₄(15mL) to the solution HNO was added dropwise₃(70%, 2 mL). The mixture was stirred at-10 ℃ for 1.5h and then poured into ice. The reaction mixture is treated with concentrated NH₄OH is neutralized. After filtration, a white precipitate was collected, dried under vacuum, dissolved in methanol (50mL) and 4M HCl in dioxane was added. After refluxing overnight, the solvent was evaporated to dryness under reduced pressure to give 1.5g (63%) of 7-nitro-1, 2, 3, 4-tetrahydro-isoquinoline-3-carboxylic acid methyl ester.

To a solution of the above ester in 1, 4-dioxane (100mL) was added 2.8g (12.7mmol) of DDQ and the reaction mixture was refluxed for 6 h. After removal of the solvent, the residue was dissolved in ethyl acetate (250mL) and washed with NaHSO₃Aqueous solution (1M solution, 100mL), water and brine. The ethyl acetate layer was dried over sodium sulfate and evaporated to dryness under reduced pressure and subjected to column chromatography (using ethyl acetate followed by EtOAc/methanol: (b) (R)) v/v 100: 5) to yield 1.0g (71%) of 7-nitro-isoquinoline-3-carboxylic acid methyl ester. LCMS: 233(M +1)⁺The methyl ester was hydrolyzed according to general procedure B to give 0.9g of 7-nitro-isoquinoline-3-carboxylic acid. LCMS: 219(M +1)⁺.

To a solution of 44mg (0.2mmol) of 7-nitro-isoquinoline-3-carboxylic acid in DMF (1mL) was added 113mg (0.3mmol) of HBTU and DIEA (0.3 mL). The mixture was stirred for 10min, then 40mg (0.16mmol) 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B) was added. The reaction was heated at 80 ℃ for 1 h. After customary work-up, the residue is purified by column chromatography eluting with DCM/methanol (v/v ═ 10: 1) to give 8mg (9%) of 7-nitro-isoquinoline-3-carboxylic acid [7- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ] -7-nitro-isoquinoline-3-carboxylic acid]-an amide. LCMS: 443(M +1)⁺.

Example 291

According to general method C, a solution of 0.5g (2.1mmol) of methyl 7-nitro-isoquinoline-3-carboxylate in methanol (25ml) is hydrogenated to give 0.42g of methyl 7-amino-isoquinoline-3-carboxylate in quantitative yield. LCMS: 203(M +1)⁺.

To a solution of 0.42g (2.1mmol) of the above amine in pyridine (2mL) at 0 deg.C was added methanesulfonyl chloride (0.2 mL). The reaction mixture was stirred at 0 ℃ for 30min, warmed to room temperature, and extracted with ethyl acetate (20 mL). The organic phase was washed with 1N HCl, water over Na ₂SO₄Dried and concentrated. The residue was purified by column chromatography eluting with ethyl acetate to give 0.35g (59%) of 7-methanesulfonylamino-isoquinoline-3-carboxylic acid methyl ester. This methyl ester was hydrolyzed according to general procedure B to give 0.3g (90%) of 7-methanesulfonylamino-isoquinoline-3-carboxylic acid. LCMS: 267(M +1)⁺.

To a solution of 30mg (0.11mmol) of 7-methanesulfonylamino-isoquinoline-3-carboxylic acid in DMF (0.8mL) were added 60mg (0.15mmol) of HBTU and DIEA (0.1 mL). The mixture was stirred for 10min, then 24mg (0.1mmol) 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B) was added. The reaction was heated at 80 ℃ for 1 h. After conventional treatmentThe residue is then purified by column chromatography eluting with DCM/methanol (v/v ═ 10: 1 to 8: 1) to give 5mg (9%) of 7-methanesulfonylamino-isoquinoline-3-carboxylic acid [7- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 491(M +1)⁺.

Example 292

To a stirred solution of 2.0g (6.8mmol) Boc-7-hydroxy-tetrahydroisoquinoline-3-carboxylic acid in a mixture of DCM (20mL) and DIEA (2.0mL) was added 1.93g (13.7mmol) iodomethane at room temperature. The reaction mixture was stirred at room temperature for 6.0 h. DCM (20mL) was added and the solvent was washed with water, brine, dried over magnesium sulphate and evaporated to dryness under reduced pressure to give 2.09g (100%) of 2-tert-butyl 7-hydroxy-3, 4-dihydro-1H-isoquinoline-2, 3-dicarboxylate 3-methyl ester which was used in the next step without further purification. LCMS: 308(M +1) ⁺.

2.09g (6.8mmol) of the above ester, 1.28g (0.89mmol) of benzyl bromide and 1.38g (10.2mmol) of K₂CO₃Stirred in DMF (30mL) at 70 ℃ overnight and extracted with ethyl acetate (50 mL). The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 2.2g (81%) of 7-benzyloxy-3, 4-dihydro-1H-isoquinoline-2, 3-dicarboxylic acid 2-tert-butyl 3-methyl ester. LCMS: 398(M +1)⁺.

2.2g (5.5mmol) of the above ester were dissolved in 4.0M HCl in dioxane (20ml) and stirred at room temperature for 1.0 h. The solvent was evaporated under vacuum and the residue was taken up in toluene (20 mL). To the stirred solution was added 2.5g (11.0mmol) of DDQ and heated under reflux for 30 min. The reaction mixture was cooled and the precipitate was filtered. The filtrate is saturated NaHSO₃(25mL), water and brine. The organic layer was dried over magnesium sulfate, evaporated to dryness under reduced pressure and purified by column chromatography using 20% ethyl acetate in hexane as eluent to give 1.0g (62.5%) of 7-benzyloxy-isoquinoline-3-carboxylic acid methyl ester. LCMS: 294(M +1)⁺.

To a stirred solution of 1.0g (3.4mmol) of the above ester in a mixture of THF (30mL) and methanol (10mL) was added at room temperature10mL of 2N LiOH. The reaction mixture was stirred at room temperature for 45 min, neutralized with 2.0N HCl (pH 6.0-7.0), and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 0.8g (81%) of 7-benzyloxy-isoquinoline-3-carboxylic acid. LCMS: 280(M +1) ⁺.

0.70g (2.5mmol) of the above synthesized 7-benzyloxy-isoquinoline-3-carboxylic acid, 1.0g (2.7mmol) of HBTU and 0.48g (2.5mmol) of methyl 2-amino-3H-benzimidazole-4-carboxylate (intermediate A) in a mixture of 7.5mL of DMF and 1.7mL of DIEA were reacted as described in general procedure A. Separating by column chromatography with ethyl acetate-hexane (1: 1) as eluent to obtain 2- [ (7-benzyloxy-isoquinoline-3-carbonyl) -amino]-1H-benzimidazole-4-carboxylic acid methyl ester (1.0g, 88%). LCMS: 453(M +1)⁺.

Example 293

0.13g (0.45mmol) of 7-benzyloxy-isoquinoline-3-carboxylic acid, 0.19g (0.5mmol) of HBTU in a mixture of 2.0mL of DMF and 0.26mL of DIEA was reacted with 0.1g (0.41mmol) of 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B) as described in general procedure A. The reaction mixture was cooled to room temperature and 5.0mL water and 5.0mL saturated NaHCO were added₃. The resulting solid was filtered, washed with water and diethyl ether and dried to give 0.055g (27%) of 7-benzyloxy-isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 504(M +1)⁺.

Example 294

A mixture of 10.12g (55.9mmol) 2-amino-3- (3-hydroxy-phenyl) -propionic acid, 20mL 37% aqueous formaldehyde, 10mL concentrated aqueous HCl and 100mL methanol was refluxed for 3 h. The solvent was evaporated to dryness to give a quantitative yield of a mixture of 6-hydroxy-1, 2, 3, 4-tetrahydro-isoquinoline-3-carboxylic acid methyl ester and 8-hydroxy-1, 2, 3, 4-tetrahydro-isoquinoline-3-carboxylic acid methyl ester as a pale yellow solid. LCMS: 208(M +1) ⁺.

A mixture of the aforementioned methyl 6-hydroxy-1, 2, 3, 4-tetrahydro-isoquinoline-3-carboxylate and methyl 8-hydroxy-1, 2, 3, 4-tetrahydro-isoquinoline-3-carboxylate and a solution of 15.3g (70mmol) of di-tert-butyl dicarbonate in 40mL of dioxane and 40mL of 2N Na₂CO₃The solution was stirred at room temperature for 80 min. The reaction mixture was partitioned between ethyl acetate (300mL) and brine (300 mL). The aqueous layer was separated and extracted with ethyl acetate (150 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness. The mixture of 6.186g (36%) of 2-tert-butyl 6-hydroxy-3, 4-dihydro-1H-isoquinoline-2, 3-dicarboxylate 3-methyl ester and 2-tert-butyl 8-hydroxy-3, 4-dihydro-1H-isoquinoline-2, 3-dicarboxylate 3-methyl ester was obtained by silica gel column chromatography. LCMS: 308(M +1)⁺.

A mixture of 6-hydroxy-3, 4-dihydro-1H-isoquinoline-2, 3-dicarboxylic acid 2-tert-butyl 3-methyl ester from the previous step with 8-hydroxy-3, 4-dihydro-1H-isoquinoline-2, 3-dicarboxylic acid 2-tert-butyl 3-methyl ester, 5.04mL (80mmol) of methyl iodide, 5.53g (40mmol) of potassium carbonate and 50mL of DMF was heated at 90 ℃ overnight. The reaction mixture was partitioned between ethyl acetate (400mL) and water (400mL) and the layers were separated. The organic layer was dried over sodium sulfate, evaporated to dryness and used directly in the next step. LCMS: 322(M +1) ⁺.

A solution of 6-methoxy-3, 4-dihydro-1H-isoquinoline-2, 3-dicarboxylic acid 2-tert-butyl 3-methyl ester and 8-methoxy-3, 4-dihydro-1H-isoquinoline-2, 3-dicarboxylic acid 2-tert-butyl 3-methyl ester from the previous step in 20mL of dichloromethane was treated with 20mL of 4N HCl in dioxane and stirred at room temperature for 3H. The solvent was evaporated under vacuum to afford a mixture of 6-methoxy-1, 2, 3, 4-tetrahydro-isoquinoline-3-carboxylic acid methyl ester hydrochloride and 8-methoxy-1, 2, 3, 4-tetrahydro-isoquinoline-3-carboxylic acid methyl ester hydrochloride which was washed with hexane and used directly in the next step. LCMS: 222(M +1)⁺.

The mixture of methyl 6-methoxy-1, 2, 3, 4-tetrahydro-isoquinoline-3-carboxylate hydrochloride and methyl 8-methoxy-1, 2, 3, 4-tetrahydro-isoquinoline-3-carboxylate hydrochloride of the previous step is taken up in 100mL of tolueneTreated with 9.50g (41mmol) of DDQ and heated at reflux for 1 h. Reaction mixture in 2MNaS₂O₃(100mL)，1M Na₂CO₃Partitioned between (100mL) and ethyl acetate (150mL) and the layers were separated. The aqueous layer was extracted again with ethyl acetate (200 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness. Purifying by silica gel column chromatography, and separating to obtain the following target products:

6-methoxy-isoquinoline-3-carboxylic acid methyl ester: 2.35g (total yield in 3 steps 52%). ¹H-NMR(400MHz，CDCl₃)：9.19(s，1H)，8.51(s，1H)，7.95(d，1H)，7.37(dd，1H)，7.21(d，1H)，4.07(s，3H)，3.98(s，3H)ppm；LCMS：218(M+1)⁺.

8-methoxy-isoquinoline-3-carboxylic acid methyl ester: 90mg (3 steps total yield 2%).¹H-NMR(400MHz，CDCl₃)：9.69(s，1H)，8.53(s，1H)，7.69(dd，1H)，7.52(d，1H)，7.04(d，1H)，4.066(s，3H)，4.064(s，3H)ppm；LCMS：218(M+1)⁺.

2.35g (10.82mmol) of methyl 6-methoxy-isoquinoline-3-carboxylate are hydrolyzed according to general procedure B to give 1.99g (90%) of 6-methoxy-isoquinoline-3-carboxylic acid. LCMS: 204(M +1)⁺.

As described in general procedure A, 224mg (1.1mmol) of 6-methoxy-isoquinoline-3-carboxylic acid are reacted with 242mg (1mmol) of intermediate B (2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide), 569mg (1.5mmol) of HBTU, 0.704mL (4mmol) of DIEA and 5mL of DMF under stirring at 80 ℃ for 2H to give 212.4mg (50%) of the title compound.¹H-NMR(400MHz，DMSO)：9.37(s，1H)，8.71(s，1H)，8.24(d，1H)，7.94(d，1H)，7.82(d，1H)，7.73(d，1H)，7.49(dd，1H)，7.34(t，1H)，6.88(s，1H)，6.76(s，1H)，3.98(s，3H)ppm；LCMS：428(M+1)⁺.

Example 295

Following general method B90 mg (0.46mmol) of methyl 8-methoxy-isoquinoline-3-carboxylate (example above)Synthesized in the examples) was hydrolyzed to yield 84mg (100%) of 8-methoxy-isoquinoline-3-carboxylic acid. LCMS: 204(M +1)⁺.

Following general procedure A, using 41mg (0.2mmol) of 8-methoxy-isoquinoline-3-carboxylic acid, 48mg (0.2mmol) of intermediate B (2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide), 100mg (0.264mmol) of HBTU, 0.167mL (0.97mmol) of DIEA and 1mL of DMF, stirring at 80 for 2H, 32.3mg (38%) of 8-methoxy-isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ] are synthesized]-an amide. LCMS: 428(M +1) ⁺.

Example 296

Starting from 2.0g (6.8mmol) boc-7-hydroxy-tetrahydroisoquinoline carboxylic acid according to the procedure described for the synthesis of 6-methoxy-isoquinoline-3-carboxylic acid (example 294), 0.25g (17% over 4 steps) of 7-methoxy-isoquinoline-3-carboxylic acid is prepared from 179mg (0.824 mmol). LCMS: 204(M +1)⁺.

Following general procedure A, 71.8mg (84%) of 7-methoxy-isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzoimidazol-2-yl ] -was prepared from 41mg (0.2mmol) of 7-methoxy-isoquinoline-3-carboxylic acid, 48mg (0.2mmol) of intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide), 100mg (0.246mmol) of HBTU, 0.07mL (0.4mmol) of DIEA and 2mL of DMF by stirring at 80 ℃ for 2H]-an amide. LCMS: 428(M +1)⁺.

Example 297

According to the method described for the synthesis of 6-methoxy-isoquinoline-3-carboxylic acid (example 294), 0.2g (4 steps overall yield 9.1%) 6-isopropoxy-1, 2, 3, 4-tetrahydro-isoquinoline-3-carboxylic acid is prepared starting from 0.67g (2.18mmol) of 2-tert-butyl 3-methyl 6-hydroxy-3, 4-dihydro-1H-isoquinoline-2, 3-dicarboxylate. LCMS: 232(M +1)⁺.

In a flask with DMF (3mL) and DIEA (1mL) was mixed 0.05g (0.23mmol) of 6-isopropoxy-isoquinoline-3-carboxylic acid and 0.19g (0.50mmol) HBTU. The reaction mixture was then treated with 0.1g (0.4mmol) 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B) and stirred at 80 ℃ for 1H. The reaction mixture was diluted with water and the resulting solid precipitate was filtered and washed with saturated NaHCO ₃And (6) washing. The solid was dissolved in MeOH, evaporated onto silica and flash column chromatographed (500mL DCM/20mL NH)₃MeOH) to yield 10mg (9%) of 6-isopropoxy-isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 456(M +1)⁺.

Example 298

1.556g (11mmol) of 3-methylsulfanyl-propionyl chloride are slowly added to a mixture of 2.20g (10mmol) of phenylalanine methyl ester hydrochloride, 4.18mL (30mmol) of triethylamine and 50mL of dichloromethane and stirred at room temperature for 2 h. The reaction mixture was stirred in DCM (50mL) and saturated NaHCO₃The solutions (100mL) were partitioned. The aqueous layer was separated and extracted again with dichloromethane (100 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. Purification by silica gel column chromatography gave 2.574g (92%) of 2- (3-methylsulfanyl-propionylamino) -3-phenyl-propionic acid methyl ester. LCMS: 282(M +1)⁺.

