HK1206740B

HK1206740B - Substituted hetero-azepinones

Info

Publication number: HK1206740B
Application number: HK15107346.9A
Authority: HK
Inventors: Andrew F. DONNELL; Xiaochun Han; Robert Francis Kester; Norman Kong; Kang Le; Yan Lou; Christophe Michoud; John Anthony Moliterni; Stacy Remiszewski; Kenneth Carey RUPERT; Weiya Yun
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2012-08-09
Filing date: 2013-08-06
Publication date: 2018-08-03

Description

Substituted hetero-azalone compounds

Technical Field

The invention relates to substituted hetero-azaKetone compounds and their use to inhibit the binding of SMAC protein to Inhibitors of Apoptotic Proteins (IAPs) and/or to inhibit the binding of activated caspase (caspase) proteins to IAPs for the treatment of human diseases, such as cancer.

Background

Cancer is a disease of uncontrolled cell growth, which leads to local enlargement of the tumor and possibly distant metastasis. One mechanism of cancer cell growth is by avoiding apoptosis (also known as programmed cell death). Alterations in apoptotic pathways have been linked to cancer cell tolerance to standard therapies (e.g., chemotherapy or radiation), and to cancer development and progression.

The two basic pathways of apoptotic cell death are the internal and external pathways. The internal apoptotic pathway may be initiated by a variety of mechanisms including cellular stress, drug-induced damage, or DNA damage. The external pathway may be initiated by chemokine activation of death receptors. Initiation of either pathway results in activation of a family of proteases known as caspases. Once activated, the caspase can cleave multiple substrates, creating a cascade of reaction events, further leading to activation of effector caspases 3 and 7, and ultimately cell death. The IAP family of proteins can bind and inhibit the activity of caspases, thus inhibiting apoptosis.

IAPs can include up to three identical domains, called Baculovirus IAP Repeat (BIR) domains: BIR1, BIR2 and BIR 3. The BIR3 domain of typical IAPs (cIAP and XIAP) can bind to and inhibit activated caspase 9. In contrast, the BIR2 domain binds to and inhibits caspases 3 and 7. The pro-apoptotic protein Smac (also known as DIABLO) can bind to BIR2 and BIR3 domains of IAPs, compete with activated caspases, leading to the release of the activated caspases from the IAPs and completion of the apoptotic program. Peptides and small molecules have been reported to bind to Bir3 regions of XIAP and cIAP, mimicking the action of SMAC proteins, releasing IAP-inhibited activated caspases. Targeting the Bir2 region of IAPs (including XIAP) with small molecules has been rarely studied.

Summary of The Invention

The present invention relates to compounds of formula 1 or pharmaceutically acceptable salts thereof:

wherein:

w, X, Y, Z, R1, R2, R3, R4, R5 and R6 are as described herein. These compounds bind to BIR2 and/or BIR3 regions of IAP (including XIAP and cIAP) proteins, leading to activation or reactivation of the caspase cascade and are therefore useful in the treatment of proliferative diseases, including cancer.

Detailed Description

The present invention relates to compounds of the formula

Wherein:

w and X are the same or different and are independently selected from H, alkyl, aralkyl, cycloalkylalkyl, alkenylalkyl or alkynylalkyl, or X and W together with the nitrogen to which they are attached may form C_2-9-heterocycle, or W together with the nitrogen to which it is attached and Y together with the carbon to which it is attached may form C_3-9-a heterocycle; y is C_1-6-alkyl or C_3-7-cycloalkyl-C_1-6-an alkyl group; r1 is selected from H, halogen, C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6Alkyl, acyl, OR7, SR7, NR8R9, N-acyl, N-sulfonyl, cyano OR SO₂R10; r2 is selected from H, halogen, C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6Alkyl, acyl, OR7, SR7, NR8R9, N-acyl, N-sulfonyl, cyano OR SO₂R10; r3 is selected from H, halogen, C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6Alkyl, acyl, OR7, SR7, NR8R9, N-acyl, N-sulfonyl, cyano OR SO₂R10; r4 is H or C_1-6-an alkyl group; r5 and R6 are the same or different and are independently selected from H, C_1-6Alkyl, aryl or C_3-7-cycloalkyl, or R5 and R6 together with the carbon to which they are attached may form C_4-7-carbocyclic or heterocyclic, with the proviso that R5 and R6 are not both hydrogen at the same time; v is S or O; z is selected from aryl, heteroaryl, polycyclic aromatic groups, polycyclic heteroaromatic groups, mixed aryl and non-aryl polycyclic or mixed aryl and non-aryl heterocyclic polycyclic; r7 is C_1-6-alkyl, aryl, heteroaryl or sulfonyl; r8 and R9 are the same or different and are independently selected from H, C_1-6Alkyl, aryl-C_1-6-alkyl or heteroaryl-C_1-6-an alkyl group; and R10 is C_1-6Alkyl, aryl, heterocyclyl or aryl-C_1-6-an alkyl group;

or a pharmaceutically acceptable salt thereof.

One aspect of the present invention pertains to compounds 1 of formula 1, wherein

W and X are the same or different and are independently selected from H, C_1-6-alkyl, hydroxy-C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6Alkyl radical, C_2-6-alkenyl-C_1-6Alkyl radical, C_2-6-alkynyl-C_1-6-alkyl and heterocycle, or

X and W together with the nitrogen to which they are attached may form C_2-9-heterocycle, or W together with the nitrogen to which it is attached and Y together with the carbon to which it is attached may form C_3-9-a heterocycle;

y is C_1-6-alkyl, hydroxy-C_1-6-alkyl or C_3-7-cycloalkyl-C_1-6-an alkyl group;

r1 is selected from H, halogen, C_1-6Alkyl, halogen-C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6-alkyl, COOH, C (O) NR8 'R9', acyl, OR7, SR7, NR8R9, N-acyl, N-sulfonyl, cyano and SO₂R10；

R2 is selected from H, halogen, C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6Alkyl, acyl, OR7, SR7, NR8R9, N-acyl, N-sulfonyl, cyano and SO₂R10；

R3 is selected from H, halogen, C_1-6Alkyl, halogen-C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6Alkyl, acyl, OR7, SR7, NR8R9, N-acyl, N-sulfonyl, cyano and SO₂R10；

R4 is H or C_1-6-an alkyl group;

r5 and R6 are the same or different and are independently selected from H, C_1-6-alkanesBase, C_1-6-alkyl-S-C_1-6Alkyl radical, C_1-6-alkyl-O-C_1-6Alkyl, aryl and C_3-7-cycloalkyl, or

R5 and R6 together with the carbon to which they are attached may form C_4-7-carbocyclic or heterocyclic ring, optionally substituted by C_1-6-alkyl-SO₂Substitution;

v is S, O or SO₂；

Z is selected from C_1-6-an alkyl group,

aryl, which is optionally substituted by C_3-7-cycloalkyl, C_1-6Alkyl radical, C_1-6Alkoxy, halogen-C_1-6Alkoxy, C (O) N (C)_1-6-alkyl radical, C_1-6Alkyl), C (O) NHSO₂-C_1-6Alkyl, C (O) N (C)_1-6-alkyl, hydroxy-C_1-6Alkyl), C (O) N (C)_1-6Alkyl radical, COOH-C_1-6-alkyl), optionally cyano, COO-C_1-6Alkyl or COOH substituted phenyl, and aryl-C_1-6-substituted by an alkyl group,

heteroaryl, optionally substituted by cyano, C_1-6Alkoxy or optionally substituted by C (O) N (H, C)_1-6Alkyl), cyano or COOH substituted phenyl,

a polycyclic aromatic group,

polycyclic heteroaromatic radicals, optionally substituted by halogen, SO₂-phenyl, C_1-6-alkyl-phenyl or phenyl optionally substituted by cyano,

mixed aryl and non-aryl polycyclic, and

mixed aryl and non-aryl heterocyclic rings, optionally SO-substituted₂-C_1-6-alkyl, oxo, halogen or C_1-6-alkyl substitution;

r7 is C_1-6-alkyl, aryl, heteroaryl or sulfonyl;

r8 and R9 are the same or different and are independentlySelected from H, C_1-6Alkyl, aryl-C_1-6-alkyl (wherein the alkyl moiety is optionally oxo-substituted), and heteroaryl-C_1-6-an alkyl group;

r8' is selected from H and C_1-6-an alkyl group;

r9' is selected from HOOC-C_1-6-alkyl, hydroxy-C_1-6Alkyl and aryl-C_1-6-alkyl, wherein the aryl moiety is substituted with COOH,

or R8 'and R9' together with the nitrogen to which they are attached form a heterocyclic group which is interrupted by hydroxy-C_1-6-alkyl substitution; and

r10 is C_1-6Alkyl, aryl, heterocyclyl or aryl-C_1-6-an alkyl group;

or a pharmaceutically acceptable salt thereof.

One aspect of the present invention relates to compounds of formula 1, wherein

W and X are the same or different and are independently selected from H, C_1-6-alkyl, hydroxy-C_1-6-alkyl and heterocycle, or

Y is C_1-6-alkyl or hydroxy-C_1-6-an alkyl group;

r1 is H, halogen, C_1-6Alkyl, halogen-C_1-6-alkyl, COOH, C (O) NR8 'R9', NR8R9, N-acyl or N-sulfonyl;

r2 is H, halogen, C_1-6-alkyl or cyano;

r3 is H or halogen-C_1-6-an alkyl group;

r4 is H or C_1-6-an alkyl group;

r5 and R6 are the same or different and are H, C_1-6Alkyl radical, C_1-6-alkyl-S-C_1-6Alkyl radical, C_1-6-alkyl-O-C_1-6-alkyl or C_3-7-cycloalkyl, or

R5 andr6 together with the carbon to which they are attached may form C_4-7-carbocyclic or heterocyclic ring, optionally substituted by C_1-6-alkyl-SO₂The substitution is carried out by the following steps,

v is S or O; SO (SO)₂，

Z is selected from C_1-6-an alkyl group,

polycyclic heteroaromatic radicals, optionally substituted by halogen, SO₂-phenyl, C_1-6-alkyl-phenyl or phenyl optionally substituted with cyano; and

r8 and R9 are the same or different and are independently selected from H, C_1-6Alkyl, aryl-C_1-6-alkyl (wherein the alkyl moiety is optionally oxo-substituted), and heteroaryl-C_1-6-an alkyl group,

r8' is selected from H and C_1-6-an alkyl group;

r10 is C_1-6Alkyl, aryl, heterocyclyl or aryl-C_1-6-an alkyl group;

or a pharmaceutically acceptable salt thereof.

One aspect of the present invention pertains to compounds of formula 1 wherein W is H.

One aspect of the present invention relates to compounds of formula 1 wherein X is C_1-6Alkyl, especially methyl.

One aspect of the present invention relates to compounds of formula 1 wherein Y is C_1-6Alkyl, especially methyl.

One aspect of the present invention relates to compounds of formula 1 wherein R1, R2, R3 and R4 are H.

One aspect of the present invention pertains to compounds of formula 1 wherein R5 and R6 are independently selected from H and C_1-6Alkyl or together form C_4-7-a carbocyclic ring.

One aspect of the present invention relates to compounds of formula 1 wherein R5 and R6 are independently selected from H, C_1-6Alkyl, especially methyl.

One aspect of the present invention relates to compounds of formula 1 wherein Z is naphthyl, optionally substituted by 0-2 substituents selected from halogen, C_1-6-alkyl and C_1-6-substituent substitution of alkoxy.

One aspect of the present invention relates to compounds of formula 1 wherein W is H, X and Y are methyl, R1, R2, R3 and R4 are H, V is O, R5 and R6 are independently selected from H, C_1-6-alkyl, in particular methyl, and Z is naphthyl, optionally substituted by 0 to 2 substituents selected from halogen, C_1-6-alkyl and C_1-6-substituent substitution of alkoxy.

One aspect of the present invention relates to compounds of formula 1 wherein W is H, X and Y are methyl, R1, R2, R3 and R4 are H, V is S, R5 and R6 are independently selected from H, C_1-6-alkyl radicalEspecially methyl, and Z is naphthyl, optionally substituted by 0-2 substituents selected from halogen, C_1-6-alkyl and C_1-6-substituent substitution of alkoxy.

One aspect of the present invention relates to compounds of formula 1 wherein W is H, X and Y are methyl, R1, R2, R3 and R4 are H, V is O, R5 and R6 together form C_4-7-carbocycle, and Z is naphthyl, optionally substituted by 0-2 substituents selected from halogen, C_1-6-alkyl and C_1-6-substituent substitution of alkoxy.

One aspect of the present invention relates to compounds of formula 1 wherein W is H, X and Y are methyl, R1, R2, R3 and R4 are H, V is S, R5 and R6 together form C_4-7-carbocycle, and Z is naphthyl, optionally substituted by 0-2 substituents selected from halogen, C_1-6-alkyl and C_1-6-substituent substitution of alkoxy.

One aspect of the present invention relates to compounds of formula 1, wherein

W and X are the same or different and are independently selected from H, C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6Alkyl radical, C_2-6-alkenyl-C_1-6-alkyl or C_2-6-alkynyl-C_1-6-alkyl, or

y is C_1-6-alkyl, or C_3-7-cycloalkyl-C_1-6-an alkyl group;

r1 is selected from H, halogen, C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6Alkyl, acyl, OR7, SR7, NR8R9, N-acyl, N-sulfonyl, cyano OR SO₂R10；

R2 is selected from H, halogen, C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6Alkyl, acyl, OR7, SR7,NR8R9, N-acyl, N-sulfonyl, cyano or SO₂R10；

R3 is selected from H, halogen, C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6Alkyl, acyl, OR7, SR7, NR8R9, N-acyl, N-sulfonyl, cyano OR SO₂R10；

R4 is H or C_1-6-an alkyl group;

r5 and R6 are the same or different and are independently selected from H, C_1-6Alkyl, aryl or C_3-7-cycloalkyl, or

R5 and R6 together with the carbon to which they are attached may form C_4-7-carbocyclic or heterocyclic, with the proviso that R5 and R6 are not both hydrogen at the same time;

v is S or O;

z is selected from

An aryl group, a heteroaryl group,

(ii) a heteroaryl group, wherein,

a polycyclic aromatic group,

polycyclic heteroaromatic radicals, mixed aryl and non-aryl polycyclic, or

Mixed aryl and non-aryl heterocyclic rings;

r7 is C_1-6-alkyl, aryl, heteroaryl or sulfonyl;

r8 and R9 are the same or different and are independently selected from H, C_1-6Alkyl, aryl-C_1-6-alkyl, or heteroaryl-C_1-6-an alkyl group,

r10 is C_1-6Alkyl, aryl, heterocyclyl or aryl-C_1-6-an alkyl group,

or a pharmaceutically acceptable salt thereof.

One aspect of the present invention pertains to compounds of formula 1 which are

Wherein:

x is selected from C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6Alkyl radical, C_2-6-alkenyl-C_1-6-alkyl or C_2-6-alkynyl-C_1-6-an alkyl group;

y is selected from C_1-6-alkyl or C_3-7-cycloalkyl-C_1-6-an alkyl group;

R2 is selected from H, halogen, C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6Alkyl, acyl, OR7, SR7, NR8R9, N-acyl, N-sulfonyl, cyano OR SO₂R10；

R4 is selected from H or C_1-6-an alkyl group;

r5 and R6 are the same or different and are independently selected from H, C_1-6Alkyl, aryl or C_3-7-cycloalkyl-C_1-6-alkyl, or R5 and R6 together with the carbon to which they are attached may form C_3-7-carbocyclic or heterocyclic, with the proviso that R5 and R6 are not both hydrogen at the same time;

v is selected from S or O;

z is selected from aryl, heteroaryl, polycyclic aromatic groups, polycyclic heteroaromatic groups, mixed aryl and non-aryl polycyclic or mixed aryl and non-aryl heterocyclic polycyclic;

r7 is selected from C_1-6-alkyl, aryl, heteroaryl or sulfonyl;

r8 and R9 are the same or different and are independently selected from H, C_1-6Alkyl, aryl-C_1-6-alkyl or heteroaryl-C_1-6-an alkyl group;

r10 is selected from C_1-6Alkyl, aryl, heterocyclyl or aryl-C_1-6-an alkyl group;

or a pharmaceutically acceptable salt thereof.

Wherein:

x is selected from C_1-6Alkyl, aryl-C_1-6-alkyl or C_3-7-cycloalkyl-C_1-6-an alkyl group;

y is selected from C_1-6-alkyl or C_3-7-cycloalkyl-C_1-6-an alkyl group;

r1 is selected from H, halogen, C_1-6Alkyl, acyl, OR7, N-acyl, N-sulfonyl, cyano OR SO₂R10；

R2 is selected from H, halogen, C_1-6Alkyl, acyl, OR7, N-acyl, N-sulfonyl, cyano OR SO₂R10；

R3 is selected from H, halogen, C_1-6Alkyl, acyl, OR7, N-acyl, N-sulfonyl, cyano OR SO₂R10；

R4 is selected from H or C_1-6-an alkyl group;

r5 and R6 are the same or different and are independently selected from H or C_1-6Alkyl radicals, not simultaneouslyBeing hydrogen, or R5 and R6 together with the carbon to which they are attached may form C_3-6-a carbocyclic or heterocyclic ring;

v is selected from S or O;

z is selected from aryl, heteroaryl, polycyclic aromatic group or polycyclic heteroaromatic group;

r7 is selected from C_1-6-alkyl, aryl, heteroaryl or sulfonyl;

or a pharmaceutically acceptable salt thereof.

One aspect of the present invention relates to compounds of formula 1, wherein

X is selected from methyl, ethyl, methyl-d 3, ethyl-d 5, n-propyl, isopropyl, 2-hydroxyethyl, 3-hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl or oxetan-3-yl;

y is selected from methyl, ethyl, cyclopropyl, methylcyclopropyl, hydroxymethyl, (S) -1-hydroxyethyl or (R) -1-hydroxyethyl;

r1 is selected from H, halogen, C_1-6-alkyl, acyl, OR7, N-acyl, N-sulfonyl OR cyano;

r2 is selected from H, halogen, C_1-6-alkyl, acyl, OR7, N-acyl, N-sulfonyl OR cyano;

r3 is selected from H, halogen, C_1-6-alkyl, acyl, OR7, N-acyl, N-sulfonyl OR cyano;

r4 is selected from H or C_1-6-an alkyl group;

r5 and R6 are the same or different and are independently selected from H or C_1-6Alkyl, but not both hydrogen, or R5 and R6 together with the carbon to which they are attached may form C_3-6-a carbocyclic or heterocyclic ring;

v is selected from S or O;

r7 is selected from C_1-6-alkyl, aryl, heteroaryl or sulfonyl;

or a pharmaceutically acceptable salt thereof.

One aspect of the present invention relates to compounds of formula 1, wherein

X is selected from methyl, ethyl, methyl-d 3, ethyl-d 5 or 2-hydroxyethyl;

y is selected from methyl, ethyl, cyclopropyl, hydroxymethyl or (S) -1-hydroxyethyl;

r1 is selected from H, halogen, C_1-6-alkyl, acyl, N-acyl or N-sulfonyl, cyano;

r2 is selected from H, halogen, C_1-6-alkyl, acyl, N-acyl or N-sulfonyl, cyano;

r3 is selected from H, halogen, C_1-6-alkyl, acyl, N-sulfonyl or cyano;

r4 is selected from H, methyl or ethyl;

v is selected from S or O;

or a pharmaceutically acceptable salt thereof.

One aspect of the present invention relates to compounds of formula 1, wherein

X is selected from methyl, ethyl, methyl-d 3, ethyl-d 5 or 2-hydroxyethyl;

y is selected from methyl, ethyl, hydroxymethyl or (S) -1-hydroxyethyl;

r1 is selected from H, F, Cl, Br, carbamoyl (carboxyamide), N-acyl, N-sulfonyl or cyano;

r2 is selected from H, F, Cl, Br, carbamoyl, N-acyl, N-sulfonyl or cyano;

r3 is selected from H, F, Cl, Br, carbamoyl, N-acyl, N-sulfonyl or cyano;

r4 is H;

v is selected from S or O;

or a pharmaceutically acceptable salt thereof.

One aspect of the present invention relates to compounds of formula 1, wherein

X is selected from methyl, ethyl, methyl-d 3 or ethyl-d 5;

y is selected from methyl, ethyl, hydroxymethyl or (S) -1-hydroxyethyl;

r1 is selected from H, F, Cl, Br, carbamoyl, N-acyl, N-sulfonyl or cyano;

r2 is selected from H, F, Cl, Br, carbamoyl, N-acyl, N-sulfonyl or cyano;

r3 is selected from H, F, Cl, Br or cyano;

r4 is H;

v is O;

z is selected from the group consisting of 2, 5-disubstituted phenyl, 2-substituted-naphthalen-1-yl, 2, 5-disubstituted-naphthalen-1-yl, 2, 6-disubstituted-naphthalen-1-yl, 2, 7-disubstituted-naphthalen-1-yl, 5-substituted-naphthalen-1-yl, 1-substituted-1H-indazol-3-yl, benzo [ d ] isoxazol-3-yl, 4-quinolinyl, 5-quinolinyl, 3-substituted-quinolin-4-yl, 1, 2-disubstituted-indol-3-yl, 1, 6-disubstituted-1H-indazol-3-yl, and mixtures thereof, 1-substituted-1, 3-dihydro-indol-2-one-4-yl, 1, 6-1H-quinolin-2-one-4-yl, 2-substituted-2, 3-dihydro-1H-isoindol-4-yl, 2- (4-methyl-indol-1-yl) -benzonitrile or 1-substituted-indol-4-yl;

or a pharmaceutically acceptable salt thereof.

One aspect of the present invention relates to compounds of formula 1, wherein

X is selected from methyl, ethyl, methyl-d 3 or ethyl-d 5;

y is selected from methyl, ethyl, hydroxymethyl or (S) -1-hydroxyethyl;

r1 is selected from H, F, Cl, Br, carbamoyl, N-acyl, N-sulfonyl or cyano;

r2 is selected from H, F, Cl, Br, carbamoyl, N-acyl, N-sulfonyl or cyano;

r3 is selected from H, F, Cl, Br or cyano;

r4 is H;

r5 and R6 are methyl or H, but not both hydrogen;

v is O;

z is selected from the group consisting of 5-bromo-2-methoxynaphthalen-1-yl, 6-bromo-2- (d 3-methoxy) -naphthalen-1-yl, 6-bromo-2-methoxy-naphthalen-1-yl, 3-methoxy-quinolin-4-yl, 2- (2,2, 2-trifluoroethoxy) naphthalen-1-yl, 2-difluoromethoxy-naphthalen-1-yl, m,

Or a pharmaceutically acceptable salt thereof.

One aspect of the present invention relates to compounds of formula 1, wherein

X is selected from methyl, ethyl, methyl-d 3 or ethyl-d 5;

y is selected from methyl, ethyl, hydroxymethyl or (S) -1-hydroxyethyl;

r1 is selected from H, F, Cl, Br, carbamoyl, N-acyl, N-sulfonyl or cyano;

r2 is selected from H, F, Cl, Br, carbamoyl, N-acyl, N-sulfonyl or cyano;

r3 is selected from H, F, Cl, Br or cyano;

r4 is H;

r5 and R6 together form a ring selected fromOr

V is O;

Or a pharmaceutically acceptable salt thereof.

One aspect of the present invention relates to compounds of formula 1, wherein

X is selected from methyl, ethyl, methyl-d 3 or ethyl-d 5;

y is selected from methyl, ethyl, hydroxymethyl or (S) -1-hydroxyethyl;

r1 is selected from H, F, Cl, Br, carbamoyl, N-acyl, N-sulfonyl or cyano;

r2 is selected from H, F, Cl, Br, carbamoyl, N-acyl, N-sulfonyl or cyano;

r3 is selected from H, F, Cl, Br or cyano;

r4 is H;

r5 is

R6 is

V is O;

Or a pharmaceutically acceptable salt thereof.

One aspect of the present invention relates to compounds of formula 1, wherein

X is selected from methyl, ethyl, methyl-d 3 or ethyl-d 5;

y is selected from methyl, ethyl, hydroxymethyl or (S) -1-hydroxyethyl;

r1 is selected from H, F, Cl, Br, carbamoyl, N-acyl, N-sulfonyl or cyano;

r2 is selected from H, F, Cl, Br, carbamoyl, N-acyl, N-sulfonyl or cyano;

r3 is selected from H, F, Cl, Br or cyano;

r4 is H;

r5 is

R6 is

V is O;

Or a pharmaceutically acceptable salt thereof.

One aspect of the present invention relates to compounds of formula 1, wherein said compounds are selected from

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -4-oxo-4, 5-dihydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,1' -cyclohexane]-3-yl) -2- (methylamino) propionamide hydrochloride;

6-methoxy-5- (((S) -3- ((S) -2- (methylamino) propionamido) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-5(4H) -yl) methyl) -2-naphthoic acid trifluoroacetate salt;

6-methoxy-5- (((S) -3- ((S) -2- (methylamino) propionamido) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-5(4H) -yl) methyl) -N- (methylsulfonyl) -2-naphthamide trifluoroacetate salt;

(R) -N- [ (S) -5- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -2, 2-dimethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-3-yl]-2-methylamino-propionamide hydrochloride;

(S) -N- (5-benzyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Thiaazepines-3-yl) -2-methylaminopropionamide hydrochloride;

n- (5-benzyl-1, 1, 4-trioxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Thiaazepines-3-yl) -2- (S) - (methylamino) propionamide hydrochloride;

n- (5- (4-phenyl-butyl) -1,1, 4-trioxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Thiaazepines-3-yl) -2- (S) - (methylamino) propionamide hydrochloride;

n- (5-biphenyl-3-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Thiaazepines-3-yl) -2- (S) -methylamino-propionamide hydrochloride;

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3R) -8, 9-difluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b)][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride;

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -8, 9-difluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b)][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride;

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3R) -9-fluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride;

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -9-fluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride, and

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3R) -9-fluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) butanamide hydrochloride。

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -9-fluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) butanamide hydrochloride;

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -8-fluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride;

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -8-fluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) butanamide hydrochloride;

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (2-hydroxyethylamino) propionamide;

(2S) -N- (5- ((3-methoxyquinoline-N-oxide-4-yl) methyl) - (3S) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide;

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methyl-d 3-amino) propionamide hydrochloride;

(2S) -N- (5- ((6-bromo-2- (methoxy-d 3) -naphthalen-1-yl) methyl) - (3S) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methyl-d 3-amino) propionamide hydrochloride;

(R) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2-aminopropionamide;

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2-aminopropionamide;

(S) -N- { (R) -9- [2- (2-methoxy-ethoxy) -acetylamino]-5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Thiaazepines-3-yl } -2-methylamino-propionamide hydrochloride;

1-acetyl-piperidine-4-carboxylic acid [ (R) -3- ((S) -2-methylamino-propionylamino) -5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Thiaazepines-9-yl]-amides, and

5-oxo-hexanoic acid [ (R) -3- ((S) -2-methylamino-propionylamino) -5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-9-yl]-amide hydrochloride.

3,4, 5-trimethoxy-N- [ (R) -3- ((S) -2-methylamino-propionylamino) -5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Thiaazepines-9-yl]-benzamide hydrochloride;

6-oxo-heptanoic acid [ (R) -3- ((S) -2-methylamino-propionylamino) -5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-9-yl]-amide hydrochloride;

(S) -N- ((R) -9-amino-5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b)][1,4]Thiaazepines-3-yl) -2-methylamino-propionamide hydrochloride;

n- [ (R) -3- ((S) -2-methylamino-propionylamino) -5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b)][1,4]Thiaazepines-9-yl]-benzamide hydrochloride;

(S) -N- [ (S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -2-methylamino-propionamide trifluoroacetate;

(S) -N- [ (S) -9- (6-cyclopropyl-2-methoxy-naphthalen-1-ylmethyl) -8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -2-methylamino-propionamide trifluoroacetate;

6-methoxy-5- (((S) -3)- ((S) -2- (methylamino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -2-naphthoic acid methyl ester trifluoroacetate salt;

6-methoxy-5- (((S) -3- ((S) -2- (methylamino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -2-naphthoic acid trifluoroacetate salt;

6-methoxy-7- [ (S) -7- ((S) -2-methylamino-propionylamino) -8-oxo-7, 8-dihydro-6H-5-oxa-9-aza-benzocycloheptatrien-9-ylmethyl ] -naphthalene-2-carboxylic acid (2-hydroxy-ethyl) -methyl-amide;

3- ({ 6-methoxy-7- [ (S) -7- ((S) -2-methylamino-propionylamino) -8-oxo-7, 8-dihydro-6H-5-oxa-9-aza-benzocycloheptatrien-9-ylmethyl ] -naphthalene-2-carbonyl } -amino) -propionic acid trifluoroacetate;

6-methoxy-7- [ (S) -7- ((S) -2-methylamino-propionylamino) -8-oxo-7, 8-dihydro-6H-5-oxa-9-aza-benzocycloheptatrien-9-ylmethyl ] -naphthalene-2-carboxylic acid dimethylamide trifluoroacetate, and

(S) -N- [ (S) -9- (7-bromo-3-methoxy-naphthalen-2-ylmethyl) -3-methyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -2-methylamino-propionamide trifluoroacetate.

(2S,3R) -2-amino-N- [ (S) -9- (7-bromo-3-methoxy-naphthalen-2-ylmethyl) -3-methyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -3-hydroxy-butyramide trifluoroacetate;

(2S,3S) -2-amino-N- [ (S) -9- (7-bromo-3-methoxy-naphthalen-2-ylmethyl) -3-methyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-azabenzocycloheptatrien-7-yl ] -3-hydroxy-butyramide trifluoroacetate;

(S) -N- ((2S,3S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -2, 8-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide trifluoroacetate;

5- (((2S,3S) -2, 8-dimethyl-3- ((S) -2- (methylamino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid methyl ester trifluoroacetate salt;

(2S,3S) -2-amino-N- [ (6S,7S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -3, 6-dimethyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl ] -3-hydroxy-butyramide trifluoroacetate;

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-7- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide trifluoroacetate;

(S) -N- [ (6S,7S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -6-methyl-8-oxo-2-trifluoromethyl-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -2-methylamino-propionamide trifluoroacetate;

(S) -2-methylamino-N- [ (S) -9- (2-methyl-naphthalen-1-ylmethyl) -8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -propionamide;

(S) -N- ((S) -5- (2-chlorobenzyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide;

(S) -N- ((S) -5- (3-chlorobenzyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide;

(S) -N- ((S) -5- (4-chlorobenzyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide;

(S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- ((S) -2- (methylamino) propanamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-9-carboxylic acid trifluoroacetate salt, and

3- { [ (S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -7- ((S) -2-methylamino-propionylamino) -8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatriene-4-carbonyl ] -amino } -propionic acid trifluoroacetate.

4- ({ [ (S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -7- ((S) -2-methylamino-propionylamino) -8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatriene-4-carbonyl ] -amino } -methyl) -benzoic acid methyl ester;

(S) -5- ((6-carboxy-2-methoxynaphthalen-1-yl) methyl) -3- ((S) -2- (methylamino) propanamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-9-carboxylic acid trifluoroacetate salt;

5- (((S) -9- ((2-hydroxyethyl) (methyl) carbamoyl) -3- ((S) -2- (methylamino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid trifluoroacetate salt;

s) -5- ((4-bromonaphthalen-1-yl) methyl) -3- ((S) -2- (methylamino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-9-carboxylic acid trifluoroacetate salt;

(S) -N- ((S) -5- ((4-bromonaphthalen-1-yl) methyl) -9- (4- (2-hydroxyethyl) piperazine-1-carbonyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide;

(S) -N- ((S) -5- ((4-bromonaphthalen-1-yl) methyl) -9- (4- (3-hydroxypropyl) piperazine-1-carbonyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide;

(S) -N- ((S) -5- ((2-chloro-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide;

(S) -N- ((S) -5- ((1- (2-cyanophenyl) -1H-indol-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide;

(S) -N- ((S) -5- ((2-chloro-1- (phenylsulfonyl) -1H-indol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide;

(S) -N- ((S) -5- ((2- (methylsulfonyl) isoindolin-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride;

(S) -N- ((S) -5- ((6-fluoro-1-methyl-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide;

(S) -N- [ (S) -9- (1-benzyl-2-chloro-1H-indol-3-ylmethyl) -8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -2-methylamino-propionamide, and

(S) -N- ((S) -5- ((1-ethyl-2-oxoindolin-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide.

(S) -2-amino-N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) propionamide;

(S) -N- ((S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide trifluoroacetate;

(S) -N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl)) Methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (oxetan-3-ylamino) propanamide;

(S) -N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (2-hydroxy-2-methylpropylamino) propionamide;

(S) -N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (2-hydroxyethylamino) propionamide;

(S) -N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide;

(S) -N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (ethyl-d 5-amino) propionamide;

(S) -N- ((S) -5- ((1- (2-cyanophenyl) -6-fluoro-1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (ethylamino) propionamide;

s) -N- ((S) -5- ((6-bromo-1- (2-cyanobenzene)Yl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide trifluoroacetate;

(S) -N- ((S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide;

(2S) -N- ((2S,3S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (ethylamino) propionamide trifluoroacetate salt;

(S) -N- ((R) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -2, 2-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Thiaazepines-3-yl) -2- (ethylamino) propionamide, and

(S) -N- ((2S,3S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide.

(S) -N- ((2S,3S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (ethylamino) propionamide;

(S) -N- ((S) -8-bromo-5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide trifluoroacetate;

(S) -N- ((S) -8-cyano-5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide 2,2, 2-trifluoroacetate salt;

3-cyano-4- (3- (((2S,3S) -2-methyl-3- ((S) -2- (methylamino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazol-1-yl) benzoic acid trifluoroacetate salt;

3-cyano-N-ethyl-4- (3- (((2S,3S) -2-methyl-3- ((S) -2- (methylamino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazol-1-yl) benzamide trifluoroacetate salt;

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) butanamide hydrochloride;

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (2-hydroxyethylamino) butanamide trifluoroacetate;

(S) -N- ((S) -5- (benzo [ d)]Isoxazol-3-ylmethyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride;

(S) -N- ((S) -5- ((2- (difluoromethoxy) naphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride;

(S) -N- ((R) -5- ((2- (difluoromethoxy) naphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride;

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9-fluoro-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride, and

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride.

(S) -2- (methylamino) -N- ((S) -5- ((2-methylnaphthalen-1-yl) methyl) -4-oxo-9- (trifluoromethyl)-2,3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-3-yl) propionamide hydrochloride;

(S) -N- ((S) -5- (benzo [ d)]Isoxazol-3-ylmethyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride;

(S) -N- ((S) -9-bromo-5- ((2-methylnaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride;

(S) -5- ((2-methoxynaphthalen-1-yl) methyl) -3- ((S) -2- (methylamino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-9-carboxylic acid trifluoroacetate salt, and

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride.

One aspect of the invention relates to compounds of formula 1 wherein W is H and X is methyl, methyl-d 3, ethyl-d 5, n-propyl, 2-hydroxyethyl, cyclobutyl or oxetan-3-yl.

In another aspect, the invention relates to a compound of formula 1, wherein Y is methyl, ethyl, hydroxymethyl, or 1-hydroxyethyl.

In another aspect, the invention relates to formula 1Compound wherein R1 is H, C_1-6-alkyl, cyano, or halogen.

In another aspect, the invention relates to compounds of formula 1 wherein R2 is H, C_1-6-alkyl, halogen, cyano, or alkoxy.

