HK1213543B

HK1213543B - Dimeric compounds

Info

Publication number: HK1213543B
Application number: HK16101392.4A
Authority: HK
Inventors: Steven Gregory Mischke
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2012-12-11
Filing date: 2013-12-09
Publication date: 2018-05-25

Description

Dimeric compounds

Technical Field

The present invention relates to dimeric compounds useful as inhibitors of SMAC proteins that bind Inhibitors of Apoptosis Proteins (IAPs), and/or as inhibitors of activated caspase proteins that bind IAPs. These molecules are useful for ameliorating, treating or controlling cancer, particularly solid tumors.

These compounds bind to BIR2 or BIR2 and BIR3 domains of IAP proteins (including XIAP and cIAP) leading to activation or reactivation of the caspase cascade and are thus useful in the treatment of proliferative diseases including cancer.

Background

Cancer is an uncontrolled cell growth disease that causes local expansion of tumors and potential distant metastasis. One mechanism by which cancer cells grow is by avoiding apoptosis or programmed cell death. Alterations in apoptotic pathways have been associated with cancer cells being resistant to standard therapies, such as chemotherapy or radiation, as well as the appearance and progression of cancer. See, e.g., E.dean et al, "X-linked inhibitor of apoptosis protein as a therapeutic target," expert Optin. Ther. targets (2007)11(11): 1459-.

The two basic pathways of apoptotic cell death are the intrinsic and extrinsic pathways. Initiation of the endogenous apoptotic pathway can be through various mechanisms, including cellular stress and drug-induced DNA damage. Initiation of the extrinsic pathway can be via activation of the death receptor by chemokines. Initiation of either pathway results in activation of a family of proteases called caspases. Once activated, caspases can be used to cleave a variety of substrates, producing a cascade of events leading to activation of effector caspases 3 and 7 and ultimately cell death. The IAP protein family can bind and inhibit the activity of caspases, thereby inhibiting apoptosis. See, e.g., Dean, supra, 1460.

IAPs can contain up to three copies of a homeodomain called the Baculovirus IAP Repeat (BIR) domain¹BIR2 and BIR 3. The BIR3 domain of the prototype IAPs, cIAP and XIAP, binds to and inhibits 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) blocks the BIR2 and BIR3 domains of IAPs from competing with the activating caspases, resulting in the release of the activating caspases from the IAPsAnd completing the apoptosis program. See, e.g., S.Wang, "Design of Small-Mobile Smac metrics as IAP oligonucleotides", CurrentTopics in Microbiology and Immunology 348, DOI10.1007/82_2010_111, pp.89-113.

Peptides and small molecules have been reported to bind to BIR3 domains of cIAP and XIAP, mimic the action of Smac proteins and release activated caspases. See, e.g., Dean, supra; and M.Gyrd-Hanse et al, "IAPs From caspase inhibitors to modulators of NF-. kappa.B, inflammation and Cancer," Nature Review/Cancer, month 8 2010, Vol 10: 561-.

Summary of The Invention

One aspect of the invention is a compound of formula I

Or a pharmaceutically acceptable salt thereof, as described herein.

The invention also relates to pharmaceutical compositions comprising one or more compounds of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

The invention further relates to a method of ameliorating, controlling or treating cancer, including in particular solid tumors, such as lung, pancreas, colon, breast, bone and prostate cancer in a mammal (in particular a human) comprising administering to said mammal a therapeutically effective amount of a compound according to the invention or a pharmaceutically acceptable salt thereof.

Detailed Description

Definition of

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used herein, the following terms shall have the following definitions.

"alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon of 1 to 12 carbon atoms. In particular embodiments, the alkyl group has 1 to 6 carbon atoms, and in more particular embodiments 1 to 4 carbon atoms (C)_1-4-an alkyl group). As used herein, "lower alkyl" denotes an alkyl group (C) having 1-6 carbon atoms_1-6-an alkyl group). The term "C_1-6-alkyl "is used alone or in combination with other terms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl (also known as n-butyl), isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. The alkyl group optionally being deuterium-enriched, e.g. -CD₃、-CD₂CD₃And the like.

"aryl" means a monovalent carbocyclic aromatic mono-, bi-or tricyclic ring system containing 6 to 19 carbon ring atoms. The term "aryl" is used alone or in combination with other terms. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl (also known as napthyl), tolyl, xylyl, pyridyl, quinolyl, pyrimidinyl, imidazolyl, thiazolyl, anthracenyl, tetrazolyl, and fluorenyl. Particular aryl groups are phenyl and naphthyl.