0.882mL (10.07mmol) of oxalyl chloride was added dropwise to a solution of 2- (3-methylsulfanyl-propionylamino) -3-phenyl-propionic acid methyl ester (from the previous step) in 30mL of dichloromethane and stirred at room temperature for 1 h. The reaction mixture was then cooled to-10 ℃ and at that temperature was quenched with 1.82g (11mmol) FeCl₃And (5) performing treatment in a grading manner. The reaction mixture was warmed to room temperature overnight. 30mL of 2N aqueous HCl was added slowly while stirring for 1 h. 20mL of dichloromethane was added, separated, washed again with water (50mL), and dried over sodium sulfate. The organic solvent was evaporated to dryness in vacuo. The remaining red solid was combined with 30mL of methanol and 1.5mL of concentrated H ₂SO₄Mix and heat to reflux overnight. Water was added to the reaction mixture, and methanol was evaporated under reduced pressure. Ammonium hydroxide was added to adjust the pH to basic. The aqueous layer was extracted with dichloromethane (2X 50mL) (ca. 50 mL). The combined organic layers were dried over sodium sulfate and evaporatedAnd (5) drying. Purification by silica gel column chromatography gave 923mg (38%) of 1- (2-methylsulfanyl-ethyl) -3, 4-dihydro-isoquinoline-3-carboxylic acid methyl ester. LCMS: 264(M +1)⁺.

1.297g (7mmol) of acetone are added to a solution of 923mg (3.5mmol) of 1- (2-methylsulfanyl-ethyl) -3, 4-dihydro-isoquinoline-3-carboxylic acid methyl ester in 10mL of dichloromethane and stirred at room temperature overnight. The reaction mixture was concentrated and purified by silica gel column chromatography to give 266mg (29%) of 1- (2-methylsulfanyl-ethyl) -isoquinoline-3-carboxylic acid methyl ester. LCMS: 262(M +1)⁺.

1- (2-methylsulfanyl-ethyl) -isoquinoline-3-carboxylic acid is prepared according to general method B with 49mg (0.187mmol) of methyl 1- (2-methylsulfanyl-ethyl) -isoquinoline-3-carboxylate, 0.28mL of a 2N aqueous LiOH solution, 2mL of THF and 0.5mL of methanol stirred at room temperature for 1 h. 42.4mg (91%) of 1- (2-methylsulfanyl-ethyl) -isoquinoline-3-carboxylic acid are obtained. LCMS: 248(M +1)⁺.

Following general procedure A, 42.4mg (0.171mmol)1- (2-methylsulfanyl-ethyl) -isoquinoline-3-carboxylic acid is reacted with 34mg (0.14mmol) intermediate B (2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide), 114mg (0.3mmol) HBTU and 0.106mL (0.6 mmol) DIEA in 0.8mL DMF at 85 ℃ for 3H with stirring. 44.3mg (55%) of 1- (2-methylsulfanyl-ethyl) -isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ]-an amide. LCMS: 472(M +1)⁺.

Example 299

559mg (0.91mmol) of oxone complex are added to a solution of 217mg (0.83mmol) of methyl 1- (2-methylsulfanyl-ethyl) -isoquinoline-3-carboxylate (synthesized in the above example 298) in 4mL of methanol and stirred at room temperature for 1.5 h. The reaction mixture was partitioned between dichloromethane (40mL) and water (40 mL). The aqueous layer was separated and extracted again with dichloromethane (40 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. Purification by silica gel column chromatography gave 169mg (69%) of 1- (2-methylsulfonyl-ethyl) -iso-propyl ether as an off-white solidQuinoline-3-carboxylic acid methyl ester. LCMS: 294(M +1)⁺The ester was hydrolyzed according to general procedure B to give 145mg (90%) of 1- (2-methylsulfonyl-ethyl) -isoquinoline-3-carboxylic acid.

Following general procedure A, 51.7mg (57%) of 1- (2-methanesulfonyl-ethyl) -isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ] -carboxylic acid is prepared from 50.3mg (0.18mmol) of 1- (2-methylsulfonyl-ethyl) -isoquinoline-3-carboxylic acid, 36.3mg (0.15mmol) of intermediate B (2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide), 114mg (0.3mmol) of HBTU, 0.106mL (0.6mmol) of DIEA and 0.8mL of DMF (0.8mL) with stirring at 85 ℃ for 3H ]-an amide. LCMS: 504(M +1)⁺.

Example 300

According to the method described for the synthesis of 1- (2-methylsulfanyl-ethyl) -isoquinoline-3-carboxylic acid (example 298), 0.25g (11% overall yield) of 1-methyl-isoquinoline-3-carboxylic acid is synthesized starting from 2.20g (10mmol) of phenylalanine methyl ester hydrochloride. LCMS: 188(M +1)⁺.

Following general procedure A, 17.6mg (15%) of 1-methyl-isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ] -carboxylate was synthesized from 55mg (0.29mmol) of 1-methyl-isoquinoline-3-carboxylic acid, 70mg (0.29mmol) of intermediate B (2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide), 144mg (0.38mmol) of HBTU, 0.264mL (1.5mmol) of DIEA in 0.8mL of DMF with stirring at 85 ℃ for 2H]-an amide.¹H-NMR(400MHz，DMSO)：8.66(s，1H)，8.38(d，1H)，8.28(d，1H)，7.89(m 4H)，7.34(m，1H)，6.85(b，2H)，3.07(s，3H)ppm.LCMS：412(M+1)⁺.

Example 301

0.083mL (1mmol) of sulfonyl chloride was added to a solution of 90mg (0.41mmol) of methyl 8-methoxy-isoquinoline-3-carboxylate (from example 295) in 1mL of acetic acid and stirred at room temperature overnight. Adding diethyl ether to the reaction mixture, filtering the precipitated solid, and adding ethyl acetateWashed with ether and then with ethyl acetate (30mL) and saturated NaHCO₃The solution (30mL) was partitioned and extracted. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo to yield 47.3mg (46%) of 7-chloro-8-methoxy-isoquinoline-3-carboxylic acid methyl ester. LCMS: 252(M +1) ⁺The ester was hydrolyzed according to general procedure B to give 40mg (88%) of 7-chloro-8-methoxy-isoquinoline-3-carboxylic acid. LCMS: 238(M +1)⁺.

According to general method A, 10mg (13%) of 7-chloro-8-methoxy-isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ] carboxylic acid is synthesized from 7-chloro-8-methoxy-isoquinoline-3-carboxylic acid (from the previous step), 36.3mg (0.15mmol) of intermediate B (2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide), 69mg (0.18mmol) of HBTU, 0.106mL (0.6mmol) of DIEA in 2mL DMF at 80 ℃ with stirring for 2H]-an amide. LCMS: 462(M +1)⁺.

Example 302

1.0g (6.8mmol) of thiophene-2, 3-dicarboxaldehyde was dissolved in DCM (50mL) and cooled to 0 ℃. 2.0g (7.4mmol) (. + -.) Boc- α -phosphonoglycine trimethyl ester was dissolved in DCM (25mL) and 1.14g (7.5mmol) DBU was added with stirring at ambient temperature. This solution is added dropwise to a cold solution of the dialdehyde with stirring. The solution was stirred at 0 ℃ for 1h, overnight at ambient temperature. The reaction mixture was concentrated and the residue was dissolved in 4M HCl in dioxane. The resulting white suspension was stirred at room temperature for 1 h. The solvent was evaporated to dryness, extracted with ethyl acetate (100ml), saturated NaHCO₃Water and brine. The organic layer was dried over magnesium sulfate, evaporated to dryness and purified by column chromatography using 20% ethyl acetate in hexane as eluent to give the following two regioisomers.

0.34g (24%) of thieno [2, 3-c]Pyridine-5-carboxylic acid methyl ester.¹H-NMR(400MHz，CDCl₃)：9.20(s，1H)，8.27(s，1H)，7.82(d，1H)，7.50(d，1H)，4.03(s，3H)ppm；LCMS：180(M+1)⁺.

0.17g (12%) thieno [3, 2-c]Pyridine-6-carboxylic acid methyl ester.¹H-NMR(400MHz，CDCl₃)：9.191(s，1H)，8.7(s，1H)，7.72(d，1H)，7.55(d，1H)ppm；LCMS：180(M+1)⁺The methyl ester was hydrolyzed to give the corresponding acid in quantitative yield as shown in general procedure B.

Following general procedure A, with 54mg (0.3mmol) of thieno [2, 3-c]Pyridine-5-carboxylic acid, 61mg (0.25mmol) of intermediate B (2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide), 114mg (0.3mmol) of HBTU, 0.106mL (0.6mmol) of DIEA in 1mL of DMF was stirred at 85 ℃ for 1H to prepare 2.6mg (3%) of thieno [2, 3-c ]]Pyridine-5-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 404(M +1)⁺.

Example 303

Following general procedure A, with 54mg (0.3mmol) of thieno [3, 2-c]Pyridine-6-carboxylic acid (synthesized in the above example), 61mg (0.25mmol) of intermediate B (2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide), 114mg (0.3mmol) of HBTU, 0.106mL (0.6mmol) of DIEA in 1mL of DMF at 85 ℃ with stirring for 1H, 5.0mg (2.9%) of thieno [3, 2-c ] was prepared]Pyridine-6-carboxylic acid [7- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 404(M +1)⁺.

Example 304

100mg (0.56mmol) of 2-methyl-1, 8 a-dihydro-imidazo [1, 2-a ] in a mixture of 1.5mL of DMF and 0.6mL of DIEA as described in general procedure A ]Pyridine-3-carboxylic acid and 234mg (0.61mmol) of HBTU were reacted with 137mg (0.56mmol) of 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B). After completion of the reaction, diluted with brine (20mL), the resulting solid was filtered, washed with water, ethyl acetate and dried under vacuum to give 40mg (17%) of 2- [ (2-methyl-imidazo [1, 2-a ] as a solid]Pyridine-3-carbonyl) -amino]-1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide. L isCMS：401(M+1)⁺.

Example 305

Hydrogenation of 1.54g (10.0mmol) of 3-methoxy-2-nitropyridine was carried out according to general procedure C to give 2-amino-3-methoxypyridine. The product was treated directly with 2.5g (12.0mmol) of ethyl bromopyruvate in 20.0mL THF overnight at room temperature, 20.0mL ethanol was added and the mixture was refluxed for 8 h. The solvent was evaporated to dryness and the resulting residue was diluted with THF, filtered and washed with THF to give 1.76g (80%) of ethyl 8-methoxy-imidazo [1, 2-a ] pyridine-2-carboxylate.

The ester was hydrolyzed according to general procedure B to give 1.5g (95%) of the corresponding 8-methoxy-imidazo [1, 2-a ] pyridine-2-carboxylic acid.

300mg (3.0mmol) of the above 8-methoxy-imidazo [1, 2-a ] in a mixture of 1.5mL DMF and 0.6mL DIEA as described in general method A ]Pyridine-2-carboxylic acid and 200mg (0.5mmol) HBTU were reacted with 60mg (0.25mmol) 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B). After completion of the reaction, diluted with brine (20mL), the resulting solid was filtered, washed with water, ethyl acetate and dried under vacuum to give 41mg (40%) of 2- [ (8-methoxy-imidazo [1, 2-a ] as a solid]Pyridine-3-carbonyl) -amino]-1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide. LCMS: 417(M +1)⁺.

The following compounds were synthesized by analogous methods as used in preparation example 290-305 and the related schemes above.

Examples	Ar	LCMS (M+1)⁺
			306	6, 7-bis- (2-methoxy-ethoxy) -isoquinolin-3-yl	546
307	Cinnolin-3-yl	417
			308	Quinoxaline-2-yl	399
309	6-bromo-pyridin-2-yl	427
			310	[1，8]Naphthyridin-2-yl	399
311	Isoquinolin-1-yl	398
			312	6, 7-dimethoxy-isoquinolin-3-yl	458
313	4-cyano-phenyl	372
			314	6-cyano-pyridin-3-yl	373
315	Isoquinolin-5-yl	398
			316	2, 6-dimethoxy-pyrimidin-4-yl	518
317	6-benzyloxy-isoquinolin-3-yl	504
			318	2, 3-dihydro- [1, 4]Dioxa [2, 3-g]Isoquinolin-8-yl	456
319	[1，3]Meta-dioxacyclopenteno [4, 5-g]Isoquinolin-7-yl	442
			320	6-cyclopentyloxyYl-isoquinolin-3-yl	482
321	1-cyclopentylmethyl-7-methoxy-isoquinolin-3-yl	510
			322	1-isopropyl-isoquinolin-3-yl	440
323	6-ethoxy-isoquinolin-3-yl	442
			324	6-butoxy-isoquinolin-3-yl	470
325	1-propyl-isoquinolin-3-yl	440
			326	1-butyl-isoquinolin-3-yl	454
327	1-isobutyl-isoquinolin-3-yl	454
			328	1-cyclopentyl-isoquinolin-3-yl	466
329	7-methoxy-1-methyl-isoquinolin-3-yl	442
			330	1-methyl-6-trifluoromethoxy-isoquinolin-3-yl	496
331	7-methanesulfonyl-1-methyl-isoquinolin-3-yl	490
			332	1- (tetrahydro-pyran-4-yl) -isoquinolin-3-yl	482
333	1-methyl-7-trifluoromethoxy-isoquinolin-3-yl	496
			334	5, 8-dimethoxy-isoquinolin-3-yl	458
335	4-methoxy-quinolin-2-yl	428
			336	7-methoxy-isoquinolin-1-yl	428
337	Imidazo [1, 2-a ]]Pyridin-2-yl	387
			338	5-methyl-imidazo [1, 2-a ]]Pyridin-2-yl	401
339	Imidazo [2, 1-b ]]Thiazol-6-yl	393
			340	8-methyl-imidazo [1, 2-a ]]Pyridin-2-yl	401
341	[ bis- (4-chloro-phenyl)]-methyl radical	505

Example 342

To a solution of 1.0g (4.9mmol) 6-bromo-pyridine-2-carboxylic acid, 0.9g (7.4mmol) phenylboronic acid, 0.4g (0.36mmol) tetrakis (triphenylphosphine) palladium in 25mL DME under nitrogen was added 9.9mL 2N Na ₂CO₃And (3) solution. After refluxing under nitrogen for 12h, the reaction was cooledThe mixture was filtered through filter paper. The filtrate was acidified to pH 5 with 2N HCl. The resulting white precipitate was filtered, washed with water and dried to yield 0.5g (51%) of 6-phenyl-pyridine-2-carboxylic acid. LCMS: 200(M +1)⁺.

0.1g (0.5mmol) of the above acid, 0.19g (0.5mmol) of HBTU in a mixture of 2.0mL DMF and 0.24mL DIEA was reacted with 0.12g (0.5mmol) of 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B) as described in general procedure A. The reaction mixture was cooled to room temperature and 5.0mL water and 5.0mL saturated NaHCO were added₃. The resulting solid was filtered, washed with water and diethyl ether and dried to give 0.04g (20%) of 2- [ (6-phenyl-pyridine-2-carbonyl) -amino group]-1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide. LCMS: 424(M +1)⁺.

Example 343

0.12g (0.51mmol)6- (3-cyano-phenyl) -pyridine-2-carboxylic acid, 0.19g (0.5mmol) HBTU in a mixture of 2.0mL DMF and 0.26mL DIEA was reacted with 0.1g (0.41mmol) 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B) as described in general procedure A. The reaction mixture was cooled to room temperature and 5.0mL water and 5.0mL saturated NaHCO were added ₃. The resulting solid was filtered, washed with water and diethyl ether and dried to give 0.04g (17.5%) of 2- { [6- (3-cyano-phenyl) -pyridine-2-carbonyl]-amino } -1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide.¹H-NMR(400 MHz₅，DMSO)：9.15(s，1H)，8.86(s，1H)，8.45(m，1H)，8.24(m，2H)，7.99(d，1H)，7.92(d，1H)，7.87(d，1H)，7.72(t，1H)，7.41(t，1H)，7.30(s，2H)ppm.LCMS：449(M+1)⁺.

Example 344

0.31g (2mmol) of methyl 5-hydroxy-nicotinate, 0.73g (4mmol) of acetone, about 1g of 4In a column containing 20mL of DCM and 2.0mL (14mmol) of Et together with 0.85g (7mmol) of phenylboronic acid₃N flask. The reaction slurry was stirred at room temperature overnight. The reaction mixture was then diluted with 200mL EtOAc and was combined with 10% K₂CO₃Washing was carried out 3 times. Then the organic layer was washed with Na₂SO₄Drying, evaporation to dryness and purification by flash column chromatography (EtOAc/hexanes ═ 1: 2) afforded 5-phenoxy-nicotinic acid methyl ester, which was subsequently hydrolyzed according to general procedure B to afford 5-phenoxy-nicotinic acid, which was used directly in the next step without further purification.