In another aspect, the invention relates to compounds of formula 1 wherein R3 is H, C_1-6-alkyl, halogen, cyano, or C_1-6-alkoxy groups. In another aspect, the invention relates to compounds of formula 1 wherein R4 is H or C_1-6-an alkyl group.

In another aspect, the invention relates to compounds of formula 1 wherein Z is aryl or aryl-C_1-6-alkyl-bicyclic.

Another aspect of the invention relates to compounds of formula II:

wherein:

x is selected from C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6Alkyl radical, C_2-6-alkenyl C_1-6-alkyl or C_2-6-alkynyl C_1-6-an alkyl group; y is selected from C_1-6-alkyl or C_3-7-cycloalkyl-C_1-6-an alkyl group; r1 is selected from H, halogen, C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6Alkyl, acyl, OR7, SR7, NR8R9, N-acyl, N-sulfonyl, cyano OR SO₂R10; r2 is selected from H, halogen, C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6Alkyl, acyl, OR7, SR7, NR8R9, N-acyl, N-sulfonyl, cyano OR SO₂R10; r3 is selected from H, halogen, C_1-6Alkyl, aryl-C_1-6Alkyl radical, C_3-7-cycloalkyl-C_1-6Alkyl, acyl, OR7, SR7, NR8R9, N-acyl, N-sulfoAcyl, cyano, or SO₂R10; r4 is selected from H or C_1-6-an alkyl group; r5 and R6 are the same or different and are independently selected from H, C_1-6Alkyl, aryl or C_3-7-cycloalkyl, or R5 and R6 together with the carbon to which they are attached may form C_3-7-carbocyclic or heterocyclic, with the proviso that R5 and R6 are not both hydrogen at the same time; v is selected from S or O; z is selected from aryl, heteroaryl, polycyclic aromatic groups, polycyclic heteroaromatic groups, mixed aryl and non-aryl polycyclic or mixed aryl and non-aryl heterocyclic polycyclic; r7 is selected from C_1-6-alkyl, aryl, heteroaryl or sulfonyl; r8 and R9 are the same or different and are independently selected from H, C_1-6Alkyl, aryl-C_1-6-alkyl or heteroaryl-C_1-6-an alkyl group; r10 is selected from C_1-6Alkyl, aryl, heterocyclyl or aryl-C_1-6-an alkyl group;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula III:

wherein:

x is selected from C_1-6Alkyl, aryl-C_1-6-alkyl or C_3-7-cycloalkyl-C_1-6-an alkyl group; y is selected from C_1-6-alkyl or C_3-7-cycloalkyl-C_1-6-an alkyl group; r1 is selected from H, halogen, C_1-6Alkyl, acyl, OR7, N-acyl, N-sulfonyl, cyano OR SO₂R10; r2 is selected from H, halogen, C_1-6Alkyl, acyl, OR7, N-acyl, N-sulfonyl, cyano OR SO₂R10; r3 is selected from H, halogen, C_1-6Alkyl, acyl, OR7, N-acyl, N-sulfonyl, cyano OR SO₂R10; r4 is selected from H or C_1-6-an alkyl group; r5 and R6 are the same or different and are independently selected from H or C_1-6Alkyl, but not both hydrogen, or R5 and R6 together with the carbon to which they are attached may form C_3-6-a carbocyclic or heterocyclic ring; v is selected from SOr O; z is selected from aryl, heteroaryl, polycyclic aromatic group or polycyclic heteroaromatic group; r7 is selected from C_1-6-alkyl, aryl, heteroaryl or sulfonyl; r10 is selected from C_1-6Alkyl, aryl, heterocyclyl or aryl-C_1-6-an alkyl group;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula III

Wherein:

x is selected from methyl, ethyl, methyl-d 3, ethyl-d 5, n-propyl; isopropyl, 2-hydroxyethyl, 3-hydroxypropyl, cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, or oxetan-3-yl;

y is selected from methyl, ethyl, cyclopropyl, hydroxymethyl, (S) -1-hydroxyethyl or (R) -1-hydroxyethyl; r1 is selected from H, halogen, C_1-6-alkyl, acyl, OR7, N-acyl, N-sulfonyl OR cyano; r2 is selected from H, halogen, C_1-6-alkyl, acyl, OR7, N-acyl, N-sulfonyl OR cyano; r3 is selected from H, halogen, C_1-6-alkyl, acyl, OR7, N-acyl, N-sulfonyl OR cyano; r4 is selected from H or C_1-6-an alkyl group; r5 and R6 are the same or different and are independently selected from H or C_1-6Alkyl, but not both hydrogen, or R5 and R6 together with the carbon to which they are attached may form C_3-6-a carbocyclic or heterocyclic ring; v is selected from S or O; z is selected from aryl, heteroaryl, polycyclic aromatic group or polycyclic heteroaromatic group; r7 is selected from C_1-6-alkyl, aryl, heteroaryl or sulfonyl;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula III

Wherein:

x is selected from methyl, ethyl, methyl-d 3, ethyl-d 5 or 2-hydroxyethyl; y is selected from methyl, ethyl, cyclopropyl, hydroxymethyl or (S) -1-hydroxyethyl; r1 is selected from H, halogen, C_1-6Alkyl, acyl, N-acylN-sulfonyl or cyano; r2 is selected from H, halogen, C_1-6-alkyl, acyl, N-sulfonyl or cyano; r3 is selected from H, halogen, C_1-6-alkyl, acyl, N-sulfonyl or cyano; r4 is selected from H, methyl or ethyl; r5 and R6 are the same or different and are independently selected from H or C_1-6Alkyl, but not both hydrogen, or R5 and R6 together with the carbon to which they are attached may form C_3-6-a carbocyclic or heterocyclic ring; v is selected from S or O; z is selected from aryl, heteroaryl, polycyclic aromatic group or polycyclic heteroaromatic group;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention relates to compounds of formula III

Wherein:

x is selected from methyl, ethyl, methyl-d 3, ethyl-d 5 or 2-hydroxyethyl; y is selected from methyl, ethyl, hydroxymethyl or (S) -1-hydroxyethyl; r1 is selected from H, F, Cl, Br, formamide, N-acyl, N-sulfonyl or cyano; r2 is selected from H, F, Cl, Br, formamide, N-acyl, N-sulfonyl or cyano; r3 is selected from H, F, Cl, Br, formamide, N-acyl, N-sulfonyl or cyano; r4 is H; r5 and R6 are the same or different and are independently selected from H or C_1-6Alkyl, but not both hydrogen, or R5 and R6 together with the carbon to which they are attached may form C₃-C₆A carbocyclic or heterocyclic ring; v is selected from S or O; z is selected from aryl, heteroaryl, polycyclic aromatic group or polycyclic heteroaromatic group;

or a pharmaceutically acceptable salt thereof.

Yet another aspect of the invention relates to compounds of formula III

Wherein:

x is selected from methyl, ethyl, methyl-d 3 or ethyl-d 5; y is selected from methyl, ethyl, hydroxymethyl or (S) -1-hydroxyethyl; r1 is selected from H, F, Cl, Br, formamide, N-acyl, N-sulfonyl or cyano; r2 is selected from H, F, Cl, Br, formamide, N-acyl, N-sulfonyl or cyano; r3 is selected from H, F, Cl, Br or cyano;r4 is H; r5 and R6 are the same or different and are independently selected from H or C_1-6Alkyl, but not both hydrogen, or R5 and R6 together with the carbon to which they are attached may form C_3-6-a carbocyclic or heterocyclic ring; v is O; z is selected from the group consisting of 2, 5-disubstituted phenyl, 2-substituted-naphthalen-1-yl, 2, 5-disubstituted-naphthalen-1-yl, 2, 6-disubstituted-naphthalen-1-yl, 2, 7-disubstituted-naphthalen-1-yl, 5-substituted-naphthalen-1-yl, 1-substituted-1H-indazol-3-yl, benzo [ d]Isoxazol-3-yl, 4-quinolyl, 5-quinolyl, 3-substituted-quinolin-4-yl, 1, 2-disubstituted-indol-3-yl, 1, 6-disubstituted-1H-indazol-3-yl, 1-substituted-1, 3-dihydro-indol-2-one-4-yl, 1, 6-1H-quinolin-2-one-4-yl, 2-substituted-2, 3-dihydro-1H-isoindol-4-yl, 2- (4-methyl-indol-1-yl) -benzonitrile, or 1-substituted-indol-4-yl;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention relates to compounds of formula III

Wherein:

x is selected from methyl, ethyl, methyl-d 3 or ethyl-d 5; y is selected from methyl, ethyl, hydroxymethyl or (S) -1-hydroxyethyl; r1 is selected from H, F, Cl, Br, formamide, N-acyl, N-sulfonyl or cyano; r2 is selected from H, F, Cl, Br, formamide, N-acyl, N-sulfonyl or cyano; r3 is selected from H, F, Cl, Br or cyano; r4 is H; r5 and R6 are methyl or H, but not both hydrogen; v is O; z is selected from the group consisting of 5-bromo-2-methoxynaphthalen-1-yl, 6-bromo-2- (d 3-methoxy) -naphthalen-1-yl, 6-bromo-2-methoxy-naphthalen-1-yl, 3-methoxy-quinolin-4-yl, 2- (2,2, 2-trifluoroethoxy) naphthalen-1-yl, 2-difluoromethoxy-naphthalen-1-yl, m,

Or a pharmaceutically acceptable salt thereof.

Yet another aspect of the invention relates to compounds of formula III

Wherein:

x is selected from methyl, ethyl, methyl-d 3 or ethyl-d 5; y is selected from methyl, ethyl, hydroxymethyl or (S) -1-hydroxyethyl; r1 is selected from H, F, Cl, Br, formamide, N-acyl, N-sulfonyl or cyano; r2 is selected from H, F, Cl, Br, formamide, N-acyl, N-sulfonyl or cyano; r3 is selected from H, F, Cl, Br or cyano; r4 is H; r5 and R6 together form a ring selected fromOrV is O; z is selected from the group consisting of 5-bromo-2-methoxynaphthalen-1-yl, 6-bromo-2- (d 3-methoxy) -naphthalen-1-yl, 6-bromo-2-methoxy-naphthalen-1-yl, 3-methoxy-quinolin-4-yl, 2- (2,2, 2-trifluoroethoxy) naphthalen-1-yl, 2-difluoromethoxy-naphthalen-1-yl, m,

Or a pharmaceutically acceptable salt thereof.

Another aspect of the invention relates to compounds of formula III

Wherein:

x is selected from methyl, ethyl, methyl-d 3 or ethyl-d 5; y is selected from methyl, ethyl, hydroxymethyl or (S) -1-hydroxyethyl; r1 is selected from H, F, Cl, Br, formamide, N-acyl, N-sulfonyl or cyano; r2 is selected from H, F, Cl, Br, formamide, N-acyl, N-sulfonyl or cyano; r3 is selected from H, F, Cl, Br or cyano; r4 is H; r5 isR6 isV is O; z is selected from the group consisting of 5-bromo-2-methoxynaphthalen-1-yl, 6-bromo-2- (d 3-methoxy) -naphthalen-1-yl, 6-bromo-2-methoxy-naphthalen-1-yl, 3-methoxy-quinolin-4-yl, 2- (2,2, 2-trifluoroethoxy) naphthalen-1-yl, 2-difluoromethoxy-naphthalen-1-yl, m,

Or a pharmaceutically acceptable salt thereof.

Another aspect of the invention relates to compounds of formula III

Wherein:

Or a pharmaceutically acceptable salt thereof.

Another aspect of the invention relates to compounds of the formula

(R) -N- [ (S) -5- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -2, 2-dimethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-3-yl]-2-methylamino-propionamide hydrochloride

n- (5-biphenyl-3-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-3-yl) -2- (S) -methylamino-propionamide hydrochloride;

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -9-fluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide saltAn acid salt;

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3R) -9-fluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) butanamide hydrochloride;

1-acetyl-piperidine-4-carboxylic acid [ (R) -3- ((S) -2-methylamino-propionylamino) -5-naphthalen-1-ylMethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Thiaazepines-9-yl]-an amide;

5-oxo-hexanoic acid [ (R) -3- ((S) -2-methylamino-propionylamino) -5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Thiaazepines-9-yl]-amide hydrochloride;

6-methoxy-5- (((S) -3- ((S) -2- (methylamino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -2-naphthoic acid methyl ester trifluoroacetate salt;

6-methoxy-7- [ (S) -7- ((S) -2-methylamino-propionylamino) -8-oxo-7, 8-dihydro-6H-5-oxa-9-aza-benzocycloheptatrien-9-ylmethyl ] -naphthalene-2-carboxylic acid dimethylamide trifluoroacetate;

(S) -N- [ (S) -9- (7-bromo-3-methoxy-naphthalen-2-ylmethyl) -3-methyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -2-methylamino-propionamide trifluoroacetate;

(S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- ((S) -2- (methylamino) propanamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-9-carboxylic acid trifluoroacetate salt;

3- { [ (S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -7- ((S) -2-methylamino-propionylamino) -8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatriene-4-carbonyl ] -amino } -propionic acid trifluoroacetate;

(S) -N- [ (S) -9- (1-benzyl-2-chloro-1H-indol-3-ylmethyl) -8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -2-methylamino-propionamide;

(S) -N- ((S) -5- ((1-ethyl-2-oxoindolin-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide;

(S) -N- ((S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl)) Methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide trifluoroacetate;

(S) -N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (oxetan-3-ylamino) propanamide;

(S) -N- ((S) -5- ((1- (2-cyanobenzene)Yl) -6-fluoro-1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (ethylamino) propionamide;

s) -N- ((S) -5- ((6-bromo-1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide trifluoroacetate;

(S) -N- ((R) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -2, 2-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Thiaazepines-3-yl) -2- (ethylamino) propionamide;

(S) -N- ((2S,3S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide;

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9-fluoro-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride;

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo[b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride;

(S) -2- (methylamino) -N- ((S) -5- ((2-methylnaphthalen-1-yl) methyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) propionamide hydrochloride;

Preferred aspects of the invention are compounds of the formula:

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -2, 2-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride;

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-4, 5-dihydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,3' -oxetane]-3-yl) -2- (methylamino) propionamide 2,2, 2-trifluoroacetate salt;

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -2- (methoxymethyl) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride;

(2S,3S) -2-amino-N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -3-hydroxybutyramide hydrochloride;

(S) -N- ((S) -5- ((3-methoxyquinolin-4-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide dihydrochloride;

(S) -2- (methylamino) -N- ((S) -4-oxo-5- (quinolin-4-ylmethyl) -2',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) propionamide dihydrochloride;

(S) -2- (methylamino) -N- ((S) -4-oxo-5- ((2- (2,2, 2-trifluoroethoxy) naphthalen-1-yl) methyl) -2',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) propionamide hydrochloride;

(S) -N- ((S) -8-cyano-5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide 2,2, 2-trifluoroacetate salt, and

3-cyano-N-ethyl-4- (3- (((2S,3S) -2-methyl-3- ((S) -2- (methylamino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazol-1-yl) benzamide trifluoroacetate salt.

A particular aspect of the invention relates to compounds as described herein for use as therapeutically active substances.

A particular aspect of the invention relates to a compound according to any one of claims 1 to 20 for use in the treatment or prevention of cancer.

A particular aspect of the invention relates to pharmaceutical compositions comprising a compound described herein and a therapeutically inert carrier.

A particular aspect of the invention relates to the use of a compound described herein for the treatment or prevention of cancer.

A particular aspect of the invention relates to the use of a compound described herein for the manufacture of a medicament for the treatment or prevention of cancer.

A particular aspect of the invention relates to a method of treating or preventing cancer, the method comprising administering an effective amount of a compound described herein.

Definition of

The following terms are used herein with the following definitions.

The term "alkyl" refers to straight or branched chain saturated hydrocarbon groups having from 1 to about 12 carbon atoms, including groups of from 1 to about 7 carbon atoms and from 1 to 6 carbon atoms. In particular embodiments, the alkyl substituent may be a lower alkyl substituent. The term "lower alkyl" refers to a group having 1 to 6 carbon atoms (C)_1-6Alkyl), preferably 1 to 4 carbon atoms (C)_1-4-alkyl) alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and sec-pentyl. The alkyl group may optionally be enriched with deuterium, e.g. -CD₃、-CD₂CD₃And the like.

The term "alkenyl" as used herein means containing at least one double bond and having 2 to 6 carbon atoms (C)_2-6Alkenyl), preferably 2 to 4 carbon atoms (C)_2-4-alkenyl) unsaturated linear or branched aliphatic hydrocarbons. Examples of such "alkenyl groups" are vinyl (vinyl or ethenyl), allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.

“C_2-6-alkenyl-C_1-6-alkyl "means attached to C as defined herein_2-6-C as defined herein of alkenyl_1-6-an alkyl group.

"alkoxy or lower alkoxy" refers to any of the aforementioned lower alkyl groups attached to the remainder of the molecule (RO-) through an oxygen atom. C_1-6-alkoxy means an alkoxy group wherein the alkyl moiety has from 1 to 6 carbon atoms. Typical lower alkoxy groups include methoxy, ethoxy, isopropoxy or propoxy, butyloxy and the like. Also included within the meaning of alkoxy are multiple alkoxy side chains such as ethoxyethoxy, methoxyethoxy, methoxyethoxyethoxy, and the like, as well as substituted alkoxy side chains such as dimethylaminoethoxy, diethylaminoethoxy, dimethoxy-phosphorylmethoxy, and the like.

The term "alkynyl" as used herein means containing a triple bond and having 2 to 6 carbon atoms (C)_2-6Alkynyl), preferably 2 to 4 carbon atoms (C)_2-4-alkynyl) unsaturated linear or branched aliphatic hydrocarbons. Examples of such "alkynyl groups" are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.

“C_2-6-alkynyl-C_1-6-alkyl "means attached to C as defined herein_2-6-C as defined herein of alkynyl_1-6-an alkyl group.

"acyl" substituents include groups of the formula-C (O) R11, wherein R11 is H, alkyl, aryl, aralkyl, heterocyclyl, e.g., acetyl, propionyl, nicotinyl (nicotinoyl), and the like.

"Sulfonyl" substituents include those of the formula-SO₂The group of R11, for example, methanesulfonyl, benzenesulfonyl, toluenesulfonyl and the like.

Amino means the radical-NH₂。

"aryl" means a monocyclic, bicyclic or polycyclic aromatic carbocyclic or heterocyclic group, preferably an aromatic ring system of 6 to 14 members. Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, xylyl, pyridyl, quinolinyl, pyrimidinyl, imidazole, thiazole, and tetrazolyl. The aryl group may be optionally substituted with: for example, lower alkyl, cycloalkyl (e.g. cyclopropyl), trihalo-lower alkyl (e.g. trifluoromethyl), hydroxy, alkoxy. When two or more substituents are present on an aryl or heteroaryl ring, they may also be present as fused rings. The fused rings include, but are not limited to, 3, 4-methylenedioxyphenyl and 3, 4-ethylenedioxyphenyl.

"aryl" means a monovalent monocyclic or bicyclic, aromatic carbocyclic hydrocarbon radical, preferably an aromatic ring system of 6 to 10 members. Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl. A specific aryl group is phenyl.

"aryl-C_1-6-alkyl "refers to a C as defined herein attached to an aryl group as defined herein_1-6-an alkyl group.

“C_3-7-cycloalkyl-C_1-6-alkyl "means that the linker is as defined herein C_3-7-C as defined herein of cycloalkyl_1-6-an alkyl group.

"carbocyclic" refers to a carbon-containing ring.

"carboxy" refers to a monovalent group-COOH. Carboxy lower alkyl means-COOR, where R is lower alkyl. "carboxy lower alkoxy" refers to-COOROH, where R is lower alkyl.

Carbonyl means a groupWherein R' and R "can independently be any of a number of chemical groups, including alkyl groups.

The term "cycloalkyl" as used herein refers to any stable monocyclic or polycyclic ring system consisting solely of carbon atoms wherein either ring is saturated, and the term "cycloalkenyl" refers to any stable monocyclic or polycyclic ring system consisting solely of carbon atoms wherein at least one ring is partially unsaturated. Specific cycloalkyl radicals are "C_3-7-cycloalkyl ", which is a cycloalkyl having 3 to 7 carbons. Examples of cycloalkyl groups include, but are not limited toLimited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicycloalkyl (including bicyclooctane, e.g. [2.2.2 ]]Bicyclo-octane or [3.3.0]Bicyclooctane), bicyclononane (e.g. [4.3.0 ]]Bicyclononane), and bicyclodecanes (e.g. [4.4.0 ]]Bicyclodecane (decahydronaphthalene), or spiro compounds. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl or cyclohexenyl.

The term "C" as used herein_3-7-cycloalkyl-C_1-6-alkyl "means attached to C_1-6C of an alkyl radical_3-7-a cycloalkyl group.

The term "halogen" as used herein refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), preferably fluorine and chlorine.

"halo-C_1-6-alkyl "means C as described herein substituted by 1 or 2 halogen groups_1-6-an alkyl group.

"heteroaryl" refers to aromatic heterocyclic systems containing up to two rings. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridyl, pyrazinyl, oxazolyl, thiazolyl (thiaxolyl), quinolinyl, pyrimidinyl, imidazole, substituted or unsubstituted triazolyl, and substituted or unsubstituted tetrazolyl.

Where aryl or heteroaryl is bicyclic, it is understood that one ring may be aryl and the other heteroaryl, with both rings substituted or unsubstituted.

"heteroatom" means an atom selected from N, O and S.

"heterocycle" or "heterocyclyl" refers to a substituted or unsubstituted 5-to 8-membered, monocyclic or bicyclic, non-aromatic hydrocarbon in which 1 to 3 carbon atoms are replaced by a heteroatom selected from nitrogen, oxygen, or sulfur atoms. Examples include pyrrolidin-2-yl; pyrrolidin-3-yl; a piperidinyl group; morpholin-4-yl, and the like, which may also be substituted.

Hydroxyl is a prefix indicating the presence of a monovalent-O-H group.

"hydroxy-C_1-6-alkyl "means C as described herein substituted by 1 or 2 hydroxy groups_1-6-an alkyl group.

"lower" in "lower alkenyl" means that the group has 1 to 6 carbon atoms.

"Mixed aryl and non-aryl polycyclic" refers to a 2-ring system wherein one ring is aryl as described herein and the other ring is cycloalkyl as described herein.

"Mixed aryl and non-aryl heterocyclic polycyclic" refers to a 2 ring system wherein one ring is aryl as described herein and the other ring is heterocyclyl as described herein.

"nitro" means-NO₂。

Oxo means a group ═ O.

"substituted" in, for example, substituted alkyl means that the substituent may be present at one or more positions, and that the substituent at each substitution position is independently selected from the indicated options, unless otherwise specified. The term "optionally substituted" refers to the following: one or more hydrogen atoms of a chemical group (having one or more hydrogen atoms) may, but need not, be substituted with another substituent. In the specification indicated, various groups may be substituted with preferably 1 to 3 substituents independently selected from H, carboxy, amido (amidi), hydroxy, alkoxy, substituted alkoxy, sulfide, sulfone, sulfonamide, sulfoxide, halogen, nitro, amino, substituted amino, lower alkyl, substituted lower alkyl, oxyalkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, acyl, acylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic.

By "pharmaceutically acceptable" (e.g., pharmaceutically acceptable carriers, excipients, etc.) is meant pharmacologically acceptable and substantially non-toxic to a subject to which a particular compound is administered.

"pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts which retain the biological effects and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric and nitric acids, and those derived from organic acids such as p-toluenesulfonic, salicylic, methanesulfonic, oxalic, succinic, citric, malic, lactic, fumaric, trifluoroacetic acids, and the like. Examples of base addition salts include those derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides (e.g., tetramethylammonium hydroxide). Chemical modifications to convert a pharmaceutical compound (i.e., drug) into a salt are well known to pharmaceutical chemists to achieve improved physical and chemical stability, hygroscopicity, flowability, and solubility of the compound. See, e.g., Ansel et al, Pharmaceutical document Forms and Drug Delivery Systems (1995) atpgs.456-457.

The term "polycyclic aromatic group" refers to an aromatic group as described herein containing 2 or more aromatic rings.

The term "polycyclic heteroaromatic group" refers to a heteroaryl group as described herein containing 2 or more aromatic rings.

The compounds of the invention may be administered in any suitable manner, including orally, topically (including buccally and sublingually), rectally, intravaginally, transdermally, parenterally, subcutaneously, intraperitoneally, intrapulmonary, intradermally, intramembranally, intradurally, and intranasally, and intralesionally if topical treatment is desired. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

The compounds of the present invention may be administered in any convenient form of administration, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. The compositions may contain ingredients conventional in pharmaceutical formulations, such as diluents, carriers, pH adjusting agents, sweeteners, fillers, and other active agents.

Typical formulations are prepared by mixing a compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in the following documents: for example Ansel, Howard C et al,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia:Lippincott,Williams&wilkins, 2004; gennaro, Alfonso R et al,Remington:The Science and Practice of Pharmacy.Philadelphia:Lippincott,Williams&wilkins, 2000; and Rowe, Raymond C.Handbook of Pharmaceutical ExcipientsChicago, pharmaceutical press, 2005. The formulations may also contain one or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents and other known additives to provide an elegant form of a drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a drug).

The compounds of formula 1 and their salts have at least one asymmetric carbon atom and may therefore exist as mixtures of different stereoisomers. The various isomers can be separated by known separation methods, such as chromatography.

Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of formula I, or a stereoisomer or pharmaceutically acceptable salt thereof. Another embodiment includes a pharmaceutical composition comprising a compound of formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

Another embodiment includes pharmaceutical compositions comprising compounds of formula I for use in treating hyperproliferative diseases. Another embodiment includes pharmaceutical compositions comprising compounds of formula I for use in treating cancer.

In general, in the present applicationNomenclature used is based on AUTONOM^TMv.4.0, a Beilstein Institute computer system used to generate IUPAC systematic nomenclature. If the drawn structure is inconsistent with the name given by the structure, the drawn structure is taken as a standard. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated (e.g., by bold or dashed lines), then the structure or portion of a structure should be interpreted as encompassing all stereoisomers.

By "therapeutically effective amount or effective amount" is meant an amount of at least one specified compound that significantly inhibits proliferation and/or prevents differentiation of human tumor cells, including human tumor cell lines.

The compounds of the invention are useful in the treatment or control of cell proliferative disorders, such as in particular neoplastic disorders. These compounds, and formulations containing the compounds, may be used in the treatment or control of hematological cancers, such as acute myeloid leukemia, or solid tumors, such as breast, colon, lung, and prostate cancers.

The compounds of the invention preferably bind to the BIR domain of IAPs, preventing IAPs from binding to other proteins. Examples of Bir binding proteins include, but are not limited to, caspase 3, caspase 7, caspase 9, Smac, and the like. Examples of IAPs include, but are not limited to, XIAP, cIAP1, cIAP2, or NAIP. In one aspect. The compounds of the invention bind to the BIR2 and/or BIR3 domains of XIAP, cIAP1 and/or cIAP 2. In another aspect, the compounds of the invention bind to the BIR2 domain of XIAP, cIAP1 and/or cIAP 2.

The compounds of the invention are useful for inducing apoptosis in cells or sensitizing cells, particularly cancer cells, to apoptotic signals. Apoptotic signals may be induced in cancer cells by, for example, radiation therapy or anti-tumor chemotherapy. Alternatively, apoptotic signals may be induced in cancer cells by activation of death receptors by death receptor agonists. Death receptor agonists may be of natural origin, such as tumor necrosis factor alpha (TNF- α), or of non-natural origin, such as synthetic antibodies, such as DR4 or DR5 antibodies.

Reaction scheme

The compounds of the invention (compounds of general formula 1) can be prepared using the general reaction scheme given in scheme 1.

Route 1

Step 1: suitably protected 2-amino-3-hydroxypropionic acid or 2-amino-3-thiopropionic acid of formula 2 (where PG1 is a group that renders the 2-amine N inert to the reaction conditions used in the remaining steps of the synthesis sequence, PG2 is an optional group that renders the 2-amine N inert to the reaction conditions used in the remaining steps of the synthesis sequence, and PG3 is an optional group that renders the carboxylic acid inert to the reaction conditions used in the remaining steps of the synthesis sequence), and the substituted or unsubstituted 1-fluoro-2-nitrobenzene of formula 3 may be reacted with a base in a suitable solvent at a suitable temperature for a sufficient time to provide the product of formula 4. The base may be an inorganic base, such as NaH, Na₂CO₃Or Cs₂CO₃Or an organic base such as sodium bis (trimethylsilyl) amide. The solvent chosen is compatible with the base and other reaction conditions (e.g., temperature), including, but not limited to, THF or DMF, for example. Suitable temperatures for the reaction may range from about-40 ℃ to about 150 ℃. Preferred selections of protecting Groups PG1, PG2, and PG3 may be made with reference to textbooks of Organic chemistry (e.g., Protective Groups in Organic Synthesis, Theodora w. greene et al), the original chemical literature, or are generally known to those skilled in the art of Organic Synthesis. In particular, when 2-amine N is mono-protected with PG1, carbamate protecting groups such as t-butyloxycarbonyl and benzyloxycarbonyl are preferred. When the 2-amine N is di-protected by PG1 and PG2, aralkyl protecting groups are preferred, such as benzyl or 4-methoxybenzyl. Other amine-protecting groups of PG1 alone or PG1 and PG2 in common are also effective. PG3 may be H or may be an alkyl group, such as methyl, ethyl, tert-butyl.

Step 2: this step involves reducing the nitro group of the compound of formula 4 to provideFor compounds of formula 5. Those skilled in the art will appreciate that there are a variety of ways to accomplish this reduction, including catalytic hydrogenation and chemical reduction. The choice of the reduction method will be influenced by the substituents on the phenyl ring (denoted R1, R2 and R3), and unwanted side reactions can be prevented by protecting groups PG1, PG2 and PG 3. For example, the compound of formula 4 can be treated with a suitable hydrogenation catalyst (e.g., 10% Pd/C), in a suitable solvent (e.g., MeOH), and at atmospheric to elevated pressures (up to about 60PSI) with hydrogen for a sufficient time to effect this conversion. Alternatively, the compound of formula 4 may be treated with a suitable chemical reducing agent (e.g. Zn or SnCl)₂) The conversion is carried out by treatment in a suitable solvent or solvent mixture (e.g., EtOAc or a mixture of EtOAc and EtOH or a mixture of EtOH and HCl) at a suitable temperature (from about 0 ℃ to about 80 ℃) for a sufficient time to effect the conversion.

And step 3: the optional carboxylic acid protecting group PG3 in the compound of formula 5 may be removed to give the compound of formula 6. As mentioned above, the choice of protecting group PG3 and the conditions used to remove PG3 in step 3 are influenced by the presence of other potentially reactive functional groups in the compound of formula 5, and it is desirable to avoid unwanted reactions in the starting materials or products of the reactions elsewhere (i.e. compounds 5 and 6, respectively). For example, if PG2 is an ester (e.g., methyl or ethyl ester), the compound of formula 4 may be treated with a base (e.g., NaOH or LiOH) in a suitable solvent or solvent mixture (e.g., THF/H)₂O or MeOH/H₂O), at a suitable temperature (from about 0 ℃ to about 80 ℃) for a time sufficient to effect the conversion. It will be apparent to those skilled in the art that there are a number of conditions for removing protecting Groups from carboxylic acids, which may be referenced to textbooks of organic chemistry (e.g., Protective Groups in organic Synthesis, Theodora W.Greene et al) or the original chemical literature. It is to be understood that the compound of formula 5 (wherein PG3 ═ H) is equivalent to the compound of formula 6.

And 4, step 4: this step achieves the conversion of the compound of formula 6 to the lactam of formula 7. Reagents that can be used to effect this conversion include diimide reagents such as dicyclohexylcarbodiimide, (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride; or an uronium reagent such as O-benzotriazol-1-yl-N, N '-tetramethyluronium hexafluorophosphate or O-benzotriazol-1-yl-N, N' -bis (tetramethylene) uronium hexafluorophosphate. In addition, a catalyst, such as 1-hydroxybenzotriazole or N-hydroxysuccinimide, may optionally be added to the reaction. Alternative reagents are also effective in carrying out this transformation, the selection of which can be made with reference to the original chemical literature or are generally known to those skilled in the art of organic synthesis.

And 5: this step comprises reacting a compound of formula 7 with a compound of formula 8 to form a compound of formula 9, wherein Q is a suitable leaving group, such as a halogen (e.g. Br or I) or a sulfonate (e.g. mesylate), or Q is hydroxy. In the case where Q is a leaving group, step 5 may be accomplished by treating the compound of formula 7 with a base and a compound of formula 9 in a suitable solvent for a sufficient time to effect the conversion. The base used may be an inorganic base, such as Cs₂CO₃Or an organic base such as lithium bis (trimethylsilyl) amide. The solvent chosen is compatible with the base and other reaction conditions (e.g., temperature) and includes, but is not limited to, THF or DMF, for example. Suitable temperatures for this reaction may range from-78 ℃ to 100 ℃. It will be apparent to those skilled in the art that a catalyst may be added to the reaction mixture. The catalyst may include, but is not limited to, for example, NaI or tetrabutylammonium iodide.

If Q is hydroxy in the compound of formula 8, the conversion of the compound of formula 7 to the compound of formula 9 can be achieved by a Mitsunobu reaction. For example, compounds of formula 7 and compounds of formula 8 (wherein Q ═ OH) can be treated with an azodicarboxylate (e.g., diethyl azodicarboxylate or diisopropyl azodicarboxylate) and a phosphine (e.g., triphenylphosphine) or another suitable phosphine in a suitable solvent for a sufficient time to effect the conversion. The solvent selected is compatible with the reaction conditions (e.g., temperature) and includes, but is not limited to, THF, toluene, CH₂Cl₂Or DMF. Suitable temperatures for the reaction may range from about 0 ℃ to 100 ℃. Other methods of effecting this conversion will be apparent to those skilled in the art of organic synthesisAre generally known, and a summary of the Mitsunobu reaction is described in the following recent review: chem.Rev.,2009,109 (6), pp 2551-.

Step 6: this step enables the removal of protecting group PG1 and optionally protecting group PG2 from the compound of formula 9 to form the amine-containing compound of formula 10. As mentioned above, the choice of protecting groups PG1 and optional PG2 and the conditions used to remove PG1 and optional PG2 in step 6 are influenced by the presence of other potentially reactive functional groups in the compound of formula 10 and it is desirable to avoid unwanted reactions in the starting materials or products of the reactions elsewhere (i.e. the compounds of formulae 9 and 10, respectively). In the case where the amine protecting group PG1 present in the compound of formula 5 is tert-butyloxycarbonyl, this protecting group can be removed under acidic conditions (e.g. trifluoroacetic acid in dichloromethane or hydrochloric acid in p-dioxane or diethyl ether). The corresponding salt of the compound of formula 10 is initially freed from the tert-butyloxycarbonyl group under acidic conditions, from which the free amine of formula 10 can optionally be freed after treatment with a base. Alternatively, if the 2-amino N is protected by protecting groups PG1 and PG2 and is, for example, benzyl di-protection, their removal may be achieved by catalytic hydrogenation using a suitable catalyst (e.g. 10% Pd/C) and subjecting the mixture to a hydrogen source (e.g. H)₂Or ammonium formate) in a suitable solvent (e.g., EtOH). It will be clear to the skilled person that there are a number of conditions for the removal of the protecting group from the nitrogen atom, which may be referred to textbooks on organic chemistry (e.g. Protective Groups in organic synthesis, Theodora W.Greene et al) or the original chemical literature.