"cyano" means-C＝N。

"cycloalkyl" refers to a stable monovalent saturated monocyclic, bicyclic, or tricyclic substituted or unsubstituted ring system consisting of 3 to 10 ring carbon atoms. In a particular embodiment cycloalkyl represents a monovalent saturated monocyclic hydrocarbon radical of 3 to 7 ring carbon atoms ("C)_3-7-cycloalkyl "). The term "C_3-7-cycloalkyl "is used alone or in combination with other terms. Particular cycloalkyl groups are monocyclic. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Bicyclic means consisting of two saturated carbocyclic rings having one or more carbon atoms in common. Examples of bicyclic cycloalkyl groups include bicyclo [2.2.1]Heptyl or bicyclo [2.2.2]And (4) octyl. Tricyclic ring is defined by three having two or more carbon atoms in commonA saturated carbocyclic ring. Examples of tricyclic cycloalkyl groups include adamantane.

When referring to two or more rings, "fused," e.g., cycloalkyl fused with an aryl group, means that each ring has at least two atoms in common. An example of a cycloalkyl group fused with an aryl group is tetralin (also known as tetralin).

"halogen" or "halo" refers to an atom selected from F, Cl, Br or I. In a particular embodiment, halogen refers to F and Cl.

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

"heteroaryl" refers to a substituted or unsubstituted heteroaromatic ring system containing up to two rings, wherein at least one ring contains 1,2 or 3 heteroatoms and the remaining ring atoms are carbon. Examples of heteroaryl groups include, but are not limited to, thienyl (thienyl) (also known as thiophenyl), furyl (furyl) (also known as "furanyl"), indolyl, pyrrolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, quinolinyl, isoquinolinyl, indazolyl, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, triazinyl, pyrazolyl, benzo [ d ] isoxazolyl, benzothiazolyl, 2-oxo-2H-chroman-4-yl (2-oxo-2H-chromen-4-yl)), benzo [ d ] isoxazolyl, benzothienyl, benzimidazolyl, naphthyridinyl, and cinnolinyl (cinnolinyl). Particular heteroaryl groups are pyrazinyl and pyridyl.

Where the heteroaryl group is bicyclic, it is understood that one ring can be aryl and the other ring heteroaryl, and both can independently be substituted or unsubstituted.

“IC₅₀By "is meant the concentration of a particular compound required to inhibit 50% of a particular measured activity. IC (integrated circuit)₅₀The measurements of (a) can be as described subsequently in example 29, in particular.

"pharmaceutically acceptable," such as pharmaceutically acceptable carriers, excipients, and the like, refers to those that are pharmacologically acceptable and substantially non-toxic to a subject to whom a particular compound is administered.

"pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts that retain the biological effectiveness 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. Sample acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric and nitric acids, as well as those derived from organic acids such as p-toluenesulfonic, salicylic, methanesulfonic, oxalic, succinic, citric, malic, lactic, fumaric, trifluoroacetic acids, and the like. Sample base addition salts include those derived from ammonium hydroxide, potassium, sodium, and quaternary amines, e.g., tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound (i.e., drug) into a salt is a technique well known to pharmaceutical chemists to achieve improved physical and chemical stability, hygroscopicity, flowability, and solubility of compounds. See, for example, Ansel et al, Pharmaceutical document Forms and Drug Delivery Systems (1995), page 456-.

"substituted" as in substituted alkyl, aryl or heteroaryl means that substitution (i.e., replacement of one hydrogen atom) can occur at one or more sites, and, unless otherwise indicated, the substituents at each substitution site are independently selected from the indicated options. The term "optionally substituted" refers to the fact that one or more hydrogen atoms of a chemical group (having one or more hydrogen atoms) may, but need not, be substituted with another substituent.

The definitions set forth herein apply regardless of whether the terms in question are used alone or in combination. It is contemplated that the definitions described herein can be appended to form chemically relevant combinations, such as "heterocycloalkylaryl", "haloalkylheteroaryl", "arylalkyl heterocycloalkyl", or "alkoxyalkyl". The last member of the combination is a group that binds to the rest of the molecule. The other members of the combination are attached to the binding group in reverse order in literal sequence, e.g., a combination arylalkyl heterocycloalkyl refers to a heterocycloalkyl group substituted with an alkyl, and the alkyl is substituted with an aryl.

As used herein, if a formula or group appears to be missing a substituent, its valence appears to be incomplete, then the missing substituent is presumed to be H.

In the structural formulae shown herein, the broken bond (a) represents the substituent below the plane of the paper and the wedge bond (b) represents the substituent above the plane of the paper.