In a flask containing 2mL of DMF and 0.25mL of DIEA, 0.07g (0.30mmol) of 5-phenoxy-nicotinic acid and 0.12g (0.32mmol) of HBTU were mixed. The reaction mixture was then treated with 0.05g (0.20mmol) 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B) and stirred at 80 ℃ for 1H. The reaction mixture was diluted with water and the resulting solid precipitate was filtered and washed with saturated NaHCO ₃And (6) washing. The solid was dissolved in MeOH, evaporated onto silica and flash column chromatographed (500mL DCM/20mL NH)₃MeOH) to yield 10mg (11%) of 2- [ (5-phenoxy-pyridine-3-carbonyl) -amino]-1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide. LCMS: 441(M +1)⁺.

Example 345

In a flask with 45mL THF and 0.31mL (3mmol) benzyl alcohol 0.31g (2mmol) methyl 5-hydroxy-nicotinate and 3.1g (4mmol) polymer supported triphenylphosphine were mixed and shaken at room temperature until the starting material was dissolved. The reaction mixture was then cooled to 0 ℃ with a water/brine bath, 0.58mL (3mmol) of DIAD was added, and the reaction slurry was stirred at room temperature overnight. The reaction mixture was filtered and the resin was washed 3 times with DCM/MeOH (1: 1). The organic layer was then evaporated to dryness and flash column chromatography (EtOAc/hexanes ═ 1: 2) afforded the desired product, 5-benzyloxy-nicotinic acid methyl ester, which was subsequently hydrolyzed according to general procedure B to afford 5-benzyloxy-nicotinic acid, which was used directly in the next step without further purification. LCMS: 230(M +1)⁺.

In a flask containing 2mL of DMF and 0.25mL of DIEA was combined 0.07g (0.30mmol) of 5-benzyloxy-nicotinic acid and 0.12g (0.32mmol) of HBTU. The reaction mixture was then treated with 0.05g (0.20mmol) 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B) and stirred at 80 ℃ for 1H. The reaction mixture was diluted with water and the resulting solid precipitate was filtered and washed with saturated NaHCO ₃And (6) washing. The solid was dissolved in MeOH, evaporated onto silica and flash column chromatographed (500mL DCM/20mL NH)₃MeOH) to yield 10mg (10%) of 2- [ (5-benzyloxy-pyridine-3-carbonyl) -amino]-1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide. LCMS: 455.0(M +1)⁺.

The following compounds were synthesized by a similar method as used in preparation example 342-345 and the related scheme described above.

Examples	Ar	LCMS (M+1)⁺
			346	6- (2-carbamoyl-phenyl) -pyridin-2-yl	467
347	6- (2-trifluoromethoxy-phenyl) -pyridin-2-yl	508
			348	6- (4-fluoro-phenyl) -pyridin-3-yl	442
349	6- (4-trifluoromethyl-phenyl) -pyridin-3-yl	492
			350	6- (4-trifluoromethoxy-phenyl) -pyridin-3-yl	508
351	5- (3-fluoro-phenyl) -pyridin-3-yl	442
			352	5- (4-trifluoromethoxy-phenyl) -pyridin-3-yl	508
353	5- (2, 4-difluoro-phenyl) -pyridin-3-yl	460
			354	5- (3-trifluoromethoxy-phenyl) -pyridin-3-yl	508
355	6- (furan-2-yl) -pyridin-2-yl	414
			356	6- (2-fluoro-phenyl) -pyridin-2-yl	442
357	6- (4-methoxy-phenyl) -pyridin-3-yl	454
			358	5-phenyl-pyridin-2-yl	424
359	5-phenyl-pyridin-3-yl	424
			360	5- (4-methoxy-phenyl) -pyridin-3-yl	454
361	4-phenyl-pyridin-2-yl	424
			362	6- (2-methoxy-phenyl) -pyridin-2-yl	454
363	6- (3-methanesulfonyl-phenyl) -pyridin-2-yl	502
			364	6- (3-aminomethyl-phenyl) -pyridin-2-yl	599
365	2- (3-cyano-phenyl) -pyridin-4-yl	449
			366	6-phenyl-pyridin-3-yl	424
367	3-cyano-phenyl	372
			368	6- (3-cyanomethyl-phenyl) -pyridin-2-yl	463
369	6- (4-methanesulfonyl-phenyl) -pyridin-2-yl	502
			370	3' -cyano-biphenyl-3-yl	448
371	4' -cyano-biphenyl-3-yl	448
			372	[2，4’]-bipyridin-6-yl	425
373	[2，3’]-bipyridin-6-yl	425
			374	2-phenoxy-pyridin-3-yl	440
375	3' -cyano-biphenyl-4-yl	448
			376	4' -cyano-biphenyl-4-yl	448
377	6- (3-cyano-phenyl) -pyridin-3-yl	449
			378	3-pyridine-3-phenyl	424
379	4-pyridine-3-phenyl	424
			380	2- (4-fluoro-phenoxy) -pyridin-3-yl	458
381	4-pyridine-4-phenyl	424
			382	6- (2-cyano-phenyl) -pyridin-2-yl	449
383	3-benzyloxy-pyridin-2-yl	454
			384	6-benzyloxy-pyridin-2-yl	454
385	6-thiophen-2-yl-pyridin-2-yl	430
			386	5-cyclopentyloxy-pyridin-3-yl	432
387	5-Cyclopentylmethoxy-pyridin-3-yl	446
			388	5- (2-cyclopentyl-ethoxy) -pyridin-3-yl	460
389	(R) -5- (1-phenyl-ethoxy) -pyridin-3-yl	468
			390	(S) -5- (1-phenyl-ethoxy) -pyridin-3-yl	468
391	3- (2-Phenylethoxy) -pyridin-2-Yl	468
			392	5-benzyloxy-pyridin-2-yl	454
393	5- (2-Phenylethoxy) -pyridin-2-Yl	468
			394	5-Cyclopentylmethoxy-pyridin-2-yl	446
395	5- (2-cyclopentyl-ethoxy) -pyridin-2-yl	460
			396	5-isopropoxy-pyridin-3-yl	406
397	5- (1-Ethyl-propoxy) -pyridin-3-yl	434
			398	5-Cyclopropylmethoxy-pyridin-3-yl	418
399	5- (1-cyclopropyl-ethoxy) -pyridin-3-yl	432
			400	5-propoxy-pyridin-3-yl	406
401	5-butoxy-pyridin-3-yl	420
			402	5-isobutoxy-pyridin-3-yl	420
403	4- (2-cyclopentyl-ethoxy) -pyridin-2-yl	460
			404	6-phenyl-pyrimidin-4-yl	425
405	6- (4-fluoro-phenyl) -pyrimidin-4-yl	443
			406	4- (5-trifluoromethyl-pyridin-2-yl) -phenyl	492
407	4- (4-trifluoromethyl-phenoxy) -phenyl	507

Example 408

To a solution of 0.66g (3.0mmol)6- (3-cyano-phenyl) -pyridine-2-carboxylic acid in DMF (10mL) was added 1.5g (3.9mmol) HBTU and DIEA (1 mL). The mixture was stirred at room temperature for 10min, then 0.8g (4.1mmol) of methyl 2-amino-3H-benzimidazole-4-carboxylate (intermediate A) was added. The reaction was heated at 90 ℃ for 1 h. After customary work-up as described in general procedure A, 1g (83%) 2- { [6- (3-cyano-phenyl) -pyridine are obtained-2-carbonyl]-amino } -3H-benzimidazole-4-carboxylic acid methyl ester. LCMS: 398(M +1) ⁺。¹H NMR(DMSO-d₆，400MHz)：δ8.85(s，1H)，8.60(d，1H)，8.23(m，2H)，8.11(m，1H)，7.95(m，2H)，7.76(dd，1H)，7.60(m，2H)，3.91(s，3H)ppm.

Hydrolysis of 0.7g (1.7mmol) of the above ester according to general procedure B gave 0.53g (82%) of 2- { [6- (3-cyano-phenyl) -pyridine-2-carbonyl]-amino } -3H-benzimidazole-4-carboxylic acid. LCMS: 384(M +1)⁺.

To a solution of 76mg (0.2mmol) of the above acid in DMF (1mL) was added 113mg (0.3mmol) of HBTU and DIEA (0.2mL), and the mixture was stirred at room temperature for 10min, followed by the addition of 0.1g (1.2mmol) of butylamine. The mixture was heated at 60 ℃ for 30 min. After cooling to room temperature, conventional work-up was carried out as indicated in general procedure A, followed by purification by column chromatography (eluting with DCM and then ethyl acetate) to give 20mg (22%) of 2- { [6- (3-cyano-phenyl) -pyridine-2-carbonyl]-amino } -3H-benzimidazole-4-carboxylic acid butylamide. LCMS: 438(M +1)⁺.

The following compounds were synthesized by analogous methods as used in the preparative example 408 and the related schemes described above.

Examples	W	LCMS(M+1)⁺
			409	Phenyl radical	459
410	Isopropyl group	425
			411	Cyclohexyl radical	465
412	Furan-2-ylmethyl	463

Example 413

0.728mL (6.5mmol) of phenylacetylene was added to a mixture of 10.1g (5mmol) of 4-bromopicolinic acid, 91mg (0.13mmol) of dichlorobis (triphenylphosphine) -palladium (II), 29mg (0.15mmol) of copper (I) iodide, 10mL of triethylamine and 2mL of DMF and heated at 80 ℃ overnight. The reaction mixture was filtered. The filtrate was concentrated to 5mL of 2N Na ₂CO₃The solution was partitioned between 25mL of water and 30mL of diethyl ether. The aqueous layer was separated and washed again with diethyl ether (30 mL). 10% aqueous HCl was added to adjust the pH to 5. The aqueous layer was extracted with dichloromethane (2X 50mL) and the combined organic layers were dried over sodium sulfate. The solvent was evaporated down in vacuo to afford 1.028g (4.61mmol, 92%) 4-phenylethynyl-pyridine-2-carboxylic acid. LCMS: 224(M +1)⁺.

0.05(0.23mmol) of the above synthesized 4-phenylethynyl group in a mixture of 2.0mL DMF and 0.20mL DIEA as described in general procedure APyridine-2-carboxylic acid, 0.095g (0.25mmol) HBTU and 0.05g (0.20mmol) 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B) were reacted. The reaction mixture was cooled to room temperature and 5.0mL water and 5.0mL saturated NaHCO were added₃And the resulting solid was filtered. The solid was washed with water and diethyl ether and dried to give 0.04g (43%) of 2- [ (4-phenylethynyl-pyridine-2-carbonyl) -amino]-1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide. LCMS: 448(M +1)⁺.

Example 414

0.1g (0.46mmol) of 5-phenylethynyl-nicotinic acid, 0.19g (0.5mmol) of HBTU in a mixture of 2.0mL of DMF and 0.30mL of DIEA was reacted with 0.1g (0.40mmol) of 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B) as described in general procedure A. The reaction mixture was cooled to room temperature and 5.0mL water and 5.0mL saturated NaHCO were added ₃And the resulting solid was filtered. The solid was washed with water, diethyl ether and dried to give 0.08g (43%) of 2- [ (5-phenylethynyl-pyridine-3-carbonyl) -amino]-1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide. LCMS: 448(M +1)⁺.

Example 415

20mg (0.44mmol) of 2- [ (5-phenylethynyl-pyridine-3-carbonyl) -amino]-1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide dissolved in 10mL CH₃OH and 0.5mL acetic acid. To the stirred solution was added 10mg of 10% Pd/C and the resulting mixture was hydrogenated (1atm) at room temperature for 3.0 h. The reaction mixture was filtered and the solid was washed with portions of methanol. The filtrate and washings were combined and evaporated to dryness to give 18mg (88%) of 2- [ (5-phenethyl-pyridine-3-carbonyl) -amino group]-1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide. LCMS: 452(M +1)⁺.

Example 416

Stirred under nitrogen 0.5g (2.4mmol) 6-bromo-pyridine-2-carboxylic acid, 0.05g (0.07mmol) dichlorobis (triphenylphosphine) -palladium (II) and 0.015g (0.07mmol) copper (I) iodide in 10mL LNEt₃、9.9mL 2N Na₂CO₃To the solution of the solution was added 0.38g (3.7mmol) of phenylacetylene. After refluxing under nitrogen for 12h, the reaction mixture was cooled and filtered. The filtrate was acidified to pH 5 with 2N HCl and the resulting white precipitate was filtered, washed with water and dried to give 0.5g (51%) 6-phenylethynyl-pyridine-2-carboxylic acid. LCMS: 224(M +1) ⁺.

0.05(0.23mmol) of the above synthesized 6-phenylethynyl-pyridine-2-carboxylic acid, 0.095g (0.25mmol) of HBTU and 0.05g (0.20mmol) of 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B) in a mixture of 2.0mL of DMF and 0.20mL of DIEA were reacted as described in general procedure A. The reaction mixture was cooled to room temperature and 5.0mL water and 5.0mL saturated NaHCO were added₃And the resulting solid was filtered. The solid was washed with water and diethyl ether and dried to give 0.04g (43%) of 2- [ (6-phenylethynyl-pyridine-2-carbonyl) -amino]-1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide.¹H-NMR(400MHz，DMSO)：8.3(d，1H)，8.21(t，1H)，8.12(bs，1H)，8.02(d，1H)，7.94(d，1H)，7.72(m，2H)，7.50(m，4H)，7.40(s，2H)ppm；LCMS：448(M+1)⁺.

Example 417

To a solution of 0.23g (1mmol) 1-bromo-3-methanesulfonyl-benzene in benzene (2mL) was added 40mg (0.1mmol) PdCl₂(Ph₃P)₂30mg (0.1mmol) of CuI, triethylamine (1mL) and 0.3mL of ethynyl-trimethyl-silane. The reaction mixture was heated at 70 ℃ for 3 h. After removal of the solvent, the residue was purified by column chromatography eluting with hexane/ethyl acetate (v/v 7: 1 first then 5: 1) to give 0.24g (95%) (3-methanesulfonyl-phenylethynyl) -trimethylsilane.¹HNMR(CDCl₃，400MHz)：δ8.4(s，1H)，7.88(d，1H)，7.70(d，1H)，7.52(dd，1H)，3.05(s，3H)，0.27(s，9H)ppm.

To a solution of 0.24g (0.95mmol) of the above (3-methanesulfonyl-phenylethynyl) -trimethyl-silane in methanol (2mL) was added K₂CO₃Aqueous solution (1M, 1mL) and the mixture was stirred at room temperature for 1 h. After conventional work-up, the residue was purified by column chromatography eluting with hexane/ethyl acetate (v/v first 5: 1, then 3: 1) to give 140mg (82%) of 1-ethynyl-3-methanesulfonyl-benzene.

Following the procedure described in the above example for the synthesis of 6-phenylethynyl-pyridine-2-carboxylic acid, 136mg (0.45mmol) of 6- (3-methanesulfonyl-phenylethynyl) -pyridine-2-carboxylic acid were synthesized starting from 100mg of 6-bromo-pyridine-2-carboxylic acid. LCMS: 302(M +1)⁺.

To a solution of 136mg (0.45mmol)6- (3-methanesulfonyl-phenylethynyl) -pyridine-2-carboxylic acid in DMF (2mL) were added 210mg (0.55mmol) HBTU (210mg) and DIEA (0.2 mL). The mixture was stirred for 5min, then 96mg (0.5mmol) of 2-amino-1H-benzimidazole-4-carboxylic acid methyl ester (intermediate A) were added. The reaction mixture was stirred at 30 ℃ for 30 min. After conventional work-up as described in general procedure A, purification by column chromatography eluting with DCM/EtOAc (v/v ═ 1: 1) and then EtOAc gave 142mg (60%) 2- { [6- (3-methanesulfonyl-phenylethynyl) -pyridine-2-carbonyl]-amino } -1H-benzimidazole-4-carboxylic acid methyl ester. LCMS: 475(M +1)⁺. The ester was hydrolyzed as described in general procedure B to give 135mg (100%) of 2- { [6- (3-methanesulfonyl-phenylethynyl) -pyridine-2-carbonyl]-amino } -1H-benzimidazole-4-carboxylic acid. LCMS: 461(M +1)⁺.