And 7: this step enables the coupling of a suitably protected α -amino acid of formula 11 with a compound of formula 10, wherein PG4 is a group that renders the α -amine N inert to the reaction conditions used in the remaining steps of the synthetic sequence, and W is as described above. The preferred choice of protecting group PG4 can be made with reference to textbooks of organic chemistry (e.g., Protective Groups in organic synthesis, Theodora w. In particular, carbamate protecting groups such as t-butyloxycarbonyl and benzyloxycarbonyl are preferred, but other amine-protecting groups are also effective. Those skilled in the art will appreciate that there are a variety of methods for converting compounds of formula 10 and compounds of formula 11 to compounds of formula 12 using known peptide coupling reaction techniques. Typical peptide coupling reagents that may be used include diimide reagents such as dicyclohexylcarbodiimide, (3-dimethylamino-propyl) -ethyl-carbodiimide hydrochloride; or an uronium reagent such as O-benzotriazol-1-yl-N, N '-tetramethyluronium hexafluorophosphate or O-benzotriazol-1-yl-N, N' -bis (tetramethylene) uronium hexafluorophosphate. In addition, a catalyst, such as 1-hydroxybenzotriazole or N-hydroxysuccinimide, may optionally be added to the reaction. Alternative peptide coupling reagents to perform this transformation are also effective. The choice of alternative peptide coupling reagents can be made with reference to the original chemical literature or are generally known to those skilled in the art of organic synthesis.

And 8: this step achieves removal of PG4 from the compound of formula 12 to provide an amine compound of formula 13. The conditions and methods for this step are similar to those described above for step 6.

In the case where X in formula 1 is H, no further reaction is required, since the compound of formula 13 is equivalent to the compound of formula 1 (where W ═ H).

Step 9 involves introducing additional substituents to the nitrogen atom carrying the group X in the compound of formula 13. One skilled in the art will appreciate that there are a variety of ways to accomplish this transformation. These methods include, but are not limited to, reductive amination or alkylation. For example, compounds of formula 13 can be prepared using an aldehyde (e.g., acetaldehyde, benzaldehyde, or 3-pyridinecarboxaldehyde) and a reducing agent (e.g., NaBH)₄Or NaBH₃CN) in a suitable solvent (e.g., MeOH or EtOH) at a suitable temperature (from about-20 ℃ to about 100 ℃) for a sufficient time to effect this conversion. Alternatively, the compound may be treated with an alkylating agent (e.g., methyl iodide, benzyl bromide, or allyl bromide) and a base (e.g., pyridine or Triethylamine (TEA)) in a suitable solvent (e.g., Dichloromethane (DCM) or THF) at a suitable temperature (from about-20 deg.C to about 100 deg.C) for a time sufficient to effect this conversionAnd (4) transforming. It will be apparent to those skilled in the art that a catalyst may be added to the reaction mixture. Such catalysts include, but are not limited to, for example, NaI or tetrabutylammonium iodide.

It will be apparent to those skilled in the art of organic synthesis that in the compounds shown in scheme 1, when one or more of the substituents labeled X, W, Y or R1 through R6, or the substituents included in their definition, are themselves chemically reactive groups, or contain chemically reactive groups, further modifications can be made to the compounds of formula 1 through 13 that contain those reactive groups. The point in the synthesis sequence at which the chemically reactive group is modified can be selected such that the new elaborated group is chemically inert to the reagents used in the remaining steps of the synthesis sequence and does not interfere with the remaining steps of the synthesis sequence shown in scheme 1. Alternatively, if the new elaborated group is not chemically inert or may interfere with the remaining steps of the synthesis sequence, it is necessary to temporarily mask the reactive functional group with a suitable protecting group or to derivatize the functional group as a group stable to the remaining steps of the synthesis sequence and will be present in the end product of the reaction sequence. If a protecting group is introduced which is not required in the final compound of formula 1, it may either be removed under the remaining conditions of the synthetic sequence shown in scheme 1 or by introducing an additional deprotection step into the synthetic sequence, depending on the nature of the protecting group used.

Route 2

It will be clear to those skilled in the art that in some cases it will be necessary to synthesize the compound when the appropriately protected 2-amino-3-hydroxypropionic acid is not known in the literature or is not commercially available. Scheme 2 illustrates a general synthesis of protected 2-amino-3-hydroxypropionic acid.

Step 10: suitably protected 2-aminoacetic acid (e.g. ethyl N, N-dibenzylglycine) may be treated with a base and a compound of formula 15 (wherein R5 and R6 are as described above) in a suitable solvent for a time sufficient to effect this conversion to give a compound of formula 2 (wherein V ═ O). The base used may be an organic base, such as lithium diisopropylamide, or an inorganic base, such as NaH. The solvent chosen is compatible with commercially available bases and other reaction conditions (e.g., temperature) and includes, but is not limited to, THF or DMF, for example. Suitable temperatures for the reaction may range from about-78 ℃ to about 80 ℃.

In some cases, it may be desirable to remove protecting group PG3 to give a compound of formula 16, which is exemplified in step 11. As mentioned above, the choice of protecting group PG3 and the conditions used to remove PG3 in step 11 are influenced by other potentially reactive functional groups in the compounds of formulae 2 and 16, respectively, and it is desirable to avoid unwanted reactions in the starting materials or products of the reactions elsewhere. In the case where PG3 is an alkyl ester, the compound of formula 2 (where V ═ O) may be treated with a base (e.g. NaOH, KOH or LiOH · H)₂O) in a suitable solvent or solvent mixture (e.g. MeOH, MeOH/H)₂O or THF/H₂O), at a suitable temperature (from about 0 c to about 100 c) for a time sufficient to effect the conversion. It will be clear to the skilled person that there are a number of conditions for the removal of protecting Groups from carboxylic acids, which may be referred to organic activity textbooks (e.g. Protective Groups in organic Synthesis, Theodora W.Greene et al) or the original chemical literature. It will be appreciated that the compounds of formula 16 are equivalent to compounds of formula 2 wherein PG3 is optionally absent and V ═ O.

The reaction conditions of the above reaction may be varied to some extent. Those skilled in the art will appreciate that the order of some of the reaction steps described in scheme 1 may be varied, as shown in scheme 3.

Route 3

The compound of formula 7 can be treated as described above in step 6 to provide a compound of formula 17.

The compound of formula 17 can be treated as described above in step 7 to provide a compound of formula 18.

The compound of formula 18 may be treated as described above in step 5 to provide a compound of formula 12.

The compound of formula 12 can be treated as described above in step 8 to provide a compound of formula 13.

The compound of formula 13 may be treated as described above in step 9 to provide the compound of formula 1.

Methods of performing the above reactions and processes will be apparent to those skilled in the art based on the present disclosure, or may be derived in analogy to the examples. The starting materials are either commercially available or can be prepared by methods analogous to those described in the examples.

The following examples illustrate preferred embodiments of the present invention, but do not limit the scope of the present invention.

Preparation of intermediates

(S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester

Step 1: to a suspension of NaH (60% in mineral oil, 2.88g,72mmol) in DMF (25mL) at 0 deg.C was added a solution of (S) -2- (tert-butoxycarbonylamino) -3-hydroxypropionic acid (7g,34mmol) in DMF (25 mL). After 2h a solution of 1-fluoro-2-nitrobenzene (5.29g,37.5mmol) in DMF (25mL) was added and the resulting mixture was stirred at 0 ℃ for 3 h. Pouring the mixture into ice/H₂In O (200mL), acidified to pH 5.0 with 1N HCl and extracted with EtOAc. Will mergeSubjecting the extract to Na₂SO₄Drying, concentration and purification by flash chromatography gave (S) -2-tert-butoxycarbonylamino-3- (2-nitro-phenoxy) -propionic acid (10.9g, 97%).

Step 2: a mixture of (S) -2-tert-butoxycarbonylamino-3- (2-nitro-phenoxy) -propionic acid (7.6g,23.3mmol,1eq) and 10% Pd/C (496mg) in MeOH (215mL) was hydrogenated at 1atm for 2 h. After theoretical absorption of hydrogen, the reaction mixture was filtered through celite and washed with MeOH. The filtrate was concentrated and the residue triturated with hexane to give a solid which was filtered and washed with hexane to give (S) -3- (2-amino-phenoxy) -2-tert-butoxycarbonylamino-propionic acid (3.8g, 55%) as a white solid which was used without purification.

And step 3: a mixture of (S) -3- (2-amino-phenoxy) -2-tert-butoxycarbonylamino-propionic acid (3.8g,12.8mmol,1eq) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (EDCI,2.46g,12.8mmol,1eq) in DMF (56.4mL) was stirred for 1h 45 min. The reaction is poured into H₂O (250mL) and extracted with EtOAc. The combined extracts are washed with H₂O washing with Na₂SO₄Drying and concentration gave the title compound (3.1g, 87%) as a tan solid, which was used without purification.

(S) -3-amino-2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -keto trifluoroacetate salt

To (S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] at 0 deg.C][1,4]Oxazazepine(iii) -3-ylcarbamic acid tert-butyl ester (2g,7.19mmol, Eq:1.00) in DCM (16.7mL) was added trifluoroacetic acid (TFA,16.4g,10.7mL,144mmol, Eq: 20.00). After 1h the mixture was concentrated and the residue was taken up in 5mL Et₂Trituration of O and 35ml pentane gave a gum. The solution was removed and the gummy residue dried to give the title compound (2.1g) as a pink foam which was used without purification.

Methyl ((S) -1-oxo-1- ((S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester

To (S) -3-amino-2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -one trifluoroacetate (500mg,1.71mmol, Eq:1.00), (S) -2- (tert-butoxycarbonyl (methyl) amino) propanoic acid (348mg,1.71mmol, Eq:1.00), O-benzotriazol-1-yl-N, N, N 'N' -tetramethyluronium hexafluorophosphate (HBTU,682mg,1.8mmol, Eq:1.05) and 1-hydroxybenzotriazole hydrate (HOBT. H2O,243mg,1.8mmol, Eq:1.05) to a mixture in DMF (5mL) was added N, N-diisopropylethylamine (DIEA,553mg,4.28mmol, Eq: 2.50). The mixture was stirred for 45 min, diluted with 50mL EtOAc and washed with H₂O、2％KHSO₄、5％NaHCO₃And 5% saturated brine. Subjecting the organic solution to Na₂SO₄Dried, filtered and concentrated to give the title compound (525mg, 84%) as a tan foam, which was used without purification.

(S) -3- (tert-Butoxycarbonylamino) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-9-Carboxylic acid methyl ester

Step 1: a suspension of NaH (60% in mineral oil, 1.48g,36.9mmol, Eq:2.10) in DMF (15mL) was cooled to 0 deg.C and a solution of (S) -2- (tert-butoxycarbonylamino) -3-hydroxypropionic acid (3.61g,17.6mmol, Eq:1.00) in DMF (15mL) was added dropwise over 15 minutes. The mixture was stirred at 0 ℃ for 30 minutes and at Room Temperature (RT) for 30 minutes. The mixture was cooled to 0 ℃ and a solution of methyl 2-fluoro-3-nitrobenzoate (3.5g,17.6mmol, Eq:1.00) in DMF (15mL) was added dropwise over 10 minutes. After 2.5 hours, the mixture was washed with ice-cold H₂Dilute O and extract with EtOAc. Subjecting the combined extracts to Na₂SO₄Drying, filtration and concentration gave a residue which was purified by chromatography to give methyl 2- ((S) -2-tert-butoxycarbonylamino-2-carboxy-ethoxy) -3-nitrobenzoate (4.3g, 50%) as a yellow foam.

Step 2: in a similar manner as described for (S) -3- (2-amino-phenoxy) -2-tert-butoxycarbonylamino-propionic acid except that the material obtained after filtration was only concentrated but not triturated, (S) -3- (2-amino-phenoxy) -2-tert-butoxycarbonylamino-propionic acid (4.3g,11.2mmol) was converted to (S) -3- (2-amino-6- (methoxycarbonyl) phenoxy) -2- (tert-butoxycarbonylamino) propionic acid (3.9g, 50%) as an off-white foam which was used without purification.

And step 3: to prepare (S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-tert-butyl 3-ylcarbamate the similar procedure was followed except that the crude product was purified by silica gel chromatography to convert (S) -3- (2-amino-6- (methoxycarbonyl) phenoxy) -2- (tert-butoxycarbonylamino) propanoic acid (3.9g,6.6mmol) to the title compound (1.46g, 65%) as a white foam.

(2R,3S) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester

Step 1: in a similar manner to that described for the preparation of (S) -2-tert-butoxycarbonylamino-3- (2-nitro-phenoxy) -propionic acid except that a mixture of (2S,3R) -2-tert-butoxycarbonylamino-3-hydroxybutyric acid and NaH (60% in mineral oil) was stirred at 0 deg.C for 30 minutes, stirred at room temperature for 1 hour and cooled to 0 deg.C to convert (2S,3R) -2-tert-butoxycarbonylamino-3-hydroxy-butyric acid (4.99g) and 1-fluoro-2-nitrobenzene (3.22g) to (2S,3R) -2-tert-butoxycarbonylamino-3- (2-nitro-phenoxy) -butyric acid (3.6g, 53%) as yellow foam.

Step 2: in a similar manner as described for (S) -3- (2-amino-phenoxy) -2-tert-butoxycarbonylamino-propionic acid except that the material obtained after filtration was concentrated but not triturated, (2S,3R) -2-tert-butoxycarbonylamino-3- (2-nitro-phenoxy) -butyric acid (3.6g,10.6mmol) was converted to (2S,3R) -3- (2-amino-phenoxy) -2-tert-butoxycarbonylamino-butyric acid (3.4g, 90%) as a purple foam which was used without purification.

And step 3: to prepare (S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-tert-butyl 3-ylcarbamate the similar procedure was followed except that the crude product was purified by silica gel chromatography to convert (S) -3- (2-amino-6- (methoxycarbonyl) phenoxy) -2- (tert-butoxycarbonylamino) propanoic acid (1.5g,4.83mmol) to the title compound (0.65g, 46%) as a white solid.

(6R,7S) -7-amino-6-methyl-6, 7-dihydro-9H-5-oxa-9-aza-benzocycloheptatrien-8-one

To (2R,3S) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] at 0 deg.C][1,4]OxazazepineTo a solution of tert-butyl (3-ylcarbamate) (0.65g,2.22mmol, Eq:1.00) in DCM (11.2mL) was added TFA (12.7g,8.26mL,111mmol, Eq: 50.00). After 1h the mixture was concentrated, the residue was dissolved in 50mL DCM and saturated NaHCO₃And (6) washing. NaHCO is added₃The mixture was extracted with DCM and the combined extracts were washed with Na₂SO₄Dried, filtered and concentrated to give the title compound (0.42g, 96%) as a yellow foam, which was used without purification.

Methyl- [ (S) -1- ((6R,7S) -6-methyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-ylcarbamoyl) -ethyl ] -carbamic acid tert-butyl ester

To prepare methyl ((S) -1-oxo-1- ((S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester the similar procedure is followed except that the mixture is stirred for 1.5 hours and the crude product is purified by silica gel chromatography to give (2R,3S) -3-amino-2-methyl-2, 3-dihydrobenzo [ b][1,4]-oxaazepine-4(5H) -one (420mg,2.19mmol) was converted to the title compound (505mg, 61%) as a white foam.

(S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- (tert-butoxycarbonylamino) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-9-Carboxylic acid methyl ester

Mixing Cs₂CO₃(1.02g,3.12mmol, Eq:1.05) and NaI (446mg,2.97mmol, Eq:1.0) to (S) -3- (tert-Butoxycarbonylamino) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] is added][1,4]Oxazazepine-methyl 9-carboxylate (1g,2.97mmol, Eq:1.00) and 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (866mg,3.03mmol, Eq:1.02) in DMF (20 mL). The mixture was stirred at room temperature for 30 minutes. Then heated to 50 ℃. After 75 min, the mixture was cooled to room temperature and treated with 1/1EtOAc/H₂And (4) diluting with oxygen. The aqueous layer was extracted with EtOAc and the combined organic phases were extracted with H₂Washing with saturated brine, and purifying with Na₂SO₄Drying and concentrating. The residue was purified by silica gel chromatography to give (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- (tert-butoxycarbonylamino) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineMethyl 9-carboxylate (1.35g, 75%) as white foam.

(S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-9-Carboxylic acid methyl ester

Step 1: to and preparation of(S) -3-amino-2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -Ketone trifluoroacetate similar procedure as described for (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- (tert-butoxycarbonylamino) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineConversion of methyl-9-carboxylate (652mg,1.11mmol) to (S) -3-amino-5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineMethyl-9-carboxylate trifluoroacetate (660mg, 99%) was used without purification.

Step 2: DIEA (712mg, 972. mu.l, 5.51mmol, Eq:5.00) was added to (S) -3-amino-5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b at 0 deg.C][1,4]OxazazepineMethyl-9-carboxylate trifluoroacetate (660mg,1.1mmol, Eq:1.00), (S) -2- (tert-butoxycarbonyl (methyl) amino) propanoic acid (224mg,1.1mmol, Eq:1.0), HBTU (418mg,1.1mmol, Eq:1.0) and HOBT. H₂O (149mg,1.1mmol, Eq:1.0) in DMF (12.5 mL). The mixture was warmed to room temperature, stirred for 1 hour, diluted with EtOAc and washed with H₂Washing with saturated brine and Na₂SO₄And (5) drying. The mixture was filtered and concentrated to give the title compound (725mg, 98%) as an off-white foam, which was used without purification.

(S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-9-carboxylic acid

Reacting LiOH & H₂O (31.3mg, 746. mu. mol, Eq:2.5) and H₂O (1.00mL) was added to (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineMethyl-9-carboxylate (200mg, 298. mu. mol, Eq:1.00) in MeOH (6.0mL) and the mixture was heated to 50 ℃. After 90 minutes the mixture was concentrated with H₂Diluted with Et₂And (4) extracting. Et to be combined₂O extract with 5% NaHCO₃And (4) extracting. The combined aqueous mixture was acidified to pH 2.0 with 1N HCl, extracted with EtOAc and the combined organic extracts were washed with saturated brine, over Na₂SO₄Dried and concentrated to give the title compound (180mg, 91%) as an off-white foam, which was used without purification.

(S) -5- ((4-bromonaphthalen-1-yl) methyl) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-9-carboxylic acid

Step 1: to react with (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- (tert-butoxycarbonylamino) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-methyl 9-carboxylate similar to the method, treatment using 0.01eq. NaI and placing the mixture in a chamberStirring for 2 hours and 45 minutes while warm, (S) -3- (tert-butoxycarbonylamino) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]OxazazepineMethyl-9-carboxylate (349mg,1.04mmol, Eq:1.00) and 1-bromo-4- (bromomethyl) naphthalene (311mg,1.04mmol, Eq:1.0) to (S) -5- ((4-bromonaphthalen-1-yl) methyl) -3- (tert-butoxycarbonylamino) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]OxazazepineMethyl 9-carboxylate (519mg, 90%) as white foam.

Step 2: with (S) -3-amino-2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -Ketone trifluoroacetate in a similar manner to that described for (S) -5- ((4-bromonaphthalen-1-yl) methyl) -3- (tert-butoxycarbonylamino) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineConversion of methyl-9-carboxylate (519mg, 934. mu. mol) to (S) -3-amino-5- ((4-bromonaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineMethyl-9-carboxylate trifluoroacetate (511mg, 96%) as a white solid.

And step 3: to prepare (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-methyl 9-carboxylate similar to that described in step 2, except that obtained in Et₂Grinding with O/pentane to obtain (S) -3-amino-5- ((4-bromonaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxa nitrogenHetero compoundMethyl-9-carboxylate 2,2, 2-trifluoroacetate (511mg, 898. mu. mol, Eq:1.00) and (S) -2- (tert-butoxycarbonyl (methyl) amino) propanoic acid (182mg, 898. mu. mol, Eq:1.0) were converted to (S) -5- ((4-bromonaphthalen-1-yl) methyl) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propanamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineMethyl 9-carboxylate (568mg, 99%) as a white solid.

And 4, step 4: reacting LiOH & H at 0 DEG C₂A0.1M solution of O (8.87mL, 887. mu. mol, Eq:1.00) was added to (S) -5- ((4-bromonaphthalen-1-yl) methyl) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]OxazazepineMethyl-9-carboxylate (568mg, 887. mu. mol, Eq:1.00) in MeOH (10 mL). The mixture was stirred at room temperature for 20 minutes and then heated to 40 ℃. After 6.5 h MeOH was removed in vacuo and the aqueous mixture was taken up with saturated NaHCO₃Diluted and Et₂And (4) extracting. The aqueous mixture was cooled to 0 ℃, acidified to pH 3 with 3N HCl and extracted with EtOAc. The combined extracts were washed with saturated brine and then with Na₂SO₄Dried, filtered and concentrated to give the title compound (433mg, 78%) as a white foam, which was used without purification.

(S) -3-amino-8-methyl-2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -keto trifluoroacetate salt

Step 1: (S) -2- (tert-Butoxycarbonylamino) -3-hydroxypropionic acid (5.5g,26.8mmol, Eq:1.00) was dissolved in DMF (90mL) at 0 deg.C, NaH (60% in mineral oil, 2.57g,64.3mmol, Eq:2.4) was added in small portions, and the mixture was stirred for 30 minutes, then a solution of 2-fluoro-4-methyl-1-nitrobenzene (4.16g,26.8mmol, Eq:1.00) in DMF (10mL) was added dropwise. The resulting mixture was stirred for 60 minutes with 1.0M KHSO₄Dilute and extract with EtOAc. The combined organic extracts were washed with water, saturated brine and then washed with Na₂SO₄Drying and concentrating. The residue was purified by silica gel chromatography to give (S) -2- (tert-butoxycarbonylamino) -3- (5-methyl-2-nitrophenoxy) propionic acid (7.60g, 83%) as a red oil.

Step 2: a mixture of (S) -2- (tert-butoxycarbonylamino) -3- (5-methyl-2-nitrophenoxy) propionic acid (7.50g,22.0mmol, Eq:1.00) and 10% Pd/C (0.75g, Eq:0.03) in MeOH (300mL) was hydrogenated at ambient pressure and room temperature for 4 h. The mixture was filtered through a silica gel pad, and the filtrate was concentrated to give (S) -3- (2-amino-5-methylphenoxy) -2- (tert-butoxycarbonylamino) propionic acid (3.85, 56%) as a yellow solid, which was used without purification.

And step 3: (S) -3- (2-amino-5-methylphenoxy) -2- (tert-butoxycarbonylamino) propionic acid (3.85g,12.4mmol, Eq:1.00) and EDCI (2.38g,12.4mmol, Eq:1.00) were dissolved in DMF (50mL), and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc and washed with water, saturated brine, and the organic solution was washed with Na₂SO₄And (5) drying. The mixture was filtered, concentrated, and the residue was purified by silica gel chromatography to give (S) -8-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]OxazazepineTert-butyl-3-ylcarbamate (2.51g, 69%) as an off-white foam.

And 4, step 4: (S) -8-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] at 0 deg.C][1,4]OxazazepineTert-butyl-3-ylcarbamate (2.50g,8.55mmol, Eq:1.00) was dissolved in dichloromethane (DCM,10mL) and TFA (10mL) was added. The mixture was stirred at 0 ℃ for 1.5 hours and concentrated to give the title compound (2.69g, 103%) which was used without purification.

(2S,3S) -3-amino-2, 8-dimethyl-2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -keto trifluoroacetate salt

Step 1: in a similar manner to that described for the preparation of (S) -2- (tert-butoxycarbonylamino) -3- (5-methyl-2-nitrophenoxy) propionic acid, (2S,3S) -2- (tert-butoxycarbonylamino) -3-hydroxybutyric acid DCHA (2.0g,5.00mmol) and 2-fluoro-4-methyl-1-nitrobenzene (1.55g,9.99mmol) were converted to (2S,3S) -2-tert-butoxycarbonylamino-3- (5-methyl-2-nitro-phenoxy) -butyric acid (0.95g, 53.6% yield) by stirring the reaction mixture at 0 deg.C for 4 hours.

Step 2: a mixture of (2S,3S) -2-tert-butoxycarbonylamino-3- (5-methyl-2-nitro-phenoxy) -butyric acid (0.95g,2.68mmol, Eq:1.00) and 5% Pd/C (200mg, 94.0. mu. mol, Eq:0.0351) in EtOH (100mL) was hydrogenated at room temperature and ambient pressure overnight, and another 10% Pd/C (100mg, 47.0. mu. mol, Eq:0.0176) was added. After 2h the mixture was filtered through celite, the filtrate was concentrated and the residue was purified by silica gel chromatography to give (2S,3S) -3- (2-amino-5-methyl-phenoxy) -2-tert-butoxycarbonylamino-butyric acid (294mg, 34%) as a solid.

And step 3: to prepare (S) -8-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester A similar procedure is described, except that 1.5 eq.E.DCI, conversion of (2S,3S) -3- (2-amino-5-methyl-phenoxy) -2-tert-butoxycarbonylamino-butyric acid (290mg, 894. mu. mol) to (2S,3S) -2, 8-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineTert-butyl-3-ylcarbamate (152mg, 55.5% yield) as a solid.

And 4, step 4: to prepare (S) -3-amino-8-methyl-2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -Ketone trifluoroacetate the similar procedure except that the reaction mixture is stirred at 0 ℃ for 30 minutes and at room temperature for 20 minutes, (2S,3S) -2, 8-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] is reacted][1,4]OxazazepineTert-butyl-3-ylcarbamate was converted to the title compound (175mg, 112%) and used without purification.

(S) -3-amino-7-trifluoromethyl-2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -keto trifluoroacetate salt

To prepare (S) -3-amino-8-methyl-2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -Ketone trifluoroacetate the similar procedure is described except that the reaction mixture is stirred in step 3 for 4 hours and the material obtained in step 4 is triturated with hexane (S) -2- (tert-butoxycarbonylamino) -3-hydroxypropionic acid (4.1g,20.0mmol) and 1-fluoro-2-nitro-4- (trifluoromethyl) benzene (4).18g,20.0mmol) was converted to the title compound (1.06g) and used without purification.

(2S,3S) -3-amino-2-methyl-7- (trifluoromethyl) -2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -keto trifluoroacetate salt

To prepare (S) -3-amino-8-methyl-2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -Ketone trifluoroacetate the similar procedure as described above except that the mixture was stirred overnight in step 1 and for 3 hours in step 2 converts (2S,3S) -dicyclohexylamine 2- (tert-butoxycarbonylamino) -3-hydroxybutyrate (2.0g,5.00mmol) and 1-fluoro-2-nitro-4- (trifluoromethyl) benzene (1.04g,5.00mmol) to the title compound (58mg) which was used without purification.

(S) -3-amino-8-trifluoromethyl-2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -keto trifluoroacetate salt

To prepare (S) -3-amino-8-methyl-2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -Ketone trifluoroacetate the similar process except that 1.2eq. EDCI was used in step 3 and the reaction mixture was stirred for 2 hours and in step 4 the mixture was stirred for 1 hour andthe resulting material was used in Et₂Trituration with O/pentane converts (S) -2- (tert-butoxycarbonylamino) -3-hydroxypropionic acid (4.96g,24.2mmol) and 2-fluoro-1-nitro-4- (trifluoromethyl) benzene (5.05g,24.2mmol) to the title compound (1.6g) as a pale yellow solid.

((R) -9-amino-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b)][1,4]Thiaazepines-3-Yl) -carbamic acid tert-butyl ester

Step 1: to a solution of 2-chloro-1, 3-dinitrobenzene (1.0g,4.9mmol) in DMF (25mL) was added Cs₂CO₃(4.0g,12.3mmol) followed by the addition of L-BOC-Cys-OH (1.1g,4.9mmol) and the resulting mixture stirred at room temperature for 15 min. The reaction was cooled to 0 deg.C, acidified with 1.0N HCl (15mL) and extracted with EtOAc. Combining the organic layers with H₂Washing with saturated brine, and purifying with Na₂SO₄Drying, filtration and concentration gave (R) -2-tert-butoxycarbonylamino-3- (2, 6-dinitro-phenylsulfanyl) -propionic acid, which was used without purification (1.9 g).

Step 2: to (R) -2-tert-butoxycarbonylamino-3- (2, 6-dinitro-phenylsulfanyl) -propionic acid (1.7g,4.4mmol) in a solution containing NH₄Cl (7.0g,130mmol) in 3:1v/v MeOH/H₂To O (80mL) was added Zn powder (5.7g,87.2mmol), and the resulting mixture was stirred for 1 hour. The mixture was filtered through a pad of celite, the amount of filtrate was reduced under vacuum, and acidified to pH 4 with 1.0M HCl. The mixture was extracted with EtOAc and the combined extracts were extracted with H₂Washing with saturated brine, and purifying with Na₂SO₄Drying, filtration and concentration gave (R) -2-tert-butoxycarbonylamino-3- (2, 6-diamino-phenylsulfanyl) -propionic acid (1.0g) which was used without purification.

And step 3: to (R) -2-tert-butoxycarbonylamino-3- (2, 6-diamino-phenyl)To a solution of thio) -propionic acid (1.0g,3.1mmol) in DMF (12mL) was added DIEA (1.6mL,9.1mmol), HOBT. H₂O (859mg,6.2mmol) and HBTU (2.3g,6.2 mmol). Mixing the mixture in N₂Stirred at room temperature under an atmosphere for 3 hours. The reaction is poured into H₂O, and extracted with EtOAc. The organic extracts were combined and washed with 0.5M HCl, H₂Washing with saturated brine, and purifying with Na₂SO₄Drying, filtering and concentrating. The residue was purified by silica gel chromatography to give the title compound (560mg, 59%).

[ (S) -1- ((R) -9-amino-5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-3-ylcarbamoyl) -ethyl]-methyl-carbamic acid tert-butyl ester

Step 1: hydrogen chloride gas was added to ((R) -9-amino-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ] at 0 deg.C][1,4]ThiaazepinesA solution of-3-yl) -carbamic acid tert-butyl ester (560mg,1.8mmol) in dioxane (15mL) was bubbled for 1 min and the reaction was warmed to room temperature. After 1 hour the mixture was concentrated and the residue was taken up in Et₂And O grinding. Filtering the obtained solid, washing with hexane, and drying to obtain (R) -3, 9-diamino-2, 3-dihydro-5H-benzo [ b ]][1,4]Thiaazepines-4-keto dihydrochloride (500 mg.99%).

Step 2: to (R) -3, 9-diamino-2, 3-dihydro-5H-benzo [ b ]][1,4]Thiaazepines-4-Ketone dihydrochloride (500mg, 1)8mmol) in DMF (10mL) was added L-BOC-Ala-OH (396mg,1.9mmol), DIEA (1.2mL,7.2mmol), HOBT. H₂O (489mg,3.6mmol) and HBTU (1.3g,3.6 mmol). After 3 hours, the reaction is run on H₂Diluted O and extracted with EtOAc. The combined extracts were washed with 0.5M HCl, H₂Washing with saturated brine, and purifying with Na₂SO₄Drying, filtering and concentrating. The residue was purified by silica gel chromatography to give (S) -1- ((R) -9-amino-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b)][1,4]Thiaazepines-3-ylcarbamoyl) -ethyl-methyl-carbamic acid tert-butyl ester (660mg, 94%).

And step 3: to (S) -1- ((R) -9-amino-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b)][1,4]Thiaazepines(iv) -3-ylcarbamoyl) -ethyl-methyl-carbamic acid tert-butyl ester (1.5g,3.9mmol) in DMF (25mL) was added K₂CO₃(2.6g,19.0mmol) and a solution of 1-bromomethyl-naphthalene (631mg,2.9mmol) in DMF (10mL) was added dropwise. After 36 h, the mixture was diluted with saturated aqueous citric acid and extracted with EtOAc. The combined extracts are washed with H₂Washing with saturated brine, and purifying with Na₂SO₄Drying, filtering and concentrating. The residue was purified by silica gel chromatography to give the title compound (1.3g, 81%).

1-benzyl-2-fluoro-3-nitro-benzene

To a mixture of 1-bromo-2-fluoro-3-nitrobenzene (800mg,3.6mmol), potassium benzyltrifluoroborate (2.2g,10.9mmol) and Cs₂CO₃(3.6g,10.9mmol) in dioxane/H₂To a mixture of O (10:1,18mL) was added [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (60mg,2 mol%) and the mixtureHeat to 100 ℃ for 8 hours. The mixture was cooled to room temperature and washed with H₂Diluted O and extracted with EtOAc. The combined extracts are washed with H₂Washing with saturated brine, and purifying with Na₂SO₄Drying, filtering and concentrating. The residue was purified by silica gel chromatography to give the title compound (520mg, 62%).

2- (dibenzylamino) -2- (1-hydroxycyclohexyl) acetic acid

Step 1: a solution of ethyl 2- (dibenzylamino) acetate (4.92g,17.4mmol, Eq:1.2) in THF (40mL) was added to a solution of LDA in THF at-40 ℃. After 15 min the mixture was cooled to-78 ℃ and a solution of cyclohexanone (1.42g,1.5mL,14.5mmol, Eq:1.00) in THF (10mL) was added. After 2 hours, 10mL of saturated NH were added₄Cl and the mixture was warmed to room temperature. After 2 hours, the mixture is washed with H₂Diluted O and extracted with EtOAc. The combined extracts are washed with H₂O washing with Na₂SO₄Drying and concentrating. The residue was purified by flash chromatography to give 2- (dibenzylamino) -2- (1-hydroxycyclohexyl) acetate as a colorless oil (1.63g, 30%). MS m/z 382.1 (MH)⁺)。

Step 2: KOH (1.44g,25.6mmol, Eq:6) in H₂A solution in O (20mL) was added to a solution of ethyl 2- (dibenzylamino) -2- (1-hydroxycyclohexyl) acetate (1.63g,4.27mmol, Eq:1.00) in MeOH (60mL) and the mixture was heated to 60 ℃. After 18 hours, the reaction was cooled to room temperature and 100mL of H was used₂And (4) diluting with oxygen. Using saturated KHSO₄The pH of the reaction was adjusted to about 4 and extracted with EtOAc. The combined extracts are washed with H₂O washing with Na₂SO₄Dried and concentrated to give the title compound as a white foam (1.44g, 95%) which was used without purification. MS m/e 354.1 (MH)⁺)。

3-amino-3H-spiro [ benzo [ b ]][1,4]Oxa nitrogenHetero compound-2,1' -cyclohexane]-4(5H) -one

Step 1: 2- (dibenzylamino) -2- (1-hydroxycyclohexyl) acetic acid (0.70g,1.98mmol, Eq:1.00) and 1-fluoro-2-nitrobenzene (293mg, 219. mu.l, 2.08mmol, Eq:1.05) were dissolved in THF (10mL) and 0.5M potassium bis (trimethylsilyl) amide in toluene (8.71mL,4.36mmol, Eq:2.2) was added. The mixture was heated to 60 ℃. After 1 hour the mixture was cooled to room temperature and 0.2mL 1-fluoro-2-nitrobenzene and an additional 9mL potassium bis (trimethylsilyl) amide (0.5M in toluene) were added and the mixture was stirred at 60 ℃ for 90 minutes. Subjecting the mixture to hydrogenation with H₂Diluting with O, and adding saturated KHSO₄Acidified and extracted with EtOAc. The combined extracts are washed with H₂Washing with saturated brine, and purifying with Na₂SO₄Drying and concentrating. The residue was purified by flash chromatography to give 2- (1- (2-aminophenoxy) cyclohexyl) -2- (dibenzylamino) acetic acid as a light brown oil (0.80g, 85%). MS m/z 475.1 (MH)⁺)。

Step 2: 2- (dibenzylamino) -2- (1- (2-nitrophenoxy) cyclohexyl) acetic acid (0.8g,1.69mmol, Eq:1.00), NH₄Cl (180mg,3.37mmol, Eq:2) and Zn (1.71g,26.1mmol, Eq:15.5) were mixed with MeOH (35.0mL) to give a grey suspension and the mixture was heated to 65 ℃ for 90 min. The mixture was filtered through celite, the filtrate was concentrated and taken up in saturated aqueous NaOAc and Et₂And (4) distributing among the O. Separating the phases and subjecting the organic layer to H₂Washing with saturated brine, and purifying with Na₂SO₄Drying and concentration gave 2- (1- (2-aminophenoxy) cyclohexyl) -2- (dibenzylamino) acetic acid as a light brown solid (0.6365g, 85%). MS m/z 475.1 (MH)⁺)。

And step 3: 2- (1- (2-aminophenoxy) cyclohexyl) -2- (dibenzyl ammonia)Yl) acetic acid (0.6365g,1.43mmol, Eq:1.00), HOBT. H₂A mixture of O (307mg,2.00mmol, Eq:1.4) and EDCI (274mg,1.43mmol, Eq:1.00) in DMF (12mL) was stirred at room temperature for 1h and the mixture was diluted with EtOAc. The mixture was washed with saturated NaHCO₃Washing with saturated brine, and purifying with Na₂SO₄Drying and concentrating. The residue was purified by flash chromatography to give 3- (dibenzylamino) -3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,1' -cyclohexane]-4(5H) -one as an off-white solid (0.387g, 64%). MS m/z 427.1 (MH)⁺)。

And 4, step 4: reacting 3- (dibenzylamino) -3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,1' -cyclohexane]-4(5H) -one (0.3875g, 908. mu. mol, Eq:1.00) and 20% Pd (OH)₂/C (0.47g,3.35mmol, Eq:3.68) was mixed with MeOH (100mL) and acetic acid (0.1mL) and the mixture was hydrogenated at 50 psi. After 18 hours, the mixture was filtered through celite, the filtrate was concentrated, and the residue was dissolved in MeCN/H₂O and lyophilized to give the title compound as an off-white solid (0.297g, 100%) which was used without purification. MS m/z 247.0 (MH)⁺)

The compounds in table 1 were prepared by a similar method.