In one embodiment, the invention relates to compounds of formula I

Wherein

Z is selected from the following groups:

a) optionally is OR³Halogen and lower alkyl substituted aryl, and

b) heteroaryl optionally substituted with aryl, said aryl being optionally substituted with cyano;

x is selected from the following groups:

a) a lower alkyl group,

b) lower alkyl-aryl-lower alkyl

c) Aryl optionally substituted by lower alkyl and-O-aryl, and

d) a heteroaryl group;

q is selected from

R¹Selected from the group H and cyano;

R²selected from the following groups:

a) an alkyl group optionally substituted with an aryl group,

b) cycloalkyl optionally fused with phenyl, in which the cycloalkyl is optionally fused with phenyl,

c) phenyl, and

d) a cycloalkyl aryl group; and is

R³Is a lower alkyl group;

or a pharmaceutically acceptable salt thereof.

The asterisk in the substituent Q in the above definition indicates the site of attachment of the group Q to the rest of the compound of formula I.

One embodiment of the present invention relates to compounds of formula I, wherein

Z is selected from the following groups:

a) optionally substituted by O-C_1-6Alkyl, halogen and C_1-6-alkyl-substituted aryl, and

b) heteroaryl optionally substituted with cyano-phenyl;

x is selected from the following groups:

a)C_1-6-an alkyl group,

b)C_1-6-alkyl-aryl-C_1-6-alkyl radical

c) Optionally is covered with C_1-6Aryl substituted by-alkyl and-O-aryl, and

d) a heteroaryl group;

q is selected from

R¹Selected from the group H and cyano;

R²selected from the following groups:

a) c optionally substituted by aryl_1-6-an alkyl group,

b)C_3-7-a cycloalkyl group,

c) phenyl, and

d) tetrahydronaphthyl (tetralinyl), and

or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention relates to compounds of formula I wherein Z is optionally substituted with O-C_1-6Alkyl, halogen and C_1-6-alkyl substituted aryl.

One embodiment of the invention relates to compounds of formula I wherein Z is naphthyl optionally substituted with bromo, methoxy and methyl.

One embodiment of the present invention relates to compounds of formula I wherein Z is 6-bromo-2-methoxy-1-naphthyl.

One embodiment of the present invention relates to compounds of formula I, wherein X is C_1-6Alkyl, heteroaryl, aryl, or C_1-6Alkyl-substituted aryl, C_1-6-alkyl-phenyl-C_1-6-alkyl or phenyl-O-phenyl.

One embodiment of the present invention relates to compounds of formula I wherein X is phenyl or naphthyl.

One embodiment of the present invention relates to compounds of formula I wherein X is pyrazinyl or pyridinyl.

One embodiment of the present invention relates to compounds of formula I, wherein Q is a.

One embodiment of the present invention relates to compounds of formula I, wherein R¹Is H.

One embodiment of the present invention relates to compounds of formula I wherein Z is naphthyl optionally substituted with bromo, methoxy and methyl, and X is C_1-6Alkyl, heteroaryl, aryl, or C_1-6Alkyl-substituted aryl, C_1-6-alkyl-phenyl-C_1-6-alkyl or phenyl-O-phenyl, Q is A and R¹Is H.

One embodiment of the present invention relates to compounds of formula I, wherein Q is B.

One embodiment of the present invention relates to compounds of formula I, wherein R²Is tetrahydronaphthyl.

One embodiment of the present invention relates to compounds of formula I, wherein they are selected from the group consisting of:

(2S) -2- (methylamino) -N- [ (3S) -1- [4- [ (3S) -3- [ [ (2S) -2- (methylamino) propanoyl group]Amino group]-5- [ (2-methyl-1-naphthyl) methyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-5- [ (2-methyl-1-naphthyl) methyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]The amino acid sequence of the amino acid is shown as propionamide,

(2S) -2-amino-N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]-2, 5-dimethyl-benzoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]The amino acid sequence of the amino acid is shown as propionamide,

(2S) -N- [ (3S) -1- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-5- [4- [ (3S) -1- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-7-cyano-3- [ [ (2S) -2- (methylamino) propanoyl]Amino group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-5-carbonyl group]Benzoyl radical]-7-cyano-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (2-methoxy-1-naphthyl) methyl group]-1- [4- [ (3S) -5- [ (2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (5-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [ (3S) -5- [ (5-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [2- [3- [2- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-2-oxo-ethyl]Phenyl radical]Acetyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [3- [ (3S) -5- [ (6-bromo-2-methyl) methylOxy-1-naphthyl) methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-3-oxo-propionyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [3- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-4-oxo-butanoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]-3-methyl-benzoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Phenoxy radical]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [5- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Pyrazine-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propaneThe acid amide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [5- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Pyridine-3-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [6- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Naphthalene-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [6- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-6-oxo-hexanoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [6- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzoDiaza derivatives-1-carbonyl group]Pyridine-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [6- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Pyridine-3-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [7- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-7-oxo-heptanoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [7- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Naphthalene-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [8- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-8-oxo-octanoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ [1- (2-cyanophenyl) indazol-3-yl]Methyl radical]-1- [4- [ (3S) -5- [ [1- (2-cyanophenyl) indazol-3-yl]Methyl radical]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -7-cyano-5- [4- [ (3S) -7-cyano-3- [ [ (2S) -2- (methylamino) propanoyl group]Amino group]-1- [ (2-methyl-1-naphthyl) methyl group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-5-carbonyl group]Benzoyl radical]-1- [ (2-methyl-1-naphthyl) methyl group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S,4S) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]-N- [ (1R) -tetrahydronaphthalen-1-yl]The pyrrolidine-2-carboxylic acid amide is a compound of formula (I),