To a solution of 46mg (0.1mmol) of the above acid in DMF (1mL) was added 60mg (0.15mmol) of HBTU and DIEA (0.1 mL). The mixture was stirred for 5min, then 40mg (0.3mmol) of 2-aminoimidazole sulfate were added in one portion. The reaction mixture was heated at 80 ℃ for 40 min. After conventional work-up as described in general procedure A, purification was carried out by column chromatography eluting with DCM/methanol (v/v from 15: 1 to 7: 1) to give 12mg (20%) of 2- { [6- (3-methanesulfonyl-phenylethynyl) -pyridine-2-carbonyl ]-amino } -1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide. LCMS: 526(M +1)⁺.

The following compounds were synthesized by analogous methods as used in preparation example 413-417 and the related schemes described above.

Examples	Ar	LCMS(M+1)⁺
			418	2-Phenylethynyl-pyridin-4-yl	448
419	2-Phenylethynyl-pyridin-2-yl	448
			420	6-Cyclohexylethynyl-pyridin-2-yl	454
421	6- (4-fluoro-phenylethynyl) -pyridin-2-yl	466
			422	6- (4-Ethyl-phenylethynyl) -pyridin-2-yl	476
423	6- (4-methoxy-phenylethynyl) -pyridin-2-yl	478
			424	6- (4-chloro-phenylethynyl) -pyridin-2-yl	482
425	3-Phenylethynyl-pyridin-2-yl	448
			426	6- (3-methyl-but-1-ynyl) -pyridin-2-yl	414
427	6- (thien-3-ylethynyl) -pyridin-2-yl	454
			428	6- (3, 3-dimethyl-but-1-ynyl) -pyridin-2-yl	428
429	6- (3-cyclopentyl-prop-1-ynyl) -pyridin-2-yl	454
			430	6- (3-hydroxy-3-methyl-but-1-ynyl) -pyridin-2-yl	430
431	6- (4-methyl-pent-1-ynyl) -pyridin-2-yl	428
			432	6- (pent-1-ynyl) -pyridin-2-yl	414
433	6- (4-dimethylamino-phenylethynyl) -pyridin-2-yl	491
			434	6- (pyridin-3-ylethynyl) -pyridin-2-yl	449
435	6- (3-methoxy-phenylethynyl) -pyridin-2-yl	478
			436	6- (2-methoxy-phenylethynyl) -pyridin-2-yl	478
437	3- (cyclohexylphenylethynyl) -pyridin-2-yl	454
			438	3- (thien-3-ylethynyl) -pyridin-2-yl	454
439	6- (Cyclopropylethynyl) -pyridin-2-yl	521
			440	3- (3, 3-dimethyl-but-1-ynyl) -pyridin-2-yl	428
441	6- (2-fluoro-phenylethynyl) -pyridin-2-yl	466
			442	6- (m-tolylethynyl) -pyridin-2-yl	462
443	6- (3-fluoro-phenylethynyl) -pyridin-2-yl	575
			444	3-chloro-6-pent-1-ynyl-pyridin-2-yl	448
445	6-ethynyl-pyridin-2-yl	372
			446	6-phenethyl-pyridin-2-yl	452

Example 447

To a solution of 4.4g (20mmol) 6-phenylethynyl-pyridine-2-carboxylic acid in DMF (30mL) was added 7.6g (20mmol) HBTU and DIEA (4 mL). The resulting mixture was stirred at room temperature for 10min, then 4g (21mmol) of methyl 2-amino-1H-benzimidazole-4-carboxylate (intermediate A) was added and stirred at room temperature for 1H. After conventional work-up as described in general procedure A, purification by column chromatography eluting with DCM/EtOAc gave 7g (88%) of 2- [ (6-phenylethynyl-pyridine-2-carbonyl) -amino ] -amide]-1H-benzimidazole-4-carboxylic acid methyl ester. LCMS: 397(M +1)⁺.¹H NMR(DMSO-d₆，400MHz)：δ8.20(dd，1H)，8.13(dd，1H)，7.96(d，1H)，7.81(d，1H)，7.74(d，1H)，7.60(m，2H)，7.50(m，3H)，7.31(t，1H)，3.95(s，3H)ppm.

Example 448

Following the procedure described in general procedure B, 4.2g (10.6mmol) of 2- [ (6-phenylethynyl-pyridine-2-carbonyl) -amino]Hydrolysis of methyl (E) -1H-benzimidazole-4-carboxylate to give 3.5g (86%) of 2- [ (6-phenylethynyl-pyridine-2-carbonyl) -amino ]-1H-benzimidazole-4-carboxylic acid. LCMS: 383 (M +1)⁺.¹H NMR(DMSO-d₆，400MHz)：δ8.29(d，1H)，8.23(dd，1H)，8.06(d，1H)，7.95(m，2H)，7.68(m，2H)，7.52(m，4H)ppm.

To a solution of 30mg (0.07mmol) of the above-mentioned 2- [ (6-phenylethynyl) residue-pyridine-2-carbonyl) -amino]To a solution of (E) -1H-benzimidazole-4-carboxylic acid in DMF (1mL) was added 40mg (0.1mmol) of HBTU and DIEA (0.1mL), and the resulting mixture was stirred at room temperature for 10min, followed by addition of 40mg (0.1mmol) of 4-methanesulfonyl-benzylamine HCl salt. After conventional work-up as described in general procedure A, purification was performed by column chromatography eluting with DCM/EtOAc (v/v from 5: 1 to 1: 1) to give 21mg (48%) of 2- [ (6-phenylethynyl-pyridine-2-carbonyl) -amino ] -amino]-1H-benzimidazole-4-carboxylic acid 4-methanesulfonyl-benzylamide. LCMS: 550(M +1)⁺.

The following compounds were synthesized by analogous methods as used in preparation example 448 and the related schemes described above.

Examples	Ar	LCMS(M+1)⁺
			449	Cyclopentyl group	450
450	Tert-butyl radical	438

Example 451

As described in general procedure A, 60mg (0.4mmol) of 3-phenyl-propionic acid and 170mg (0.45mmol) of HBTU in a mixture of 1.0mL of DMF and 0.5mL of DIEA with 120mg (0.3mmol) of isoquinoline-3-carboxylic acid [ 6-amino-4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]Amide (see example 130). After completion of the reaction, it was diluted with brine (20 mL). The resulting solid was filtered, washed with water, ethyl acetate and dried under vacuum to give 101mg (66%) of isoquinoline-3-carboxylic acid [7- (1H-imidazol-2-ylcarbamoyl) -5- (3-phenyl-propionylamino) -1H-benzimidazol-2-yl as a solid ]-an amide. LCMS: 545(M +1)⁺.

Example 452

82mg (0.2mmol) of isoquinoline-3-carboxylic acid [ 6-amino-4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]The amide (see example 130) was dissolved in pyridine (0.6 mL). To this stirred solution was added a solution of 0.2mmol of benzenesulfonyl chloride in 0.2mL of DCM at 0 deg.C in one portion. The reaction mixture was stirred at room temperature for 2 h. Brine (5mL) was added and stirred for 10 min. The resulting solid was collected, washed with water (3X 2mL) and ethyl acetate (3X 3mL), and dried to give 55mg (50%) of isoquinoline-3-carboxylic acid [ 5-benzenesulfonylamino-7- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ] as a solid]-an amide. LCMS: 553(M +1)⁺.

Example 453

Isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -6-methanesulfonylamino-1H-benzimidazol-2-yl ] is synthesized in the same manner as above, except that methanesulfonyl chloride is used instead of benzenesulfonyl chloride]-amide (20 mg). LCMS: 491(M +1)⁺.

Example 454

15.1g (100mmol) 2-amino-5-methyl-benzoic acid are refluxed with 60mL ethyl chloroformate for 6h, then 60mL acetyl chloride is added followed by an additional 3h reflux. The solid was collected and washed with hexane to give 14.2g (80%) of 5-methylisatoic anhydride.

6.9g (40mmol) of the above 5-methylisatoic anhydride are suspended in 40mL of concentrated H at-10 deg.C ₂SO₄And cooled to-20 ℃. Subsequently, 1.05 equivalents of potassium nitrate was dissolved in 12mL of sulfuric acid, cooled to 0 ℃, and then added dropwise to the above solution of 5-methylisatoic anhydride. The reaction mixture was stirred at-20 ℃ for 15min and then held between-5 ℃ and 0 ℃ for 3 h. The mixture was poured into a beaker containing ice. The resulting solid was collected, washed with cold water and dried to yield 3.9g (44%) of 5-methyl-3-nitro isatoic anhydride as a solid.

A solution of 3.9g (17.6mmol) of the above 5-methyl-3-nitro-isatoic anhydride in ethyl acetate (50mL) was treated with NaOH at room temperature for 2 h. The mixture was neutralized with dilute HCl solution and the resulting solid was filtered, washed with water and dried to give 2.5g (72%) of 2-amino-5-methyl-3-nitrobenzoic acid.

According to the described method for the synthesis of 2-amino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide (intermediate B), 0.25g of 2-amino-6-methyl-1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide is synthesized starting from 2.5g (12.7mmol) of the above synthesized 2-amino-5-methyl-3-nitrobenzoic acid. LCMS: 257(M +1)⁺.

96mg (0.5mmol) of isoquinoline-3-carboxylic acid and 200mg (0.52mmol) of HBTU in a mixture of 3.0mL of DMF and 0.3mL of DIEA are reacted with 40mg (0.16mmol) of the above synthesized 2-amino-6-methyl-1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide, as described in general procedure A. After completion of the reaction, it was diluted with brine (20 mL). The resulting solid was filtered, washed with water, ethyl acetate and dried under vacuum to give 32mg (50%) of isoquinoline-3-carboxylic acid [ 7-1H-imidazol-2-ylcarbamoyl) -5-methyl-1H-benzimidazol-2-yl ]-an amide. LCMS: 412(M +1)⁺.

Example 455

To a solution of 2.23g (10.4mmol) of methyl 2-amino-3-nitro-benzoate in 12mL of acetic acid was added dropwise 0.53mL (10.4mmol) of Br₂Solution in 2.0mL of acetic acid. The mixture was stirred at room temperature for 30min and poured into 100g of ice. The solid was collected by filtration and dried to give 2.5g (82%) of methyl 2-amino-5-bromo-3-nitro-benzoate.¹H NMR(CDCl₃，400MHz)：δ8.6(d，1H)，8.53(s，1H)，3.95(s，3H)ppm.

A solution of 0.5g (1.8mmol) of the above ester, 0.9g (2.7mmol) of tributyl-propenyl-stannane, 0.18g (0.18mmol) of tetrakis (triphenylphosphine) palladium (0) in 25mL of dioxane was degassed with nitrogen for 20min and then refluxed under nitrogen for 12 h. The reaction mixture was cooled and 20mL of a 2M KF solution was added. The mixture was stirred for 20min, extracted with ethyl acetate and washed with water and brine. The residue was purified by column chromatography eluting with 8: 2 hexane-ethyl acetate to give 0.35g (77%) of methyl 2-amino-3-nitro-5-propenyl-benzoate as a solid. LCMS: 239(M +1)⁺.

According to the method for synthesizing methyl 2-amino-1H-benzimidazole-4-carboxylate (intermediate A), 0.3g (total yield 85%) of methyl 2-amino-6-propyl-1H-benzimidazole-4-carboxylate is synthesized, starting from 0.35g (1.5mmol) of the methyl 2-amino-5-methyl-3-nitrobenzoate synthesized above. LCMS: 234(M +1) ⁺.

Synthesis of 0.4g (75%) of 2- [ (isoquinoline-3-carbonyl) -amino ] -4-carboxylic acid from 0.25g (1.4mmol) of isoquinoline-3-carboxylic acid, 0.6g (1.6mmol) of HBTU and 0.3g (1.3mmol) of the methyl 2-amino-6-propyl-1H-benzimidazole-4-carboxylate synthesized above as described in general procedure A]-6-propyl-1H-benzimidazole-4-carboxylic acid methyl ester. LCMS: 389(M +1)⁺.

Example 456

Hydrolysis of 0.2g (0.5mmol) of 2- [ (isoquinoline-3-carbonyl) according to general procedure B) -amino group]-6-propyl-1H-benzimidazole-4-carboxylic acid methyl ester to give 0.17g (89%) of 2- [ (isoquinoline-3-carbonyl) -amino ] as a solid]-6-propyl-1H-benzimidazole-4-carboxylic acid. LCMS: 375(M +1)⁺.

0.1(0.27mmol) of the above synthesized acid, 0.11g (0.29mmol) of HBTU and 0.05g (0.27mmol) of 4-methanesulfonyl-benzylamine in a mixture of 2.0mL DMF and 0.20mL DIEA as described in general procedure A. The reaction mixture was cooled to room temperature and 5.0mL water and 5.0mL saturated NaHCO were added₃And the resulting solid was filtered. The solid was washed with water, diethyl ether and dried to give 0.05g (33%) of isoquinoline-3-carboxylic acid [4- (4-methanesulfonyl-benzylcarbamoyl) -6-propyl-1H-benzimidazol-2-yl]-an amide. LCMS: 542(M +1)⁺.

Example 457

1.0g (3.6mmol) of methyl 2-amino-5-bromo-3-nitro-benzoate, 0.9g (7.2mmol) of pyridine-4-boronic acid, 0.42g (0.36mmol) of tetrakis (triphenylphosphine) palladium (0) in 50mL of DMDMME and 8.4mL of 2N Na are placed under nitrogen ₂CO₃The solution in (A) was degassed for 20min and then heated at 90 ℃ for 12 h. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (100mL), and washed with water, brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with 8: 2 hexane-ethyl acetate to give 0.5g (50%) of methyl 2-amino-3-nitro-5-pyridin-4-yl-benzoate as a solid. LCMS: 273(M +1)⁺.

According to the method described for the synthesis of methyl 2-amino-1H-benzimidazole-4-carboxylate (intermediate a), 0.25g (total yield 50%) of methyl 2-amino-6-pyridin-4-yl-1H-benzimidazole-4-carboxylate was synthesized starting from 0.5g (1.8mmol) of the methyl 2-amino-3-nitro-5-pyridin-4-yl-benzoate synthesized above. LCMS: 269(M +1)⁺.

As described in general procedure A, starting from 0.16g (0.09mmol) of isoquinoline-3-carboxylic acid, 0.4g (1mmol) of HBTU and 0.25g (0.09mmol) of the above synthesized 2-amino-6-pyridin-4-yl-1H-benzimidazole-4-carboxylic acidMethyl ester Synthesis 0.3g (75%) of 2- [ (isoquinoline-3-carbonyl) -amino group]-6-pyridin-4-yl-3H-benzimidazole-4-carboxylic acid methyl ester. LCMS: 424(M +1)⁺.

Example 458

Hydrolysis of 0.2g (0.5mmol) of the above ester according to general method B gave 0.17g (89%) of 2- [ (isoquinoline-3-carbonyl) -amino ] as a solid ]-6-pyridin-4-yl-1H-benzimidazole-4-carboxylic acid. LCMS: 414(M +1)⁺.

0.1(0.25mmol) of the above synthesized acid, 0.11g (0.29mmol) of HBTU and 0.05g (0.27mmol) of 4-methanesulfonyl-benzylamine in a mixture of 2.0mL DMF and 0.20mL DIEA as described in general procedure A. The reaction mixture was cooled to room temperature and 5.0mL water and 5.0mL saturated NaHCO were added₃And the resulting solid was filtered. The solid was washed with water, diethyl ether and dried to give 0.05g (33%) of isoquinoline-3-carboxylic acid [4- (4-methanesulfonyl-benzylcarbamoyl) -6-pyridin-4-yl-1H-benzimidazol-2-yl]LCMS: 577(M +1)⁺.

Example 459

To 4.48g (20mmol) of 2-chloro-5-trifluoromethyl-benzoic acid was suspended in 40mL of concentrated H at-20 deg.C₂SO₄To the stirred solution of (3) was added dropwise a solution of 1.05 equivalents of potassium nitrate dissolved in 12mL of sulfuric acid. The reaction mixture was stirred at-20 ℃ for 15min, then warmed to room temperature overnight. The mixture was poured into a beaker containing ice. The resulting solid was collected, washed with cold water and dried to yield 4.8g (90%) of 2-chloro-3-nitro-5-trifluoromethyl-benzoic acid as a solid. LCMS: 270(M +1)⁺.