TABLE 1

Methyl- (tert-butyl) - (2S) -1-oxo-1- ((3R) - (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,1' -cyclohexane]-3-ylamino)) propan-2-ylcarbamate and methyl- (tert-butyl) - (2S) -1-oxo-1- ((3S) - (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,1' -cyclohexane]-3-ylamino)) propan-2-ylcarbamate

Reacting 3-amino-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,1' -cyclohexane]-4(5H) -one (0.29g,1.18mmol, Eq:1.00), BOC-N-Me-Ala-OH (287mg,1.41mmol, Eq:1.2) and TEA (357mg, 492. mu.l, 3.53mmol, Eq:3) were mixed with DMF (10mL) and HBTU (536mg,1.41mmol, Eq:1.2) and HOBT. H were added₂A solution of O (216mg,1.41mmol, Eq:1.2) in DMF (10 mL). After 1h, the mixture was diluted with EtOAc and saturated with 1:1 NaHCO₃Washing with saturated saline solution and saturated saline solution, and adding Na₂SO₄Drying and concentrating. The residue was purified by flash chromatography to give the two diastereomers, methyl- (tert-butyl) - (2S) -1-oxo-1- ((3R) - (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,1' -cyclohexane]-3-ylamino)) propan-2-ylcarbamate, which is eluted first, and methyl- (tert-butyl) - (2S) -1-oxo-1- ((3S) - (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,1' -cyclohexane]-3-ylamino)) propan-2-ylcarbamate, which is eluted next. Dissolving each diastereoisomer in MeCN/H respectively₂O, and lyophilized to give each diastereomer as a white solid: methyl- (tert-butyl) - (2S) -1-oxo-1- ((3R) - (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,1' -cyclohexane]-3-ylamino)) propan-2-ylcarbamate (98.2mg) and methyl- (tert-butyl) - (2S) -1-oxo-1- ((3S) - (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,1' -cyclohexane]-3-ylamino)) propan-2-ylcarbamate (44.1 mg).

Methyl ((S) -1-oxo-1- ((S) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester

HBTU (43.2g,114mmol, Eq:1.2) and HOBT. H₂A solution of O (17.4g,114mmol, Eq:1.2) in DMF (300mL) was added to 3-amino-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-4(5H) -keto hydrochloride (27g,94.8mmol, Eq:1.00), BOC-N-Me-Ala-OH (23.1g,114mmol, Eq:1.2), and TEA (38.4g,52.9mL,379mmol, Eq:4) in a mixture of DMF (300 mL). After 18 h, the mixture was poured into saturated brine (750mL) and the mixture was extracted with EtOAc. The combined extracts were saturated with 1:1 NaHCO₃Washing with saturated saline solution and saturated saline solution, and adding Na₂SO₄Dried and concentrated. The residue was purified by flash chromatography to give a mixture of diastereomers (36.2g), which was purified by flash chromatographyAs a bright yellow solid. The diastereomers were separated as follows: by supercritical liquid chromatography (SFC) using a Daicel AD column (5X25cm) with 15% MeOH/CO₂Elution, detection at 200 mL/min and 220nM, 100bar back pressure and 35 ℃ oven temperature. The first diastereomer eluted from the column to give the title compound (15.29g, 37%) as an off-white foam. MS m/z 434.1 (MH)⁺)。

3-amino-2, 2-dimethyl-2, 3-dihydrobenzo [ b ]][1,4]Thiaazepines-4(5H) -one

2, 2-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]ThiaazepinesBenzyl-3-ylcarbamate (0.67g,1.88mmol, Eq:1.00, WO96/11940) and 33% HBr/HOAc (9mL,54.7mmol, Eq:29) were combined to give a yellow solution. After 75 min the mixture was taken up in 100mL Et₂And (4) diluting with oxygen. The resulting precipitate was collected by filtration and washed with Et₂O washes and adds to 100mL saturated NaHCO₃In (1). The mixture was extracted with EtOAc and DCM. Subjecting the combined extracts to Na₂SO₄Drying, filtration and concentration of the filtrate gave the title compound as a white solid (0.3370g, 81%) which was used without purification. MS m/z 379.0 (MH)⁺)。

(S) -1- ((S) -2, 2-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester and (S) -1- ((R) -2, 2-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester

Reacting 3-amino-2, 2-dimethyl-2, 3-dihydrobenzo [ b ]][1,4]Thiaazepines-4(5H) -one (0.337g,1.52mmol, Eq:1.00), BOC-N-Me-Ala-OH (370mg,1.82mmol, Eq:1.2) and TEA (460mg, 634. mu.l, 4.55mmol, Eq:3) were mixed with DMF (5mL), HBTU (690mg,1.82mmol, Eq:1.2) and HOBT. H were added₂A solution of O (279mg,1.82mmol, Eq:1.2) in DMF (5 mL). After 15 h, the mixture was diluted with EtOAc and saturated with 1:1 NaHCO₃Washing with saturated saline solution and saturated saline solution, and adding Na₂SO₄Drying and concentrating. The residue was purified by flash chromatography. Two diastereomers were separated, (S) -1- ((S) -2, 2-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (elution first, 0.241g, white foam) and (S) -1- ((R) -2, 2-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (elution second, 0.207g, white foam).

(S) -1- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester

Reacting 3-amino-2, 3-dihydro-1, 5-benzothiazepine-4(5H) -keto hydrochloride (1.0g,5.15mmol, Eq:1.00), BOC-N-Me-Ala-OH (1.26g,1.62mmol, Eq:1.2) and TEA (2.2mL,15.45mmol, Eq:3.00) were dissolved in DMF (30mL) and HOBT. H was added₂O (697mg,5.14mmol, Eq:1.20) and HBTU (2.34g,6.18mmol, Eq: 1.20). After 1h 20 min the mixture was diluted with 1N HCl and extracted with EtOAc. The organic extract was washed with 1N NaOH, saturated brine, and Na₂SO₄Dried and concentrated to give the title compound (1.66g, 85% yield) which was used without purification.

3-amino-8, 9-difluoro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-4(5H) -one

Step 1: A1M solution of potassium bis (trimethylsilyl) amide in THF (4.22mL,4.22mmol, Eq:3.00) was added to a solution of 2- (dibenzylamino) -2- (4-hydroxytetrahydro-2H-pyran-4-yl) -acetic acid (0.5g,1.41mmol, Eq:1.00) in THF (10mL) at room temperature and the mixture was stirred for 15 minutes. The mixture was cooled to 0 deg.C, 2,3, 4-trifluoronitrobenzene (1.25g,0.83mL,7mmol, Eq:5.00) was added, and the mixture was stirred at 0 deg.C for 45 minutes. The mixture is washed with H at 0 deg.C₂O diluted and warmed to room temperature. With saturated KHSO₄The pH was adjusted to 2-3 and the mixture was extracted with EtOAc. The combined extracts were washed with saturated brine and then with Na₂SO₄Drying, concentrating, and purifying the residue by flash chromatography to give 2- (dibenzylamino) -2- (4- (5, 6-difluoro-2-nitrophenoxy)tetrahydro-2H-pyran-4-yl) -acetic acid (0.23g, 32% yield). MS m/z 513.0 (MH)⁺)。

Step 2: reacting NH₄Cl (48.0mg,0.90mmol, Eq:2) and Zn powder (440mg,6.73mmol, Eq:15) were added to a solution of 2- (dibenzylamino) -2- (4- (2, 3-difluoro-6-nitrophenoxy) tetrahydro-2H-pyran-4-yl) -acetic acid (230mg, 449. mu. mol, Eq:1.00) in MeOH (10mL) and the mixture was heated to 65 ℃. After 2 hours the mixture was filtered through celite. The filtrate was concentrated and partitioned between 1N NaOAc and EtOAc. Subjecting the organic layer to Na₂SO₄Drying and then concentrating under reduced pressure to give [4- (6-amino-2, 3-difluoro-phenoxy) -tetrahydro-pyran-4-yl]-dibenzylamino-acetic acid (185mg), used without purification.

And step 3: HOBT.H₂O (70.5mg, 460. mu. mol, Eq:1.2) and EDCI (88.2mg, 460. mu. mol, Eq:1.2) were added to [4- (6-amino-2, 3-difluoro-phenoxy) -tetrahydro-pyran-4-yl]-dibenzylamino-acetic acid (185mg, 383. mu. mol, Eq:1.00) in DMF (5 mL). The mixture was stirred at room temperature overnight with H₂Diluted O and extracted with EtOAc. The combined extracts were washed with saturated brine and then with Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography to give 3- (dibenzylamino) -8, 9-difluoro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-4(5H) -one (102mg, 57% yield). MS m/z 465.0 (MH)⁺)。

And 4, step 4: reacting 3- (dibenzylamino) -8, 9-difluoro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-4(5H) -one (100mg, 215. mu. mol, Eq:1.00) was added to MeOH (10mL) and the mixture was warmed to 40 ℃ to give a bright yellow suspension. Add 20% Pd (OH)₂C (100mg, 215. mu. mol, Eq:1.00), degassing the mixture and reacting at room temperature in H₂Stirred for 6.5 hours. Will be provided withThe mixture was filtered through celite and concentrated under reduced pressure to give 3-amino-8, 9-difluoro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]4(5H) -one (60mg, 98% yield) as a colorless oil, which was used without purification. MS m/z 285.0 (MH)⁺)

(2S) -1-oxo-1- ((3R) - (8, 9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester and (2S) -1-oxo-1- ((3S) - (8, 9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester

HOBT.H₂O (38.8mg, 253. mu. mol, Eq:1.2) and HBTU (96.1mg, 253. mu. mol, Eq:1.2) were added to 3-amino-8, 9-difluoro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] s][1,4]Oxazazepine-2,4' -pyrane]-4(5H) -one (60mg, 211. mu. mol, Eq:1.00), BOC-N-Me-Ala-OH (51.5mg, 253. mu. mol, Eq:1.2) and TEA (53.4mg, 74.2. mu.l, 528. mu. mol, Eq:2.5) in a mixture of DMF (3 mL). After 2 hours, the mixture is washed with H₂O diluted/1N HCl and extracted with EtOAc. The combined extracts were washed with 1N NaOH, saturated brine and Na₂SO₄Drying and concentrating. The residue was purified by flash chromatography to give (2S) -1-oxo-1- ((3R) - (8, 9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b)][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester (eluting first, 40mg, 40%) and (2S) -1-oxo-1- ((3S) - (8, 9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester (elution second, 42mg, 42% yield).

3-amino-9-fluoro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-4(5H) -one

To prepare 3-amino-8, 9-difluoro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-4(5H) -one similar procedure except that the mixture was hydrogenated in step 4 overnight to convert 2, 3-difluoronitrobenzene (4.48g,2.98mL,28.1mmol) to the title compound as an off-white solid (480mg) which was used without purification. MS m/z 266.9 (MH)⁺)

(2S) -1-oxo-1- ((3R) - (9-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester and (2S) -1-oxo-1- ((3S) - (9-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester

To prepare (2S) -1-oxo-1- ((3R) - (8, 9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester and (2S) -1-oxo-1- ((3S) - (8, 9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester the similar procedure except that the mixture is stirred for 1 hour and 3-amino-9-fluoro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] is][1,4]Oxazazepine-2,4' -pyrane]Conversion of-4 (5H) -one (80mg, 300. mu. mol, Eq:1.00) and BOC-N-Me-Ala-OH (73.3mg, 361. mu. mol, Eq:1.2) to (2S) -1-oxo-1- ((3R) - (9-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester (elution first, 64mg, 47%, MS m/z 492.0 (MH)⁺) And (2S) -1-oxo-1- ((3S) - (9-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester (second elution, 49mg, 36%, MS m/z 492.0 (MH)⁺))。

(2S) -1-oxo-1- ((3R) - (9-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) but-2-yl (methyl) carbamate tert-butyl ester and (2S) -1-oxo-1- ((3S) - (9-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) but-2-yl (methyl) carbamic acid tert-butyl ester

To prepare (2S) -1-oxo-1- ((3R) - (8, 9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester and (2S) -1-oxo-1- ((3S) - (8, 9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester the similar procedure except that the mixture is stirred for 1 hour and 3-amino-9-fluoro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] is][1,4]Oxazazepine-2,4' -pyrane]Conversion of (4 (5H) -one (80mg, 300. mu. mol, Eq:1.00) and (S) -2- (tert-butoxycarbonyl (methyl) amino) butanoic acid (78mg, 361. mu. mol, Eq:1.20) to (2S) -1-oxo-1- ((3R) - (9-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) but-2-yl (methyl) carbamic acid tert-butyl ester (elution first, 50mg, 36%, MS m/z 488.0(MH +)) and (2S) -1-oxo-1- ((3S) - (9-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b [ ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) but-2-yl (methyl) carbamic acid tert-butyl ester (second elution, 40mg, 36%, MS m/z 488.0 (MH)⁺))。

3-amino-8-fluoro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-4(5H) -one

To prepare 3-amino-8, 9-difluoro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-4(5H) -one similar procedure except that 2.5eq.NH was used in step 2₄Cl and 12eq.zn, the mixture was stirred for 6 hours in step 3 and hydrogenated overnight in step 4 to convert 2, 4-difluoronitrobenzene (2.69g,1.79mL,16.9mmol) to the title compound as an off-white solid (110mg) which was used without purification.

(2S) -1-oxo-1- ((3R) - (8-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester and (2S) -1-oxo-1- ((3S) - (8-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester

To prepare (2S) -1-oxo-1- ((3R) - (8, 9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester and (2S) -1-oxo-1- ((3S) - (8, 9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester the similar procedure except that the mixture is stirred for 1.5 hours and 3-amino-8-fluoro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] is added][1,4]Oxazazepine-2,4' -pyrane]Conversion of-4 (5H) -one (59mg, 222. mu. mol, Eq:1.00), BOC-N-Me-Ala-OH (54.0mg, 266. mu. mol, Eq:1.2) to (2S) -1-oxo-1- ((3R) - (8-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester (elution first, 42mg, 42%, MS M/z 474.0(M + Na)⁺) And (2S) -1-oxo-1- ((3S) - (8-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester (eluting second,42mg,42％,MS m/z 474.0(M+Na⁺))。

(2S) -1-oxo-1- ((3R) - (8-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) but-2-yl (methyl) carbamic acid tert-butyl ester and (2S) -1-oxo-1- ((3S) - (8-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) but-2-yl (methyl) carbamic acid tert-butyl ester

To prepare (2S) -1-oxo-1- ((3R) - (8, 9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester and (2S) -1-oxo-1- ((3S) - (8, 9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester the similar procedure except that the mixture is stirred for 1.5 hours and 3-amino-8-fluoro-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] is added][1,4]Oxazazepine-2,4' -pyrane]-4(5H) -one (54mg, 203. mu. mol, Eq:1.00), (S) -2- (tert-butoxycarbonyl (methyl) amino) butanoic acid (52.9mg, 243. mu. mol, Eq:1.2) was converted to (2S) -1-oxo-1- ((3R) - (8-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) but-2-yl (methyl) carbamic acid tert-butyl ester (elution first, 40mg, 42%, MS M/z 488.0(M + Na)⁺) And (2S) -1-oxo-1- ((3S) - (8-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) but-2-yl (methyl) carbamic acid tert-butyl ester (second elution, 42mg, 44%, MS M/z 488.0(M + Na)⁺)。

BOC-N- (methyl-d 3) -Ala-OH

Sodium hydride (1.27g,31.7mmol, Eq:3.00) was added to a mixture of (S) -2- (tert-butoxycarbonylamino) propionic acid (2g,10.6mmol, Eq:1.00) and iodomethane-d 3(12.3g,5.26mL,84.6mmol, Eq:8.00) in THF (40mL) at 0 deg.C, and the mixture was stirred for 5 minutes and then at room temperature. After 4 hours the mixture was diluted with water and Et₂And (4) extracting. The pH of the aqueous mixture was adjusted to 2 and Et₂The pH was adjusted to O, and the combined extracts were washed with brine and Na₂SO₄Drying and concentration gave the title compound as a colorless oil which solidified on standing (2.1g, 96% yield) and was used without purification.

Methyl-d 3- (tert-butyl) - (2S) -1-oxo-1- ((3R) - (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-ylcarbamate and methyl-d 3- (tert-butyl) - (2S) -1-oxo-1- ((3S) - (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-ylcarbamate

To prepare (2S) -1-oxo-1- ((3R) - (8, 9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester and (2S) -1-oxo-1- ((3S) - (8, 9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester the similar procedure was followed except that the mixture was stirred for 2.5 hours and 3-amino-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] is][1,4]Oxazazepine-2,4' -pyrane]-4(5H) -keto hydrochloride (80mg, 281. mu. mol, Eq:1.00), BOC-N- (methyl-d 3) -Ala-OH (69.5mg, 337. mu. mol, Eq:1.2) to methyl-d 3- (tert-butyl) - (2S) -1-oxo-1- ((3R) - (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-ylcarbamate (elution first, 41mg, 33%, MS M/z 459.1(M + Na)⁺) And methyl-d 3- (tert-butyl) - (2S) -1-oxo-1- ((3S) - (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-ylcarbamate (second elution, 50mg, 41%, MS M/z 459.1(M + Na)⁺))。

6-bromo-1-chloromethyl-2- (methoxy-d 3) -naphthalene

Step 1: iodomethane-d 3(3.9g,1.67mL,26.9mmol, Eq:1.2) was added to 6-bromo-2-naphthol (5g,22.4mmol, Eq:1.00) and K₂CO₃(4.65g,33.6mmol, Eq:1.5) in DMF (100mL) and the mixture was stirred overnight. Subjecting the mixture to hydrogenation with H₂The resulting precipitate was filtered, dissolved in EtOAc and washed successively with 1N NaOH and brine. Subjecting the organic solution to Na₂SO₄Drying and concentration gave 6-bromo-2- (d 3-methoxy) -naphthol as an off-white solid (5g, 93%) which was used without purification.

Step 2: A1.0M solution of titanium tetrachloride in DCM (18.3mL,18.3mmol, Eq:2.2) and dichloromethyl methyl ether (1.05g, 817. mu.l, 9.16mmol, Eq:1.1) were mixed with DCM (70mL) and the solution was cooled to 0 ℃. A solution of 6-bromo-2- (d 3-methoxy) -naphthol (2g,8.33mmol, Eq:1.00) in DCM (10mL) was added and the mixture was warmed to room temperature. After 2.5 h the mixture was diluted with 1N HCl (150mL) and extracted with DCM. The combined extracts were washed with saturated brine and then with Na₂SO₄Drying and concentration gave 6-bromo-2- (d 3-methoxy) -naphthalene-1-carbaldehyde (2.11g, 95%) which was used without purification.

And step 3: sodium borohydride (1.19g,31.3mmol, Eq:4.00) was added in three portions to a solution of 6-bromo-2- (d 3-methoxy) -naphthalene-1-carbaldehyde (2.1g,7.83mmol, Eq:1.00) in MeOH (50mL) at room temperature. After 10 minutes, the mixture was washed with 1N HCl and H₂O dilution, filtration of the resulting precipitate, and purification by flash chromatography gave (6-bromo-2- (d 3-methoxy) -naphthalen-1-yl) -methanol (1.38g, 65%). MS M/z 253.9 (M-H)₂O+H)⁺。

And 4, step 4: pyridine (606mg, 618. mu.l, 7.66mmol, Eq:1.5) and thionyl chloride (912mg, 559. mu.l, 7.66mmol, Eq:1.5) were added to (6-bromo-2- (d 3-methoxy) -naphthalen-1-yl)Methanol (1.38g,5.11mmol, Eq:1.00) in DCM (30mL) and the mixture was stirred at room temperature overnight. The mixture was washed with saturated NaHCO₃Diluted, extracted with DCM and the organic extracts are taken over Na₂SO₄Drying and concentration gave the desired compound as an off-white solid (1.4g, 95% yield).

2- (2-chloro-3- (hydroxymethyl) -1H-indol-1-yl) benzonitrile

Step 1: NaH (60% in mineral oil, 223mg,5.57mmol, Eq:1.00) was added to a solution of 2-chloro-1H-indole-3-carbaldehyde (1g,5.57mmol, Eq:1.00) in 1-methyl-2-pyrrolidone (NMP,5mL) in a microwave bottle. After 10 min, 2-fluorobenzonitrile (3.37g,3.02mL,27.8mmol, Eq:5) was added. The reaction was sealed and heated at 150 ℃. After 16 hours the mixture was saturated with NH₄The Cl solution was diluted, extracted with EtOAc, and the combined extracts were concentrated to give a residue which was purified by silica gel chromatography to give 2- (2-chloro-3-formyl-1H-indol-1-yl) benzonitrile (120mg, 8%) as a light brown solid.

Step 2: NaBH is reacted at 0 DEG C₄(6mg, 159. mu. mol, Eq:0.387) was added to a solution of 2- (2-chloro-3-formyl-1H-indol-1-yl) benzonitrile (115mg, 410. mu. mol, Eq:1.00) in DCM (3mL) and MeOH (3.00mL), and the mixture was brought to room temperature. After 2 hours and 15 minutes the mixture was saturated with NH₄Diluted with Cl, extracted with DCM and the extract concentrated to give the title compound (116mg, 100%) which was used without purification.

2- (4- (hydroxymethyl) -1H-indol-1-yl) benzonitrile

Step 1: NaH (60% in mineral oil, 303mg,7.58mmol, Eq:1.1) was added at 0 deg.CTo a solution of 1H-indole-4-carbaldehyde (1g,6.89mmol, Eq:1.00) in DMF (12 mL). After 10 minutes, the mixture was warmed to room temperature and sonicated for 2 minutes. 2-fluorobenzonitrile (918mg, 822. mu.l, 7.58mmol, Eq:1.1) was added, and the mixture was sonicated for 3 minutes. After 3 hours the mixture was saturated with NH₄Dilute Cl, extract with EtOAc, and combine extracts with H₂O wash and concentrate. The residue was taken up in hexane/Et₂Trituration with O afforded 2- (4-formyl-1H-indol-1-yl) benzonitrile (1.2g, 70.7%) as a gray solid.

Step 2: NaBH is reacted at 0 DEG C₄(50mg,1.35mmol Eq:0.4) was added to a solution of 2- (4-formyl-1H-indol-1-yl) benzonitrile (810mg,3.29mmol, Eq:1.00) in EtOH (30mL) and DCM (15mL) and the mixture was warmed to room temperature. After 3 hours, the mixture was concentrated to remove DCM. The resulting mixture was washed with saturated NH₄Dilute Cl, extract with DCM, and concentrate the combined extracts. The residue was purified by silica gel chromatography to give the title compound (810mg, 99%) as a white solid.

(2-chloro-1- (phenylsulfonyl) -1H-indol-3-yl) methanol

Step 1: mixing Cs₂CO₃(996mg,3.06mmol) was added to a solution of 2-chloro-1H-indole-3-carbaldehyde (0.5g,2.78mmol) and benzenesulfonyl chloride (0.39mL,3.06mmol) in DMF (5mL) and the mixture was heated to 60 ℃. After 3 hours the mixture was diluted with brine and extracted with EtOAc. The combined extracts were passed over MgSO₄Drying, filtering and concentrating. The residue was purified by silica gel chromatography to give 2-chloro-1- (phenylsulfonyl) -1H-indole-3-carbaldehyde (33mg, 5%) as a white solid.

Step 2: reacting NaBH₄(7.81mg,0.206mmol) was added to a solution of 2-chloro-1- (phenylsulfonyl) -1H-indole-3-carbaldehyde (33mg,0.103mmol) in DCM/MeOH 1:1(10 mL). After 16 hours, theSaturated NH for the mixture₄Cl and EtOAc dilution, separation of the organic layer and application of H₂O washing over MgSO₄Drying, filtration and concentration of the filtrate gave the title compound (33mg, 99%) which was used without purification.

(2- (methylsulfonyl) isoindolin-4-yl) methanol

Step 1: DIEA (0.438g,3.39mmol) was added to a solution of isoindoline-4-carboxylic acid methyl ester (0.5g,2.82mmol) and methanesulfonyl chloride (0.36g,3.1mmol) in DCM (10 mL). After 12h the mixture was concentrated and the residue was purified by silica gel chromatography to give methyl 2- (methylsulfonyl) isoindoline-4-carboxylate (0.37g 52%) as an off-white solid.

Step 2: lithium aluminum hydride (LAH,1M in THF, 2mL,2.0mmol) was added to a solution of methyl 2- (methylsulfonyl) isoindoline-4-carboxylate in THF (15 mL). After 10 hours the mixture was diluted with 5% NaOH solution and extracted with EtOAc. The combined organic extracts were passed over MgSO₄Dried and concentrated. The residue was recrystallized from DCM to give the title compound (200mg, 61%) as a grey solid.

4- (bromomethyl) -6-fluoro-1-methylquinolin-2 (1H) -one

Step 1: MeI (130mg,0.914mmol) was added to 6-fluoro-4-methylquinolin-2 (1H) -one (135mg,0.762mmol) and Cs₂CO₃(248mg,0.762mmol) in DMF (10 mL). The reaction mixture was stirred overnight and over Na₂CO₃The solution was partitioned with EtOAc. The organic layer was washed with saturated brine and then with MgSO 2₄Dried and concentrated. Washing the obtained solid with hexane, and drying to obtain6-fluoro-1, 4-dimethylquinolin-2 (1H) -one (100mg, 68%) as a white solid, which was used without purification.

Step 2: 2, 2' -azobis (2-methylpropionitrile) (AIBN,17.2mg,0.105mmol) and N-bromosuccinimide (NBS,97.7mg,0.549mmol) were added to 6-fluoro-1, 4-dimethylquinolin-2 (1H) -one (100mg,0.523mmol) in CCl at 70 deg.C₄(10 mL). After 1 hour, another 2eq. nbs and 0.4eq. aibn were added and the mixture was heated at 70 ℃ for 1 hour. The mixture was concentrated and the residue was purified by preparative TLC to give the desired title compound (55mg, 31%) as a white solid.

1-benzyl-2-chloro-1H-indole-3-methanol

Reacting NaBH₄(71.5mg,1.89mmol) was added to a solution of 1-benzyl-2-chloro-1H-indole-3-carbaldehyde (0.51g,1.89mmol) in MeOH (10 mL). After 12 hours the mixture was taken up in saturated NH₄Dilute Cl and extract with EtOAc. The combined extracts are washed with H₂O washing over MgSO₄Drying, filtration and concentration gave the title compound (350mg, 68%) as a white solid which was used without purification.

(1-Ethyl-1H-indol-4-yl) methanol

NaBH is reacted at 0 DEG C₄(49.8mg,1.32mmol, Eq:0.3) was added to a solution of 1-ethyl-1H-indole-4-carbaldehyde (800mg,4.39mmol, Eq:1.00) in EtOH (30mL) and DCM (15mL) and the mixture was warmed to room temperature and stirred overnight. The mixture was concentrated to remove DCM and the resulting mixture was washed with NH₄Dilute Cl, extract with DCM, and concentrate. The residue was purified by silica gel chromatography to give the title compound (700mg, 91%) as yellowAn oil.

2- (3- (bromomethyl) -1H-indazol-1-yl) benzonitrile

Step 1: mixing Cs₂CO₃(1.56g,4.8mmol) was added to a solution of 3-methylindazole (0.634g,4.8mmol) and 2-fluorobenzonitrile (1mL,9.6mmol) in DMF (20mL) and the mixture was stirred at room temperature for 12 h. The mixture was washed with saturated NH₄Cl diluted to form a precipitate. Filtering the solid with H₂O, hexanes and dried in vacuo to give 2- (3-methyl-1H-indazol-1-yl) benzonitrile (1g, 89%) which was used without purification.

Step 2: AIBN (141mg,0.857mmol) and NBS (839mg,4.72mmol) are added to 2- (3-methyl-1H-indazol-1-yl) benzonitrile (1g,4.29mmol) in CCl₄(20mL) and the mixture was heated to reflux for 2 hours. The mixture was concentrated and the residue was purified by silica gel chromatography to give the title compound (1.25g, 93%) as an off-white solid.

3- (bromomethyl) -1- (2-cyanophenyl) -1H-indole-2-carbonitrile

Step 1: 3-methyl-1H-indole-2-carbonitrile (500mg,3.2mmol), 2-fluorobenzonitrile (388mg,3.2mmol) and Cs₂CO₃A mixture of (1.05g,3.2mmol) in DMF (10mL) was heated at 60 ℃ overnight. Pouring the mixture into H₂O, a precipitate is formed. The solid was collected by filtration and washed with H₂O and hexane were washed and dried under vacuum to give 1- (2-cyanophenyl) -3-methyl-1H-indole-2-carbonitrile (780mg, 94.6%) as an off-white solid, which was used without purification.

Step 2: in a similar manner to that described for the preparation of 3- (bromomethyl) -1- (2-cyanophenyl) -1H-indole-2-carbonitrile step 2, except that the mixture was heated to reflux for 1.5H, 1- (2-cyanophenyl) -3-methyl-1H-indole-2-carbonitrile was converted to the title compound (1.0g, 98%) as an off-white solid.

(S) -2- (benzyloxycarbonyl-ethyl (d5) -amino) -propionic acid

NaH (60% in mineral oil, 480mg,12mmol) was added to a solution of (S) -2- (benzyloxycarbonylamino) propionic acid (0.892g,4mmol) and d 5-iodoethane (5.15g,2.64mL,32mmol) in THF (20mL) and the mixture was heated to 60 ℃ overnight. The mixture was dissolved in EtOAc and H₂Partitioning between O and using H for organic layer₂And O washing. The combined aqueous mixture was acidified to pH 4 with citric acid solution, extracted with EtOAc and the combined organic extracts were passed over MgSO₄Drying, filtration and concentration of the filtrate gave the title compound (440mg, 40%) as a colourless oil, which was used without purification.

2- (3- (bromomethyl) -6-fluoro-1H-indazol-1-yl) benzonitrile

In a similar manner to that described for the preparation of 2- (3- (bromomethyl) -1H-indazol-1-yl) benzonitrile except that in step 1 the mixture is treated with H₂Dilution with O and heating the mixture at reflux overnight in step 2 converted 6-fluoro-3-methyl-1H-indazole (2g,13.3mmol) and 2-fluorobenzonitrile (1.73mL,16mmol) to the title compound (800mg, 61%) as an off-white solid.

2- (3- (bromomethyl) -6-bromo-1H-indazol-1-yl) benzonitrile

In a similar manner to that described for the preparation of 2- (3- (bromomethyl) -1H-indazol-1-yl) benzonitrile except that in step 1 the mixture is treated with H₂Dilution with O and heating the mixture at reflux overnight in step 2 converted 6-bromo-3-methyl-1H-indazole (1g,4.74mmol) and 2-fluorobenzonitrile (0.617mL,5.69mmol) to the title compound (800mg, 64%) as an off-white solid.

(R) -3-amino-2, 2-dimethyl-2, 3-dihydrobenzo [ b ]][1,4]Thiaazepines-4(5H) -one

Step 1: NaHCO is added₃(14.5g,172mmol, Eq:2.5) and H₂O (210mL) was added to a slurry of (R) -2- (benzyloxycarbonylamino) -3-mercapto-3-methylbutyric acid (19.5g,68.8mmol, Eq:1.00) in EtOH (70.0 mL). After 20 minutes the mixture became homogeneous, 1-fluoro-2-nitrobenzene (9.71g,7.00mL,68.8mmol, Eq:1.00) was heated and the mixture was heated under reflux for 6 hours. The mixture was cooled to room temperature and poured into H₂O (300mL) and extracted with MTBE. The aqueous layer was acidified to pH 5 with 1N HCl and Et₂And (4) extracting. The combined organic extracts are passed over Na₂SO₄Drying, filtration and concentration gave (R) -2- (benzyloxycarbonylamino) -3-methyl-3- (2-nitrophenylthio) butanoic acid (18.7g, 67.2%) as a bright yellow oil, which was used without purification.

Step 2: mixing (R) -2- (benzyloxycarbonylamino) -3-methyl-3- (2-nitrophenylthio) butanoic acid (18.3g,45.2mmol, Eq:1.00), NH₄A mixture of Cl (4.84g,90.5mmol, Eq:2) and Zn (45.9g,701mmol, Eq:15.5) in MeOH (500mL) was heated at reflux for 6h and the mixture was filtered through celite. The filter cake was washed with hot MeOH. The filtrate was concentrated and the residue was taken up with H₂O、1:3Et₂Triturate with O/hexane and azeotrope with toluene. The resulting material was dried under vacuum to give (R) -3- (2-aminophenylthio) -2- (benzyloxycarbonylamino) -3-methylbutyric acid (16.9g, 100%) which was used without purification.

And step 3: DIEA (4.14g,5.6mL,32.0mmol, Eq:2) and (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP,12.5g,24.0mmol, Eq:1.5) were added to a solution of (R) -3- (2-aminophenylthio) -2- (benzyloxycarbonylamino) -3-methylbutyric acid (6g,16.0mmol, Eq:1.00) in DMF (200 mL). The mixture was stirred at room temperature overnight and then heated to 80 ℃ for 3 hours. The mixture was poured into saturated NH₄Cl and extracted with EtOAc. The combined extracts are washed with H₂O washing, concentrating, and purifying the residue by silica gel chromatography to obtain (R) -2, 2-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Thiaazepines-benzyl 3-ylcarbamate (3g, 52%).