(2S,4S) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl ] methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]-N- [ (1S) -tetrahydronaphthalen-1-yl]The pyrrolidine-2-carboxylic acid amide is a compound of formula (I),

(2S,4S) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl ] methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-N-cyclohexyl-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]The pyrrolidine-2-carboxylic acid amide is a compound of formula (I),

(2S,4S) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl ] methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]-N-isopropyl-pyrrolidine-2-carboxamide, and

(2S,4S) -N-benzyl-4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]The pyrrolidine-2-carboxylic acid amide is a compound of formula (I),

or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention relates to compounds of formula I wherein Z is optionally OR³Halogen and C_1-6-alkyl substituted aryl, or a pharmaceutically acceptable salt of said compound.

One embodiment of the present invention relates to compounds of formula I wherein Z is naphthyl.

One embodiment of the present invention relates to compounds of formula I wherein Z is heteroaryl optionally substituted with aryl, optionally substituted with cyano, or a pharmaceutically acceptable salt of said compound.

One embodiment of the present invention relates to compounds of formula I wherein Z is indazolyl optionally substituted with cyanophenyl.

One embodiment of the present invention relates to compounds of formula I, wherein X is C_1-6-alkyl, or a pharmaceutically acceptable salt of said compound.

One embodiment of the present invention relates to compounds of formula I wherein X is optionally substituted with C_1-6-alkyl substituted aryl, or a pharmaceutically acceptable salt of said compound.

One embodiment of the present invention relates to compounds of formula I, wherein X is phenyl optionally substituted with methyl, or a pharmaceutically acceptable salt of said compound.

One embodiment of the present invention relates to compounds of formula I, wherein X is naphthyl, or a pharmaceutically acceptable salt of said compound.

One embodiment of the present invention relates to compounds of formula I, wherein X is heteroaryl, or a pharmaceutically acceptable salt of said compound.

One embodiment of the present invention relates to compounds of formula I wherein X is selected from the group consisting of pyridinyl and pyrazinyl.

One embodiment of the present invention relates to compounds of formula I, wherein Q is a group a, or a pharmaceutically acceptable salt of said compound.

One embodiment of the present invention relates to compounds of formula I, wherein Q is a group B, or a pharmaceutically acceptable salt of said compound.

One embodiment of the present invention relates to compounds of formula I, wherein R¹Is H, or a pharmaceutically acceptable salt of said compound.

One embodiment of the present invention relates to compounds of formula I, wherein R²Is lower alkyl optionally substituted by phenyl, or a pharmaceutically acceptable salt of said compound.

One embodiment of the present invention relates to compounds of formula I, wherein R²Is C_3-7-cycloalkyl, or a pharmaceutically acceptable salt of said compound.

One embodiment of the present invention relates to compounds of formula I, wherein R²Is cyclohexyl.

One embodiment of the present invention relates to compounds of formula I, wherein R²Is C condensed with phenyl_3-7-cycloalkyl, or a pharmaceutically acceptable salt of said compound.

One embodiment of the present invention relates to compounds of formula I, wherein R²Is tetralin.

One embodiment of the present invention relates to compounds of formula I, wherein Z is optionally OCH₃Halogen and C_1-6-alkyl substituted naphthyl; x is phenyl or naphthyl, each of which is optionally substituted by C_1-6-alkyl substitution; q is a group A; and R is¹Is H; or a pharmaceutically acceptable salt of said compound.

An embodiment of the inventionEmbodiments relate to compounds of formula I, wherein Z is OCH₃And Br-substituted naphthyl; x is phenyl; q is a group A; and R is¹Is H; or a pharmaceutically acceptable salt of said compound.

One embodiment of the present invention relates to compounds of formula I, wherein Z is CH₃Substituted naphthyl; x is phenyl; q is a group A; and R is¹Is H; or a pharmaceutically acceptable salt of said compound.

One embodiment of the invention relates to compounds of formula I, wherein Z is OCH₃And Br-substituted naphthyl; x is phenyl; q is a group A; and R is¹Is cyano, or a pharmaceutically acceptable salt of said compound.