To a stirred solution of 0.81g (3.0mmol) of the above 2-chloro-3-nitro-5-trifluoromethyl-benzoic acid in 6.0mL of DMF was added 6.0mL of TEA followed by 3.0mmol of benzylamine. The mixture was heated at 80 ℃ for 6 h. After cooling to room temperature, 3.0mL of 6N HCl solution was added. The solid was collected and washed with fresh water to give 2-benzylamino-3-nitro-5- Trifluoromethyl-benzoic acid. LCMS: 341(M +1)⁺. This product was hydrogenated according to general procedure C to give 0.25g of 2, 3-diamino-5-trifluoromethyl-benzoic acid. LCMS: 221(M +1)⁺.

According to the described method for the synthesis of methyl 2-amino-3H-benzimidazole-4-carboxylate, 0.25g of 2-amino-6-trifluoromethyl-1H-benzimidazole-4-carboxylic acid was synthesized starting from 0.25g of the above 2, 3-diamino-5-trifluoromethyl-benzoic acid. The acid was refluxed in methanol and HCl/ether to give 0.26g of methyl 2-amino-6-trifluoromethyl-1H-benzimidazole-4-carboxylate. LCMS: 260(M +1)⁺.

166mg (0.9mmol) of isoquinoline-3-carboxylic acid and 364mg (0.9mmol) of HBTU in a mixture of DMF (5mL) and DIEA (1.0mL) are reacted with 0.25g (0.9mmol) of the above aminomethyl ester as described in general method A to give 2- [ (isoquinoline-3-carbonyl) -amino ] -methyl ester]-6-trifluoromethyl-1H-benzimidazole-4-carboxylic acid methyl ester. LCMS: 416(M +1)⁺. The ester was hydrolyzed according to general procedure B to give 0.2g of 2- [ (isoquinoline-3-carbonyl) -amino group]-6-trifluoromethyl-1H-benzimidazole-4-carboxylic acid LCMS: 401(M +1)⁺.

50mg (0.25mmol) of the above acid and 190mg (0.5mmol) of HBTU in a mixture of 1.0mL of DMF and 0.5mL of DIEA were reacted with 100mg (0.75mmol) of 2-aminoimidazole sulfate as described in general method A. After completion of the reaction, it was diluted with brine (20 mL). The resulting solid was filtered, washed with water, ethyl acetate and dried in vacuo to give 29mg (25%) of isoquinoline-3-carboxylic acid [7- (1H-imidazol-2-ylcarbamoyl) -5-trifluoromethyl-1H-benzimidazol-2-yl ] as a solid ]-an amide. LCMS: 467(M +1)⁺.

Example 460

5.0g (18.2mmol) of methyl 2-amino-5-bromo-3-nitro-benzoate was dissolved in 50ml of NMP, treated with 2.5g (27.3mmol) of CuCN and heated to reflux until disappearance of the starting material as detected by TLC (EtOAc/hexane ═ 1: 3). After completion of the reaction, the reaction contents were poured into EtOAc, then into water. The organic layer was extracted, dried, evaporated to dryness and separated by flash column chromatography (gradient elution of EtOAc/hexane from 1: 9 to 3: 7) to give 1.0g (22%) of 2-amino-5-cyano-3-nitro-benzoic acid methyl ester.

According to the described method for the synthesis of methyl 2-amino-3H-benzimidazole-4-carboxylate, 0.28g (total yield 50%) of methyl 2-amino-6-cyano-3H-benzimidazole-4-carboxylate is synthesized starting from 1.0g of methyl 2-amino-5-cyano-3-nitro-benzoate. LCMS: 269(M +1)⁺.

According to general method A, 0.28g (1.3mmol) methyl 2-amino-6-cyano-1H-benzimidazole-4-carboxylate is added to a mixture of 0.22g (1.3mmol) isoquinoline-3-carboxylic acid monohydrate, 0.49g (1.3mmol) HBTU, 3mL DMF and 1mL DIEA to give 6-cyano-2- [ (isoquinoline-3-carbonyl) -amino ] -2-carboxylic acid]-1H-benzimidazole-4-carboxylic acid methyl ester. LCMS: 373.0(M +1)⁺.

Example 461

Hydrolysis of 0.2g (0.56mmol) of methyl 6-cyano-2- [ (isoquinoline-3-carbonyl) -amino ] -1H-benzimidazole-4-carboxylate according to general procedure B gives 2-amino-6-cyano-1H-benzimidazole-4-carboxylic acid, which is used directly in the next step without further purification.

0.20g (0.56mmol) 6-cyano-2- [ (isoquinoline-3-carbonyl) -amino]-1H-benzimidazole-4-carboxylic acid and 0.21g (0.56mmol) HBTU were combined in a flask containing 3mL DMF and 1mL DIEA. The reaction mixture was then treated with 0.07g (0.56mmol) of 2-amino-imidazole sulfate and stirred at 80 ℃ for 1 h. The reaction mixture was diluted with water, the resulting solid precipitate was filtered and washed with saturated NaHCO₃And (6) washing. The solid was dissolved in MeOH, evaporated onto silica and flash column chromatographed (500mL DCM/20mL NH)₃MeOH) to yield 10mg of isoquinoline-3-carboxylic acid [ 6-cyano-4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 424.0(M +1)⁺.

The following compounds were synthesized by analogous methods as used in preparation example 454-461 and the related schemes above.

Examples	W	R	LCMS(M+1)⁺
				462	4-methanesulfonyl-benzyl	Phenyl radical	577
463	4-methanesulfonyl-benzyl	Isopropyl group	543
				464	1H-imidazol-2-yl	Phenyl radical	475
465	4-methanesulfonyl-benzyl	Furan-3-yl	567
				466	4-methanesulfonyl-benzyl	Trifluoromethyl radical	569
467	1H-imidazol-2-yl	Pyridin-4-yl	476
				468	4-methanesulfonyl-benzyl	Thien-3-yl	583
469	Ethyl radical	Pyridin-4-yl	438
				470	Cyclopentyl group	Pyridin-4-yl	478

Example 471

First 20.0mL of concentrated H at 0 deg.C₂SO₄Then treated with 6.4g (40mmol) of 3, 5-difluorobenzoic acid to 10.0mL of concentrated HNO₃. The reaction mixture was warmed to room temperature, stirred overnight, and then poured into a beaker containing ice. The resulting solid was collected, washed with cold water and dried to yield 8.0g (80%) of 3, 5-difluoro-2-nitro-benzoic acid. LCMS: 204(M +1)₊.

6.0g (30.0mmol)3, 5-difluoro-2-nitro-benzoic acid were dissolved in DMF with 8.5g (60.0mmol) MeI and 9.5g (90.0mmol) Na₂CO₃Treating, and heating at 80 deg.C for 2 h. Water was added to the reaction mixture and extracted with EtOAc to give 3, 5-difluoro-2-nitro-benzoic acid methyl ester. LCMS: 218(M +1)⁺.

6.0g (27.5mmol) of methyl 3, 5-difluoro-2-nitro-benzoate were dissolved in DMF and treated with 2.9g (30.25mmol) of ammonium carbonate. The reaction was heated at 60 ℃ for 6 h. Water was added to the reaction mixture. The resulting solid was collected by filtration and washed with water to give 3-amino-5-fluoro-2-nitro-benzoic acid methyl ester. LCMS: 215(M +1)⁺.

5.0g (23.3mmol) of 3-amino-5-fluoro-2-nitro-benzoic acid methyl ester are dissolved in ethanol and treated with 2.6g (25.6mmol) of triethylamine and 1.8g (25.6mmol) of NaOEt. The reaction was heated at 60 ℃ for 0.5h to give 3-amino-5-ethoxy-2-nitro-benzoic acid ethyl ester. LCMS: 255(M +1) ⁺.

Hydrogenation of 5.0g (19.7mmol) of 3-amino-5-ethoxy-2-nitro-benzoic acid ethyl ester according to general procedure C gave 2, 3-diamino-5-ethoxy-benzoic acid ethyl ester. LCMS: 225(M +1)⁺.

4.0g (17.9mmol) of 2, 3-diamino-5-ethoxy-benzoic acid ethyl ester was subjected to similar cyclisation conditions as described in intermediate A using 5.7g (53.7mmol) of BrCN in methanol to give 2-amino-6-ethoxy-1H-benzimidazole-4-carboxylic acid ethyl ester. LCMS: 250(M +1)⁺.

600mg (3.0mmol) of isoquinoline-3-carboxylic acid and 1200mg (3.1mmol) of HBTU are dissolved in 3.0mL of DMF and 0.6mL of DIEA and reacted with 500mg (2.0mmol) of 2-amino-6-ethoxy-1H-benzoImidazole-4-carboxylic acid ethyl ester. After completion of the reaction, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc and dried in vacuo to give 500mg (62%) of 6-ethoxy-2- [ (isoquinoline-3-carbonyl) -amino]-3H-benzimidazole-4-carboxylic acid ethyl ester. LCMS: 406(M +1)⁺.

Example 472

Hydrolysis of 0.3g (0.74mmol) 6-ethoxy-2- [ (isoquinoline-3-carbonyl) -amino]-3H-benzimidazole-4-carboxylic acid ethyl ester to give 2- [ (isoquinoline-3-carbonyl) -amino]-6-ethoxy-1H-benzimidazole-4-carboxylic acid. LCMS: 378(M +1) ⁺.

As described in general method A, 100mg (0.3mmol) of 2- [ (isoquinoline-3-carbonyl) -amino]-6-ethoxy-1H-benzimidazole-4-carboxylic acid and 200mg (0.53mmol) HBTU were dissolved in 1.0mL DMF and 0.5mL DIEA and reacted with 132mg (1.0mmol) 2-aminoimidazole sulfate. After completion of the reaction, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc and dried in vacuo to give 30mg (23%) of isoquinoline-3-carboxylic acid [ 5-ethoxy-7- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 443(M +1)⁺.

Example 473

3.0g (14.0mmol) of methyl 3-amino-5-fluoro-2-nitro-benzoate and 2.1g (15.4mmol) NaOBn/BnOH in 1.6g (15.4mmol) triethylamine were heated at 60 ℃ for 0.5h to give benzyl 3-amino-5-benzyloxy-2-nitro-benzoate. LCMS: 380(M +1)⁺.

5.4g (23.7mmol) SnCl at 80 deg.C₂·2H₂O in 30mL ethanol 3.0g (7.9mmo1) 3-amino-5-benzyloxy-2-nitro-benzyl benzoate was reduced for 3h to give 2, 3-diamino-5-benzyloxy-benzyl benzoate. LCMS: 350(M +1)⁺.

2.5g (7) were made up with a solution of 2.3g (21.6mmol) BrCN in methanol.2mmol)2, 3-diamino-5-benzyloxy-benzyl benzoate under similar cyclization conditions as described in intermediate A gave benzyl 2-amino-6-benzyloxy-1H-benzimidazole-4-carboxylate. LCMS: 375(M +1) ⁺.

600mg (3.0mmol) of isoquinoline-3-carboxylic acid and 1200mg (3.1mmol) of HBTU are dissolved in 3.0mL of DMF and 0.6mL of DIEA and reacted with 1.1g (3.0mmol) of benzyl 2-amino-6-benzyloxy-1H-benzimidazole-4-carboxylate as described in general procedure A to give 6-benzyloxy-2- [ (isoquinoline-3-carbonyl) -amino ] -benzimidazole]-3H-benzimidazole-4-carboxylic acid benzyl ester. LCMS: 530(M +1)⁺.

0.7g (1.3mmol) 6-benzyloxy-2- [ (isoquinoline-3-carbonyl) -amino) -is hydrolyzed according to general method B]-3H-benzimidazole-4-carboxylic acid benzyl ester to give 6-benzyloxy-2- [ (isoquinoline-3-carbonyl) -amino]-3H-benzimidazole-4-carboxylic acid. LCMS: 440(M +1)⁺.

As described in general procedure A, 300mg (0.75mmol) of 6-benzyloxy-2- [ (isoquinoline-3-carbonyl) -amino ] -amino]-3H-benzimidazole-4-carboxylic acid and 600mg (1.58mmol) HBTU were dissolved in 2.0mL DMF and 1.0mL DIEA and reacted with 390mg (3.0mmol) 2-aminoimidazole sulfate. After completion of the reaction, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc and dried in vacuo to give 300mg (80%) of isoquinoline-3-carboxylic acid [ 5-benzyloxy-7- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 505(M +1)⁺.

The following compounds were synthesized by a similar method to that used in preparation example 471-473 and the related schemes described above.

Examples	W	R	LCMS(M+1)⁺
				474	1H-imidazol-2-yl	Methyl radical	429
475	4-methanesulfonyl-benzyl	Methyl radical	531
				476	1H-imidazol-2-yl	Propyl radical	457
477	1H-imidazol-2-yl	Isopropyl group	457
				478	1H-imidazol-2-yl	Butyl radical	471

Example 479

To a solution of 2.65mL (52.0mmol) of bromine in 10mL of acetic acid was added dropwise a solution of 8.89g (52.0mmol) of 2-amino-4-chloro-benzoic acid in 60mL of acetic acid over 15 min. The mixture was stirred at room temperature for 1h and poured into 500g of ice. The solid was collected by filtration, washed with cold water and dried to give 11.2g (86%) of 2-amino-5-bromo-4-chloro-benzoic acid. LCMS: 251(M +1)⁺.

7.5g (30mmol) 2-amino-5-bromo-4-chloro-benzoic acid are heated under reflux with 18mL ethyl chloroformate for 6h, after addition of 18mL acetyl chloride, under further heating under reflux for 3 h. The solid was collected and washed with hexane to give 5.8g (70%) of 5-bromo-4-chloroisatoic anhydride. LCMS: 277(M +1)⁺.

5.4g (20mmol) of 5-bromo-4-chloroamphatic anhydride are suspended in 20ml of concentrated H at-10 DEG₂SO₄And cooled to-20 ℃. 2.1g (21mmol) of potassium nitrate was dissolved in 6mL of sulfuric acid, cooled to 0 ℃ and then added dropwise to the reaction mixture. The reaction mixture was then stirred at-10 ℃ for 15min and warmed to room temperature overnight. The mixture was poured into a beaker containing ice. The resulting solid was collected by filtration, washed with cold water and dried to give 3.2g (50%) of 5-bromo-4-chloro-3-nitro-isatoic anhydride. LCMS: 323(M +1) ⁺.

2.0g (6.2mmol) of 5-bromo-4-chloro-3-nitro-isatoic anhydride are dissolved in methanol and treated with 2.02g (37.4mmol) of NaOMe. The reaction mixture was heated at 100 ℃ for 12h to give 2-amino-5-bromo-4-methoxy-2-nitro-benzoic acid. LCMS: 292(M +1)⁺.

Hydrogenation of 1.5g (5.15mmol) 2-amino-5-bromo-4-methoxy-2-nitro-benzoic acid according to general procedure C gave 2, 3-diamino-4-methoxy-benzoic acid. LCMS: 183(M +1)⁺.

Using a solution of 2.6g (24.5mmol) BrCN in methanol0.9g (4.9mmol) of 2, 3-diamino-4-methoxy-benzoic acid under similar cyclization conditions as described in intermediate A gave 2-amino-7-methoxy-1H-benzimidazole-4-carboxylic acid. LCMS: 208(M +1)⁺.

1.0g (4.8mmol) 2-amino-7-methoxy-1H-benzimidazole-4-carboxylic acid was heated under reflux in methanol and HCl/diethyl ether to give methyl 2-amino-7-methoxy-1H-benzimidazole-4-carboxylate. LCMS: 222(M +1)⁺.

300mg (1.5mmol) of isoquinoline-3-carboxylic acid and 570mg (1.50mmol) of HBTU are dissolved in 1.0mL of DMF and 0.8mL of DIEA and reacted with 110mg (0.5mmol) of methyl 2-amino-7-methoxy-1H-benzimidazole-4-carboxylate, as described in general procedure A. After completion of the reaction, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc and dried in vacuo to give 70mg (37%) of 2- [ (isoquinoline-3-carbonyl) -amino group ]-7-methoxy-3H-benzimidazole-4-carboxylic acid methyl ester. LCMS: 378(M +1)⁺.