And 4, step 4: reacting (R) -2, 2-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]ThiaazepinesBenzyl-3-ylcarbamate (0.67g,1.88mmol, Eq:1.00) was added to a solution of 33% HBr in AcOH (13.4g,9mL,54.7mmol, Eq: 29.1). The mixture was stirred at room temperature for 75 minutes and poured into 100mL Et₂In O, a precipitate is formed, which is filtered and Et-treated₂And O washing. The solid material was added to saturated NaHCO₃The mixture was extracted with DCM and the combined extracts were concentrated to give the title compound (343mg, 82.2%) as an oil which was used without purification.

3-cyano-4- (3- (bromomethyl) -1H-indazol-1-yl) benzoic acid methyl ester

In a similar manner to that described for the preparation of 2- (3- (bromomethyl) -1H-indazol-1-yl) benzonitrile except that in step 1 the mixture is treated with H₂O dilution and recrystallization of the product from MeOH and use of 1, 2-dichloroethane in step 2 instead of CCl₄3-methyl-1H-indazole (1g,7.57mmol)) and methyl 3-cyano-4-fluorobenzoate (1.36g,7.57mmol) were converted to the product as a white solid.

(S) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester

Step 1: a solution of BOC-Ser-OH (981mg,4.78mmol) in DMF (5.00mL) was added to a suspension of NaH (60% in mineral oil, 402mg,10.0mmol) in DMF (5 mL). The mixture was stirred at 0 ℃ for 1h and a solution of 2-fluoro-1-nitro-3- (trifluoromethyl) benzene (1g,4.78mmol) in DMF (5mL) was added. After 2 hours the mixture was washed with H₂Diluted O and acidified to pH 3 with 1N HCl. The mixture was extracted with EtOAc and the combined extracts were passed over MgSO₄Drying, filtration and concentration of the filtrate gave a residue which was purified by silica gel level to give (S) -2- (tert-butoxycarbonylamino) -3- (2-nitro-6- (trifluoromethyl) phenoxy) propanoic acid (1.53g, 81%) as a bright yellow solid. MS M/z 417(M + Na)⁺。

Step 2: 10% Pd/C (150mg) was added to a solution of (S) -2- (tert-butoxycarbonylamino) -3- (2-nitro-6- (trifluoromethyl) phenoxy) propanoic acid (1.5g,3.8mmol) in MeOH, and the mixture was taken up in H₂Stirring the mixture. After 4 hours the mixture was filtered through celite, the filter cake was washed with MeOH, and the filtrate was concentrated to give (S) -3- (2-amino-6- (trifluoromethyl) phenoxy) -2- (tert-butoxycarbonylamino) propionic acid (1.23g, 89%) which was used without purification.

And step 3: a solution of (S) -3- (2-amino-6- (trifluoromethyl) phenoxy) -2- (tert-butoxycarbonylamino) propionic acid (1.23g,3.38mmol) and EDCI (803mg,4.19mmol) in DMF (25mL) was stirred at room temperature for 6H, diluted with EtOAc and treated with H₂And O washing. The combined aqueous washes were extracted with EtOAc, and the combined organic solutions were extracted over MgSO₄Drying and filtering. The filtrate was concentrated to give a residue which was purified by silica gel chromatography to give the title compound (1.04g, 89%) as a light brown oil. MS M/z 369(M + Na)⁺。

Methanesulfonic acid (2- (difluoromethoxy) naphthalen-1-yl) methyl ester

Step 1: reacting NaBH₄(255mg,6.73mmol) was added to a suspension of 2- (difluoromethoxy) -1-naphthaldehyde (0.997g,4.49mmol) in EtOH (29.9 mL). After 3 hours the mixture was washed with H₂Diluted with O, extracted with EtOAc and the combined extracts washed with saturated brine (200mL) over Na₂SO₄Drying, filtration and concentration of the filtrate gave a residue which was purified by silica gel chromatography to give (2- (difluoromethoxy) naphthalen-1-yl) methanol (387mg, 39%) as an orange solid.

Step 2: methanesulfonyl chloride (160 μ L,2.07mmol) was added to (2- (difluoromethoxy) naphthalen-1-yl) methanol (387mg,1.73mmol) in CH₂Cl₂(8.63mL) and TEA (505. mu.L, 3.62 mmol). The mixture was washed with CH for 20 hours₂Cl₂Diluting with H₂Washing with saturated brine, and purifying with Na₂SO₄Drying, filtration, and concentration of the filtrate afforded methanesulfonic acid (2- (difluoromethoxy) naphthalen-1-yl) methyl ester (342mg) as a brown oil, which was used without further purification.

Examples

Example 1

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -4-oxo-4, 5-dihydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,1' -cyclohexane]-3-yl) -2- (methylamino) propionamide hydrochloride

Step 1: methyl- (tert-butyl) - (2S) -1-oxo-1- ((3S) - (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,1' -cyclohexane]-3-ylamino)) propan-2-ylcarbamate (44.1mg, 102. mu. mol, Eq:1.00), 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (43.8mg, 153. mu. mol, Eq:1.5), NaI (23.0mg, 153. mu. mol, Eq:1.5) and Cs₂CO₃A mixture of (49.9mg, 153. mu. mol, Eq:1.5) in DMF (2mL) was heated to 65 ℃. After 18 h the mixture was diluted with EtOAc, washed with saturated NaCl and over Na₂SO₄Drying and concentrating. The residue was purified by flash chromatography to give (2S) -1- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -4-oxo-4, 5-dihydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,1' -cyclohexane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (33.7mg, 48%) as white foam. MS m/z 682.0 (MH)⁺)。

Step 2: mixing (2S) -1- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -4-oxo-4, 5-dihydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,1' -cyclohexane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (33.7mg, 49.5. mu. mol, Eq:1.00) and 2M HCl in Et₂O solution (2mL,4.00mmol, Eq:80.8) was mixed with MeOH (0.5mL) to give a colorless solution. After 90 minutes the mixture was concentrated and the residue was dissolved in MeCN/H₂O, and lyophilized to give the title compound (26.0mg, white solid, 85%). MS m/z 582.0 (MH)⁺)。

According to the preparation of methyl- (tert-butyl) - (2S) -1-oxo-1- ((3R) - (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,1' -cyclohexane]-3-ylamino)) propan-2-ylcarbamate, methyl- (tert-butyl) - (2S) -1-oxo-1- ((3S) - (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,1' -cyclohexane]-3-ylamino)) propan-2-ylcarbamate and the preparation of (2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -4-oxo-4, 5-dihydro-3H-spiro [ benzo [ b ] in example 1][1,4]Oxazazepine-2,1' -cyclohexane]The compounds in Table 2 were prepared in analogy to the procedure described for (3-yl) -2- (methylamino) propionamide hydrochloride.

TABLE 2

The intermediates obtained in the preparation of the products listed in table 2 can be derivatized to further provide other compounds, as shown below.

Example 2

6-methoxy-5- (((S) -3- ((S) -2- (methylamino) propionamido) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-5(4H) -yl) methyl) -2-naphthoic acid trifluoroacetate salt

Step 1: reacting (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (0.17g, 249. mu. mol, Eq:1.00), Pd (OAc)₂(2.24mg, 9.96. mu. mol, Eq:0.04) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos) (11.5mg, 19.9. mu. mol, Eq:0.08) were mixed in a 5mL microwave tube, which was evacuated and charged with N₂. MeOH (79.8mg, 101. mu.l, 2.49mmol, Eq:10) and TEA (0.5mL) were added, the tube was purged with CO gas for about 30 seconds, and placed in an oil bath and heated to 70 ℃. After 18 hoursThe mixture was cooled, diluted with EtOAc, and washed with 1N HCl, H₂And washing with saturated brine. Subjecting the organic mixture to Na₂SO₄Drying, concentrating, and purifying the residue by flash chromatography to give 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] b)][1,4]Oxazazepine-2,4' -pyrane]-5(4H) -yl) methyl) -6-methoxy-2-naphthoic acid methyl ester (110.5mg, 67%) as a bright yellow foam. MS m/z 662.3 (MH)⁺)。

Step 2: reacting LiOH & H₂O (35.0mg, 835. mu. mol, Eq:5) in H₂A solution in O (4mL) was added to 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-5(4H) -yl) methyl) -6-methoxy-2-naphthoic acid methyl ester (110.5mg, 167. mu. mol, Eq:1.00) in THF (3 mL). After 18 h, the mixture was poured into 1M HCl (20mL) and extracted with EtOAc. The combined organic extracts are washed with H₂Washing with saturated brine, and purifying with Na₂SO₄Drying and concentrating. The residue was dissolved in MeCN/H₂O and freeze-drying to obtain 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-5(4H) -yl) methyl) -6-methoxy-2-naphthoic acid (95.2mg, 88%) as a white solid, which was used without purification. MS m/z648.2 (MH)⁺)。

And step 3: TFA (0.2mL, 56.4. mu. mol, Eq:1.00) was added to 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-5(4H) -yl) methyl) -6-methoxy-2-naphthoic acid (36.5mg, 56.4. mu. mol, Eq:1.00) in DCM (1 mL). After 1 hour, the mixture was concentrated and the residue was dissolved in MeCN/H₂O, and lyophilized to give the title compound (31.0mg, 83%) as an off-white solid. MS m/z 548.4 (MH)⁺)。

Example 3

6-methoxy-5- (((S) -3- ((S) -2- (methylamino) propionamido) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-5(4H) -yl) methyl-N- (methylsulfonyl) -2-naphthamide trifluoroacetate salt

Methanesulfonamide (10.9mg, 115. mu. mol, Eq:1.25) was added to 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-5(4H) -yl) methyl) -6-methoxy-2-naphthoic acid (59.4mg, 91.7. mu. mol, Eq:1.00), EDCI (22.0mg, 115. mu. mol, Eq:1.25) and DMAP (14.0mg, 115. mu. mol, Eq:1.25) in a mixture of DCM (5 mL). After 2h, the mixture was diluted with DCM, washed with 1M HCl, brine, and Na₂SO₄Drying and concentrating to obtain 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b)][1,4]Oxazazepine-2,4' -pyrane]-5(4H) -yl) Methyl) -6-methoxy-N- (methylsulfonyl) -2-naphthamide (65.4mg) as a white foam, which was used without purification.

Step 2: reacting 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-5(4H) -yl) methyl) -6-methoxy-N- (methylsulfonyl) -2-naphthamide was dissolved in DCM (1mL) and 0.25mL TFA was added. After 90 minutes the mixture was concentrated and the residue was dissolved in MeCN/H₂O, and lyophilized to give the title compound (45.4mg, 67%) as a white solid. MSm/z 625.4 (MH)⁺)。

Example 4

(S) -1- ((R) -2, 2-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] was reacted in a similar manner as described in example 1 except that the mixture was heated for 15 hours in step 1 and stirred for 2 hours in step 2][1,4]ThiaazepinesTert-butyl (0.2067g, 507. mu. mol, Eq:1.00) and 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (217mg, 761. mu. mol, Eq:1.5) 3-ylamino) -1-oxoprop-2-yl (methyl) carbamate were converted to the title compound (49.0mg) as a yellow solid. MS m/z 557.7 (MH)⁺)。

Example 5

(S) -N- (5-benzyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Thiaazepines-3-yl) -2-methylaminopropionamide hydrochloride

Step 1: NaH (60% in mineral oil, 16mg,0.40mmol, Eq:1.50) was added to (S) -1- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] at room temperature][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (100mg,0.26mmol, Eq:1.00) in DMF. After 5 min benzyl bromide (35. mu.L, 0.29mmol, Eq:1.10) was added and the mixture was stirred for 35 min, diluted with 1N HCl and extracted with EtOAc. The organic extract was washed with saturated NaHCO₃Washing with saturated brine, and purifying with Na₂SO₄Drying and concentrating. The residue was purified by flash chromatography to give (S) -1- (5-benzyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (96mg, 77%).

Step 2: et with 1M HCl₂O solution (2mL,2.00mmol, Eq:26.7) was added to (S) -1- (5-benzyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (35mg, 75. mu. mol, Eq:1.00) in MeOH (1 mL). After 2 hours at room temperature, the mixture is cooledThe mixture was stored overnight in the refrigerator, removed from the refrigerator and stirred at room temperature for an additional 2 hours. The mixture was concentrated and the residue was dissolved in MeCN/H₂O, and lyophilized to give the title compound (25mg, 83%). MS m/z 370.0 (MH)⁺)。

Example 6

N- (5-benzyl-1, 1, 4-trioxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Thiaazepines-3-yl) -2- (S) - (methylamino) propionamide hydrochloride

Step 1: 77% 3-Chloroperoxybenzoic acid (mCPBA,72mg, 319. mu. mol, Eq:2.50) was added to (S) -1- (5-benzyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ] b][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (60mg, 128. mu. mol, Eq:1.00) in DCM (1.5 mL). After 45 min, the reaction was diluted with 1N NaOH and extracted with EtOAc. Subjecting the organic extract to Na₂SO₄Drying and concentrating to obtain (S) -1- (5-benzyl-1, 1, 4-trioxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (52mg, 81% yield) as a colorless oil which solidified on standing and was used without purification.

Step 2: et with 1M HCl₂O solution (4mL,4.00mmol, Eq:40) was added to (S) -1- (5-benzyl-1, 1, 4-trioxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester in MeOH (1.5 mL). After 3 hours, the mixture was concentrated and the residue was dissolved in MeCN/H₂O, and lyophilized to give the title compound (45mg, 100%). MS m/z 402.0 (MH)⁺)。

Example 7

N- (5- (4-phenyl-butyl) -1,1, 4-trioxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Thiaazepines-3-yl) -2- (S) - (methylamino) propionamide hydrochloride

Step 1: 77% mCPBA (62mg, 274. mu. mol, Eq:2.50) was added to (S) -1- (4-oxo-5- (4-phenyl-butyl) -2,3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (56mg, 109. mu. mol, Eq:1.00) in DCM (1.5 mL). And the mixture was stirred overnight. The mixture was diluted with 1N NaOH and extracted with EtOAc. The combined extracts were washed with saturated brine and then with Na₂SO₄Drying, filtering and concentrating to obtain (S) -1- (5- (4-phenyl-butyl) -1,1, 4-trioxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]ThiaazepinesTert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (56mg, 95%) was used without purification.

Step 2: in a similar manner to that described in step 2 of example 1, except that the mixture was stirred2 hours, (S) -1- (5- (4-phenyl-butyl) -1,1, 4-trioxo-2, 3,4, 5-tetrahydro-benzo [ b ] is added][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (56mg, 103. mu. mol) was converted to the title compound (48mg, 85%). MSm/z 440.0 (MH)⁺)。

Example 8

N- (5-biphenyl-3-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-3-yl) -2- (S) -methylamino-propionamide hydrochloride

Step 1: mixing (S) -1- (4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (200mg, 527. mu. mol, Eq:1.00), 3-bromomethyl-biphenyl (195mg,0.79mmol, Eq:1.5) and Cs₂CO₃A mixture of (49.9mg, 153. mu. mol, Eq:1.5) in DMF (6mL) was heated to 60 ℃. After 1 hour the mixture was diluted with 1N HCl and extracted with EtOAc. Subjecting the combined extracts to Na₂SO₄Drying, filtering and concentrating. The residue was purified by flash chromatography to give (S) -1- ((5-biphenyl-3-ylmethyl) -4-oxo-2, 3,4, 5-tetrahydro-benzo [ b [][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (264mg, 92%).

Step 2: by the steps of example 1In a similar manner as described in step 2, except that the mixture is stirred for 3 hours, (S) -1- ((5-biphenyl-3-ylmethyl) -4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Thiaazepines-tert-butyl 3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (44mg, 80. mu. mol) was converted to the title compound (38mg, 100%). MS m/z445.9 (MH)⁺)。

Example 9

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3R) -8, 9-difluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b)][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride

(2S) -1-oxo-1- ((3R) - (8, 9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] in a similar manner as described in example 1, except that the mixture is heated at 60 ℃ in step 1 and stirred for 6 hours in step 2][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-yl (methyl) carbamic acid tert-butyl ester (40mg, 85.2. mu. mol) was converted to the title compound (40 mg). MS m/z619.8 (MH)⁺)。

Example 10

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -8, 9-difluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b)][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride

(2S) -1-oxo-1- ((3S) - (8, 9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] in a similar manner as described in example 1, except that the mixture is heated at 60 ℃ in step 1 and stirred for 6 hours in step 2][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-ylcarbamic acid tert-butyl ester (42mg, 89.5. mu. mol) was converted to the title compound (36 mg). MS m/z619.8 (MH)⁺)。

Example 11

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3R) -9-fluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride

(2S) -1-oxo-1- ((3R) - (9-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] is subjected to a similar procedure as described in example 1, except that the mixture is stirred for 4.5 hours in step 1 and overnight in step 2][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-ylcarbamic acidTert-butyl ester (64mg, 142. mu. mol) was converted to the title compound (63 mg). MS m/z601.9 (MH)⁺)。

Example 12

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -9-fluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride

In a similar manner to that described in example 1, except that the mixture was stirred for 4.5 hours in step 1 and overnight in step 2, (2S) -1-oxo-1- ((3S) - (9-difluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] was][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-ylcarbamic acid tert-butyl ester (49mg, 109. mu. mol) was converted to the title compound (49 mg). MS m/z601.9 (MH)⁺)。

Example 13

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3R) -9-fluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) butanamide hydrochloride

In a similar manner to that described in example 1, except that the mixture was stirred for 4 hours in step 1 and overnight in step 2, methyl- (tert-butyl) - (2S) -1-oxo-1- ((3R) - (9-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] is added][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) but-2-ylcarbamate (50mg, 107. mu. mol) was converted to the title compound (57 mg). MS m/z616.0 (MH)⁺)。

Example 14

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -9-fluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) butanamide hydrochloride

Methyl- (tert-butyl) - (2S) -1-oxo-1- ((3S) - (9-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] in a similar manner as described in example 1, except that the mixture was stirred for 4 hours in step 1 and overnight in step 2][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) but-2-ylcarbamate (51.5mg, 180. mu. mol) was converted to the title compound (58 mg). MS m/z615.9 (MH)⁺)。

Example 15

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -8-fluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride

(2S) -1-oxo-1- ((3S) - (8-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] is subjected to a similar procedure as described in example 1, except that the mixture is stirred for 4 hours in step 1 and for 4 hours in step 2][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-ylcarbamic acid tert-butyl ester (39.8mg, 140. mu. mol) was converted to the title compound (30 mg). MS m/z601.9 (MH)⁺)。

Example 16

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -8-fluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) butanamide hydrochloride

In a similar manner to that described in example 1, except that the mixture was stirred for 4 hours in step 1 and for 4 hours in step 2, methyl- (tert-butyl) - (2S) -1-oxo-1- ((3S) - (8-fluoro-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] is][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) but-2-ylcarbamate (38.6mg, 135. mu. mol) was converted to the title compound (29 mg). MS m/z616.0 (MH)⁺)。

Example 17

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (2-hydroxyethylamino) propionamide

Sodium cyanoborohydride (5.14mg, 81.8. mu. mol, Eq:1.50) was added to (S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2-amino-propionamide (31mg, 54.5. mu. mol, Eq:1.00), glycolaldehyde dimer (3.6mg, 30.0. mu. mol, Eq:0.55) and acetic acid (3.27mg, 3.15. mu.l, 54.5. mu. mol, Eq:1.00) in MeOH (1mL), and the mixture was stirred at room temperature overnight. The mixture was diluted with 1N HCl and H was added₂O/1N NaOH to adjust the pH to 8-9. The mixture was extracted with EtOAc and the combined extracts were washed with brine, over Na₂SO₄Drying and concentrating. The resulting material was purified by flash chromatography to give the title compound (30mg, 90% yield). MS m/z 613.8 (MH)⁺)。

Example 18

(2S) -N- (5- ((3-methoxyquinoline-N-oxide-4-yl)) Methyl) - (3S) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide

Step 1: 77% mCPBA (23.3mg, 104. mu. mol, Eq:2.1) was added to (S) -1- ((S) -5- ((3-methoxyquinolin-4-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (30mg, 49.6. mu. mol, Eq:1.00) in DCM (1mL) and the mixture was stirred at room temperature overnight. The mixture was diluted with 0.1N NaOH, extracted with EtOAc and the combined extracts were washed with saturated brine, over Na₂SO₄Drying and concentrating. The residue was purified by flash chromatography to give (S) -1- ((S) -5- ((3-methoxyquinoline-N-oxide-4-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (22mg, 71%). MS m/z 621.1 (MH)⁺)。

Step 2: A2M ethereal HCl solution (403. mu.l, 806. mu. mol, Eq:25) was added to (S) -1- ((S) -5- ((3-methoxyquinoline-N-oxido-4-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (20mg, 32.2. mu. mol, Eq:1.00) in MeOH (0.5 mL). 2.5 hoursThereafter, the mixture was concentrated and the residue was dissolved in MeCN/H₂O, and freeze-drying the solution. The resulting material was partitioned between EtOAc and 1N HCl, the layers were separated, and the aqueous layer was basified with 10N NaOH and extracted with EtOAc. The combined organic layers were washed with saturated brine and Na₂SO₄Drying and concentration under reduced pressure to give a material which is derived from MeCN/H₂Lyophilization in O yielded the title compound (14mg, 84%). MS m/z 521.1 (MH)⁺)。

Example 19

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methyl-d 3-amino) propionamide hydrochloride

Step 1: mixing Cs₂CO₃(56.0mg, 172. mu. mol, Eq:1.5) and NaI (25.8mg, 172. mu. mol, Eq:1.5) were added to methyl-d 3- (tert-butyl) - (2S) -1-oxo-1- ((3S) - (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-ylcarbamate (50mg, 115. mu. mol, Eq:1.00) and 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (49.1mg, 172. mu. mol, Eq:1.5), and the mixture was stirred at 65 ℃ overnight. Subjecting the mixture to hydrogenation with H₂Diluted O and extracted with EtOAc and the combined extracts washed with saturated brine, over Na₂SO₄Dried and concentrated under reduced pressure. Purifying the obtained material by flash chromatography to obtain (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxa nitrogenHetero compound-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl-d 3) carbamic acid tert-butyl ester (57mg, 73%). MSm/z 687.0 (MH)⁺)。

Step 2: in a similar manner to that described in example 1, step 2, except that the mixture was stirred for 3 hours, (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] is][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl-d 3) carbamic acid tert-butyl ester (57mg, 83.1. mu. mol) was converted to the title compound (42mg, 81%). MS m/z 587.0 (MH)⁺)。

Example 20

(2S) -N- (5- ((6-bromo-2- (methoxy-d 3) -naphthalen-1-yl) methyl) - (3S) -4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methyl-d 3-amino) propionamide hydrochloride

In a similar manner to that described in example 19, except that NaI was not used in step 1 and the mixture was stirred for 2 hours in step 2, methyl-d 3- (tert-butyl) - (2S) -1-oxo-1- ((3S) - (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] is][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino)) propan-2-ylcarbamate (65mg, 149. mu. mol, Eq:1.00) and 6-bromo-1-chloromethyl-2- (methoxy-d 3) -naphthalene (64.5mg223. mu. mol, Eq:1.5) to the title compound (35 mg). MS m/z 589.8 (MH)⁺)。

Example 21

(R) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2-aminopropionamide, and

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2-aminopropionamide

Step 1: HBTU (550mg,1.45mmol, Eq:1.2) and HOBT. H₂O (222mg,1.45mmol, Eq:1.2) in DMF (8mL) was added to 3-amino-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-4(5H) -one (0.3g,1.21mmol, Eq:1.00), BOC-Ala-OH (229mg,1.21mmol, Eq:1.00), and TEA (367mg, 505. mu.l, 3.62mmol, Eq:3) in DMF (8 mL). After 2d, the mixture was poured into EtOAc and saturated NaHCO with 1:1₃Saturated NaCl, saturated brine, washed with Na₂SO₄Drying and concentrating. The residue was purified by flash chromatography to give (2S) -1-oxo-1- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) T-butyl propan-2-ylcarbamate (0.46g, 91%) as a white foam. MS m/z 420.0 (MH)⁺)。

Step 2: in a similar manner to that described in example 1, step 1, except that the mixture was heated at 60 ℃ for 6 hours, (2S) -1-oxo-1- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] is added][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) propan-2-ylcarbamic acid tert-butyl ester (0.46g,1.1mmol, Eq:1.00) and 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (470mg,1.64mmol, Eq:1.5) were converted to (2S) -1- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] benzo [ b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-ylcarbamic acid tert-butyl ester (0.5222g, 71.2%) as white foam. MS m/z 669.9 (MH)⁺)。

And step 3: et 2.0M HCl₂O solution (25mL,50.0mmol, Eq:64.0) was added to (2S) -1- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-ylcarbamic acid tert-butyl ester (0.5222g, 781. mu. mol, Eq:1.00) in MeOH (5 mL). After 90 min the reaction was concentrated to remove Et₂O, the resulting solution was poured into 1M NaOH, and the mixture was extracted with DCM. The combined organic extracts are washed with H₂Washing with saturated brine, and purifying with Na₂SO₄Drying and concentration gave a diastereomeric mixture of the compound (0.4186g) as a white solid. Separating the diastereomers by chiral SFC to obtain (R) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2-aminopropionamide (47.5mg), which was eluted first (MS m/z 569.9 (MH)⁺) And (S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2-aminopropionamide (42.7mg), which was eluted next. MS m/z 569.9 (MH)⁺)。

Example 22

(S) -N- { (R) -9- [2- (2-methoxy-ethoxy) -acetylamino]-5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Thiaazepines-3-yl } -2-methylamino-propionamide hydrochloride

Step 1: (2-methoxy-ethoxy) -acetyl chloride (29.8 μ L,224 μmol) was added to [ (S) -1- ((R) -9-amino-5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ] ][1,4]Thiaazepines-3-ylcarbamoyl) -ethyl]Methyl-carbamic acid tert-butyl ester (100mg, 187. mu. mol), DMAP (1.1mg, 9.4. mu. mol) and TEA (104. mu.L, 748. mu. mol) in pyridine (2 mL). After 6h the mixture was poured into 0.5M HCl (5mL) and extracted with EtOAc. The combined extracts are washed with H₂Washing with saturated brine, and purifying with Na₂SO₄Drying, filtering and concentrating. The residue was purified by silica gel chromatography to give ((S) -1- { (R) -9- [2- (2-methoxy-ethoxy) -acetylamino group]-5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Sulfur nitrogen hetero compoundHetero compound-3-ylcarbamoyl } -ethyl) -methyl-carbamic acid tert-butyl ester (80mg, 66%).

Step 2: hydrogen chloride gas was bubbled through ((S) -1- { (R) -9- [2- (2-methoxy-ethoxy) -acetylamino group at 0 deg.C]-5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Thiaazepines-3-ylcarbamoyl } -ethyl) -methyl-carbamic acid tert-butyl ester (70mg,108 μmol) in dioxane (5mL) for 1 min, the mixture was warmed to room temperature and stirred for 1 h. The mixture was concentrated and the residue was taken up in Et₂Triturate with O and filter the resulting solid with Et₂O wash and dry to give the title compound (25mg, 40%). HR-MS: calculated value C₂₉H₃₄N₄O₅S(MH⁺)551.2326, found 551.2323.

The compounds in Table 3 were prepared according to the procedure described for the preparation of example 22.

TABLE 3

Example 23

1-acetyl-piperidine-4-carboxylic acid [ (R) -3- ((S) -2-methylamino-propionylamino) -5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Thiaazepines-9-yl]-amides of

In a similar manner to that described in example 22, [ (S) -1- ((R) -9-amino-5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-3-ylcarbamoyl) -ethyl]Conversion of-methyl-carbamic acid tert-butyl ester and 1-acetyl-piperidine-4-carbonyl chloride to 1-acetyl-piperidine-4-carboxylic acid [ (R) -3- ((S) -2-methylamino-propionylamino) -5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Thiaazepines-9-yl]-amide hydrochloride. The material obtained after trituration was purified by reverse phase HPLC to give 1-acetyl-piperidine-4-carboxylic acid [ (R) -3- ((S) -2-methylamino-propionylamino) -5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Thiaazepines-9-yl]Amide trifluoroacetate and reaction of this material in EtOAc (10mL) and NaHCO₃The saturated solution (5mL) was partitioned between. Subjecting the organic layer to H₂Washing with saturated brine, and purifying with Na₂SO₄Drying, filtration and concentration gave the title compound. HRMS: calculated value C₃₂H₃₇N₅O₄S(MH⁺)588.2639, found 588.2639.

Example 24

5-oxo-hexanoic acid [ (R) -3- ((S) -2-methylamino-propionylamino) -5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Thiaazepines-9-yl]-amide hydrochloride

Phosphorus oxychloride (34.4mg,0.22mmol) was added to [ (S) -1- ((R) -9-amino-5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ] b][1,4]Thiaazepines-3-ylcarbamoyl) -ethyl]-methyl-carbamic acid tert-butyl ester (80mg,0.15mmol) and 5-oxo-hexanoic acid (29.2mg,0.22mmol) in pyridine (1.0 mL). After 2h, the mixture was poured into 0.5M HCl (5mL) and extracted with EtOAc, and the combined extracts were washed with water, saturated brine, and Na₂SO₄Drying, filtering and concentrating. The residue was purified by silica gel chromatography to give the title compound. HR-MS: calculated value C₃₀H₃₄N₄O₄S(MH⁺)547.2374, found 547.2374.

Example 25

3,4, 5-trimethoxy-N- [ (R) -3- ((S) -2-methylamino-propionylamino) -5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Thiaazepines-9-yl]-benzamide hydrochloride

In a similar manner to that described in example 24, [ (S) -1- ((R) -9-amino-5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-3-ylcarbamoyl) -ethyl]-methyl-carbamic acid tert-butyl ester and 3,4, 5-trimethoxy-benzoic acid were converted into the title compound. HR-MS: calculated value C₃₄H₃₆N₄O₆S(MH⁺)629.2429, found 629.2428.

Example 26

6-oxo-heptanoic acid [ (R) -3- ((S) -2-methylamino-propionylamino) -5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-9-yl]-amide hydrochloride

In a similar manner to that described in example 24, [ (S) -1- ((R) -9-amino-5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-3-ylcarbamoyl) -ethyl]-methyl-carbamic acid tert-butyl ester and 6-oxo-heptanoic acid into the title compound. HR-MS: calculated value C₃₁H₃₆N₄O₄S(MH⁺)561.2530, found 561.2530.

Example 27

(S) -N- ((R) -9-amino-5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b)][1,4]Thiaazepines-3-yl) -2-methylamino-propionamide hydrochloride

In a similar manner to that described in example 22, step 2, [ (S) -1- ((R) -9-amino-5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-3-ylcarbamoyl) -ethyl]-methyl-carbamic acid tert-butyl ester is converted into the title compound. HR-MS: calculated value C₂₄H₂₆N₄O₂S(MH⁺)435.1849, found 435.1850.

Example 28

N- [ (R) -3- ((S) -2-methylamino-propionylamino) -5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b)][1,4]Thiaazepines-9-yl]-benzamide hydrochloride

In a similar manner to that described in example 22, [ (S) -1- ((R) -9-amino-5-naphthalen-1-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-3-ylcarbamoyl) -ethyl]-methyl-carbamic acid tert-butyl ester and benzoyl chloride to the title compound. MS m/z 539 (MH)⁺)。

Example 29

(S) -N- [ (S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -2-methylamino-propionamide trifluoroacetate

Step 1: reacting methyl ((S) -1-oxo-1- ((S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester (1.1g,3.03mmol, Eq:1.00) (example 1), 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (951mg,3.33mmol, Eq:1.10), Cs₂CO₃A mixture of (1.08g,3.33mmol, Eq:1.10) and NaI (499mg,3.33mmol, Eq:1.1) in DMF (20mL) was stirred at room temperature for 3.5 hours, then heated at 50 ℃ for 1 hour, then at 60 ℃ for 30 minutes. The mixture was cooled, diluted with EtOAc, washed with water and brine. Subjecting the organic solution to Na₂SO₄Drying and concentrating. The residue was purified by silica gel chromatography to give (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (1.00g,1.63mmol, 53.9%) as a bright yellow foam.

Step 2: TFA (1.48g,1mL,13.0mmol, Eq:153) was added to (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] at 0 deg.C][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (52mg, 84.9. mu. mol, Eq:1.00) in DCM. After 1 hour the mixture was concentrated and the residue was taken up in Et₂Trituration with O afforded the title compound (30mg,58.5 μmol, 69.0%) as a light brown solid. MS m/z (MH)⁺)363.0。

In a similar manner to that described in example 29, the conditions may be varied such that the temperature may be from 50 ℃ to 70 ℃, the reaction time may be from 2 to 24 hours and 1 to 3eq. NaI may optionally be added, and the methyl ((S) -1-oxo-1- ((S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] may be reacted][1,4]Oxazazepine-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester was converted to the compound in table 4.

TABLE 4

Example 30

(S) -N- [ (S) -9- (6-cyclopropyl-2-methoxy-naphthalen-1-ylmethyl) -8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -2-methylamino-propionamide trifluoroacetate

Step 1: will N₂Bubbling to (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (200mg, 327. mu. mol, Eq:1.00), cyclopropylboronic acid (33.7mg, 392. mu. mol, Eq:1.20), Na₂CO₃(408. mu.l, 816. mu. mol, Eq:2.50) in 1, 4-dioxane (2mL) for 5 minutes, followed by addition of Pd (Ph)₃P)₄(18.9mg, 16.3. mu. mol, Eq: 0.05). The mixture was heated to reflux overnight, cooled, and diluted with EtOAc. The mixture was washed with water and saturated brine, and then washed with Na₂SO₄Drying and concentrating to obtain (S) -1- ((S) -5- ((6-cyclopropyl-2-methoxynaphthalene-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]OxazazepineTert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (24mg,41.8 μmol, 12.8%) was used without purification.

Step 2: (S) -1- ((S) -5- ((6-cyclopropyl-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] is reacted in a similar manner as described in example 29, step 2, except that the mixture is stirred at 0 ℃ for 1 hour and at room temperature for 1 hour][1,4]OxazazepineTert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (24mg,41.8 μmol) was converted to the title compound (23mg, 96%). MS m/z (MH)⁺)474.1。

Example 31

6-methoxy-5- (((S) -3- ((S) -2- (methylamino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -2-naphthoic acid methyl ester trifluoroacetate salt

Step 1: mixing (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (1.8g,2.94mmol, Eq:1.00), Pd (OAc)₂(33.0mg, 147. mu. mol, Eq:0.05) and 4, 5-bis (E)A mixture of diphenylphosphino) -9, 9-dimethylxanthene (Xantphos) (170mg, 294. mu. mol, Eq:0.10) in a microwave tube was evacuated and charged with N₂. MeOH (1.43g,1.8mL,44.5mmol, Eq:15.1) and TEA were added, the tube was flushed with CO and heated at 70 deg.C under CO overnight. The mixture was concentrated and the residue was purified by silica gel chromatography to give 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid methyl ester (1.24g,2.1mmol, 71.3%).