One embodiment of the present invention relates to compounds of formula I, wherein Z is optionally OCH₃And halogen substituted naphthyl; x is phenyl; q is a group B; r¹Is H; and R is²Is selected from C_3-7-cyclohexyl, and phenyl-fused C_3-7-cyclohexyl and optionally phenyl-substituted C_1-6-an alkyl group; or a pharmaceutically acceptable salt of said compound.

One embodiment of the invention relates to compounds of formula I, wherein Z is OCH₃And Br-substituted naphthyl; x is phenyl, Q is a group B; r¹Is H; and R is²Is selected from C_3-7-cyclohexyl, and phenyl-fused C_3-7-cyclohexyl and optionally phenyl-substituted C_1-6-alkyl, or a pharmaceutically acceptable salt of said compound.

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [3- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radicalBase of]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [6- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Pyridine-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [5- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Pyridine-3-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [6- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Naphthalene-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]-3-methyl-benzoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Phenoxy radical]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [6- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Pyridine-3-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -2-amino-N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]-2, 5-dimethyl-benzoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Propionamide;

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [3- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-3-oxo-propionyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-4-oxo-butanoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [6- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-6-oxo-hexanoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [7- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-7-oxo-heptanoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [8- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-8-oxo-octanoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [5- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Pyrazine-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [7- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Naphthalene-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [2- [3- [2- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-2-oxo-ethyl]Phenyl radical]Acetyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -5- [ (5-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [ (3S) -5- [ (5-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -2- (methylamino) -N- [ (3S) -1- [4- [ (3S) -3- [ [ (2S) -2- (methylamino) propanoyl group]Amino group]-5- [ (2-methyl-1-naphthyl) methyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-5- [ (2-methyl-1-naphthyl) methyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Propionamide;

(2S) -N- [ (3S) -5- [ [1- (2-cyanophenyl) indazol-3-yl]Methyl radical]-1- [4- [ (3S) -5- [ [1- (2-cyanophenyl) indazol-3-yl]Methyl radical]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -5- [ (2-methoxy-1-naphthyl) methyl group]-1- [4- [ (3S) -5- [ (2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -7-cyano-5- [4- [ (3S) -7-cyano-3- [ [ (2S) -2- (methylamino) propanoyl group]Amino group]-1- [ (2-methyl-1-naphthyl) methyl group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-5-carbonyl group]Benzoyl radical]-1- [ (2-methyl-1-naphthyl) methyl group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propionylAn amine;

(2S) -N- [ (3S) -1- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-5- [4- [ (3S) -1- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-7-cyano-3- [ [ (2S) -2- (methylamino) propanoyl]Amino group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-5-carbonyl group]Benzoyl radical]-7-cyano-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide; and

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

or a pharmaceutically acceptable salt of any of the foregoing.

(2S,4S) -N-benzyl-4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]Pyrrolidine-2-carboxamide dihydrochloride;

(2S,4S) -4- [ [4- [ (3S) -5- [ (6-bromo-)-2-methoxy-1-naphthyl) methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]-N- [ (1R) -tetrahydronaphthalen-1-yl]Pyrrolidine-2-carboxamide;

(2S,4S) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl ] methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]-N- [ (1S) -tetrahydronaphthalen-1-yl]Pyrrolidine-2-carboxamide;

(2S,4S) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl ] methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-N-cyclohexyl-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]Pyrrolidine-2-carboxamide; and

(2S,4S) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl ] methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]-N-isopropyl-pyrrolidine-2-carboxamide;

or a pharmaceutically acceptable salt of any of the foregoing.

(2S,4S) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl ] methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]-N- [ (1R) -tetrahydronaphthalen-1-yl]Pyrrolidine-2-carboxamide;

(2S,4S) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl ] methyl]-3-[ [ (2S) -2- (methylamino) propanoyl group]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]-N-isopropyl-pyrrolidine-2-carboxamide;

or a pharmaceutically acceptable salt of any of the foregoing.

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [7- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzoDiaza derivatives-1-yl]-7-oxo-heptanoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

(2S) -N- [ (3S) -7-cyano-5- [4- [ (3S) -7-cyano-3- [ [ (2S) -2- (methylamino) propanoyl group]Amino group]-1- [ (2-methyl-1-naphthyl) methyl group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-5-carbonyl group]Benzoyl radical]-1- [ (2-methyl-1-naphthyl) methyl group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide;

or a pharmaceutically acceptable salt of any of the foregoing.

One embodiment of the present invention is directed to a pharmaceutical composition comprising as an active ingredient any of the compounds described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

One embodiment of the present invention relates to compounds of formula I according to the invention for use as therapeutically active substances.

One embodiment of the present invention relates to compounds of formula I according to the invention for the therapeutic and/or prophylactic treatment of cancer.

One embodiment of the present invention relates to the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of cancer.