Example 480

Hydrolysis of 0.06g (0.16mmol) of 2- [ (isoquinoline-3-carbonyl) -amino ] -amino]-7-methoxy-3H-benzimidazole-4-carboxylic acid methyl ester to give 0.05g (0.14mmol, 87%) of 2- [ (isoquinoline-3-carbonyl) -amino ] -2- [ (methyl ester]-7-methoxy-1H-benzimidazole-4-carboxylic acid. LCMS: 363(M +1)⁺.

As described in general method A, 33mg (0.1mmol) of 2- [ (isoquinoline-3-carbonyl) -amino]-7-methoxy-1H-benzimidazole-4-carboxylic acid and 100mg (0.25mmol) HBTU were dissolved in 1.0mL DMF and 0.4mL DIEA and reacted with 32mg (0.15mmol) 4-methanesulfonyl-benzylamine hydrochloride. After completion of the reaction, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc and dried in vacuo to give 14mg (26%) of isoquinoline-3-carboxylic acid [7- (4-methanesulfonyl-benzylcarbamoyl) -4-methoxy-1H-benzimidazol-2-yl]-an amide. LCMS: 530(M +1)⁺.

Example 481

First, 10.0mL of concentrated H was used at 0 deg.C₂SO₄Then slowly treat 5.0mL of concentrated HNO with 3.2g (20mmol) of 2, 6-difluoro-benzoic acid₃. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was poured into a beaker containing ice. The resulting solid was collected by filtration, washed with cold water and dried to give 4.0g (80%) of 2, 6-difluoro-3-nitro-benzoic acid as a white solid. LCMS: 204(M +1) ⁺.

A solution of 2.0g (9.9mmol)2, 6-difluoro-3-nitro-benzoic acid in methanol and 3.0g (30.0mmol) ammonium acetate were stirred at room temperature for 12 h. The solvent was evaporated to dryness and dilute HCl solution was added. The precipitated solid was collected by filtration and washed with water to give 2-amino-6-fluoro-3-nitro-benzoic acid. LCMS: 201(M +1)⁺.

A solution of 1.8g (9.0mmol) 2-amino-6-fluoro-3-nitro-benzoic acid in methanol was heated with 2.9g (54mmol) NaOMe at 90 ℃ overnight to give 1.6g (7.5mmol, 83%) 2-amino-6-methoxy-3-nitro-benzoic acid. LCMS: 213(M +1)⁺.

Hydrogenation of 1.0g (4.7mmol) of 2-amino-6-methoxy-3-nitro-benzoic acid was carried out according to general procedure C to give 2, 3-diamino-6-methoxy-benzoic acid. LCMS: 183(M +1)⁺.

Using a solution of 0.7g (6.6mmol) BrCN in methanol to subject 0.8g (4.4mmol)2, 3-diamino-6-methoxy-benzoic acid to analogous cyclization conditions as described in intermediate a gives 2-amino-5-methoxy-1H-benzimidazole-4-carboxylic acid. LCMS: 208(M +1)⁺.

0.9g (4.3mmol) 2-amino-5-methoxy-1H-benzimidazole-4-carboxylic acid was heated under reflux in methanol and HCl/diethyl ether to give methyl 2-amino-5-methoxy-1H-benzimidazole-4-carboxylate. LCMS: 222(M +1)⁺.

400mg (2.0mmol) of isoquinoline-3-carboxylic acid and 800mg (2.1mmol) of HBTU are dissolved in 2.0mL of DMF and 1.3mL of DIEA and are quenched with 300mg (1.5mmol) of 2-amino-5-methoxy-1H-benzimidazole-4 -carboxylic acid methyl ester treatment. After completion of the reaction, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc and dried in vacuo to give 160mg (28%) of 2- [ (isoquinoline-3-carbonyl) -amino group]-5-methoxy-3H-benzimidazole-4-carboxylic acid methyl ester. LCMS: 377(M +1)⁺.

Example 482

According to general method B0.14 g (0.38mmol)2- [ (isoquinoline-3-carbonyl) -amino]Hydrolysis of methyl (E) -5-methoxy-3H-benzimidazole-4-carboxylate to give 0.12g (0.33mmol, 87%) of 2- [ (isoquinoline-3-carbonyl) -amino ] -4-carboxylic acid]-5-methoxy-1H-benzimidazole-4-carboxylic acid. LCMS: 363(M +1)⁺.

As described in general method A, 66mg (0.18mmol) of 2- [ (isoquinoline-3-carbonyl) -amino]-5-methoxy-1H-benzimidazole-4-carboxylic acid and 200mg (0.53mmol) HBTU were dissolved in 1.0mL DMF and 0.5mL DIEA and treated with 132mg (1.0mmol) 2-aminoimidazole sulfate. After completion of the reaction, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc and dried in vacuo to give 26mg (34%) of isoquinoline-3-carboxylic acid [7- (1H-imidazol-2-ylcarbamoyl) -6-methoxy-1H-benzimidazol-2-yl]-an amide. LCMS: 428(M +1)⁺.

Example 483

As described in general method A, 33mg (0.1mmol) of 2- [ (isoquinoline-3-carbonyl) -amino ]-5-methoxy-1H-benzimidazole-4-carboxylic acid and 100mg (0.25mmol) HBTU were dissolved in 1.0mL DMF and 0.4mL DIEA and treated with 32mg (0.15mmol) 4-methanesulfonyl-benzylamine hydrochloride. After completion of the reaction, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc and dried in vacuo to give 25mg (47%) of isoquinoline-3-carboxylic acid [7- (4-methanesulfonyl-benzylcarbamoyl) -6-methoxy-1H-benzimidazol-2-yl]-an amide. LCMS: 530(M +1)⁺.

Example 484

2.0g (8.44mmol)6, 7-dimethoxy-1, 2, 3, 4-tetrahydro-isoquinoline-3-carboxylic acid are heated to reflux in methanol and HCl/diethyl ether to give 2.1g (8.40mmol, 99%) methyl 6, 7-dimethoxy-1, 2, 3, 4-tetrahydro-isoquinoline-3-carboxylate. LCMS: 252(M +1)⁺.

1.8g (6.26mmol)6, 7-dimethoxy-1, 2, 3, 4-tetrahydro-isoquinoline-3-carboxylic acid methyl ester and 3.3g (37.6mmol) MnO₂Heated to reflux in toluene/dioxane/THF overnight. After gravity filtration, the hot filtrate was evaporated to dryness to yield 0.4g (1.62mmol, 26%) of methyl 6, 7-dimethoxy-isoquinoline-3-carboxylate. LCMS: 248(M +1)⁺.

0.4g (1.62mmol) of methyl 6, 7-dimethoxy-isoquinoline-3-carboxylate are hydrolyzed according to general method B to give 0.38g (1.60mmol, 98%) of 6, 7-dimethoxy-isoquinoline-3-carboxylic acid. LCMS: 234(M +1) ⁺.

235mg (1.0mmol) of 6, 7-dimethoxy-isoquinoline-3-carboxylic acid and 400mg (1.0mmol) of HBTU are dissolved in 1.5mL of DMF and 0.5mL of DIEA and treated with 249mg (1.0mmol) of ethyl 2-amino-6-ethoxy-1H-benzimidazole-4-carboxylate (prepared in example 471) as described in general procedure A. After completion of the reaction, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc and dried in vacuum to give 290mg (0.63mmol, 63%) of 2- [ (6, 7-dimethoxy-isoquinoline-3-carbonyl) -amino group]-6-ethoxy-1H-benzimidazole-4-carboxylic acid ethyl ester. LCMS: 465(M +1)⁺.

The 2- [ (6, 7-dimethoxy-isoquinoline-3-carbonyl) -amino group is reacted according to general procedure B]Hydrolysis of (E) -6-ethoxy-1H-benzimidazole-4-carboxylic acid ethyl ester to give 2- [ (6, 7-dimethoxy-isoquinoline-3-carbonyl) -amino]-6-ethoxy-1H-benzimidazole-4-carboxylic acid. LCMS: 437(M +1)⁺.

As described in general method A, 100mg (0.25mmol) of 2- [ (6, 7-dimethoxy-isoquinoline-3-carbonyl) -amino]-6-ethoxy-1H-benzimidazole-4-carboxylic acid and 200mg (0.53mmol) of HBTU was dissolved in 1.0mL DMF and 0.5mL DIEA and treated with 200mg (1.5mmol) 2-aminoimidazole sulfate. After completion of the reaction, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc and dried in vacuo to give 60mg (47%) of 6, 7-dimethoxy-isoquinoline-3-carboxylic acid [ 5-ethoxy-7- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ]-an amide. LCMS: 502(M +1)⁺.

Example 485

First, 10.0mL of concentrated H was used at 0 deg.C₂5O₄Then slowly treat 5.0mL of concentrated HNO with 3.52g (20.0mmol) of 3, 4, 5-trifluoro-benzoic acid₃. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was poured into a beaker containing ice. The resulting solid was collected by filtration, washed with cold water and dried to give 3.4g (16.0mmol, 80%) of 2-nitro-3, 4, 5-trifluoro-benzoic acid. LCMS: 222(M +1)⁺.

Treatment of 1.4g (6.3mmol) of 2-nitro-3, 4, 5-trifluoro-benzoic acid with ammonium hydroxide gave 3-amino-4, 5-difluoro-2-nitro-benzoic acid. LCMS: 219(M +1)⁺.

1.2g (5.5mmol) 3-amino-4, 5-difluoro-2-nitro-benzoic acid was heated with an excess of 21% NaOEt in ethanol at 90 ℃ for 6h to give 3-amino-5-ethoxy-4-fluoro-2-nitro-benzoic acid. LCMS: 245(M +1)⁺.

Hydrogenation of 1.0g (4.1mmol) of 3-amino-5-ethoxy-4-fluoro-2-nitro-benzoic acid according to general procedure C gave 2, 3-diamino-5-ethoxy-4-fluoro-benzoic acid. LCMS: 215 (M +1)⁺.

0.8g (3.7mmol) of 2, 3-diamino-5-ethoxy-4-fluoro-benzoic acid was subjected to similar cyclisation conditions as described in intermediate A using a solution of 1.2g (11.2mmol) of BrCN in methanol to give 2-amino-6-ethoxy-7-fluoro-1H-benzimidazole-4-carboxylic acid. LCMS: 240(M +1) ⁺.

0.8g (3.3mmol) of 2-amino-6-ethoxy-7-fluoro-1H-benzimidazole-4-carboxylic acid in methylHeating and refluxing the mixture in alcohol and HCl/diethyl ether to obtain 2-amino-6-ethoxy-7-fluoro-1H-benzimidazole-4-carboxylic acid methyl ester. LCMS: 254(M +1)⁺.

As described in general procedure A, 0.3g (1.5mmol) of isoquinoline-3-carboxylic acid and 0.6g (1.6mmol) of HBTU are dissolved in 3.0mL of DMF and 0.6mL of DIEA and treated with 0.25g (1.0mmol) of methyl 2-amino-6-ethoxy-7-fluoro-1H-benzimidazole-4-carboxylate to give 0.18g (0.44mmol, 44%) of 6-ethoxy-7-fluoro-2- [ (isoquinoline-3-carbonyl) -amino ] -2- [ (]-3H-benzimidazole-4-carboxylic acid methyl ester. LCMS: 409(M +1)⁺.

According to general method B0.17 g (0.42mmol) 6-ethoxy-7-fluoro-2- [ (isoquinoline-3-carbonyl) -amino]Hydrolysis of methyl (E) -3H-benzimidazole-4-carboxylate to give 0.16g (0.41mmol, 98%) 6-ethoxy-7-fluoro-2- [ (isoquinoline-3-carbonyl) -amino]-3H-benzimidazole-4-carboxylic acid. LCMS: 395(M +1)⁺.

30mg (0.08mmol) of 6-ethoxy-7-fluoro-2- [ (isoquinoline-3-carbonyl) -amino]-3H-benzimidazole-4-carboxylic acid and 100mg (0.25mmol) HBTU were dissolved in 1.0mL DMF and 0.3mL DIEA and treated with 30mg (0.14mmol) 4-methanesulfonyl-benzylamine hydrochloride. After completion of the reaction, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc and dried in vacuo to give 19mg (45%) of isoquinoline-3-carboxylic acid [ 5-ethoxy-4-fluoro-7- (4-methanesulfonyl-benzylcarbamoyl) -1H-benzimidazol-2-yl ]-an amide. LCMS: 562(M +1)⁺.

Example 486

60mg (0.15mmol) of 6-ethoxy-7-fluoro-2- [ (isoquinoline-3-carbonyl) -amino]-3H-benzimidazole-4-carboxylic acid (from example 485) and 100mg (0.25mmol) HBTU were dissolved in 1.0mL DMF and 0.2mL DIEA and treated with 50mg (0.5mmol) 2-aminoimidazole sulfate. After completion of the reaction, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc, and dried in vacuo to give 32mg (46%) of isoquinoline-3-carboxylic acid [ 5-ethoxy-4-fluoro-7- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 460(M +1)⁺.

Example 487

First, 10.0mL of concentrated H was used at 0 deg.C₂SO₄Then slowly treated with 4.12g (20mmol) of 3-methoxy-2, 4, 5-trifluoro-benzoic acid 5.0mL of concentrated HNO₃. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was poured into a beaker containing ice. The resulting solid was collected by filtration, washed with cold water and dried to give 4.0g (16mmol, 80%) of 3-methoxy-6-nitro-2, 4, 5-trifluoro-benzoic acid. LCMS: 252(M +1)⁺.

Treatment of 2.0g (8mmol) of 3-methoxy-6-nitro-2, 4, 5-trifluoro-benzoic acid with ammonium hydroxide gave 1.6g (6.45mmol, 80%) of 3-amino-4, 6-difluoro-5-methoxy-2-nitro-benzoic acid. LCMS: 249(M +1) ⁺.

Hydrogenation of 1.6g (6.45mmol) of 3-amino-4, 6-difluoro-5-methoxy-2-nitro-benzoic acid was carried out according to general procedure C to give 2, 3-diamino-4, 6-difluoro-5-methoxy-benzoic acid. LCMS: 219(M +1)⁺.

1.2g (5.5mmol)2, 3-diamino-4, 6-difluoro-5-methoxy-benzoic acid was subjected to similar cyclization conditions as described in intermediate A using a solution of 1.7g (16.5mmol) BrCN in methanol to give 2-amino-5, 7-difluoro-6-methoxy-1H-benzimidazole-4-carboxylic acid. LCMS: 244(M +1)⁺.

1.0g (4.1mmol) 2-amino-5, 7-difluoro-6-methoxy-1H-benzimidazole-4-carboxylic acid was heated under reflux in methanol and HCl/diethyl ether to give 0.9g (3.6mmol, 88%) methyl 2-amino-5, 7-difluoro-6-methoxy-1H-benzimidazole-4-carboxylate. LCMS: 258(M +1)⁺.

As described in general procedure A, 0.4g (2.0mmol) of isoquinoline-3-carboxylic acid and 800mg (2.1mmol) of HBTU are dissolved in 3.0mL of DMF and 0.6mL of DIEA and 0.35g (1.5mmol) of 2-amino-5, 7-difluoro-6-methoxy-1H-benzimidazoleOxazole-4-carboxylic acid methyl ester treatment gave 0.3g (0.73mmol, 49%) of 5, 7-difluoro-2- [ (isoquinoline-3-carbonyl) -amino]-6-methoxy-3H-benzimidazole-4-carboxylic acid methyl ester. LCMS: 413(M +1)⁺.

Following general method B0.21 g (0.5mmol)5, 7-difluoro-2- [ (isoquinoline-3-carbonyl) -amino ]Hydrolysis of methyl (6-methoxy-3H-benzimidazole-4-carboxylate) to give 0.20g (0.5mmol, 100%) of 5, 7-difluoro-2- [ (isoquinoline-3-carbonyl) -amino]-6-methoxy-3H-benzimidazole-4-carboxylic acid. LCMS: 399(M +1)⁺.

60mg (0.15mmol) of the above-mentioned 5, 7-difluoro-2- [ (isoquinoline-3-carbonyl) -amino group are reacted as described in general method A]-6-methoxy-3H-benzimidazole-4-carboxylic acid and 100mg (0.25mmol) HBTU were dissolved in 1.0mL DMF and 0.5mL DIEA and treated with 68mg (0.5mmol) 2-aminoimidazole sulfate. After completion of the reaction, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc and dried in vacuo to give 24mg (35%) of isoquinoline-3-carboxylic acid [4, 6-difluoro-7- (1H-imidazol-2-ylcarbamoyl) -5-methoxy-1H-benzimidazol-2-yl]-an amide. LCMS: 464(M +1)⁺.