Step 2: in a similar manner to that described in example 29, step 2, 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b ] b][1,4]Oxazazepine-methyl 5(2H) -yl) methyl) -6-methoxy-2-naphthoate (100mg, 169. mu. mol) was converted to the title compound (75mg, 124. mu. mol, 73.3%). MSm/z (MH)⁺)492.2。

Example 32

6-methoxy-5- (((S) -3- ((S) -2- (methylamino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -2-naphthoic acid trifluoroacetate salt

Step 1: reacting LiOH & H₂O (24.0mg, 573. mu. mol, Eq:3) was dissolved in water, and the solution was added to 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b ] b][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid methyl ester (113mg, 191. mu. mol, Eq:1.00) in MeOH (3mL) and the mixture was heated to 50 ℃ for 1 hour and then at 60 ℃ for 1 hour. Cooling the mixture, adding KHSO₄Solution and the mixture was extracted with EtOAc. The combined extracts were concentrated and the residue was purified by silica gel chromatography to give 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid (103mg, 93%) as a white powder.

Step 2: in a similar manner to that described in example 29, step 2, 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b ] b][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid (102mg, 177. mu. mol) was converted to the title compound (73mg, 58%). MS m/z (MH)⁺)478.2。

Example 33

6-methoxy-7- [ (S) -7- ((S) -2-methylamino-propionylamino) -8-oxo-7, 8-dihydro-6H-5-oxa-9-aza-benzocycloheptatrien-9-ylmethyl ] -naphthalene-2-carboxylic acid (2-hydroxy-ethyl) -methyl-amide

Step 1: reacting 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid (100mg, 173. mu. mol, Eq:1.00), 2- (methylamino) ethanol (26.0mg, 27.8. mu.l, 346. mu. mol, Eq:2.00), HOBT. H₂O(31.8mg,208μmol,Eq:1.20)、HBTU(78.8mg,208μmol,Eq:1.2)、DIEAA mixture of (67.1mg, 90.5. mu.l, 519. mu. mol, Eq:3.00) in DMF was stirred at 0 ℃ for 2 hours. The mixture was diluted with EtOAc, washed with water, brine and Na₂SO₄Drying and concentrating. The residue was purified by silica gel chromatography to give (S) -1- ((S) -5- ((6- ((2-hydroxyethyl) (methyl) carbamoyl) -2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (94mg, 85% yield) as an oil.

Step 2: TFA (1.48g,1mL,13.0mmol, Eq:88.6) was added to (S) -1- ((S) -5- ((6- ((2-hydroxyethyl) (methyl) carbamoyl) -2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] at 0 deg.C][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (93mg, 147. mu. mol, Eq:1.00) in DCM. After 1h, the mixture was concentrated and the residue was taken up in Et₂And O grinding. The resulting material was dissolved in DCM and saturated NaHCO₃The solution was washed and the organic layer was concentrated. The residue was purified by silica gel chromatography to give the title compound as a white powder. MS m/z (MH)⁺)535.2。

Example 34

3- ({ 6-methoxy-7- [ (S) -7- ((S) -2-methylamino-propionylamino) -8-oxo-7, 8-dihydro-6H-5-oxa-9-aza-benzocycloheptatrien-9-ylmethyl ] -naphthalene-2-carbonyl } -amino) -propionic acid trifluoroacetate

Step 1: reacting 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid (100mg, 173. mu. mol, Eq:1.00), DIEA (90.5. mu.l, 519. mu. mol, Eq:3.00), HOBT. H₂A mixture of O (31.8mg, 208. mu. mol, Eq:1.20), HBTU (78.8mg, 208. mu. mol, Eq:1.2), tert-butyl 3-aminopropionate hydrochloride (31.6mg, 173. mu. mol, Eq:1.00) in DMF was stirred at 0 ℃ for 2 hours. The mixture was diluted with EtOAc, washed with water and brine. Subjecting the organic solution to Na₂SO₄Drying, filtering, concentrating, and purifying the residue by silica gel chromatography to give 3- [ (5- { (S) -7- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino]-8-oxo-7, 8-dihydro-6H-5-oxa-9-aza-benzocycloheptan-9-ylmethyl } -6-methoxy-naphthalene-2-carbonyl) -amino]-tert-butyl propionate (93mg, 76%).

Step 2: in a similar manner to that described in step 2 of example 29, 3- [ (5- { (S) -7- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino]-8-oxo-7, 8-dihydro-6H-5-oxa-9-aza-benzocycloheptan-9-ylmethyl } -6-methoxy-naphthalene-2-carbonyl) -amino]Tert-butyl propionate (91mg, 129. mu. mol) was converted to the title compound. MS m/z (MH)⁺)549.5。

Example 35

6-methoxy-7- [ (S) -7- ((S) -2-methylamino-propionylamino) -8-oxo-7, 8-dihydro-6H-5-oxa-9-aza-benzocycloheptatrien-9-ylmethyl ] -naphthalene-2-carboxylic acid dimethylamide trifluoroacetate

In a similar manner to that described in example 33, except that DIEA was not used in step 1, THF was used instead of DMF and the resulting material was not purified, 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b ] b][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid (96mg, 166. mu. mol, Eq:1.00) and dimethylamine (249. mu.l, 499. mu. mol, Eq:3.00) were converted to the title compound (99 mg). MS m/z (MH)⁺)505.2。

Example 36

(S) -N- [ (S) -9- (7-bromo-3-methoxy-naphthalen-2-ylmethyl) -3-methyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -2-methylamino-propionamide trifluoroacetate

Step 1: reacting (S) -3-amino-8-methyl-2, 3-dihydrobenzo [ b ]][1,4]OxazazepineA mixture of (E) -4(5H) -one trifluoroacetate (1.60g,5.23mmol, Eq:1.00), (S) -2- (tert-butoxycarbonyl (methyl) amino) propionic acid (1.06g,5.23mmol, Eq:1.00), HOBT (801mg,5.23mmol, Eq:1.00), HBTU (1.98g,5.23mmol, Eq:1.00) at 0 deg.C and DIEA (2.03g,2.73mL,15.7mmol, Eq:3.00) in DMF (50mL) was stirred at 0 deg.C for 1H, diluted with EtOAc, washed with water, saturated brine, Na over₂SO₄Drying, filtering and concentrating. The residue is colored by silica gelSpectral purification to give methyl- [ (S) -1- ((S) -3-methyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-ylcarbamoyl) -ethyl]Tert-butyl carbamate (2.04g) was used without purification.

Step 2: reacting methyl- [ (S) -1- ((S) -3-methyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-ylcarbamoyl) -ethyl]-carbamic acid tert-butyl ester (241mg, 639. mu. mol, Eq:1.00), NaI (95.7mg, 639. mu. mol, Eq:1.00), Cs₂CO₃A mixture of (312mg, 958. mu. mol, Eq:1.50), 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (219mg, 766. mu. mol, Eq:1.20) in DMF (3mL) was stirred at room temperature for 1 hour and at 50 ℃ for 1 hour. The mixture was diluted with EtOAc, washed with water, brine and Na₂SO₄Drying, filtering and concentrating. The resulting material was purified by silica gel chromatography to give { (S) -1- [ (S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -3-methyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-ylcarbamoyl]-ethyl } -methyl-carbamic acid tert-butyl ester (63mg, 16%) as an oil.

And step 3: in a similar manner to that described in example 29, step 2, { (S) -1- [ (S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -3-methyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ylcarbamoyl]-Ethyl } -methyl-carbamic acid tert-butyl ester (60mg, 95.8. mu. mol) was converted to the title compound (37 mg). MS m/zMH⁺527.8。

Example 37

(2S,3R) -2-amino-N- [ (S) -9- (7-bromo-3-methoxy-naphthalen-2-ylmethyl) -3-methyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -3-hydroxy-butyramide trifluoroacetate salt

Step 1: to example 36 step 1 in a similar manner except that (S) -3-amino-8-methyl-2, 3-dihydrobenzo [ b ] is stirred at 0 ℃ for 2 hours using 4 equivalents of DIEA and the mixture][1,4]OxazazepineConversion of (4- (5H) -one trifluoroacetate salt (0.50g,1.63mmol) and (2S,3R) -2- (tert-butoxycarbonylamino) -3-hydroxybutyric acid (358mg,1.63mmol) to (2S,3R) -3-hydroxy-1- ((S) -8-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-ylamino) -1-oxobut-2-ylcarbamic acid tert-butyl ester (500mg, 78%) as a light yellow foam.

Step 2: in a similar manner to that described in example 36, step 2, except that the mixture was heated at 50 ℃ for 2 hours, (2S,3R) -3-hydroxy-1- ((S) -8-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] was reacted][1,4]Oxazazepine-3-ylamino) -1-oxobut-2-ylcarbamic acid tert-butyl ester (160mg, 407. mu. mol, Eq:1.00) and 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (174mg, 610. mu. mol, Eq:1.50) were converted into (2S,3R) -1- ((S) -5- ((6-bromo-2-methoxynaphthalene-1-yl) methyl) -8-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -3-hydroxy-1-oxobut-2-ylcarbamic acid tert-butyl ester (128mg, 49%) as a white powder.

And step 3: (2S,3R) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -8-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] in a similar manner to that described in example 29 step 2][1,4]Oxazazepine-3-ylamino) -3-hydroxy-1-oxobut-2-ylcarbamic acid tert-butyl ester (80mg, 125. mu. mol) was converted to the title compound (54mg, 66%). MS m/z MH⁺543.9。

Example 38

(2S,3S) -2-amino-N- [ (S) -9- (7-bromo-3-methoxy-naphthalen-2-ylmethyl) -3-methyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-azabenzocycloheptatrien-7-yl ] -3-hydroxy-butyramide trifluoroacetate

Step 1: (S) -3-amino-8-methyl-2, 3-dihydrobenzo [ b ] was reacted in a similar manner as described in step 1, example 36, except that 4 equivalents of DIEA were used and the mixture was stirred at 0 ℃ for 2 hours][1,4]Oxazazepine-4(5H) -Ketone trifluoroacetate (0.3g, 980. mu. mol) and (2S,3S) -2- (tert-Butoxycarbonylamino) -3-hydroxybutyric acid dicyclohexylamine salt (0.39mg, 980. mu. mol, Eq:1.00) were converted into [ (1S,2S) -2-hydroxy-1- ((S) -3-methyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ylcarbamoyl) -propyl]Tert-butyl carbamate (0.37g, 99%).

Step 2: in a similar manner to that described in example 36, step 2, except that the mixture was heated at 50 ℃ for 2 hours, [ (1S,2S) -2-hydroxy-1- ((S) -3-methyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-ylcarbamoyl) -propyl ] -carbamic acid tert-butyl ester (280mg, 712. mu. mol) and 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (244mg, 854. mu. mol) were converted to { (1S,2S) -1- [ (S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -3-methyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-ylcarbamoyl ] -2-hydroxy-propyl } -carbamic acid tert-butyl ester (190mg, 42%).

And step 3: in a similar manner to that described in example 29, step 2, { (1S,2S) -1- [ (S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -3-methyl-8-oxo-6, 7,8, 9-tetrakisHYDRO-5-OXA-9-AZA-BENZOCYCLOHEPTANE-7-YLCARBAMOYL]-2-hydroxy-propyl } -carbamic acid tert-butyl ester (185mg, 288. mu. mol) was converted to the title compound (180mg, 274. mu. mol). MS m/z MH⁺544.1。

Example 39

(S) -N- ((2S,3S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -2, 8-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide trifluoroacetate salt

Step 1: in a similar manner to that described in example 36, step 1, except that 4 equivalents of DIEA were used, (2S,3S) -3-amino-2, 8-dimethyl-2, 3-dihydrobenzo [ b ]][1,4]OxazazepineConversion of (E) -4(5H) -keto trifluoroacetate (100mg, 278. mu. mol) and (S) -2- (tert-butoxycarbonyl (methyl) amino) propanoic acid (56.5mg, 278. mu. mol) to (S) -1- ((2S,3S) -2, 8-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (95mg, 87%).

Step 2: (S) -1- ((2S,3S) -2, 8-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] is heated at 60 ℃ for 1 hour and without NaI in a similar manner to that described in example 36, step 2][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl esterEster (92mg, 235. mu. mol) and 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (101mg, 352. mu. mol) were converted to (S) -1- ((2S,3S) -5- ((6-bromo-2-methoxynaphthalene-1-yl) methyl) -2, 8-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (89mg, 59%).

And step 3: in a similar manner to that described in example 29, step 2, except that the product was not triturated, (S) -1- ((2S,3S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -2, 8-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (15mg, 23.4. mu. mol) was converted to the title compound (12.4mg, 81%) MS m/z MH⁺542.2。

Example 40

5- (((2S,3S) -2, 8-dimethyl-3- ((S) -2- (methylamino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid methyl ester trifluoroacetate salt

Step 1: mixing (S) -1- ((2S,3S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -2, 8-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (70mg, 109. mu. mol, Eq:1.00), Pd (OAc)₂A mixture of (2.45mg, 10.9. mu. mol, Eq:0.1), Xantphos (12.6mg, 21.9. mu. mol, Eq:0.2), MeOH (35.0mg, 44.2. mu.l, 1.09mmol, Eq:10), and TEA in a microwave tube was charged with CO and left overnight at 70 ℃ under CO. The mixture was diluted with EtOAc, washed with water, brine and Na₂SO₄Drying and concentrating. The residue was purified by silica gel chromatography to give 5- (((2S,3S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -2, 8-dimethyl-4-oxo-3, 4-dihydrobenzo [ b][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid methyl ester (43mg, 63%).

Step 2: in a similar manner to that described in example 29, step 2, 5- (((2S,3S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -2, 8-dimethyl-4-oxo-3, 4-dihydrobenzo [ b ] b][1,4]Oxazazepine-methyl 5(2H) -yl) methyl) -6-methoxy-2-naphthoate (41mg, 66.2. mu. mol) was converted to the title compound (35mg, 83%). MS m/z MH⁺520.2。

EXAMPLE 41

(2S,3S) -2-amino-N- [ (6S,7S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -3, 6-dimethyl-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -3-hydroxy-butyramide trifluoroacetate

Step 1: (2S,3S) -3-amino-2, 8-dimethyl-2, 3-dihydrobenzo [ b ] was reacted in a similar manner as described in step 1, example 36, except that 4 equivalents of DIEA were used and the mixture was stirred at 0 ℃ for 2 hours][1,4]OxazazepineConversion of (4 (5H) -Ketone trifluoroacetate (75mg, 208. mu. mol) and (2S,3S) -2- (tert-Butoxycarbonylamino) -3-hydroxybutyric acid dicyclohexylamine salt (83.4mg, 208. mu. mol, Eq:1.00) to (2S,3S) -1- ((2S,3S) -2, 8-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) -3-hydroxy-1-oxobut-2-ylcarbamic acid tert-butyl ester (72mg, 85%).

Step 2: in a similar manner to that described in example 36, step 2, except that the mixture was heated at 60 ℃ for 2 hours and no NaI was used, (2S,3S) -1- ((2S,3S) -2, 8-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] was reacted with methanol to obtain a mixture][1,4]Oxazazepine-3-ylamino) -3-hydroxy-1-oxobut-2-ylcarbamic acid tert-butyl ester (70mg, 172. mu. mol, Eq:1.00) and 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (73.6mg, 258. mu. mol, Eq:1.50) were converted into (2S,3S) -1- ((2S,3S) -5- ((6-bromo-2-methoxynaphthalene-1-yl) methyl) -2, 8-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -3-hydroxy-1-oxobut-2-ylcarbamic acid tert-butyl ester (3.5mg, 3%).

And step 3: in a similar manner to that described in example 29, step 2, except that the product was not triturated, (2S,3S) -1- ((2S,3S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -2, 8-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -3-hydroxy-1-oxobut-2-ylcarbamic acid tert-butyl ester (3.5mg, 5.33. mu. mol) was converted to the title compound (3.1mg, 86%). MS m/z MH⁺558.1。

Example 42

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-7- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide trifluoroacetate salt

Step 1: (S) -3-amino-8-trifluoromethyl-2, 3-dihydrobenzo [ b ] was reacted in a similar manner as described in example 36, step 1, except that 6 equivalents of DIEA were used and the mixture was stirred at 0 ℃ for 30 minutes and the product was used without purification][1,4]Oxazazepine-4(5H) -Ketone trifluoroacetate (0.70g,1.97mmol, Eq:1.00) and (S) -2- (tert-Butoxycarbonyl (methyl) amino) propionic acid (0.40g,1.97mmol, Eq:1.00) were converted to methyl ((S) -1-oxo-1- ((S) -4-oxo-7- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester (0.90 g).

Step 2: in a similar manner to that described in step 2 of example 36, except that 1 equivalent of Cs is used₂CO₃Methyl ((S) -1-oxo-1- ((S) -4-oxo-7- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester (863mg,2mmol) and 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (571mg,2.00mmol) were converted to (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalene-1-yl) methyl) -4-oxo-7- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (0.51g, 38%) as yellow foam.

And step 3: (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-7- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b ] in a similar manner as described in example 29 step 2][1,4]OxazazepineTert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (0.50g, 735. mu. mol) was converted to the title compound (245mg, 48%). MS m/z MH⁺582.0。

Example 43

(S) -N- [ (6S,7S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -6-methyl-8-oxo-2-trifluoromethyl-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -2-methylamino-propionamide trifluoroacetate

Step 1: in a similar manner to that described in example 36, step 1, except that 4 equivalents of DIEA were used, (2S,3S) -3-amino-2-methyl-7- (trifluoromethyl) -2, 3-dihydrobenzo [ b ] was reacted][1,4]Oxazazepine-4(5H) -Ketone trifluoroacetate (58mg,0.155mmol) and (S) -2- (tert-butoxycarbonyl (methyl) amino) propionic acid (31.5mg, 155. mu. mol) were converted to a material which was purified by silica gel chromatography to give methyl- [ (S) -1- ((6S,7S) -6-methyl-8-oxo-2-trifluoromethyl-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-ylcarbamoyl) -ethyl ] -ethyl]-carbamic acid tert-butyl ester (52mg, 75%).

Step 2: to the step of example 362 in a similar manner except that 2 equivalents of Cs are used₂CO₃And heating the mixture at 50 ℃ for 2 hours to convert methyl- [ (S) -1- ((6S,7S) -6-methyl-8-oxo-2-trifluoromethyl-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-ylcarbamoyl) -ethyl]-conversion of tert-butyl carbamate (52mg,0.117mmol) and 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (66.7mg,0.233mmol) to (S) -1- ((2S,3S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -2-methyl-4-oxo-7- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (72mg, 88%).

And step 3: (S) -1- ((2S,3S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -2-methyl-4-oxo-7- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b ] in a similar manner as described in example 29 step 2][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (70mg, 101. mu. mol) was converted to the title compound (55mg, 77%). MS m/z MH⁺596.2。

Example 44

(S) -2-methylamino-N- [ (S) -9- (2-methyl-naphthalen-1-ylmethyl) -8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -propionamide

Step 1: a 1M solution of lithium bis (trimethylsilyl) amide in THF (3.07mL,1eq) was added to a solution of ((S) -8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl) -carbamic acid-tert-butyl ester (855mg,3.07mmol,1.0eq) in THF (10mL) at-78 ℃. Heating 1- (chloromethyl) after 30 minutesYl) -2-methylnaphthalene (586mg,3.07mmol,1eq) and NaI (461mg,3.07mmol,1eq) and the mixture was warmed to room temperature over 2 hours. The solvent was removed and the residue was suspended in EtOAc and washed with H₂And O washing. The aqueous extract was extracted with EtOAc and the combined organic layers were Na filtered₂SO₄Drying, filtering and concentrating. The residue was purified by silica gel chromatography to give (S) -5- ((2-methylnaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]OxazazepineTert-butyl-3-ylcarbamate (1.01g, 75%) as a yellow foam.

Step 2: TFA (7.68g,67.3mmol, Eq:28.8) was added to (S) -5- ((2-methylnaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester (1.01g,2.34mmol, Eq:1.00) and the mixture was stirred for 2 hours and the solvent was removed. The residue was taken up in saturated NaHCO₃The aqueous mixture was treated and extracted with EtOAc. The combined organic extracts are passed over Na₂SO₄Drying, filtering and concentrating. The residue was purified by silica gel chromatography to give (S) -3-amino-5- ((2-methylnaphthalen-1-yl) methyl) -2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -one (606mg, 76%) as white foam.

And step 3: DIEA (146mg,1.13mmol, Eq:2.50) was added to (S) -3-amino-5- ((2-methylnaphthalen-1-yl) methyl) -2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -one (150mg, 451. mu. mol, Eq:1.00), (S) -2- (methylamino) propionic acid (46.5mg, 451. mu. mol, Eq:1.00), HBTU (180mg, 474. mu. mol, Eq:1.05), and HOBT. H₂O (64.0mg, 474. mu. mol, Eq:1.05) in DMF. In thatAfter 2H at rt the mixture was diluted with EtOAc and washed with H₂O、2％KHSO₄、5％NaHCO₃And 5% saturated brine. Subjecting the organic mixture to Na₂SO₄Drying, filtration and concentration gave a residue which was combined with a second batch of material prepared according to the same procedure. This material was purified by silica gel chromatography to give a material which was purified in Et₂Trituration in O/pentane gave the title compound (51 mg). HRMS: calculated value C₂₅H₂₇N₃O₃(MH⁺)418.2124, found 418.2125.

Example 45

(S) -N- ((S) -5- (2-chlorobenzyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide

Step 1: mixing Cs₂CO₃(229mg, 702. mu. mol, Eq:1.50) to methyl ((S) -1-oxo-1- ((S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester (170mg, 468. mu. mol, Eq:1.00) and 1- (bromomethyl) -2-chlorobenzene (144mg, 702. mu. mol, Eq:1.50) in DMF and the mixture was stirred at room temperature overnight. Pouring the mixture into H₂O, and extracted with EtOAc. Subjecting the combined extracts to Na₂SO₄Drying, filtering and concentrating. The residue was purified by silica gel chromatography to give (S) -1- ((S) -5- (2-chlorobenzyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (170mg, 75%) as yellow foam.

Step 2: TFA (794mg,6.97mmol, Eq:20.00) was added to (S) -1- ((S) -5- (2-chlorobenzyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] at 0 deg.C][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (170mg, 348. mu. mol, Eq:1.00) in DCM (1.42 mL). After 30 min the solvent was removed and the residue was taken up in 1/1 DCM/5% NaHCO₃A slurry was formed in the mixture and the layers were separated. The aqueous layer was extracted with DCM and the combined extracts were washed with Na₂SO₄Drying, filtering and concentrating. The residue was purified by silica gel chromatography to give a material which was washed with Et₂Trituration with O/pentane gave the title compound (118mg, 87%) as a pale yellow foam.¹H NMR(DMSO-d₆):8.21(d,J＝7.8Hz,1H),7.47-7.56(m,1H),7.38-7.45(m,1H),7.17-7.36(m,6H),5.30(d,J＝16.8Hz,1H),5.00(d,J＝16.8Hz,1H),4.83(dt,J＝11.1,8.2Hz,1H),4.33-4.50(m,2H),2.93(q,J＝6.9Hz,1H),2.18(s,3H),2.06(br.s.,1H),1.08(d,J＝6.9Hz,3H)。

Example 46

(S) -N- ((S) -5- (3-chlorobenzyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide

In a similar manner to that described in example 45, except that the mixture was stirred at room temperature for 2 hours in step 1, methyl ((S) -1-oxo-1- ((S) -4-oxo-2, 3,4, 5-tetrakisHydrobenzo [ b][1,4]OxazazepineTert-butyl-3-ylamino) propan-2-yl) carbamate (175mg, 482. mu. mol) and 1- (bromomethyl) -3-chlorobenzene (104mg, 506. mu. mol) were converted to the title compound (125mg) as an off-white foam. HRMS: calculated value C₂₀H₂₂N₃O₃Cl:(MH⁺)388.1421, found 388.1423.

Example 47

(S) -N- ((S) -5- (4-chlorobenzyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide

In a similar manner to that described in example 45, except that the chromatographed material in step 2 was not triturated, methyl ((S) -1-oxo-1- ((S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]OxazazepineTert-butyl-3-ylamino) propan-2-yl) carbamate (173mg, 476. mu. mol) and 1- (bromomethyl) -4-chlorobenzene (103mg, 500. mu. mol) were converted to the title compound (113mg) as an off-white foam. HRMS: calculated value C₂₀H₂₂N₃O₃Cl:(MH⁺)388.1422, found 388.1423.

Example 48

(S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- ((S) -2- (methylamino) propanamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-9-Carboxylic acid trifluoroacetic acid salt

In a similar manner to that described in example 45, step 2, (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-9-carboxylic acid (68mg,104 μmol) was converted to the title compound (51mg, 73%) as an off-white solid.¹HNMR(300MHz,DMSO-d₆)ppm 13.09(br.s.,1H)9.08(d,J＝7.8Hz,1H)8.77(br.s.,2H)8.02-8.09(m,2H)7.82(d,J＝9.4Hz,1H)7.77(d,J＝8.2Hz,1H)7.52(dd,J＝9.1,2.1Hz,1H)7.45(dd,J＝7.8,1.5Hz,1H)7.36(d,J＝9.1Hz,1H)7.25(t,J＝8.0Hz,1H)5.91(d,J＝14.8Hz,1H)5.26(d,J＝14.8Hz,1H)4.69-4.86(m,1H)4.46(dd,J＝9.8,7.4Hz,1H)4.20(dd,J＝11.6,9.8Hz,1H)3.81-3.95(m,1H)3.80(s,3H)2.512.53(m,3H)1.42(d,J＝6.9Hz,3H)。

Example 49

(S) -5- ((2-methoxynaphthalen-1-yl) methyl) -3- ((S) -2- (methylamino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-9-Carboxylic acid trifluoroacetic acid salt

Step 1: reacting (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- ((S) -2- (tert-butoxycarbonyl (methyl) ammoniaYl) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineA mixture of methyl-9-carboxylate (100mg, 149. mu. mol, Eq:1.00) and 10% Pd/C (5.22mg, 4.92. mu. mol, Eq:0.033) in MeOH (5mL) was hydrogenated at room temperature overnight. The mixture was filtered through celite, and the filtrate was concentrated to give (S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -5- ((2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]OxazazepineMethyl 9-carboxylate (95mg, 97%) as a tan foam.

Step 2: reacting LiOH & H₂O (9.1mg, 217. mu. mol, Eq:1.5) and H₂O (1mL) was added to (S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -5- ((2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-methyl 9-carboxylate (95mg, 145. mu. mol, Eq:1.00) in MeOH (4 mL). The mixture was heated to 50 ℃. After 2 hours, LiOH. H was added₂O (18mg, 429. mu. mol, Eq:2.95) and the temperature was raised to 60 ℃. After 4 hours, the mixture was concentrated to a volume of about 1.5 mL. The mixture was acidified to pH 2 with 1N HCl and extracted with EtOAc. The combined extracts were washed with saturated brine and then with Na₂SO₄Drying, filtering and concentrating to obtain a material, which is purified by silica gel chromatography to obtain (S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -5- ((2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-9-carboxylic acid (31mg, 37%) as an off-white foam.

And step 3: TFA (1.22g, 797. mu.L, 10.7mmol, Eq:200.00) was added to (A), (B), (C), (S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -5- ((2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-9-carboxylic acid (31mg, 53.7. mu. mol, Eq:1.00) in DCM (806. mu.L). After 45 minutes the mixture was concentrated. The residue was dissolved in minimal DCM and Et was added₂O, which leads to the formation of a white solid. Pentane was added, the supernatant decanted, and the resulting material dried under vacuum to give the title compound (29mg, 91%).¹HNMR(300MHz,DMSO-d₆)ppm 13.06(br.s.,1H)9.09(d,J＝8.8Hz,1H)8.75(br. s.,2H)8.10(d,J＝8.8Hz,1H)7.79(t,J＝8.0Hz,3H)7.40-7.47(m,2H)7.16-7.37(m,3H)5.94(d,J＝14.5Hz,1H)5.28(d,J＝14.5Hz,1H)4.75(br.s.,1H)4.45(t,J＝8.6Hz,1H)4.13-4.26(m,1H)3.82-3.90(m,1H)3.80(s,3H)2.51-2.52(m,3H)1.42(d,J＝6.9Hz,3H)。

Example 50

3- { [ (S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -7- ((S) -2-methylamino-propionylamino) -8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatriene-4-carbonyl ] -amino } -propionic acid trifluoroacetate

Step 1: DIEA (177mg, 242. mu.l, 1.37mmol, Eq:5.00) was added to (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-9-Carboxylic acid (180mg, 274. mu. mol, Eq:1.00), tert-butyl 3-aminopropionate hydrochloride (49.8mg, 274. mu. mol, Eq:1.00), HBTU (104mg, 274. mu. mol, Eq:1.0) and HOBT. H₂O (37.0mg, 274. mu. mol, Eq:1.0) at DMF (3.41mL), and the mixture was warmed to room temperature. After 45 min the mixture was diluted with EtOAc and washed with H₂Washing with saturated brine, and purifying with Na₂SO₄Drying, filtering and concentrating. The residue was purified by silica gel chromatography to give 3- ({ (S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -7- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino-)]-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatriene-4-carbonyl } -amino) -propionic acid tert-butyl ester (150mg, 69%) as an off-white foam.

Step 2: in a similar manner to that described in example 49, step 3, ({ (S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -7- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino]-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatriene-4-carbonyl } -amino) -propionic acid tert-butyl ester (60mg, 76.6. mu. mol) was converted to the title compound (54mg, 95%) as an off-white solid.¹H NMR(300MHz,DMSO-d₆)ppm 12.23(br.s.,1H)9.06(d,J＝6.9Hz,1H)8.77(br.s.,2H)8.31(br.s.,1H)8.02-8.12(m,2H)7.82(d,J＝9.4Hz,1H)7.68(d,J＝7.5Hz,1H)7.52(d,J＝9.4Hz,1H)7.37(d,J＝9.1Hz,1H)7.16-7.32(m,2H)5.89(d,J＝14.8Hz,1H)5.26(d,J＝14.8Hz,1H)4.77(br.s.,1H)4.37-4.50(m,1H)4.14-4.28(m,1H)3.83(br.s.,1H)3.79(s,3H)3.23-3.36(m,2H)2.41(t,J＝6.8Hz,2H)1.44(d,J＝6.6Hz,3H)。

Example 51

4- ({ [ (S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -7- ((S) -2-methylamino-propionylamino) -8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatriene-4-carbonyl ] -amino } -methyl) -benzoic acid methyl ester

Step 1: (S) -5- ((6-bromo-2-methoxy) was reacted in a similar manner to that described in example 50, step 1, except that the reaction mixture was stirred for 1 hour 15 minutesPhyphthalen-1-yl) methyl) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineConversion of-9-carboxylic acid (80mg, 122. mu. mol) and methyl 4- (aminomethyl) benzoate hydrochloride (25mg, 122. mu. mol) to 4- [ ({ (S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -7- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino- ] -methyl]-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatriene-4-carbonyl } -amino) -methyl]-methyl benzoate (67mg, 68%) as an off-white foam.

Step 2: TFA (340mg, 222. mu.l, 2.99mmol, Eq:200.00) was added to 4- [ ({ (S) -9- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -7- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino) at 0 ℃]-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatriene-4-carbonyl } -amino) -methyl]A solution of methyl benzoate (12mg, 14.9. mu. mol, Eq:1.00) in DCM (300. mu.l). After 1 hour the mixture was concentrated and the residue was dissolved in DCM. The solution was saturated with NaHCO₃Washing and separating NaHCO₃The solution was extracted with DCM. The combined organic extracts are passed over Na₂SO₄Drying, filtering and concentrating. The residue was dissolved in minimal DCM. Et was added₂O pentane was then added, which resulted in precipitation. The supernatant was decanted off, and the residue was washed with pentane and dried under vacuum to give the title compound (10mg, 95%) as a white solid.¹H NMR(DMSO-d₆):8.81(br.s.,1H),8.22(d,J＝8.2Hz,1H),8.03-8.12(m,2H),7.87(d,J＝8.5Hz,2H),7.79(d,J＝9.1Hz,1H),7.65(d,J＝7.8Hz,1H),7.53(dd,J＝9.2,2.0Hz,1H),7.32-7.40(m,3H),7.25-7.31(m,1H),7.16-7.25(m,1H),5.87(d,J＝14.8Hz,1H),5.24(d,J＝14.8Hz,1H),4.66-4.82(m,1H),4.13-4.52(m,4H),3.78(s,3H),2.94(d,J＝6.9Hz,1H),2.20(s,3H),1.08(d,J＝6.9Hz,3H)。

Example 52

(S) -5- ((6-carboxy-2-methoxynaphthalen-1-yl)Methyl) -3- ((S) -2- (methylamino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-9-Carboxylic acid trifluoroacetic acid salt

Step 1: will N₂Bubbling to (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- (tert-butoxycarbonylamino) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-9-Carboxylic acid methyl ester (100mg, 171. mu. mol, Eq:1.00), Pd (OAc)₂(1.53mg, 6.83. mu. mol, Eq:.04), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (7.91mg, 13.7. mu. mol, Eq:0.08), TEA (0.7mL) and MeOH (82.1mg, 104. mu.l, 2.56mmol, Eq:15.00) in a mixture in a microwave tube for 5 minutes. CO was then bubbled into the mixture for 5 minutes, and the mixture was heated at 70 ℃ overnight. The mixture was diluted with EtOAc and then 0.5N HCl, H₂And washing with saturated brine. Subjecting the organic mixture to Na₂SO₄Drying, filtering and concentrating to give a residue which is purified by silica gel chromatography to give (S) -3- (tert-butoxycarbonylamino) -5- ((2-methoxy-6- (methoxycarbonyl) naphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-9-Carboxylic acid methyl ester (90mg, 90%).

Step 2: in a similar manner to that described in example 49, step 3, (S) -3- (tert-butoxycarbonylamino) -5- ((2-methoxy-6- (methoxycarbonyl) naphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-methyl 9-carboxylate (169mg,299 μmol) to (S) -3-amino-5- ((2-methoxy-6- (methoxycarbonyl) naphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineMethyl-9-carboxylate trifluoroacetate (173mg, 99%) was used without purification.

And step 3: DIEA (193mg, 264. mu.l, 1.5mmol, Eq:5.00) was added to (S) -3-amino-5- ((2-methoxy-6- (methoxycarbonyl) naphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b at 0 deg.C][1,4]OxazazepineMethyl (9-carboxylate trifluoroacetate) (173mg, 299. mu. mol, Eq:1.00), (S) -2- (tert-butoxycarbonyl (methyl) amino) propanoic acid (60.8mg, 299. mu. mol, Eq:1.0), HBTU (113mg, 299. mu. mol, Eq:1.0) and HOBT. H₂O (40.4mg, 299. mu. mol, Eq:1.0) in DMF (4 mL). The mixture was warmed to stir for 1.5 hours and diluted with EtOAc. Subjecting the mixture to hydrogenation with hydrogen₂Washed with saturated brine and then with Na₂SO₄And (5) drying. The mixture was filtered and concentrated to give a residue which was purified by silica gel chromatography to give (S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -5- ((2-methoxy-6- (methoxycarbonyl) naphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineMethyl 9-carboxylate (169mg, 87%) as white foam.

And 4, step 4: reacting LiOH & H₂O (22.0mg, 523. mu. mol, Eq:2.00) and H₂O (0.5mL) was added to (S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -5- ((2-methoxy-6- (methoxycarbonyl) naphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-methyl 9-carboxylate (170mg, 262. mu. mol, Eq:1.00) in MeOH (5 mL).The mixture was heated to 50 ℃. After 3.5 hours, LiOH H was added₂O (44mg,1.04mmol) and the temperature was raised to 60 ℃. After 1.5 h, MeOH was removed in vacuo, the aqueous mixture was diluted with water and Et₂And (4) extracting. The aqueous mixture was acidified to pH 2.0 with 1N HCl and extracted with EtOAc. The combined organic extracts were washed with brine and concentrated to give a residue which was washed with Et₂O grinding to obtain (S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -5- ((6-carboxyl-2-methoxynaphthalene-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-9-carboxylic acid (47mg) as a white solid.