One embodiment of the present invention relates to compounds of formula I wherein Z is optionally OR³Halogen and lower alkyl substituted aryl, or a pharmaceutically acceptable salt of said compound. In a particular embodiment, Z is optionally asThe above-mentioned substituted naphthyl group.

Another embodiment of the invention relates to compounds of formula I wherein Z is heteroaryl optionally substituted with aryl, optionally substituted with cyano, or a pharmaceutically acceptable salt of said compound. In a particular embodiment, Z is indazolyl optionally substituted with cyanophenyl.

Another embodiment of the present invention relates to compounds of formula I wherein X is lower alkyl, or a pharmaceutically acceptable salt of said compound.

Another embodiment of the present invention relates to compounds of formula I, wherein X is aryl optionally substituted with lower alkyl, or a pharmaceutically acceptable salt of said compound. In a particular embodiment, X is phenyl optionally substituted with methyl. In another embodiment, X is naphthyl.

Another embodiment of the present invention relates to compounds of formula I, wherein X is heteroaryl, or a pharmaceutically acceptable salt of said compound. In another embodiment, X is pyridyl. In another embodiment, X is pyrazinyl.

Another embodiment of the present invention relates to compounds of formula I, wherein Q is a, or a pharmaceutically acceptable salt of said compound.

Another embodiment of the present invention relates to compounds of formula I, wherein Q is B, or a pharmaceutically acceptable salt of said compound.

Another embodiment of the invention relates to compounds of formula I, wherein R¹Is H, or a pharmaceutically acceptable salt of said compound.

Another embodiment of the invention relates to compounds of formula I, wherein R²Is lower alkyl optionally substituted by phenyl, or a pharmaceutically acceptable salt of said compound.

Another embodiment of the invention relates to compounds of formula I, wherein R²Is cycloalkyl, or a pharmaceutically acceptable salt of said compound.

In another embodiment, R²Is cycloalkyl fused to phenyl, or a pharmaceutically acceptable salt of said compound. In a particular embodiment, R²Is tetralin.

Another embodiment of the invention relates to compounds of formula I, wherein Z is optionally OCH₃Halogen and lower alkyl substituted naphthyl; x is phenyl or naphthyl, each of which is optionally substituted with lower alkyl; q is A; and R is¹Is H; or a pharmaceutically acceptable salt of said compound.

In a particular embodiment of the invention, Z is OCH₃And Br-substituted naphthyl; x is phenyl; q is A; and R is¹Is H; or a pharmaceutically acceptable salt of said compound.

In a particular embodiment of the invention, Z is CH₃Substituted naphthyl; x is phenyl; q is A; and R is¹Is H; or a pharmaceutically acceptable salt of said compound.

In another particular embodiment of the invention, Z is OCH₃And Br-substituted naphthyl; x is phenyl; q is a group A; and R is¹Is cyano; or a pharmaceutically acceptable salt of said compound.

Another embodiment of the invention relates to compounds of formula I, wherein Z is optionally OCH₃And halogen substituted naphthyl; x is phenyl; q is a group B; r¹Is H; and R is²Selected from cyclohexyl, and phenyl fused cyclohexyl and lower alkyl optionally substituted with phenyl; or a pharmaceutically acceptable salt of said compound.

In a particular embodiment of the invention, Z is OCH₃And Br-substituted naphthyl; x is phenyl; q is a group B; r¹Is H; and R is²Selected from cyclohexyl, and phenyl fused cyclohexyl and lower alkyl optionally substituted with phenyl; or a pharmaceutically acceptable salt of said compound.

Compounds according to the invention wherein Q is a include:

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [3- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 6);

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [6- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Pyridine-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 7);

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [5- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Pyridine-3-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 8);

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [6- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Naphthalene-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 9);

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]-3-methyl-benzoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 10);

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Phenoxy radical]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 11);

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [6- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Pyridine-3-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 12);

(2S) -2-amino-N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]-2, 5-dimethyl-benzoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Propionamide (example 13);

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [3- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-3-oxo-propionyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 14);

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-4-oxo-butanoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 15);

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [6- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-6-oxo-hexanoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 16);

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [7- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-7-oxo-heptanoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 17);

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [8- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-8-oxo-octanoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 18);

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [5- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Pyrazine-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 19);

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [7- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Naphthalene-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 20);

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [2- [3- [2- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-2-oxo-ethyl]Phenyl radical]Acetyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 21);

(2S) -N- [ (3S) -5- [ (5-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [ (3S) -5- [ (5-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 22);

(2S) -2- (methylamino) -N- [ (3S) -1- [4- [ (3S) -3- [ [ (2S) -2- (methylamino) propanoyl group]Amino group]-5- [ (2-methyl-1-naphthyl) methyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-5- [ (2-methyl-1-naphthyl) methyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Propionamide (example 23);