Example 488

A mixture of 2.01g (10mmol) of methyl 2-hydroxy-3-nitro-benzoate, 0.8g palladium (10% by weight in carbon powder) and 30mL methanol was hydrogenated at 40psi overnight. The reaction mixture was filtered through celite. The solvent was evaporated to dryness in vacuo to give 3-amino-2-hydroxy-benzoic acid methyl ester. LCMS: 168(M +1)⁺.

A mixture of 913mg (5.46mmol) of methyl 3-amino-2-hydroxy-benzoate, 894mg (8.19mmol) of cyanogen bromide, 14.4mL of ethanol and 1.6mL of water was heated under reflux for 1 h. The ethanol was evaporated under reduced pressure and 20mL of 2N Na was added to the residue ₂CO₃An aqueous solution. The precipitated solid was filtered and washed with water. The remaining product was treated with methanol and the dissolved filtrate containing the product was evaporated to dryness in vacuo to give 797mg (4.15mmol, 76%) of methyl 2-amino-benzoxazole-7-carboxylate. LCMS: 193 (M)+1)⁺.

Preparation of 2- [ (isoquinoline-3-carbonyl) -amino ] -carboxylic acid was prepared according to general procedure A from 1.052g (5.5mmol) of isoquinoline-3-carboxylic acid hydrate, 797mg (4.15mmol) of methyl 2-amino-benzooxazole-7-carboxylate, 2.09g (5.5mmol) of HBTU, 1.58mL (9mmol) of DIEA and 14mL of DMF by stirring at 90 ℃ for 3h]-benzoxazole-7-carboxylic acid methyl ester to yield 684mg (1.97mmol, 48%) of product. LCMS: 348(M +1)⁺.

Following general method B, 417mg (1.2mmol) of 2- [ (isoquinoline-3-carbonyl) -amino]-benzoxazole-7-carboxylic acid methyl ester, 2.4mL of 2N LiOH aqueous solution, 12mL of THF and 3mL of methanol were reacted at 40 ℃ for 4h to synthesize 2- [ (isoquinoline-3-carbonyl) -amino group]-benzoxazole-7-carboxylic acid. 141mg (0.423mmol, 35%) of product are obtained. LCMS: 334(M +1)⁺.

Following general method A, with 137mg (0.411mmol) of 2- [ (isoquinoline-3-carbonyl) -amino]Synthesis of isoquinoline-3-carboxylic acid [7- (1H-imidazol-2-ylcarbamoyl) -benzooxazol-2-yl ] -isoquinoline-7-carboxylic acid, 111mg (0.822mmol) 2-aminoimidazole sulfate, 171mg (0.45mmol) HBTU, 0.29mL (1.65mmol) DIEA and 2mL DMF at 90 ℃ with stirring for 2H ]-an amide. 98.9mg (0.248mmol, 60%) of product are obtained. LCMS: 399(M +1)⁺.

Example 489

First 20.0mL of concentrated H at 0 deg.C₂SO₄Then slowly treated with 7.6g (40mmol) of ethyl 3, 5-difluoro-benzoate 10.0mL of concentrated HNO₃. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was poured into a beaker containing ice. The resulting mixture was extracted with ethyl acetate, washed with cold water and evaporated to dryness to give 7.4g (32mmol, 80%) of ethyl 3, 5-difluoro-2-nitro-benzoate. LCMS: 232(M +1)⁺.

4.64g (20mmol) of ethyl 3, 5-difluoro-2-nitro-benzoate in DMF were heated with 2.1g (22mmol) of ammonium carbonate at 60 ℃ for 6 h. The reaction mixture was treated with water. The resulting solid was collected by filtration and washed with water to give 3.4g (15.0mmol, 75%) of 3-ammoniaEthyl-5-fluoro-2-nitro-benzoate, LCMS: 229(M +1)⁺.

A solution of 2.31g (10mmol) of ethyl 3-amino-5-fluoro-2-nitro-benzoate in DMF, 1.1g (11mmol) of triethylamine and 1.4g (16mmol) of NaSEt were heated at 80 ℃ for 6 h. After cooling to room temperature, extraction with EtOAc afforded 3-amino-5-ethylsulfanyl-2-nitro-benzoic acid ethyl ester. LCMS: 271(M +1)⁺.

Using 2.9g (16.6mmol) Na at 80 deg.C₂5₂O₄1.5g (5.5mmol) of 3-amino-5-ethylsulfanyl-2-nitro-benzoic acid ethyl ester are reduced in 28mL of ethanol/ethyl acetate/water (3: 1) for 3h to give 2, 3-diamino-5-ethylsulfanyl-benzoic acid ethyl ester. LCMS: 241(M +1) ⁺.

0.9g (3.75mmol) of 2, 3-diamino-5-ethylsulfanyl-benzoic acid ethyl ester were subjected to similar cyclization conditions as described in intermediate A with 1.2g (11.3mmol) of BrCN in methanol to give 0.9g (3.4mmol, 90%) of 2-amino-6-ethylsulfanyl-1H-benzimidazole-4-carboxylic acid ethyl ester. LCMS: 266(M +1)⁺.

As described in general procedure A, 0.4g (2.0mmol) of isoquinoline-3-carboxylic acid and 800mg (2.1mmol) of HBTU are dissolved in 3.0mL of DMF and 0.6mL of DIEA and treated with 0.26g (1.0mmol) of ethyl 2-amino-6-ethylsulfanyl-1H-benzimidazole-4-carboxylate to give 0.35g (0.83mmol, 83%) of 6-ethylsulfanyl-2- [ (isoquinoline-3-carbonyl) -amino ] -4-carboxylic acid]-3H-benzimidazole-4-carboxylic acid ethyl ester. LCMS: 421(M +1)⁺.

According to general method B0.34 g (0.81mmol) 6-ethylsulfanyl-2- [ (isoquinoline-3-carbonyl) -amino ] -carbonyl]Hydrolysis of ethyl (E) -3H-benzimidazole-4-carboxylate to give 0.30g (0.77mmol, 95%) of 6-ethylsulfanyl-2- [ (isoquinoline-3-carbonyl) -amino ] -carbonyl]-3H-benzimidazole-4-carboxylic acid. LCMS: 393(M +1)⁺.

As described in general method A, 80mg (0.2mmol) of 6-ethylsulfanyl-2- [ (isoquinoline-3-carbonyl) -amino ] -amino]-3H-benzimidazole-4-carboxylic acid and 300mg (0.76mmol) HBTU were dissolved in 1.0mL DMF and 0.5mL DIEA with 132mg (1.0 mm) ol) 2-aminoimidazole sulfate treatment. After completion of the reaction, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc and dried in vacuo to give 66mg (71%) of isoquinoline-3-carboxylic acid [ 5-ethylsulfanyl-7- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 458(M +1)⁺.

Example 490

Except using NaS (CH)₂)₃CH₃Isoquinoline-3-carboxylic acid [ 5-butylsulfanyl-7- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ] was synthesized in analogy to the procedure used for the preparation of example 489, but instead of NaSEt]Amide (15 mg).

Example 491

A solution of 0.26g (1.0mmol) of ethyl 2-amino-6-ethylsulfanyl-1H-benzimidazole-4-carboxylate (see example 489) in DCM is admixed with 0.35g (2.0mmol) of MCPBA and 0.34g (4.0mmol) of NaHCO₃Stirred together at room temperature for 3 h. The reaction mixture is washed with Na₂S₂O₃The solution was worked up and stirred at room temperature for 0.5 h. Extraction with EtOAc followed by washing with dilute NaOH solution and brine and evaporation of the solvent to dryness afforded 0.28g (0.94mmol, 94%) of ethyl 2-amino-6-ethylsulfonyl-1H-benzimidazole-4-carboxylate. LCMS: 298(M +1)⁺.

As described in general procedure A, 0.30g (1.5mmol) of isoquinoline-3-carboxylic acid and 800mg (2.1mmol) of HBTU are dissolved in 3.0mL of DMF and 0.6mL of DIEA and treated with 0.28g (0.94mmol) of ethyl 2-amino-6-ethylsulfonyl-1H-benzimidazole-4-carboxylate to give 6-ethylsulfonyl-2- [ (isoquinoline-3-carbonyl) -amino ] -4-carboxylic acid ]-3H-benzimidazole-4-carboxylic acid ethyl ester. LCMS: 453(M +1)⁺.

0.36g (0.79mmol) of 6-ethylsulfonyl-2- [ (isoquinoline-3-carbonyl) -amino ] -are hydrolyzed according to general method B]-3H-benzimidazole-4-carboxylic acid ethyl ester, to yield 0.30g (0.71mmol, 90%) 6-ethylsulfonyl-2- [ (isoquinoline-3-carbonyl) -amino ] -amide]-3H-benzimidazole-4-carboxylic acid. LCMS: 425(M +1)⁺.

As described in general method A, 62mg (0.15mmol) of 6-ethylsulfonyl-2- [ (isoquinoline-3-carbonyl) -amino ] -carbonyl]-3H-benzimidazole-4-carboxylic acid and 200mg (0.53mmol) HBTU were dissolved in 1.0mL DMF and 0.5mL DIEA and treated with 132mg (1.0mmol) 2-aminoimidazole sulfate. After completion of the reaction, the reaction was diluted with brine (10mL) of water. The resulting solid was filtered, washed with water, EtOAc and dried in vacuo to give 36mg (57%) of isoquinoline-3-carboxylic acid [ 5-ethanesulfonyl-7- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl]-an amide. LCMS: 490(M +1)⁺.

The following compounds were synthesized by analogous methods as used in the preparation of example 491 and the related schemes described above.

Examples	W	R	LCMS(M+1)⁺
				492	1H-imidazol-2-yl	Methyl radical	477
493	1H-imidazol-2-yl	Phenyl radical	539
				494	1H-imidazol-2-yl	Butyl radical	519

Example 495

A solution of 1.53g (10mmol) of 3-nitro-benzene-1, 2-diamine in 20mL of methanol was treated with 1.3g (12.5mmol) of BrCN and the mixture heated at reflux for 1.0 h. After cooling to room temperature, the reaction was concentrated and the residue was taken up with saturated NaHCO ₃And (4) washing the solution. The solid was collected, washed with water and dried to give 1H-benzoimidazol-4-nitro-2-amine. LCMS: 179(M +1)⁺.

1.6g (8mmol) of isoquinoline-3-carboxylic acid and HBTU are dissolved in DMF and DIEA and treated with 1.4g (8mmol) of 1H-benzimidazol-4-nitro-2-amine as described in general procedure A to give 1.9g (6mmol, 75%) of isoquinoline-3-carboxylic acid (1H-benzimidazol-4-nitro-2-yl) -amide. LCMS: 335(M +1)⁺.

Hydrogenation of 1.6g (6mmol) of isoquinoline-3-carboxylic acid (1H-benzoimidazol-4-nitro-2-yl) -amide follows general procedure C to give 0.9g (3mmol, 50%) of isoquinoline-3-carboxylic acid (4-amino-1H-benzoimidazol-2-yl) -amide. LCMS: 305(M +1)⁺.

66mg (0.2mmol) of isoquinoline-3-carboxylic acid (4-amino-1H-benzimidazol-2-yl) -amide are dissolved in pyridine (0.6 mL). Adding the stirred solution at 0 deg.C in one portionA solution of 0.2mmol of benzenesulfonyl chloride in 0.2mL of DCM was added. The reaction mixture was stirred at room temperature for 2 h. Brine (5mL) was added and stirred for 10 min. The resulting solid was collected by filtration, washed with water (3X 2mL) and EtOAc (3X 3mL), and dried to give 46mg (52%) of isoquinoline-3-carboxylic acid (7-benzenesulfonylamino-1H-benzimidazol-2-yl) -amide. LCMS: 444(M +1)⁺.

Example 496

A solution of 0.10g (0.30mmol) isoquinoline-3-carboxylic acid (4-amino-1H-benzimidazol-2-yl) -amide in 2mL pyridine is treated with 0.06mL (0.75mmol) methanesulfonyl chloride, shaking at room temperature for about 4 hours. After this time, the crude reaction mixture was treated with 0.10mL of hydrazine monohydrate and heated at 60 ℃ for about 1 hour. The reaction mixture was diluted with water and the resulting solid isoquinoline-3-carboxylic acid (4-methanesulfonylamino-1H-benzimidazol-2-yl) -amide was collected by filtration without further purification. LCMS: 382.9(M +1) ⁺.

Embodiment 497

7.6g (50mmol) of 4-nitro-o-phenylenediamine are dissolved in 100mL of ethanol and 20mLH₂And (4) in O. To this stirred solution was added 7.9g (75mmol) BrCN in one portion and the resulting mixture was heated under reflux for 1.0 h. The reaction mixture was cooled to room temperature and concentrated to 20mL, then saturated NaHCO was used₃The solution was neutralized to a pH of about 8 and the resulting solid 5-nitro-1H-benzimidazol-2-ylamine was collected by filtration and used directly in the next step without further purification.

Isoquinoline-3-carboxylic acid (5-nitro-1H-benzimidazol-2-yl) -amide was synthesized as described in general procedure A using 3.5g (20mmol) of isoquinoline-3-carboxylic acid monohydrate, 7.6g (20mmol) of HBTU and 3.56g (20mmol) of the above synthesized 5-nitro-1H-benzimidazol-2-ylamine. 0.50g (1.5mmol) of this isoquinoline-3-carboxylic acid (5-nitro-1H-benzimidazol-2-yl) -amide is subsequently hydrogenated according to general method C to give isoquinoline-3-carboxylic acid (5-amino-1H-benzimidazol-2-yl) -amide. LCMS: 304(M +1)⁺.

Example 498

A solution of 0.10g (0.30mmol) isoquinoline-3-carboxylic acid (5-amino-1H-benzoimidazol-2-yl) -amide in 2mL pyridine is treated with 0.06mL (0.75mmol) methanesulfonyl chloride, shaking at room temperature for about 4 hours. After this time, the crude reaction mixture was treated with 0.10mL of hydrazine monohydrate and heated at 60 ℃ for about 1 hour. The reaction mixture was diluted with water and the resulting solid isoquinoline-3-carboxylic acid (5-methanesulfonylamino-1H-benzimidazol-2-yl) -amide was collected by filtration without further purification. LCMS: 382(M +1) ⁺.¹H NMR(DMSO-d₆，400MHz)：δ9.49(s，1H)，9.45(s，1H)，8.78(s，1H)，8.30(t，2H)，7.94-7.87(m，2H)，7.46-7.44(m，2H)，7.03(d，1H)，2.89(s，3H)ppm.

The following compounds were synthesized by analogous methods as used in preparation example 498 and the related schemes above.

Examples	R	LCMS(M+1)⁺
			499	4-biphenylyl group	521
500	Propyl radical	411
			501	Isopropyl group	411

Biological analysis

The following assay was used to identify and evaluate compounds of formula (I) that are effective in reducing the proteolytic activity of BACE.

BACE Fluorescence Resonance Energy Transfer (FRET) assay

In the following assay, the proteolytic activity of BACE was determined by observing the cleavage of the fluorophore of the peptide substrate containing the rhodamine fluorescence donor and the quencher acceptor.

The inhibitory activity of the compound of formula (I) was compared with that of the statin-derived control inhibitor STA200(KTEEISEVN(Statine) VAEF-OH, MP Biomedical catalog number STA-200). Cleavage reactions occurred when a BACE-1 substrate (Rhodamine-EVNLDAEFK-Quencher, Invitrogen, Cat. No. P2947) was added to the reaction mixture containing BACE-1 and allowed to proceed for 1 hour. Fluorescence used as a marker for BACE activity was monitored with an excitation wavelength of 540nm and an emission wavelength of 585nm (Envision, Perkin Elmer).

A typical assay reaction contains BACE in assay buffer (50mM sodium acetate, pH 4-4.5, 0.0125% CHAPS (3- [ (3-cholamidopropyl) dimethylammonium ] -1-propanesulfonate), 0.0125% TritonX-100, 0.006% EDTA) which was previously incubated with test compounds in 7.5% DMSO for 30 minutes. BACE-1 substrate was added to assay buffer, the reaction was initiated, and allowed to proceed for 1 hour at room temperature. The analysis was performed in a black 384 well microtiter plate, scanned at room temperature with an excitation wavelength of 540nm and an emission wavelength of 585 nm.