And 5: in a similar manner to that described in example 49, step 3, (S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -5- ((6-carboxy-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-9-carboxylic acid (47mg,75.6 μmol) was converted to the title compound (48mg, 99%) as an off-white solid. MS m/z 522.4 (MH)⁺)。

Example 53

5- (((S) -9- ((2-hydroxyethyl) (methyl) carbamoyl) -3- ((S) -2- (methylamino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid trifluoroacetate salt

Step 1: 0.1M LiOH. H₂Aqueous O solution (5.98mL, 598. mu. mol, Eq:1.00) was added to (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- (tert-butoxycarbonylamino) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-methyl 9-carboxylate (0.35g, 598. mu. mol, Eq:1.00) in MeOH (20mL) and the mixture was warmed to 45-50 ℃. After 7 h, MeOH was removed in vacuo and the mixture was washed with saturated NaHCO₃Diluted and then extracted with EtOAc. The aqueous mixture was cooled to 0 ℃, acidified to pH 3.0 with 3N HCl, and extracted with EtOAc. The combined organic extracts were washed with saturated brine and concentrated to give a material which was purified by silica gel chromatography to give (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- (tert-butoxycarbonylamino) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] n][1,4]Oxazazepine9-Carboxylic acid (310mg, 90%) as a white foam.

Step 2: in a similar manner to that described in example 50, step 1, (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- (tert-butoxycarbonylamino) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineConversion of-9-carboxylic acid (150mg,263 μmol, Eq:1.00) and 2- (methylamino) ethanol (21.7mg,289 μmol, Eq:1.1) to (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9- ((2-hydroxyethyl) (methyl) carbamoyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester (128mg) as a white foam.

And step 3: in a similar manner to that described in example 52, step 1, (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9- ((2-hydroxyethyl) (methyl) carbamoyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo[b][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester (123mg, 196. mu. mol, Eq:1.00), Pd (OAc)₂(2.42mg, 10.8. mu. mol, Eq:.055), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (9.06mg, 15.7. mu. mol, Eq:0.08), TEA (896. mu.l) and MeOH (94.1mg, 119. mu.l, 2.94mmol, Eq:15.00) to give a substance, which was purified by silica gel chromatography to give (S) -5- ((3- (tert-butoxycarbonylamino) -9- ((2-hydroxyethyl) (methyl) carbamoyl) -4-oxo-3, 4-dihydrobenzo [ b ] b][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid methyl ester (103mg, 87%) as an off-white foam.

And 4, step 4: in a similar manner to that described in example 49, step 3, (S) -5- ((3- (tert-butoxycarbonylamino) -9- ((2-hydroxyethyl) (methyl) carbamoyl) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-methyl 5(2H) -yl) methyl) -6-methoxy-2-naphthoate (103mg, 170. mu. mol) was converted to (S) -5- ((3-amino-9- ((2-hydroxyethyl) (methyl) carbamoyl) -4-oxo-3, 4-dihydrobenzo [ b ] b][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid methyl ester trifluoroacetate (104mg, 98%) as an off-white solid.

And 5: to prepare (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-methyl 9-carboxylate similar to the procedure described in step 1, (S) -5- ((3-amino-9- ((2-hydroxyethyl) (methyl) carbamoyl)-4-oxo-3, 4-dihydrobenzo [ b ]][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid methyl ester trifluoroacetate (104mg, 167. mu. mol, Eq:1.00) and (S) -2- (tert-butoxycarbonyl (methyl) amino) propanoic acid (34.0mg, 167. mu. mol, Eq:1.0) are converted to 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -9- ((2-hydroxyethyl) (methyl) carbamoyl) -4-oxo-3, 4-dihydrobenzo [ b ] -, c][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid methyl ester (59mg, 50%).

Step 6: reacting LiOH & H₂O (7.15mg, 170. mu. mol, Eq:2.00) and H₂O (200. mu.L) was added to 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -9- ((2-hydroxyethyl) (methyl) carbamoyl) -4-oxo-3, 4-dihydrobenzo [ b][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid methyl ester (59mg, 85.2. mu. mol, Eq:1.00) in MeOH (2mL) and the mixture was heated to 50 ℃. After 4 hours, another portion of LiOH H was added₂O (2mg, 48. mu. mol, Eq. 0.65). After 1 hour the mixture was taken up in saturated NaHCO₃Diluted and Et₂And (4) extracting. The aqueous mixture was acidified to pH 2.0 with 1N HCl, extracted with EtOAc and the combined organic extracts were washed with saturated brine, washed with Na₂SO₄Drying and concentrating to give 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -9- ((2-hydroxyethyl) (methyl) carbamoyl) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid (43mg, 74%) was used without purification.

And 7: to example 49Similar to the procedure described in step 3, 5- (((S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -9- ((2-hydroxyethyl) (methyl) carbamoyl) -4-oxo-3, 4-dihydrobenzo [ b][1,4]Oxazazepine-5(2H) -yl) methyl) -6-methoxy-2-naphthoic acid (43mg, 63.4. mu. mol) was converted to the title compound (40mg, 91%) as a white solid.¹H NMR(MeOH-d₄):8.41(d,J＝8.5Hz,1H),8.01-8.11(m,2H),7.91-8.00(m,1H),7.79-7.90(m,1H),7.53(d,J＝7.5Hz,2H),7.30(d,J＝9.1Hz,1H),7.11(d,J＝7.2Hz,1H),6.96(d,J＝7.2Hz,1H),6.02(d,J＝14.2Hz,1H),5.39(d,J＝14.8Hz,1H),4.28(d,J＝11.2Hz,2H),3.95(s,5H),2.95(s,2H),2.64(s,3H),1.61(d,J＝6.3Hz,3H)。

Example 54

(S) -5- ((4-bromonaphthalen-1-yl) methyl) -3- ((S) -2- (methylamino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-9-Carboxylic acid trifluoroacetic acid salt

In a similar manner to that described in example 49, step 3, (S) -5- ((4-bromonaphthalen-1-yl) methyl) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-9-Carboxylic acid (25mg, 39.9. mu. mol) was converted to the title compound (21mg, 82%). MS m/z 527.4 (MH)⁺)。

Example 55

(S) -N- ((S) -5- ((4-bromonaphthalen-1-yl) methyl) -9- (4- (2-hydroxyethyl) piperazine-1-carbonyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide

Step 1: in a similar manner to that described in example 50, step 1, except that material was not purified, (S) -5- ((4-bromonaphthalen-1-yl) methyl) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-9-carboxylic acid (130mg,208 μmol, Eq:1.00) and 2- (piperazin-1-yl) ethanol (27mg,208 μmol, Eq:1) were converted to (S) -1- ((S) -5- ((4-bromonaphthalen-1-yl) methyl) -9- (4- (2-hydroxyethyl) piperazine-1-carbonyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (130mg, 86%) as white foam.

Step 2: in a similar manner to that described in example 51, step 2, (S) -1- ((S) -5- ((4-bromonaphthalen-1-yl) methyl) -9- (4- (2-hydroxyethyl) piperazine-1-carbonyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (130mg,176 μmol) was converted to the title compound (83mg, 74%) as a white solid. MS m/z 639 (MH)⁺)。

Example 56

(S) -N- ((S) -5- ((4-bromonaphthalen-1-yl) methyl) -9- (4- (3-hydroxypropyl) piperazine-1-carbonyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide

Step 1: in a similar manner to that described in example 50, step 1, except that material was not purified, (S) -5- ((4-bromonaphthalen-1-yl) methyl) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-9-carboxylic acid (70mg,112 μmol, Eq:1.00) and 3- (piperazin-1-yl) propan-1-ol (16.1mg,112 μmol, Eq:1.00) were converted to (S) -1- ((S) -5- ((4-bromonaphthalen-1-yl) methyl) -9- (4- (3-hydroxypropyl) piperazine-1-carbonyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (79mg, 94%) as white foam.

Step 2: in a similar manner to that described in example 51, step 2, (S) -1- ((S) -5- ((4-bromonaphthalen-1-yl) methyl) -9- (4- (3-hydroxypropyl) piperazine-1-carbonyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineTert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (79mg,105 μmol) was converted to the title compound (50mg, 73%) as a white solid. MS m/z 653 (MH)⁺)。

Example 57

(S) -N- ((S) -5- ((2-chloro-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide

Step 1: 40 wt.% toluene solution of diethyl azodicarboxylate (DEAD 40% w/w,360mg, 377. mu.l, 828. mu. mol, Eq:2) was added to methyl ((S) -1-oxo-1- ((S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester (226mg, 621. mu. mol, Eq:1.5), 2- (2-chloro-3- (hydroxymethyl) -1H-indol-1-yl) benzonitrile (117mg, 414. mu. mol, Eq:1.00) and Ph₃A solution of P (217mg, 828. mu. mol, Eq:2) in THF (5mL) was added and the mixture was stirred at room temperature for 2.5 d. The mixture was diluted with MeOH (10mL), concentrated, and the residue was purified by preparative TLC to give (S) -1- ((S) -5- ((2-chloro-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (130mg, 50%) as a yellow solid.

Step 2: TFA (5mL) was added to (S) -1- ((S) -5- ((2-chloro-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine(iii) A solution of tert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (130mg, 207. mu. mol, Eq:1.00) in DCM (5mL)In (1). The mixture was stirred at room temperature for 16 hours, then concentrated. Adding saturated NaHCO₃To residue, and the mixture was extracted with DCM. The combined organic extracts were concentrated and the residue was purified by preparative TLC to give the title compound (50mg, 43%) as a white solid. MS m/z529 (MH)⁺)。

Example 58

(S) -N- ((S) -5- ((1- (2-cyanophenyl) -1H-indol-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide

In a similar manner to that described in example 57, except that in step 1 the mixture was heated at 60 ℃ for 2.5d and in step 2 the material was purified by silica gel chromatography, the methyl group ((S) -1-oxo-1- ((S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] was purified][1,4]OxazazepineTert-butyl (3-ylamino) propan-2-yl) carbamate (250mg, 688. mu. mol, Eq:1.00), 2- (4- (hydroxymethyl) -1H-indol-1-yl) benzonitrile (440mg,1.77mmol, Eq:2.58) was converted to the title compound (35mg) as a white solid. MS m/z494 (MH)⁺)。

Example 59

(S) -N- ((S) -5- ((2-chloro-1- (phenylsulfonyl) -1H-indol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methyl)Amino) propionamides

Step 1: DEAD 40% w/w (119mg, 124. mu.l, 273. mu. mol, Eq:2) was added to (2-chloro-1- (phenylsulfonyl) -1H-indol-3-yl) methanol (44mg, 137. mu. mol, Eq:1.00), methyl ((S) -1-oxo-1- ((S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester (99.4mg, 273. mu. mol, Eq:2) and Ph₃P (71.7mg, 273. mu. mol, Eq:2) in THF (10.0 mL). After stirring at room temperature for 12 hours, the mixture was diluted with saturated brine and extracted with EtOAc. The combined extracts were passed over MgSO₄Dried, filtered, and the filtrate concentrated. The residue was purified by preparative TLC to give (S) -1- ((S) -5- ((2-chloro-1- (phenylsulfonyl) -1H-indol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (36mg, 36%) as a white solid.

Step 2: in a similar manner to that described in example 57, step 2, (S) -1- ((S) -5- ((2-chloro-1- (phenylsulfonyl) -1H-indol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineTert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (42mg,63.0 μmol) was converted to the title compound (32mg, 89.6%) as a waxy solid. MS m/z568 (MH)⁺)。

Example 60

(S) -N- ((S) -5- ((2- (A)Methylsulfonyl) isoindolin-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride

Step 1: in a similar manner to that described in example 57, step 1, except that the mixture was stirred for 16 hours, methyl ((S) -1-oxo-1- ((S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] was reacted][1,4]Oxazazepine-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester (150mg,413 μmol, Eq:1.00), (2- (methylsulfonyl) isoindolin-4-yl) methanol (250mg,1.1mmol, Eq:2.66) is converted to methyl ((S) -1- ((S) -5- ((2- (methylsulfonyl) isoindolin-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl) carbamic acid tert-butyl ester (170mg, 72%).

Step 2: a solution of 4M HCl in dioxane (8.4g,7mL,28.0mmol, Eq:94.3) and methyl ((S) -1- ((S) -5- ((2- (methylsulfonyl) isoindolin-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl) carbamic acid tert-butyl ester (170mg, 297. mu. mol, Eq:1.00) were mixed and the mixture was stirred at room temperature. After 16 h the mixture was concentrated and the residue was taken up in Et₂Trituration with O afforded the title compound (120mg, 79%). MS m/z473 (MH)⁺)。

Example 61

(S) -N- ((S) -5- ((6-fluoro-1-methyl-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide

Step 1: in a similar manner to that described in example 1, step 1, except that no NaI was used and the product was purified by preparative TLC, methyl ((S) -1-oxo-1- ((S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester (87.5mg,0.241mmol) and 4- (bromomethyl) -6-fluoro-1-methylquinolin-2 (1H) -one (50mg,0.185mmol) were converted to (S) -1- ((S) -5- ((6-fluoro-1-methyl-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (40mg, 40%).

Step 2: a solution of 3M HCl in dioxane (36.0g,30mL,120mmol, Eq:1660) and (S) -1- ((S) -5- ((6-fluoro-1-methyl-2-oxo-1, 2-dihydroquinolin-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]OxazazepineA mixture of tert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (40mg, 72.4. mu. mol, Eq:1.00) was stirred at room temperature overnight. The mixture was washed with saturated NaHCO₃Diluted and extracted with DCM and the combined extracts were taken with H₂O wash and concentrate. The residue was purified by preparative TLC to give the title compound(26mg, 95%) as a white solid. MS m/z 453 (MH)⁺)。

Example 62

(S) -N- [ (S) -9- (1-benzyl-2-chloro-1H-indol-3-ylmethyl) -8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptatrien-7-yl ] -2-methylamino-propionamide

In a similar manner to that described in example 59, step 1, except that 3eq₃P and DEAD of (1-benzyl-2-chloro-1H-indol-3-yl) methanol (310mg,1.14mmol, Eq:3.03) and methyl ((S) -1-oxo-1- ((S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester (137mg, 377. mu. mol, Eq:1.00) into (S) -1- ((S) -5- ((1-benzyl-2-chloro-1H-indol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (90mg, 39%) as a viscous oil.

Step 2: et with 1M HCl₂O solution (24.0g,20mL,20.0mmol, Eq:137) was added to (S) -1- ((S) -5- ((1-benzyl-2-chloro-1H-indol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (90mg, 146. mu. mol, Eq:1.00) and the mixture was stirred at room temperature overnight. The precipitate formed was filtered, washed with diethyl ether and dried under vacuum to give the title compound (8mg, 12%). MS m/z 517 (MH)⁺)

Example 63

(S) -N- ((S) -5- ((1-ethyl-2-oxoindolin-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide

Step 1: DEAD 40% w/w (359mg, 376. mu.l, 826. mu. mol, Eq:3) was added to methyl ((S) -1-oxo-1- ((S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester (100mg, 275. mu. mol, Eq:1.00), (1-ethyl-1H-indol-4-yl) methanol (48.2mg, 275. mu. mol, Eq:1.00) and polymer bound Ph₃P (500mg, 275. mu. mol, Eq:1.00) in a mixture of THF (10 mL). After 2.5 days, another portion of (1-ethyl-1H-indol-4-yl) methanol (48.2mg, 275. mu. mol, Eq:1.00), polymer bound Ph was added₃P (1eq) and DEAD (1 eq). After 1d, the mixture was filtered and the filter cake was washed with MeOH and THF. The filtrate was concentrated and the residue was purified by preparative TLC to give (S) -1- ((S) -5- ((1-ethyl-1H-indol-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (73mg, 51%).

Step 2: a solution of N-chlorosuccinimide (NCS,17.2mg, 129. mu. mol, Eq:1.00) in DMF (2mL) was added dropwise to (S) -1- ((S) -5- ((1-ethyl-1H-indol-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b at 0 deg.C][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (67mg, 129. mu. mol, Eq:1.00) in DMF (12 mL). After 2 hours at 0 ℃ the mixture was washed with saturated NaHCO₃Diluted and extracted with EtOAc. The combined extracts are washed with H₂O washing, concentration and purification of the residue by preparative TLC to give (S) -1- ((S) -5- ((3-chloro-1-ethyl-1H-indol-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (65mg, 91%).

And step 3: phosphoric acid (13.2mg,2mL, 108. mu. mol, Eq:1.00) was added to (S) -1- ((S) -5- ((3-chloro-1-ethyl-1H-indol-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (60mg, 108. mu. mol, Eq:1.00) and the mixture was stirred at room temperature for 2 hours. The mixture was washed with saturated NaHCO₃Diluted and extracted with DCM. The combined extracts were concentrated and the residue was purified by preparative TLC to give the title compound (7mg, 14%) as a solid. MS m/z 437 (MH)⁺)。

Example 64

(S) -2-amino-N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) propanamide

Step 1: (S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] was purified by preparative TLC in a similar manner as described in step 1 of example 1, except that NaI was not used and the product was purified by preparative TLC][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester (589mg,1.8mmol) and 2- (3- (bromomethyl) -1H-indazol-1-yl) benzonitrile (673mg,2.16mmol) were converted to (S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester (915mg, 100%).

Step 2: (S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] benzo [ b ] in a similar manner to that described in example 57, step 2, except that the mixture was stirred at 0 ℃ for 1 hour and the product was purified by silica gel chromatography][1,4]OxazazepineConversion of tert-butyl (915mg,1.8mmol) of the (3-ylcarbamate to (S) -2- (3- ((3-amino-4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazol-1-yl) benzonitrile (650mg, 88%).

And step 3: (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP,486mg,1.1mmol, Eq:1.5) was added to (S) -2- (3- ((3-amino-4-oxo-3, 4-dihydrobenzo [ b ] b][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazol-1-yl) benzonitrile (300mg, 733. mu. mol, Eq:1.00), (S) -2- (tert-butoxycarbonylamino) propionic acid (208mg,1.1mmol, Eq:1.5) and DIEA (284mg, 383. mu.l, 2.2mmol, Eq:3) inTHF (10.0mL) and the mixture was stirred at rt overnight. The mixture was diluted with brine and extracted with EtOAc, and the combined extracts were taken over Na₂SO₄And (5) drying. The mixture was filtered, concentrated, and the residue was purified by silica gel chromatography to give (S) -1- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-ylcarbamic acid tert-butyl ester (380mg, 89%).

And 4, step 4: in a similar manner to that described in example 57, step 2, (S) -1- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-ylcarbamic acid tert-butyl ester (30mg, 51.7. mu. mol) was converted to the title compound (18mg, 72.5%). MS m/z481 (MH)⁺)。

Example 65

(S) -N- ((S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide trifluoroacetate salt

Step 1: in a similar manner to that described in example 1, step 1, except that the mixture was stirred at room temperature for 16 hours without NaI and the product was purified by preparative TLC, methyl ((S) -1-oxo-1- ((S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] was purified][1,4]Oxazazepine-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester (30mg, 82.6. mu. mol, Eq:1.00) and 3- (bromomethyl) -1- (2-cyanophenyl) -1H-indole-2-carbonitrile (40mg, 119. mu. mol, Eq:1.44) were converted to (S) -1- ((S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (45mg, 88%).

Step 2: TFA (1.48g,1mL,13.0mmol, Eq:178) was added to (S) -1- ((S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] at 0 deg.C][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (45mg, 72.7. mu. mol, Eq:1.00) in DCM (1.7 mL). After 1h, the mixture was concentrated and the residue was taken up in Et₂O/Hexane trituration to give a solid, which was removed from MeCN/H₂Lyophilization in O afforded the title compound (43mg, 93.5%) as a solid. MS m/z519 (MH)⁺)。

Example 66

(S) -N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (oxetan-3-ylamino) propanamide

Reacting NaBH₃CN (10mg, 159. mu. mmol) and AcOH (1mL) were added to (S) -2-amino-N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) propionamide (40mg, 83.2. mu. mol) and oxetan-3-one (19mg, 264. mu. mmol) in MeOH (5 mL). After 16 h the mixture was concentrated and the residue was taken up with saturated NaHCO₃Work up and extract the resulting mixture with DCM. The combined extracts are washed with H₂O wash, concentrate, and purify the residue by preparative TLC to give the title compound (10mg, 22.4%). MS m/z537 (MH)⁺)。

Example 67

(S) -N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (2-hydroxy-2-methylpropylamino) propanamide

Reacting (S) -2-amino-N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) propionamide (50mg, 104. mu. mol, Eq:1.00), LiClO₄(11.1mg, 4.56. mu.l, 104. mu. mol, Eq:1.00) and 2, 2-dimethyloxirane (1mL) were mixed with EtOH (7mL) in a microwave reaction vial, the vial was sealed, and heated in the microwave at 100 ℃. After 2 hours, 20eq of 2, 2-dimethyloxirane were heated and heating at 100 ℃ for 3 hours was continued under microwave. The mixture was concentrated and the residue was purified by preparative TLC to give the titleCompound (34mg, 59.1%) as a solid. MS m/z553 (MH)⁺)。

Example 68

(S) -N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (2-hydroxyethylamino) propionamide

Mixing Na (OAc)₃BH (14.2mg, 67.0. mu. mol, Eq:1.4) was added to (S) -2-amino-N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) propionamide (23mg, 47.9. mu. mol, Eq:1.00) and glycolaldehyde dimer (3.16mg, 26.3. mu. mol, Eq:0.55) in DCM (1.5 mL). After 72 hours at room temperature, the mixture was washed with NaHCO₃Diluted and extracted with DCM. The combined extracts were concentrated. The residue was purified by preparative TLC to give the title compound (16mg, 95%) as a solid. MS m/z525 (MH)⁺)。

Example 69

(S) -N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide

Step 1: in a similar manner to that described in example 1, step 1, except that no NaI was used and the product was purified by preparative TLC, methyl ((S) -1-oxo-1- ((S) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] is purified][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester (55mg, 127. mu. mol, Eq:1.00) and 2- (3- (bromomethyl) -1H-indazol-1-yl) benzonitrile (78mg, 250. mu. mol, Eq:1.97) into (S) -2-amino-N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) propionamide (60mg, 71.1%).

Step 2: in a similar manner to that described in example 57, step 2, except that the mixture was stirred at 0 ℃ for 1 hour, (S) -1- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (60mg, 90.3. mu. mol) was converted to the title compound (48mg, 94.2%). MS m/z565 (MH)⁺)。

Example 70

(S) -N- ((S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (ethyl-d 5-amino) propionamide

Step 1: PyBOP (215mg, 414. mu. mol, Eq:1.5) was added to (S) -2- (benzyloxycarbonyl-ethyl (d5) -amino) -propionic acid (106mg, 414. mu. mol, Eq:1.5), (S) -2- (3- ((3-amino-4-oxo-3, 4-dihydrobenzo [ b ] b][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazol-1-yl) benzonitrile (113mg, 276. mu. mol, Eq:1.00) and DIEA (71.3mg, 96.4. mu.l, 552. mu. mol, Eq:2) in a mixture of THF (2.00 mL). After 2h, the mixture was diluted with EtOAc and saturated NaHCO₃And NH₄And (5) washing with Cl. The organic mixture was concentrated and the residue was purified by preparative TLC to give ((S) -1- { (S) -9- [1- (2-cyano-phenyl) -1H-indazol-3-ylmethyl)]-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptan-7-ylcarbamoyl } -ethyl) -ethyl-d 5-carbamic acid benzyl ester (77mg, 43.1%).

Step 2: 5% Pd/C (35mg) was added to ((S) -1- { (S) -9- [1- (2-cyano-phenyl) -1H-indazol-3-ylmethyl)]-8-oxo-6, 7,8, 9-tetrahydro-5-oxa-9-aza-benzocycloheptan-7-ylcarbamoyl } -ethyl) -ethyl-d 5-carbamic acid benzyl ester (77mg, 119. mu. mol, Eq:1.00) in MeOH (70mL) and the mixture was dissolved in H₂Stirring the mixture. After 4 hours, the mixture was filtered through celite, and the filter cake was washed with MeOH. The filtrate was concentrated, and the residue was purified by preparative TLC to give the title compound (40mg, 65%). MS m/z514 (MH)⁺)。

Example 71

(S) -N- ((S) -5- ((1- (2-cyanophenyl) -6-fluoro-1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (ethylamino) propionamide

Step 1: (S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] is used in a similar manner as described in step 1 of example 1, except that NaI is not used and the product is used without purification][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester (0.125g, 449. mu. mol) and 2- (3- (bromomethyl) -6-fluoro-1H-indazol-1-yl) benzonitrile (162mg, 494. mu. mol) were converted to (S) -5- ((1- (2-cyanophenyl) -6-fluoro-1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester (237mg, 100%).

Step 2: in a similar manner to that described in example 57, step 2, except that the mixture was stirred at 0 ℃ for 1.5 hours and the product was used without purification, (S) -5- ((1- (2-cyanophenyl) -6-fluoro-1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineConversion of tert-butyl (150mg, 284. mu. mol) of the-3-ylcarbamate to (S) -2- (3- ((3-amino-4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -6-fluoro-1H-indazol-1-yl) benzonitrile (121mg, 100%).

And step 3: PyBOP (223mg, 428. mu. mol, Eq:1.5) was added to (S) -2- (3- ((3-amino-4-oxo-3, 4-dihydrobenzo [ b ]][1,4]Oxazazepine-5(2H) -yl) methyl) -6-fluoro-1H-indazol-1-yl) benzonitrile (122mg, 285. mu. mol, Eq:1.00) (S) -2- ((benzyloxycarbonyl) (ethyl) amino) propionic acid (Tetrahedron: Asymmetry2008,19, 970-. After 3 hours, the mixture is washed with NH₄Dilute Cl and extract with EtOAc. The combined extracts were washed with saturated NaHCO₃Washed and concentrated. The residue was purified by preparative TLC to give (S) -1- ((S) -5- ((1- (2-cyanophenyl) -6-fluoro-1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (ethyl) carbamate (150mg, 79.5%).

And 4, step 4: in a similar manner to that described in example 70, except that the mixture is in H₂Stirring was continued for 4 hours and (S) -1- ((S) -5- ((1- (2-cyanophenyl) -6-fluoro-1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (ethyl) carbamate (150mg,227 μmol) was converted to the title compound (30mg, 23%). MS m/z527 (MH)⁺)。

Example 72

(S) -N- ((S) -5- ((6-bromo-1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide trifluoroacetate salt

Step 1: mixing Cs₂CO₃(163mg, 494. mu. mol) to (S) -4-oxo-2, 34, 5-tetrahydrobenzo [ b ]][1,4]OxazazepineTert-butyl-3-ylcarbamate (0.125g, 449. mu. mol) and 2- (3- (bromomethyl) -6-bromo-1H-indazol-1-yl) benzonitrile (193mg, 494. mu. mol) in DMF (5mL) and the mixture was heated at 70 ℃ overnight. The mixture was cooled and poured into saturated NH₄In Cl, a precipitate was generated. Filtering the solid with H₂O, hexanes and drying in vacuo to give (S) -5- ((6-bromo-1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineTert-butyl (237mg, 100%) 3-ylcarbamate was used without purification.

Step 2: in a similar manner to that described in example 57, step 2, except that the mixture was stirred at 0 ℃ for 1.5 hours and the product was used without purification, (S) -5- ((6-bromo-1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineConversion of tert-butyl (95mg, 161. mu. mol) 3-ylcarbamate to (S) -2- (3- ((3-amino-4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -6-bromo-1H-indazol-1-yl) benzonitrile (79mg, 100%).

And step 3: in a similar manner to that described in example 71, step 3, (S) -2- (3- ((3-amino-4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -6-bromo-1H-indazol-1-yl benzonitrile (78mg,160 μmol, Eq:1.00) and (S) -2- (tert-butoxycarbonyl (methyl) amino) propanoic acid (65mg,320 μmol, Eq:2.00) were converted to (S) -1- ((S) -5- ((6-bromo-1- (2-cyanobenzene)Yl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (75mg, 70%) as a white solid.

And 4, step 4: in a similar manner to that described in example 65, (S) -1- ((S) -5- ((6-bromo-1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineTert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (75mg,111 μmol) was converted to the title compound (65mg, 85%) as a white powder. MS m/z575 (MH)⁺)。

Example 73

(S) -N- ((S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide

Step 1: mixing Cs₂CO₃(9.58g,29.4mmol, Eq:1.5) to 3- (bromomethyl) -1- (2-cyanophenyl) -1H-indole-2-carbonitrile (9.89g,29.4mmol, Eq:1.5) and methyl ((S) -1-oxo-1- ((S) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester (8.5g,19.6mmol, Eq:1.00) in DMF (20mL)To the mixture, and the mixture was heated to 70 ℃ for 1 hour. The mixture was cooled and saturated NH was used₄Dilute Cl and extract with EtOAc. The combined extracts are washed with H₂O washing with Na₂SO₄Drying and concentrating to obtain a material, which is purified by silica gel chromatography to obtain (S) -1- ((S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] l][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (13g, 96.3%) as a bright yellow solid.

Step 2: TFA (37.0g,25mL,324mmol, Eq:55.9) was added dropwise to (S) -1- ((S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] over 2H at 0 deg.C][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (4g,5.81mmol) in DCM (50 mL). After 30 minutes, the mixture was added to saturated NaHCO₃/H₂In O1:1, the organic phase is separated and passed over Na₂SO₄Drying, filtration and concentration gave the title compound (3.4g, 97%) as a bright yellow solid. MS m/z589 (MH)⁺)。

Example 74

(2S) -N- ((2S,3S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (ethylamino) propionamide trifluoroacetate salt

Step 1: in a similar manner to that described in example 71, step 3, except that 1.3eq₃Washing, and reacting (2S,3S) -3-amino-2-methyl-2, 3-dihydrobenzo [ b ]][1,4]OxazazepineConversion of (4- (5H) -one (113mg, 588. mu. mol, Eq:1.00) and (S) -2- (tert-butoxycarbonyl (ethyl) amino) propanoic acid (Peptides: struct. Funct., Proc. am. Pept. Symp.1983,8, 143. sub.6, 166mg, 764. mu. mol, Eq:1.3) to ethyl ((S) -1- ((2S,3S) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl) carbamic acid tert-butyl ester (35mg, 82%).

Step 2: in a similar manner to that described in example 65, except that the product was not lyophilized, (2S) -1- ((2S,3S) -5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]OxazazepineTert-butyl (3-ylamino) -1-oxoprop-2-yl (ethyl) carbamate (35mg,56.2 μmol) was converted to the title compound (30mg, 80%) as an off-white solid. MS m/z523 (MH)⁺)。

Example 75

(S) -N- ((R) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -2, 2-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Thiaazepines-3-yl) -2- (ethylamino) propionamide

Step 1: in a similar manner to that described in step 3 of example 71, except that the reaction was stirred at room temperature for 16 hours, (R) -3-amino-2, 2-dimethyl-2, 3-dihydrobenzo [ b ]][1,4]ThiaazepinesConversion of (E) -4(5H) -one (343mg,1.54mmol, Eq:1.00) and (S) -2- (tert-Butoxycarbonyl (ethyl) amino) propionic acid (436mg,2.01mmol, Eq:1.3) to ethyl ((S) -1- ((2S,3S) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl) carbamic acid tert-butyl ester (500mg, 77%).

Step 2: in a similar manner to that described in example 1, step 1, except that no NaI was used and the product was purified by preparative TLC, ethyl ((S) -1- ((2S,3S) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] was purified][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl) carbamic acid tert-butyl ester (27mg,69.0 μmol, Eq:1.00) and 2- (3- (bromomethyl) -1H-indazol-1-yl) benzonitrile (32.3mg,103 μmol, Eq:1.5) were converted to (S) -1- ((R) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -2, 2-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (ethyl) carbamic acid tert-butyl ester (35mg, 81.5%).

And step 3: in a similar manner to that described in example 57, step 2, except that the mixture was stirred at 0 ℃ for 1 hour, (S) -1- ((R) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -2, 2-dimethyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Thiaazepines-3-ylamino) -1-oxoprop-2-yl (ethyl) carbamate (200mg, 295. mu. mol) was converted to the title compound (82mg, yield 45.7%). MS m/z577 (MH)⁺)。

Example 76

(S) -N- ((2S,3S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide

Step 1: (2S,3S) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] was purified by preparative TLC in a similar manner to that described in step 1, example 1, except that instead of NaI, the reaction mixture was heated at 65 ℃ for 1.5 hours and the product was purified by preparative TLC][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester (bioorg. Med. chem. Lett.1994,4,1789-94,400mg,1.37mmol, Eq:1.00) and 3- (bromomethyl) -1- (2-cyanophenyl) -1H-indole-2-carbonitrile (598mg,1.78mmol, Eq:1.3) to (2S,3S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester (320mg, 43%).

Step 2: in a similar manner to that described in step 2 of example 57, except that the mixture was stirred at 0 ℃ for 1 hour and the product was not purified, (2S,3S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -2-methyl-4-oxo-2,3,4, 5-tetrahydrobenzo [ b ]][1,4]OxazazepineConversion of tert-butyl (3-ylcarbamate) (320mg, 584. mu. mol) to 3- (((2S,3S) -3-amino-2-methyl-4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -1- (2-cyanophenyl) -1H-indole-2-carbonitrile (261mg, 99%) was used without purification.

And step 3: in a similar manner to that described in example 71, step 3, except that the reaction was stirred at room temperature for 16 hours and 1.5eq.diea and PyBOP were used, 3- (((2S,3S) -3-amino-2-methyl-4-oxo-3, 4-dihydrobenzo [ b ] b][1,4]Oxazazepine-5(2H) -yl) methyl) -1- (2-cyanophenyl) -1H-indole-2-carbonitrile (95mg, 212. mu. mol, Eq:1.00) and (S) -2- (tert-butoxycarbonyl (methyl) amino) propionic acid (64.7mg, 318. mu. mol, Eq:1.5) were converted to (S) -1- ((2S,3S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (102mg, 76%).

And 4, step 4: in a similar manner to that described in example 57, step 2, except that the mixture was stirred at 0 ℃ for 1 hour, (S) -1- ((2S,3S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (102mg, 161. mu. mol) was converted to the title compound (78mg, 95%). MS m/z533 (MH)⁺)。

Example 77

(S) -N- ((2S,3S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (ethylamino) propionamide

Step 1: in a similar manner to that described in example 71, step 3, except that the reaction was stirred at room temperature for 16 hours and 1.5eq.diea and PyBOP were used, 3- (((2S,3S) -3-amino-2-methyl-4-oxo-3, 4-dihydrobenzo [ b ] b][1,4]Oxazazepine-5(2H) -yl) methyl) -1- (2-cyanophenyl) -1H-indole-2-carbonitrile (95mg, 212. mu. mol, Eq:1.00) and (S) -2- (tert-butoxycarbonyl (ethyl) amino) propionic acid (69.2mg, 318. mu. mol, Eq:1.5) were converted to (S) -1- ((2S,3S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (ethyl) carbamic acid tert-butyl ester (120mg, 87%).