(2S) -N- [ (3S) -5- [ [1- (2-cyanophenyl) indazol-3-yl]Methyl radical]-1- [4- [ (3S) -5- [ [1- (2-cyanophenyl) indazol-3-yl]Methyl radical]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 24);

(2S) -N- [ (3S) -5- [ (2-methoxy-1-naphthyl) methyl group]-1- [4- [ (3S) -5- [ (2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 25);

(2S) -N- [ (3S) -7-cyano-5- [4- [ (3S) -7-cyano-3- [ [ (2S) -2- (methylamino) propanoyl group]Amino group]-1- [ (2-methyl-1-naphthyl) methyl group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-5-carbonyl group]Benzoyl radical]-1- [ (2-methyl-1-naphthyl) methyl group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 26);

(2S) -N- [ (3S) -1- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-5- [4- [ (3S) -1- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-7-cyano-3- [ [ (2S) -2- (methylamino) propanoyl]Amino group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-5-carbonyl group]Benzoyl radical]-7-cyano-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 27); and

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide (example 28);

or a pharmaceutically acceptable salt of any of the foregoing.

Compounds according to the invention wherein Q is B include:

(2S,4S) -N-benzyl-4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]Pyrrolidine-2-carboxamide dihydrochloride (example 1);

(2S,4S) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl ] methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]-N- [ (1R) -tetrahydronaphthalen-1-yl]Pyrrolidine-2-carboxamide (example 2);

(2S,4S) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl ] methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]-N- [ (1S) -tetrahydronaphthalen-1-yl]Pyrrolidine-2-carboxamide (example 3);

(2S,4S) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl ] methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-N-cyclohexyl-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]Pyrrolidine-2-carboxamide (example 4); and

(2S,4S) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl ] methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]-N-isopropyl-pyrrolidine-2-carboxamide (example 5);

or a pharmaceutically acceptable salt of any of the foregoing.

Another embodiment of the invention relates to a compound selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing.

The compounds of formula I and their salts have at least one asymmetric carbon atom and can therefore be present as mixtures of different stereoisomers. The separation of the various isomers can be carried out by known separation methods, for example chromatography (chromatography).

The compounds disclosed herein and encompassed by formula I may exhibit tautomerism or structural isomerism. The present invention is intended to encompass any tautomeric or structurally isomeric form of these compounds, or mixtures of such forms, and is not limited to any one tautomeric or structurally isomeric form depicted in the above formula.

Dosage form

The compounds of the invention preferentially 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 cIAP1 and/or cIAP2, BIR2 and/or BIR3 domains of XIAP. In another aspect, the compounds of the invention bind to the BIR2 domain of cIAP1 and/or cIAP2, XIAP.

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

The compounds of the invention are therefore useful for ameliorating, controlling or treating cell proliferative disorders, for example, in particular neoplastic disorders. These compounds, and formulations containing the compounds, are expected to be useful in the treatment or control of hematological cancers, such as acute myeloid leukemia, or solid tumors, such as breast, colon, lung and prostate tumors.

A "therapeutically effective amount" or "effective amount" of a compound according to the present invention refers to an amount of the compound effective to prevent, slow or ameliorate symptoms of disease or prolong survival of the treated subject. Determining a therapeutically effective amount is within the skill of the art.

The therapeutically effective amount or dose of the compounds according to the invention may vary within wide limits and may be determined in a manner known in the art. This dosage will be adjusted to the individual requirements in each particular case, including the particular compound administered, the route of administration, the condition being treated, and the patient being treated. Generally, in the case of oral or parenteral administration to an adult weighing about 70Kg, a daily dose of about 10mg to about 10,000mg, preferably about 200mg to about 1,000mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dose may be administered as a single dose or in divided doses, or for parenteral administration it may be given as one or more boluses or as a continuous infusion.

Pharmaceutical formulations for use in the practice of the invention (i.e., comprising a compound of the invention) may be administered internally, for example, orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration can also be effected parenterally, for example intramuscularly or intravenously (for example in the form of injection solutions). In addition, administration can be effected topically (e.g., in the form of an ointment, cream, or oil).

Composition/formulation

In an alternative embodiment, the present invention encompasses a pharmaceutical composition comprising at least one compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and/or carrier.

These pharmaceutical compositions may be adapted for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. These formulations may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound of formula I which produces a therapeutic effect. Typically, this amount will range from about 1% to about 99% active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30% of 100%.

Methods of preparing these formulations or compositions include the step of bringing into association a compound of the invention with a carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compounds of the invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

The compounds of formula I and their pharmaceutically acceptable salts and esters can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, polyvinylpyrrolidone, hypromellose, hydroxypropyl cellulose, microcrystalline cellulose, corn starch or its derivatives, talc, stearic acid or its salts and the like can be used, for example, as adjuvants for tablets, dragees and hard capsules.