Activity of test Compounds with IC₅₀And (6) reporting. Compounds of examples 1-501 in FRET assays with IC's of less than 30. mu.M₅₀Inhibiting the proteolytic activity of BACE.

A beta cell-based assay

In the following analysis, A.beta.secreted by HEK293 cells (human embryonic kidney epithelial cell line) (HEK-APPwt cells) stably expressing wild-type human APP695 protein was examined_1-40To determine the proteolytic activity of BACE in exposed cells at different concentrations of the compound in question.

HEK-APPwt cells in the presence of 4500mg glucose/L, L-glutamine, NaHCO₃Pyrdoxin HCl, 10mM HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid) (pH7.4), 0.1mM NEAA (non-essential amino acids) (GIBCO Cat. No. 11140-₂And growth under humidity controlled conditions.

Test compounds were first prepared in DMSO and diluted with DMEM medium containing 2% FBS (fetal bovine serum) and 0.05% Tween 20. 10 solutions of standard compounds were prepared with a range of concentrations. Determining the EC of a test compound using a solution of the standard compound ₅₀. The choice of concentration range depends on the expected potency of the compound.

To prepare cells for analysis, flasks containing HEK-APPwt cells were briefly trypsinized (1mL trypsin) and, once the cells shed, 4mL 10% FBS-DMEM was added to the flasks. The exfoliated cells were centrifuged at 900rpm for 5min to form a pellet.

The HEK-APPwt cell pellet was resuspended in 10mL of DMEM medium containing 2% FBS. Into each well of a 96-well culture plate80 μ L of each cell suspension was added to achieve 100,000 cells/well. To each well of a 96-well culture plate, 10. mu.L of the standard compound solution was added, followed by 10. mu.L of Alamar blue solution. Incubate cells for 1h at room temperature, then CO₂Incubate at 37 ℃ for 5h in an incubator.

At the end of incubation, the plate was removed from the incubator and the supernatant collected. With commercially available Abeta_1-40ELISA kit (IBL, Japan) for measuring A.beta.in culture Medium_1-40And (4) concentration. Briefly, ELISA plates were coated with anti-human A β_35-40Murine IgG monoclonal antibodies. Detection was performed using horseradish peroxidase in combination with anti-human Abeta 11-28 murine IgG monoclonal antibody. The cell culture supernatant was diluted 4-fold with protease inhibitor-containing EIA buffer (1mL protease inhibitor/30 mL buffer). Aliquots of 100. mu.L of diluted supernatant were added to each well of the ELISA plate and incubated for 6 hours at 4 ℃. The ELISA plate was washed 8 times with Phosphate Buffered Saline (PBS) containing 0.05% Tween 20.

Then 100. mu.L of detection antibody was added and incubated at 4 ℃ for 1 hour. The ELISA plates were washed 8 times with PBS buffer containing 0.05% Tween20, and then 100. mu.L of substrate containing chromogen Tetramethylbenzidine (TMB) was added. The ELISA plates were incubated in the dark at room temperature for about 30min and stop solution (1 NH) was added₂SO₄)。

The density of the color formed was determined at 450 nm. Optical density at 450nm (OD450) and human Abeta secreted by cells_1-40Is in proportion. By N- [ N- (3, 5-difluorophenylacetyl-L-alanyl)]-S-phenylglycine tert-butyl ester (DAPT, gamma-secretase inhibitor) as reference, representing 100% inhibition of BACE activity. Thus, the assay measures the reduction of A.beta.by the compound in question_1-40The ability to secrete. By calculating the percent inhibition at all concentration levels, in EC₅₀The potency of the compounds was reported and the data were fitted using the non-linear curve fitting algorithm used in GraphPad Prism.

Various compounds of the invention, including examples 58, 140, 155, 165, 176, 193, 198, 212, 247, 289, 294, 295, 296, 300, 311, 312, 318,343, 351, 355, 414, 416, 417, 428, 434, 439, 458, 472 and 491 all exhibited an EC of less than or equal to 2.0 μ M in the cell-based assay described above ₅₀The value is obtained.

While the invention has been described and illustrated with reference to certain embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, an effective dose may be used instead of the doses described herein as a result of a change in responsiveness of the subject being treated. Similarly, the particular pharmacological responses observed may vary according to and depending upon the particular active compound selected, or whether there are present pharmaceutical carriers, and the type of formulation and mode of administration employed, and such expected variations or differences in the results are consistent with the objectives and practices of the present invention. Furthermore, all compounds set forth in the written description may be applicable to any of the described methods, processes, compositions, and/or compounds presented in the written description and appended claims.

Claims

1. A compound of the following formula (Ia):

wherein

L₁is-NH-C (O) -, -NH-or a direct bond;

Q₁is a direct bond;

G₁is phenyl, biphenyl, naphthyl, indole, isoquinolineA quinoline group, a pyridine or a pyrimidine,

wherein G is₁Optionally substituted 1-7 times, wherein the substituents are independently selected from:

a) -a halogen;

b) -a cyano group;

c) -a nitro group;

d) -perhaloalkyl;

e)-R₈；

f)-L₂-R₈；

g)-L₂-Q₂-R₈(ii) a And

h)-Q₂-L₂-R₈；

wherein

R₈Is selected from hydrogen, -C_1-10Alkyl, -aryl and-C_1-10Alkylene-aryl;

Q₂is selected from C_1-10Alkylene radical, C_2-10Alkenylene and C_2-10An alkynylene group;

Wherein R is₉And R₁₀Independently selected from: hydrogen, -C_1-10Alkyl, -aryl and-C_1-10Alkylene-aryl;

R₁，R₂，R₃and R₄Is independently selected from

a)-H；

b)-C_1-10An alkyl group;

c) -an aryl group;

d)-C_1-10alkylene-aryl;

e)-K-C_1-10an alkyl group;

f) -K-aryl;

g)-K-C_1-10alkylene-aryl; and

h)-L₃-G₂-G₃；

wherein

R₁-R₄In which at least one group is-L₃-G₂-G₃Wherein

L₃Selected from:

a)-CO₂-；

b) -C (O) NH-; and

c)-NH-，

wherein

G₂is a direct bond or C_1-10An alkylene group; and is

G₃Selected from imidazole and benzimidazole, wherein G₃Optionally substituted 1-7 times with a group selected from:

a) -a halogen;

b) -a cyano group;

c) -a nitro group;

d) -perhaloalkyl;

e)-R₁₆；

f)-L₄-R₁₆；

g)-L₄-Q₄-R₁₆(ii) a And

h)-Q₂-L₄-R₁₆；

wherein

R₁₆Is selected from hydrogen, -C_1-10Alkyl, -aryl and-C _1-10Alkylene-aryl;

Q₄is selected from-C_1-10Alkylene group, -C_2-10Alkenylene and-C_2-10An alkynylene group;

R₁₈and R₁₉Independently selected from: hydrogen, -C_1-10Alkyl, -aryl and-C_1-10Alkylene-aryl;

R₅selected from:

a) -hydrogen; and

b)-C_1-10an alkyl group;

wherein R is₁To R₁₉，L₁To L₄Aryl and/or C in (1)_1-10Alkyl groups may be optionally substituted 1-4 times with substituents selected from:

a)-H；

b) -a halogen;

c) -a hydroxyl group;

d) -a cyano group;

e) -a carbamoyl group;

f) -a carboxyl group;

g)-Z-C_1-10an alkyl group;

h) -Z-aryl; and

i)-Z-C_1-10alkylene-aryl;

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L₁is-NH-C (O) -.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein G₁Is isoquinoline.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, represented by the formula:

5. the compound of claim 1, or a pharmaceutically acceptable salt thereof, represented by the formula:

6. the compound of claim 1 selected from the group consisting of:

2-isoquinolin-3-yl-1H-benzimidazole-4-carboxylic acid (4-phenyl-1H-imidazol-2-yl) -amide,

2-pyridin-2-yl-1H-benzimidazole-5-carboxylic acid (1H-benzimidazol-2-yl) -amide,

2-naphthalen-2-yl-1H-benzimidazole-5-carboxylic acid (1H-benzimidazol-2-yl) -amide,

2- (isoquinolin-3-ylamino) -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- (isoquinolin-3-ylamino) -3H-benzimidazole-5-carboxylic acid (1H-imidazol-2-yl) -amide,

2- (pyridin-2-ylamino) -3H-benzimidazole-5-carboxylic acid (1H-imidazol-2-yl) -amide,

2- (pyridin-2-ylamino) -3H-benzimidazole-5-carboxylic acid (1H-benzimidazol-2-yl) -amide,

isoquinoline-3-carboxylic acid [7- (1H-imidazol-2-ylcarbamoyl) -1H-benzoimidazol-2-yl ] -amide,

2- (4-chloro-benzoylamino) -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

isoquinoline-3-carboxylic acid [7- (1H-benzoimidazol-2-ylcarbamoyl) -1H-benzoimidazol-2-yl ] -amide,

2- [ (1H-indole-2-carbonyl) -amino ] -1H-benzimidazole-4-carboxylic acid (1H-benzimidazol-2-yl) -amide,

isoquinoline-3-carboxylic acid [5- (1H-benzoimidazol-2-ylcarbamoyl) -1H-benzoimidazol-2-yl ] -amide,

2-benzoylamino-3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- [ (naphthalene-2-carbonyl) -amino ] -1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- [ (biphenyl-4-carbonyl) -amino ] -1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- [ (1H-indole-2-carbonyl) -amino ] -1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- (3, 5-difluoro-benzoylamino) -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- (4-fluoro-benzoylamino) -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

isoquinoline-3-carboxylic acid {4- [ (1-methyl-1H-benzimidazol-2-ylmethyl) -carbamoyl ] -1H-benzimidazol-2-yl } -amide,

isoquinoline-3-carboxylic acid {4- [2- (1H-benzimidazol-2-yl) -ethylcarbamoyl ] -1H-benzimidazol-2-yl) -amide,

2- [2- (4-fluoro-phenyl) -acetylamino ] -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- (4-fluoro-3-methoxy-benzoylamino) -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- (3, 4-dimethoxy-benzoylamino) -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

isoquinoline-3-carboxylic acid {4- [ (1H-benzoimidazol-2-ylmethyl) -carbamoyl ] -1H-benzoimidazol-2-yl } -amide,

2- (4-trifluoromethyl-benzoylamino) -1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- (4-phenoxy-benzoylamino) -1H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- (4-tert-butyl-benzoylamino) -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- (4-nitro-benzoylamino) -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- (4-methoxy-benzoylamino) -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- (4-isopropyl-benzoylamino) -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- (3-fluoro-benzoylamino) -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- (2-fluoro-benzoylamino) -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

6, 7-dimethoxy-isoquinoline-3-carboxylic acid [7- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ] -amide,

2- (3-chloro-benzoylamino) -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- (2-chloro-benzoylamino) -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- [ (1-methyl-1H-indole-2-carbonyl) -amino ] -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

isoquinoline-3-carboxylic acid [4- (5-phenyl-1H-imidazol-2-ylcarbamoyl) -1H-benzoimidazol-2-yl ] -amide,

2- [ (5-methyl-1H-indole-2-carbonyl) -amino ] -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- [ (6-phenoxy-pyridine-2-carbonyl) -amino ] -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- [ (1-benzyl-1H-indole-2-carbonyl) -amino ] -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- [ (1-propyl-1H-indole-2-carbonyl) -amino ] -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

2- [ (1, 5-dimethyl-1H-indole-carbonyl) -amino ] -3H-benzimidazole-4-carboxylic acid (1H-imidazol-2-yl) -amide,

isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -6-isobutyrylamino-1H-benzimidazol-2-yl ] -amide,

isoquinoline-3-carboxylic acid [ 6-benzoylamino-4- (1H-imidazol-2-ylcarbamoyl) -1H-benzimidazol-2-yl ] -amide,

isoquinoline-3-carboxylic acid [4- (1H-imidazol-2-ylcarbamoyl) -6- (3-methyl-butyrylamino) -1H-benzimidazol-2-yl ] -amide,

isoquinoline-3-carboxylic acid [7- (1H-imidazol-2-ylcarbamoyl) -5-phenylacetamido-1H-benzimidazol-2-yl ] -amide,

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is isoquinoline-3-carboxylic acid [7- (1H-imidazol-2-ylcarbamoyl) -1H-benzoimidazol-2-yl ] -amide.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, which is the hydrochloride salt of isoquinoline-3-carboxylic acid [7- (1H-imidazol-2-ylcarbamoyl) -1H-benzoimidazol-2-yl ] -amide.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8.

10. The pharmaceutical composition of claim 9, further comprising a pharmaceutically acceptable carrier, excipient, diluent, or mixture thereof.

11. The pharmaceutical composition of claim 9 or 10, further comprising one or more therapeutic agents selected from the group consisting of:

anti-Alzheimer's disease agents, other beta secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, non-steroidal anti-inflammatory drugs, N-methyl-D-aspartate receptor antagonists, cholinesterase inhibitors, vitamin E, CB-1 receptor antagonists or CB-1 receptor inverse agonists, antibiotics, agents that bind to or induce antibodies that bind to A β, anti-A β antibodies, A β vaccines and RAGE/RAGE ligand interaction antagonists.

12. A combination comprising a compound according to any one of claims 1 to 8 and one or more additional therapeutic agents.

13. The combination of claim 12, wherein the one or more therapeutic agents are selected from the group consisting of: anti-Alzheimer's disease agents, other beta secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, non-steroidal anti-inflammatory drugs, N-methyl-D-aspartate receptor antagonists, cholinesterase inhibitors, vitamin E, CB-1 receptor antagonists or CB-1 receptor inverse agonists, antibiotics, agents that bind to or induce antibodies that bind to A β, anti-A β antibodies, A β vaccines and RAGE/RAGE ligand interaction antagonists.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound according to any one of claims 1 to 8, in an amount sufficient to treat a condition or disease selected from: alzheimer's disease, mild cognitive impairment, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type Alzheimer's disease or central or peripheral amyloid diseases.

15. The pharmaceutical composition of claim 14, wherein the disease or disorder to be treated is dementia of the alzheimer's type and is selected from the group consisting of early-onset dementia of the simple alzheimer's type, dementia with delusions of the early-onset alzheimer's type, dementia with depressed mood of the early-onset alzheimer's type, dementia with late-onset simple alzheimer's type, dementia with delusions of the late-onset alzheimer's type and dementia with depressed mood of the late-onset alzheimer's type.

16. The pharmaceutical composition of any one of claims 9, 10, 11, 14 or 15 in unit dosage form containing from 5mg to 500mg of the compound of any one of claims 1-8.

17. Use of a compound according to any one of claims 1 to 8 or a combination according to claim 12 or 13 in the manufacture of a medicament for use in inhibiting the interaction of BACE with its physiological ligands.

18. Use of a compound according to any one of claims 1 to 8 or a combination according to claim 12 or 13 for the manufacture of a medicament for the treatment of a condition or disease selected from: alzheimer's disease, mild cognitive impairment, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type Alzheimer's disease or central or peripheral amyloid diseases.

19. The use according to claim 18, wherein the disease or disorder to be treated is dementia of the alzheimer's type and is selected from the group consisting of early-onset dementia of the simple alzheimer's type, dementia with delusions of the early-onset alzheimer's type, dementia with depressed mood of the early-onset alzheimer's type, dementia with late-onset simple alzheimer's type, dementia with delusions of the late-onset alzheimer's type and dementia with depressed mood of the late-onset alzheimer's type.

20. The pharmaceutical composition of claim 11, wherein the non-steroidal anti-inflammatory drug is ibuprofen, naproxen, or diclofenac.

21. The pharmaceutical composition of claim 11, wherein the N-methyl-D-aspartate receptor antagonist is memantine.

22. The pharmaceutical composition of claim 11 wherein the cholinesterase inhibitor is galantamine, rivastigmine, donepezil or tacrine.

23. The pharmaceutical composition of claim 11, wherein the antibiotic is doxycycline or rifampin.

24. The pharmaceutical composition of claim 13, wherein the non-steroidal anti-inflammatory drug is ibuprofen, naproxen, or diclofenac.

25. The pharmaceutical composition of claim 13, wherein the N-methyl-D-aspartate receptor antagonist is memantine.

26. The pharmaceutical composition of claim 13 wherein the cholinesterase inhibitor is galantamine, rivastigmine, donepezil or tacrine.

27. The pharmaceutical composition of claim 13, wherein the antibiotic is doxycycline or rifampin.