Step 2: in a similar manner to that described in example 57, step 2, except that the mixture was stirred at 0 ℃ for 1 hour, (S) -1- ((2S,3S) -5- ((2-cyano-1- (2-cyanophenyl) -1H-indol-3-yl) methyl) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (ethyl) carbamic acid tert-butyl ester (120mg, 186. mu. mol) was converted to the title compound (69mg, 68%). MS m/z547 (MH)⁺)。

Example 78

(S) -N- ((S) -8-bromo-5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide trifluoroacetate salt

Step 1: mixing Cs₂CO₃(331mg,1.01mmol, Eq:2.2) to methyl ((S) -1-oxo-1- ((S) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] is added][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester (200mg, 461. mu. mol, Eq:1.00) in DMF (10mL) and the mixture was cooled to 0 ℃ and a solution of NBS (82.1mg, 461. mu. mol, Eq:1.00) in 2mL DMF was added dropwise over 5 minutes and the mixture was warmed to room temperature. After 10 hours the mixture was saturated with NH₄Dilute Cl and extract with EtOAc. The combined extracts are washed with H₂O washing, concentration and purification of the residue by preparative TLC to give (S) -1- ((S) -8-bromo-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (300mg, 98%).

Step 2: in a similar manner to that described in example 1, step 1, except that (S) -1- ((S) -8-bromo-4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] is purified by preparative TLC without NaI and the product][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (300mg, 585. mu. mol, Eq:1.00) and 2- (3- (bromomethyl) -1H-indazol-1-yl) benzonitrile (274mg, 878. mu. mol, Eq:1.5) were converted to (S) -1- ((S) -8-bromo-5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (300mg, 69%).

And step 3: in a similar manner to that described in example 65, step 2, (S) -1- ((S) -8-bromo-5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]Tert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (33.5mg,45.0 μmol) was converted to the title compound (30mg, 88%) as an off-white solid. MS m/z644.8 (MH)⁺)。

Example 79

(S) -N- ((S) -8-cyano-5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide 2,2, 2-trifluoroacetate salt

Step 1: (S) -1- ((S) -8-bromo-5- ((1- (2-cyanobenzene) with argonYl) -1H-indazol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] s][1,4]Oxazazepine-2,4' -pyrane]A solution of tert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (50mg, 67.2. mu. mol, Eq:1.00) in DMF (1.5mL) was degassed and Zn (CN) was added₂(15.8mg, 134. mu. mol, Eq:2) and Pd (Ph)₃P)₄(23.3mg, 20.2. mu. mol, Eq: 0.3). Heating the mixture in a microwave at 110 deg.C for 30 min, cooling, and adding saturated NH₄Dilute Cl and extract with EtOAc. The combined extracts are washed with H₂O is washed, then concentrated, and the residue is purified by preparative TLC to give (S) -1- ((S) -8-cyano-5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] f][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (43.5mg, 94%).

Step 2: in a similar manner to that described in example 65, step 2, (S) -1- ((S) -8-cyano-5- ((1- (2-cyanophenyl) -1H-indazol-3-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]Tert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (43.5mg,63.1 μmol) was converted to the title compound (40mg, 86%). MS m/z590 (MH)⁺)。

Example 80

3-cyano-4- (3- (((2S,3S) -2-methyl-3- ((S) -2- (methylamino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazole-1-yl) benzoic acid trifluoroacetate salt

Step 1: in a similar manner to that described in example 72, step 1, except that the mixture was heated at 70 ℃ for 1 hour, (2S,3S) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] was reacted][1,4]OxazazepineConversion of (E) -3-ylcarbamate (200mg,0.684mmol) and methyl 4- (3- (bromomethyl) -1H-indazol-1-yl) -3-cyanobenzoate to 4- (3- (((2S,3S) -3- (tert-butoxycarbonylamino) -2-methyl-4-oxo-3, 4-dihydrobenzo [ b ] b][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazol-1-yl) -3-cyanobenzoic acid methyl ester (395mg, 97%) as a white solid.

Step 2: in a similar manner to that described in step 2 of example 57, except that the reaction mixture was stirred at 0 ℃ for 1 hour, 4- (3- (((2S,3S) -3- (tert-butoxycarbonylamino) -2-methyl-4-oxo-3, 4-dihydrobenzo [ b ] was][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazol-1-yl) -3-cyanobenzoic acid methyl ester (254mg, 437. mu. mol) was converted to 4- (3- (((2S,3S) -3-amino-2-methyl-4-oxo-3, 4-dihydrobenzo [ b ] b][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazol-1-yl) -3-cyanobenzoic acid methyl ester (210mg, 99%) as a brown oil.

And step 3: PyBop (295mg, 567. mu. mol, Eq:1.3) was added to 4- (3- (((2S,3S) -3-amino-2-methyl-4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazol-1-yl) -3-cyanobenzoic acid methyl ester (210mg, 436. mu. mol, Eq:1.00), (S) -2- (tert-butoxycarbonyl (methyl) amino) propionic acid (115mg, 567. mu. mol, Eq:1.3) and DIEA (73.3mg, 99.0. mu.l, 567. mu. mol, Eq:1.3) in a mixture of THF (7 mL). After 16 hours, the mixture was taken up with saturated NH₄Cl and H₂Diluted O and extracted with EtOAc. The combined extracts are washed with H₂O washing, concentration, and purification of the residue by preparative TLC to give 4- (3- (((2S,3S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -2-methyl-4-oxo-3, 4-dihydrobenzo [ b ] b][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazol-1-yl) -3-cyanobenzoate (230mg, 79.1%).

And 4, step 4: LiOH (1N, 448. mu.l, 448. mu. mol, Eq:1.3) was added to 4- (3- (((2S,3S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -2-methyl-4-oxo-3, 4-dihydrobenzo [ b ] at 0 deg.C][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazol-1-yl) -3-cyanobenzoate (230mg, 345. mu. mol, Eq:1.00) in THF (7mL) and addition of H₂O (3 mL). After 7 hours the mixture was acidified to pH4-5 with citric acid and extracted with EtOAc. The combined extracts are washed with H₂O washing with Na₂SO₄Drying and concentrating to obtain 4- (3- (((2S,3S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -2-methyl-4-oxo-3, 4-dihydrobenzo [ b)][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazol-1-yl) -3-cyanobenzoic acid (220mg, 97.7%) was used without purification.

And 5: in a similar manner to that described in example 65, step 2, 4- (3- (((2S,3S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino)Propionamido) -2-methyl-4-oxo-3, 4-dihydrobenzo [ b][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazol-1-yl) -3-cyanobenzoic acid (28.5mg,43.7 μmol) was converted to the title compound (26mg, 85%). MS m/z553 (MH)⁺)。

Example 81

3-cyano-N-ethyl-4- (3- (((2S,3S) -2-methyl-3- ((S) -2- (methylamino) propionamido) -4-oxo-3, 4-dihydrobenzo [ b][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazol-1-yl) benzamide trifluoroacetate salt

Step 1: ethyl amine (100. mu.l, 200. mu. mol, Eq:3.11) was added to 4- (3- (((2S,3S) -3- ((S) -2- (tert-butoxycarbonyl (methyl) amino) propionamido) -2-methyl-4-oxo-3, 4-dihydrobenzo [ b][1,4]Oxazazepine-5(2H) -yl) methyl) -1H-indazol-1-yl) -3-cyanobenzoic acid (42mg, 64.3. mu. mol, Eq:1.00), DIEA (37.0mg, 50. mu.l, 286. mu. mol, Eq:4.45) and PyBOP (43.5mg, 83.7. mu. mol, Eq: 1.3). After 16 hours the mixture was saturated with NH₄Dilute Cl and extract with EtOAc. The combined extracts were washed with saturated NaHCO₃、NH₄Cl and H₂O washing, then Na₂SO₄Drying and concentration gave a residue which was purified by preparative TLC to give (S) -1- ((2S,3S) -5- ((1- (2-cyano-4- (ethylcarbamoyl) phenyl) -1H-indazol-3-yl) methyl) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (40mg, 92%).

Step 2: in a similar manner to that described in example 65, step 2, (S) -1- ((2S,3S) -5- ((1- (2-cyano-4- (ethylcarbamoyl) phenyl) -1H-indazol-3-yl) methyl) -2-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]OxazazepineTert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (40mg,58.8 μmol) was converted to the title compound (30mg, 75%). MS m/z 580 (MH)⁺)。

Example 82

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) butanamide hydrochloride

Step 1: reacting (S) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester (1.412g,5.07mmol), 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (1.59g,5.58mmol), Cs₂CO₃A mixture of (1.98g,6.09mmol) and NaI (913mg,6.09mmol) in DMF (16.9mL) was stirred at room temperature for 22H with H₂Diluted O and extracted with EtOAc. The combined extracts were washed with saturated brine and then with Na₂SO₄Drying and concentrating the filtrate to give a residue which is purified by silica gel chromatography,to obtain (S) -5- ((6-bromo-2-methoxynaphthalene-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineTert-butyl-3-ylcarbamate (1.804g, 67%) as an off-white solid. MS m/z 549/551(MNa)⁺。

Step 2: reacting (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineA solution of tert-butyl-3-ylcarbamate (1.803g,3.42mmol) in 4M HCl in dioxane (17.1mL) was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was taken up in Et₂O grinding to provide (S) -3-amino-5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -keto hydrochloride (1.415g, 89%) as an off-white solid. MS m/z427/429MH⁺。

And step 3: reacting (S) -3-amino-5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -2, 3-dihydrobenzo [ b][1,4]OxazazepineA mixture of (E) -4(5H) -one hydrochloride (54mg, 116. mu. mol), (S) -2- (tert-butoxycarbonyl (methyl) amino) butanoic acid (27.8mg, 128. mu. mol), DIEA (80.6. mu.L, 466. mu. mol) and HBTU (48.6mg, 128. mu. mol) in DMF (388. mu.L) was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc and saturated NaHCO₃、H₂Washed with saturated brine and then with Na₂SO₄Dried and filtered. The filtrate was concentrated to give a residue which was purified by silica gel chromatography to give (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxobut-2-yl (methyl) carbamic acid tert-butyl ester (67.5mg, 93%) as a white solid. MSm/z 648/650(MNa)⁺。

And 4, step 4: et 2M HCl₂O solution (419. mu.L) was added to (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxobut-2-yl (methyl) carbamic acid tert-butyl ester (65.7mg, 105. mu. mol) in MeOH (105. mu.L). After 4 hours the mixture was concentrated and the residue was dissolved in MeCN/H₂O, and the solution was lyophilized to provide the title compound (55.9mg, 95%) as a white solid. MS m/z 526/528(MH)⁺。

Example 83

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (2-hydroxyethylamino) butanamide trifluoroacetate salt

Step 1: reacting (S) -3-amino-5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -2, 3-dihydrobenzo [ b][1,4]OxazazepineA mixture of (E) -4(5H) -one hydrochloride (348mg, 750. mu. mol), (S) -2- (tert-butoxycarbonylamino) butanoic acid (168mg, 825. mu. mol), DIEA (519. mu.L, 3.00mmol) and HBTU (313mg, 825. mu. mol) in DMF (2.5mL) was stirred at room temperature for 30 min. The mixture was diluted with EtOAc and saturated NaHCO₃、H₂Washing with saturated salt solutionWashing, then passing through Na₂SO₄Dried and filtered. The filtrate was concentrated to give a residue which was purified by silica gel chromatography to give (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxobut-2-ylcarbamic acid tert-butyl ester (431mg, 94%) as a white solid. MS m/z634/636(MNa)⁺。

Step 2: mixing (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]OxazazepineA solution of tert-butyl (3-ylamino) -1-oxobut-2-ylcarbamate (430mg,702 μmol) in 4M HCl in dioxane (3.51mL) was stirred at room temperature for 1 hour and concentrated. The residue was taken up in Et₂O trituration to provide (S) -2-amino-N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) butanamide hydrochloride (357mg, 93%) as a white solid.

And step 3: mixing (S) -2-amino-N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-3-yl) butanamide hydrochloride (283mg) in 25% MeOH/CH₂Cl₂The solution in (a) is treated with silica-supported carbonate (SiliCycle, 3eq) for 1 hour, filtered and the filtrate is concentrated to afford (S) -2-amino-N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-yl) butanamide (264mg), which isIs a white foam. MS m/z 512/514(MH)⁺。

And 4, step 4: mixing Na (OAc)₃BH (45.1mg, 213. mu. mol) was added to (S) -2-amino-N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) butanamide (77.8mg, 152. mu. mol) and glycolaldehyde dimer (9.57mg, 79.7. mu. mol) in dichloroethane (1.52 mL). After 30 minutes the mixture was taken up with saturated NaHCO₃Diluted and extracted with EtOAc. The combined extracts were washed with saturated brine and then with Na₂SO₄Drying, filtration and concentration of the filtrate gave a residue which was purified by preparative reverse phase HPLC to afford the title compound (36.9mg, 36%) as a white solid after lyophilization. MS m/z 556/558(MH)⁺。

Example 84

(S) -N- ((S) -5- (benzo [ d)]Isoxazol-3-ylmethyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride

Step 1: reacting methyl ((2S) -1-oxo-1- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester (156mg, 360. mu. mol), 3- (bromomethyl) benzo [ d]Isoxazole (83.9mg, 396. mu. mol), Cs₂CO₃(141mg, 432. mu. mol) and NaI (64.7mg, 432. mu. mol) in DMThe mixture in F (900. mu.L) was stirred at room temperature for 18H, diluted with EtOAc and washed with H₂Washing with saturated brine, and purifying with Na₂SO₄Drying, filtration and concentration of the filtrate gave a residue which was purified by silica gel chromatography. Purifying the obtained material by supercritical liquid chromatography (SFC) to obtain (S) -1- ((S) -5- (benzo [ d)]Isoxazol-3-ylmethyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (54.5mg, 27%) as white foam.

Step 2: in a similar manner to that described in example 82, step 4, (S) -1- ((S) -5- (benzo [ d ] will]Isoxazol-3-ylmethyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]Tert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (51.6mg,91.4 μmol) was converted to the title compound (42.2mg, 92%) as a white solid. MS m/z 465(MH)⁺。

Example 85

(S) -N- ((S) -5- ((2- (difluoromethoxy) naphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride

Step 1: reacting methyl ((2S) -1-oxo-1- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) propan-2-yl) carbamic acid tert-butyl ester (118mg, 272. mu. mol), methanesulfonic acid (2- (difluoromethoxy) naphthalen-1-yl) methyl ester (98.7mg, 327. mu. mol) and Cs₂CO₃A mixture of (115mg, 354. mu. mol) in DMF (681. mu.L) was stirred at room temperature for 20 hours. The mixture was diluted with EtOAc and washed with H₂Washed with saturated brine and then with Na₂SO₄Dried and filtered. The filtrate was concentrated to give a residue which was purified by silica gel chromatography. Purifying the obtained material by SFC to obtain (S) -1- ((S) -5- ((2- (difluoromethoxy) naphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (52.6mg, 30%) as a white foam (MS m/z 662(MNa)⁺) And (S) -1- ((R) -5- ((2- (difluoromethoxy) naphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (72.8mg, 42%) as white foam (MS m/z 662(MNa)⁺)。

Step 2: in a similar manner to that described in example 82, step 4, (S) -1- ((S) -5- ((2- (difluoromethoxy) naphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]Tert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (52.6mg,82.2 μmol) was converted to the title compound (46.3mg, 98%) as a white solid. MS m/z 540(MH)⁺。

Example 86

(S) -N- ((R) -5- ((2- (difluoromethoxy) naphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride

In a similar manner to that described in example 82, step 4, (S) -1- ((R) -5- ((2- (difluoromethoxy) naphthalen-1-yl) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] b][1,4]Oxazazepine-2,4' -pyrane]-3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (72.8mg,114 μmol) was converted to the title compound (61.7mg, 94%) as a white solid. MS m/z 540(MH)⁺。

Example 87

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9-fluoro-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride

Step 1: a solution of BOC-Ser-OH (2.58g,12.6mmol) in DMF (10.00mL) was added over 10 minutes to a suspension of NaH (60% in mineral oil, 1.06g,26.4mmol) in DMF (10mL) at 0 ℃. After 1 hour at 0 deg.C, 1, 2-difluoro-3-nitrobenzene (2g,12.6 m) was addedmol) in DMF (10mL) and the mixture was stirred at 0 ℃ for 2 h. Subjecting the mixture to hydrogenation with H₂Diluted O and acidified to pH 3 with 1N HCl, then extracted with EtOAc. The combined extracts were passed over MgSO₄Drying and concentration of the filtrate gave a residue which was purified by silica gel chromatography to give (S) -2- (tert-butoxycarbonylamino) -3- (2-fluoro-6-nitrophenoxy) propionic acid (2.94g, 68%) as a yellow foam.

Step 2: a mixture of (S) -2- (tert-butoxycarbonylamino) -3- (2-fluoro-6-nitrophenoxy) propionic acid (2.94g,8.54mmol) and 10% Pd/C (150mg) in MeOH₂Stirred for 4 hours. The mixture was filtered through celite, and the filter cake was washed with MeOH. The filtrate was concentrated to give (S) -3- (2-amino-6-fluorophenoxy) -2- (tert-butoxycarbonylamino) propionic acid (2.6g, 97%) which was used without purification.

And step 3: a solution of (S) -3- (2-amino-6-fluorophenoxy) -2- (tert-butoxycarbonylamino) propionic acid (2.6g,8.27mmol) and EDCI (1.97mg,10.3mmol) in DMF (40mL) was stirred at room temperature for 6 h. The mixture was diluted with EtOAc and washed with H₂And O washing. The combined aqueous layers were extracted with EtOAc. The combined organic extracts were passed over MgSO₄Drying, filtering and concentrating the filtrate to give a residue which is purified by silica gel chromatography to give (S) -9-fluoro-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]OxazazepineTert-butyl-3-ylcarbamate (1.03g, 42%) as an orange solid. MS M/z 319(M + Na)⁺。

And 4, step 4: in a similar manner to that described in example 82, step 1, (S) -9-fluoro-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester (0.503g,1.7mmol) and 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (582mg,2.04mmol) were converted to (S) -5- ((6-bromo-2-methoxynaphthalene-1-yl) methyl) -9-fluoro-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineTert-butyl-3-ylcarbamate (634mg, 69%) as an orange solid. MS m/z 567/569(MNa)⁺。

And 5: in a similar manner to that described in example 82, step 2, (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9-fluoro-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineConversion of tert-butyl (634mg,1.16mmol) of-3-ylcarbamate to (S) -3-amino-5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9-fluoro-2, 3-dihydrobenzo [ b][1,4]Oxazazepine-4(5H) -one hydrochloride (545mg, 97%) as a bright yellow solid. MS m/z 445/447(MH)⁺。

Step 6: in a similar manner to that described in example 82, step 3, (S) -3-amino-5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9-fluoro-2, 3-dihydrobenzo [ b ]][1,4]OxazazepineConversion of (4) (5H) -one hydrochloride (86.8mg, 180. mu. mol) and Boc-N-methyl-L-alanine (40.3mg, 198. mu. mol) to (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9-fluoro-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (103.2mg, 91%) as a bright yellow solid. MS m/z 652/654(MNa)⁺。

And 7: in a similar manner to that described in example 82, step 4, (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9-fluoro-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester was converted to the title compound (85.9mg, 94%) as an off-white solid. MSm/z 530/532(MH)⁺。

Example 88

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride

Step 1: reacting (S) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester (389mg,1.12mmol), 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (481mg,1.68mmol), NaI (253mg,1.68mmol), and Cs₂CO₃A mixture of (549mg,1.68mmol) in DMF (15.6mL) was stirred at room temperature for 6h and diluted with EtOAc. The mixture was washed with saturated brine and then with Na₂SO₄Drying, filtering and concentrating the filtrate to give a residue which is purified by silica gel chromatography to give (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b ] b][1,4]OxazazepineTert-butyl-3-ylcarbamate (321mg, 48%) as a colorless waxy solid. MS m/z 617/619(MNa)⁺。

Step 2: in a similar manner to that described in step 2 of example 82, will (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineConversion of tert-butyl (320mg, 537. mu. mol) 3-ylcarbamate to (S) -3-amino-5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9- (trifluoromethyl) -2, 3-dihydrobenzo [ b][1,4]Oxazazepine-4(5H) -keto hydrochloride (252mg, 88%) as a bright yellow solid. MS m/z 495/497(MH)⁺。

And step 3: in a similar manner to that described in example 82, step 3, (S) -3-amino-5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9- (trifluoromethyl) -2, 3-dihydrobenzo [ b ]][1,4]OxazazepineConversion of (4) (5H) -one hydrochloride (77.9mg, 146. mu. mol) and Boc-N-methyl-L-alanine (32.8mg, 161. mu. mol) to (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (78.7mg, 79%) as a white solid. MSm/z 702/704(MNa)⁺。

And 4, step 4: in a similar manner to that described in example 82, step 4, (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester was converted to the title compound (64.1mg, 92%) as a white solid. MS m/z 580/582(MH)⁺。

Example 89

(S) -2- (methylamino) -N- ((S) -5- ((2-methylnaphthalen-1-yl) methyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) propionamide hydrochloride

Step 1: in a similar manner to that described in example 88, step 1, (S) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b ]][1,4]OxazazepineConversion of tert-butyl (3-ylcarbamate) (200mg, 578. mu. mol) and 1- (chloromethyl) -2-methylnaphthalene (165mg, 866. mu. mol) to (S) -5- ((2-methylnaphthalen-1-yl) methyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineTert-butyl-3-ylcarbamate (184mg, 64%) as a colorless oil. MS m/z523 (MNa)⁺。

Step 2: TFA (533. mu.l) was added to (S) -5- ((2-methylnaphthalen-1-yl) methyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b ] at 0 ℃][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester (71mg, 142. mu. mol) in DCM (2 mL). After 2.5 h the mixture was concentrated and the residue was azeotroped with MeCN to give (S) -3-amino-5- ((2-methylnaphthalen-1-yl) methyl) -9- (trifluoromethyl) -2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -Ketone trifluoroacetate salt (73mg, 100)%) was used without purification.

And step 3: in a similar manner to that described in example 82, step 3, (S) -3-amino-5- ((2-methylnaphthalen-1-yl) methyl) -9- (trifluoromethyl) -2, 3-dihydrobenzo [ b ]][1,4]OxazazepineConversion of (E) -4(5H) -one trifluoroacetate (73mg, 142. mu. mol) and (S) -2- (tert-butoxycarbonyl (methyl) amino) propionic acid (32mg, 156. mu. mol) to methyl ((S) -1- ((S) -5- ((2-methylnaphthalen-1-yl) methyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl) carbamic acid tert-butyl ester (66mg, 79%) as a colorless oil. MSm/z 608(MNa)⁺。

And 4, step 4: et 2M HCl₂O solution (1.26mL) was added to methyl ((S) -1- ((S) -5- ((2-methylnaphthalen-1-yl) methyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl) carbamic acid tert-butyl ester (66mg, 113. mu. mol) in MeOH (400. mu.l). After 2.5 hours the mixture was concentrated, MeCN was added to the residue and the mixture was concentrated. The residue was taken up from MeCN/H₂O lyophilized to give the title compound (48mg, 82%) as a white powder. MS m/z 486(MH)⁺。

Example 90

(S) -N- ((S) -5- (benzo [ d)]Isoxazol-3-ylmethyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride

Step 1: in a similar manner to that described in example 88, step 1, (S) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester (200mg, 578. mu. mol) and 3- (bromomethyl) benzo [ d]Conversion of isoxazole (184mg, 866. mu. mol) to (S) -5- (benzo [ d ]]Isoxazol-3-ylmethyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylcarbamic acid tert-butyl ester (168mg, 61%) as white foam. MS m/z 500(MNa)⁺。

Step 2: in a similar manner to that described in step 2 of example 89, (S) -5- (benzo [ d ]]Isoxazol-3-ylmethyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineConversion of tert-butyl (73mg, 153. mu. mol) of the-3-ylcarbamate to (S) -3-amino-5- (benzo [ d ]]Isoxazol-3-ylmethyl) -9- (trifluoromethyl) -2, 3-dihydrobenzo [ b][1,4]Oxazazepine-4(5H) -keto trifluoroacetate salt (75mg, 100%) was used without purification.

And step 3: in a similar manner to that described in step 3 of example 89, (S) -3-amino-5- (benzo [ d ]]Isoxazol-3-ylmethyl) -9- (trifluoromethyl) -2, 3-dihydrobenzo [ b][1,4]Oxazazepine-4(5H) -Ketone trifluoroacetate (75mg, 153. mu. mol) and (S) -2- (tert-butoxycarbonyl (methyl) amino) propionic acid (34)mg, 168. mu. mol) into (S) -1- ((S) -5- (benzo [ d)]Isoxazol-3-ylmethyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (76mg, 89%) as a colorless oil. MS m/z 585(MNa)⁺。

And 4, step 4: in a similar manner to that described in example 89, step 4, (S) -1- ((S) -5- (benzo [ d ] will]Isoxazol-3-ylmethyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineTert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (76mg,135 μmol) was converted to the title compound (55mg, 82%) as a white powder. MS m/z 463(MH)⁺。

Example 91

(S) -N- ((S) -9-bromo-5- ((2-methylnaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride

Step 1: in an analogous manner to that described in example 87, step 1, BOC-Ser-OH (1.87g,9.09mmol) and 3-bromo-2-fluoronitrobenzene (2g,9.09mmol) were converted to (S) -3- (2-bromo-6-nitrophenoxy) -2- (tert-butoxycarbonylamino) propionic acid (2.45g, 67%) as a yellow gum.

Step 2: (S) -3- (2-bromo-6-nitrophenoxy) -2- (tert-butoxycarbonylamino) propionic acid (2.1g,5.18mmol), zinc powder (3.39g,51.8 mmol)l) and NH₄A mixture of Cl (2.77g,51.8mmol) in MeOH/THF 1:1(40mL) was stirred at room temperature until TLC indicated completion of the reaction. The mixture was then filtered and the filtrate was concentrated. The residue is reacted with H₂O/EtOAc (50mL/50mL) was mixed and extracted with EtOAc. The combined organic extracts were passed over MgSO₄Drying, filtration and concentration of the filtrate yielded (S) -3- (2-amino-6-bromophenoxy) -2- (tert-butoxycarbonylamino) propionic acid (1.88g, 97%) as an off-white foam, which was used without purification.

And step 3: in a similar manner to that described in example 87, step 3, except that the reaction mixture was stirred overnight, (S) -3- (2-amino-6-bromophenoxy) -2- (tert-butoxycarbonylamino) propionic acid (1.88g,5.02mmol) and EDCI (1.19g,6.22mmol) were converted to (S) -9-bromo-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineTert-butyl-3-ylcarbamate (452mg, 25%) as a brown oil.

And 4, step 4: in a similar manner to that described in example 88, step 1, (S) -9-bromo-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]OxazazepineConversion of tert-butyl (3-ylcarbamate) (200mg, 560. mu. mol) and 1- (chloromethyl) -2-methylnaphthalene (160mg, 840. mu. mol) to (S) -9-bromo-5- ((2-methylnaphthalene-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineTert-butyl-3-ylcarbamate (95mg, 33%) as an orange foam. MS m/z 533/535(MNa)⁺。

And 5: in a similar manner to that described in example 89, step 2, except that the reaction was stirred for 45 minutes, (S) -9-bromo-5- ((2-methylnaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineA solution of tert-butyl-3-ylcarbamate (40mg, 78.2. mu. mol) in DCM (2mL) was cooled to 0 ℃ and treated with TFA (300. mu.l). After 45 min, the mixture was concentrated to dryness and the residue was azeotroped with MeCN to give (S) -3-amino-9-bromo-5- ((2-methylnaphthalen-1-yl) methyl) -2, 3-dihydrobenzo [ b ]][1,4]Oxazazepine-4(5H) -keto trifluoroacetate (41mg) was used without purification.

Step 6: (S) -3-amino-9-bromo-5- ((2-methylnaphthalen-1-yl) methyl) -2, 3-dihydrobenzo [ b ] was reacted in a similar manner as described in example 82, step 3, except that 1.5eq.HBTU and 6.4eq.DIEA were used and the mixture was stirred for 1 hour][1,4]OxazazepineConversion of (4- (5H) -one trifluoroacetate (41mg, 76. mu. mol) and (S) -2- (tert-butoxycarbonyl (methyl) amino) propanoic acid (22mg, 107. mu. mol) to (S) -1- ((S) -9-bromo-5- ((2-methylnaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (37mg, 64%) as a colorless oil. MS m/z 618/620(MNa)⁺。

And 7: in a similar manner to that described in example 89, step 4, (S) -1- ((S) -9-bromo-5- ((2-methylnaphthalen-1-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineTert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (35mg,58.7 μmol) was converted to the title compound (29mg, 93%) as a white powder. MS m/z 496/498(MH)⁺。

Example 92

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride

Step 1: in an analogous manner to that described in example 87, step 1, BOC-Ser-OH (1.98g,9.67mmol) and 2-fluoro-1-methyl-3-nitrobenzene (1.5g,9.67mmol) were converted to (S) -2- (tert-butoxycarbonylamino) -3- (2-methyl-6-nitrophenoxy) propionic acid (2.93g, 89%) as a yellow oil.

Step 2: in a similar manner to that described in example 87, step 2, (S) -2- (tert-butoxycarbonylamino) -3- (2-methyl-6-nitrophenoxy) propionic acid (2.93g,8.61mmol) was converted to (S) -3- (2-amino-6-methylphenoxy) -2- (tert-butoxycarbonylamino) propionic acid (2.60g, 97%) as a brown oil.

And step 3: in a similar manner to that described in example 87, step 3, (S) -3- (2-amino-6-methylphenoxy) -2- (tert-butoxycarbonylamino) propionic acid (2.60g,8.38mmol) was converted to (S) -9-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]OxazazepineTert-butyl-3-ylcarbamate (846mg, 35%) as a white solid. MS m/z315(MNa)⁺。

And 4, step 4: in a similar manner to that described in example 88, step 1, (S) -9-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]OxazazepineConversion of tert-butyl (3-ylcarbamate) (150mg, 513. mu. mol) and 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (220mg, 770. mu. mol) to (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineTert-butyl-3-ylcarbamate (122mg, 44%) as a colorless oil. MS m/z 563/565(MNa)⁺。

And 5: reacting (S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]OxazazepineA solution of tert-butyl-3-ylcarbamate (122mg, 225. mu. mol) in DCM (5mL) was cooled to 0 ℃ and treated with TFA (750. mu.l). After 2.5 h, the mixture was concentrated to dryness and the residue was azeotroped with MeCN to give (S) -3-amino-5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9-methyl-2, 3-dihydrobenzo [ b ] b][1,4]Oxazazepine-4(5H) -keto trifluoroacetate (125mg), used without purification.

Step 6: in a similar manner to that described in example 82, step 3, except that the mixture was stirred for 5 hours, (S) -3-amino-5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9-methyl-2, 3-dihydrobenzo [ b ] c][1,4]OxazazepineConversion of (E) -4(5H) -one trifluoroacetate (125mg, 225. mu. mol) and (S) -2- (tert-butoxycarbonyl (methyl) amino) propanoic acid (50mg, 248. mu. mol) to (S) -1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ] b][1,4]Oxazazepine-3-ylamino) -1-oxoprop-2-yl (methyl) carbamic acid tert-butyl ester (117mg, 83%) as a colorless waxy solid. MS m/z 648/650(MNa)⁺。

And 7: to harmonize withExample 89A similar procedure as described in step 4, example 1- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -9-methyl-4-oxo-2, 3,4, 5-tetrahydrobenzo [ b][1,4]OxazazepineTert-butyl (3-ylamino) -1-oxoprop-2-yl (methyl) carbamate (114mg,182 μmol) was converted to the title compound (95mg, 93%) as a bright yellow powder. MS m/z 526/528(MH)⁺。

Example 93

Biochemical analysis

TR-FRET assays for BIR2 and BIR3

The ability of the test compounds to inhibit binding of BIR2 and/or BIR3 domains of XIAP proteins to peptide a (SMAC-derived peptides as described below) indicates that the test compounds act as SMAC-mimetics, leading to reactivation of the apoptotic pathway of the cell.

The peptide AVPIAQKSEK- (-biotin) -OH 1:2TFA ("peptide a") was identified as a substrate for the TR-FRET assay by screening the BIR2 domain and BIR3 domain of 6x histidine-tagged XIAP against a panel of 29 peptides synthesized from sequences reported by Sweeny et al (Biochemistry,2006,45, 1474014748). The peptides were labeled with the fluorescent label FITC or TAMRA, and Kd values were determined by fluorescence polarization analysis. The determination of the sequence AVPIAQKSEK is most suitable for the use of the assay. The peptide sequence was derivatized with biotin to provide AVPIAQKSEK- (-biotin) -OH 1:2TFA as a substrate for TR-FRET assays.

XIAP protein sequences were obtained from the SWISS-PROT protein sequence database, and BIR2 and BIR3 domains were derived therefrom. The sequence of the BIR2 domain used in the TR-FRET assay is: MRHHHHHHRDHFALDRPSETHADYLLRTGQVVDISDTIYPRNPAMYSEEARLKSFQNWPDYAHLTPRELASAGLYYTGIGDQVQCFACGGKLKNWEPGDRAWSEHRRHFPNCFFVLGRNLNIRSE are provided.

The sequence of the BIR3 domain used in the TR-FRET assay is:

MRHHHHHHRSDAVSSDRNFPNSTNLPRNPSMADYEARIFTFGTWIYSVNK

EQLARAGFYALGEGDKVKCFHCGGGLTDWKPSEDPWEQHAKWYPGCKYLL

EQKGQEYINNIHLTHSLEECLVRTT.

10nM of the 6 × histidine-tagged BIR2 domain (corresponding to amino acid 124-240 of XIAP), or BIR3 domain (corresponding to amino acid 241-356 of XIAP) was mixed with the 20nM peptide AVPIAQKSEK- (-biotin) -OH 1:2TFA in the presence of 50mM Tris-Cl, pH 7.5, 100mM NaCl, 1mM Dithioreitol (DTT) and 0.1mg/mL Bovine Serum Albumin (BSA). After incubation at 37 ℃ for 45 min, europium-streptavidin and allophycocyanin-binding anti-histidine antibodies were added to final concentrations of 1.5nM and 15nM, respectively. The time resolved fluorescence resonance energy transfer (TR-FRET) signal was measured after 1 hour at room temperature. Test compound potency was assessed at 10-fold serial dilution concentrations. The percent inhibition at each concentration was determined to yield the IC of each test compound₅₀The value is obtained.

BIR2 BIR3

Claims

1. A compound selected from

n- (5-biphenyl-3-ylmethyl-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Thiaazepines-3-yl) -2- (S) -methylamino-propionylAmine hydrochloride;

(2S) -N- (5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) - (3S) -9-fluoro-4-oxo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ]][1,4]Oxazazepine-2,4' -pyrane]-3-yl) -2- (methylamino) propionamide hydrochloride;

(S) -N- ((S) -5- ((1-ethyl-2-oxoindolin-4-yl) methyl) -4-oxo-2, 3,4, 5-tetrahydrobenzeneAnd [ b ]][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide;

(S) -N- ((S) -5- ((6-bromo-2-methoxynaphthalen-1-yl) methyl) -4-oxo-9- (trifluoromethyl) -2,3,4, 5-tetrahydrobenzo [ b)][1,4]Oxazazepine-3-yl) -2- (methylamino) propionamide hydrochloride;

(S) -5- ((2-methoxynaphthalen-1-yl) methyl) -3- ((S) -2- (methylamino) propionamido) -4-oxo-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-9-carboxylic acid trifluoroacetate salt; and

2. A pharmaceutical composition comprising a compound of claim 1 and a therapeutically inert carrier.

3. Use of a compound of claim 1 in the manufacture of a medicament for the treatment or prevention of cancer.