Suitable adjuvants for soft capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, liquid polyols and the like. Suitable adjuvants for the production of solutions and syrups are, for example, H₂O, polyols, sucrose, invert sugar, glucose, and the like. Suitable adjuvants for injection solutions are, for example, H₂O, alcohol, polyhydric alcohol, glycerin, vegetable oil and the like. Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like. Suitable adjuvants for topical formulations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

In addition, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutic substances.

The compounds of the invention (compounds of formula I) may be prepared using the general reaction scheme outlined in the following schemes.

Scheme 1

Suitably protected 2 i.e. 2-amino-3-aminopropionic acid and substituted or unsubstituted 3 i.e. 1-fluoro-2-nitrobenzene may be reacted with a base to give a compound of formula 4. The compound of formula 4 may be reacted under reducing conditions to provide the compound of formula 5. The reduction process may include catalytic hydrogenation and chemical reduction. The compound of formula 5 may be subjected to dehydration conditions to give the compound of formula 6. A compound of formula 6 may be reacted with a compound of formula 7 (where Q is a suitable leaving group) to form a compound of formula 8. The amine protecting group PG1 may be removed to give a compound of formula 9. An appropriately protected compound of formula 10, i.e. 2-methylamino-propionic acid, can be coupled to a compound of formula 9 to provide a compound of formula 11. The compound of formula 11 can be reacted with a carboxylic acid of formula 12 under dehydration conditions to provide a compound of formula 13. The amine protecting group PG2 may be removed to give a compound of formula 14.

Scheme 2

An appropriately protected 4-amino-pyrrolidine-2-carboxylic acid of formula 15, wherein the protecting groups PG4 and PG5 are selected so as to be removable independently of each other, can be reacted with an amine of formula 16 under dehydration conditions to provide a compound of formula 17. The protecting group PG4 of the compound of formula 17 may be removed to give a compound of formula 18. Appropriately protected compound of formula 19, i.e., α - (methylamino) -cyclohexaneacetic acid, can be coupled to the compound of formula 18 to provide the compound of formula 20. The protecting group PG6 in the compound of formula 20 may be removed to give the compound of formula 21. The compound of formula 21 and an appropriately protected compound of formula 10, i.e. 2-methylamino-propionic acid, can be coupled to provide a compound of formula 22. The protecting group PG5 in the compound of formula 22 may be removed to give the compound of formula 23.

Scheme 3

The compound of formula 14 can be coupled with the compound of formula 23 under dehydration conditions to give the compound of formula 24. Protecting groups PG2 and PG7 may be removed to give compounds of formula 25.

Scheme 4

The compound of formula 11 can be reacted with a dicarbonyl chloride of formula 26 to give a compound of formula 27. Protecting group PG2 may be removed from the compound of formula 27 to provide a compound of formula 28.

Scheme 5

Where the appropriate dicarbonyl chloride is not commercially available or known in the literature, compounds of formula 27 can be prepared by reacting a compound of general structure 11 and a dicarboxylic acid of formula 29 under dehydrating conditions. Such conditions include, but are not limited to, the use of POCl₃、SOCl₂Or other dehydration reagents known to those skilled in the art.

One skilled in the art will recognize that alternative synthetic routes may be available to provide the above-described intermediates. For example, an alternative route to the compounds of formula 22 is depicted in scheme 6.

Scheme 6

The carboxylic acid in the compounds of general structure 15 may be protected with protecting group PG8 to provide compounds of general formula 30, wherein PG8 is a group that renders the carboxylic acid inert to the reaction conditions used in the remaining synthetic sequences. The protecting group PG8 may be preferentially selected by reference to textbooks of Organic chemistry (e.g., Protective Groups in Organic Synthesis, TheodoraW. Greene et al), the literature of Organic chemistry, or will be well known to those skilled in the art of Organic Synthesis. The protecting group PG4 of the compound of formula 30 may be removed to give the compound of formula 31. Appropriately protected compound of formula 19, i.e., α - (methylamino) -cyclohexaneacetic acid, can be coupled to the compound of formula 31 to provide the compound of formula 32. The protecting group PG6 in the compound of formula 32 may be removed to give the compound of formula 33. Compounds of general formula 33 and appropriately protected general structure 10, i.e. 2-methylamino-propionic acid, can be coupled to provide compounds of general formula 34. The carboxylic acid protecting group PG8 in the compound of formula 34 may be removed to give a compound of formula 35. The compound of general structure 35 may be reacted with the amine of general structure 16 under dehydration conditions to provide the compound of general structure 22.

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

Crystal form

When the compounds of the present invention are solids, those skilled in the art will understand that these compounds, and their salts, may exist in different crystalline or polymorphic forms, all of which are intended to be encompassed within the scope of the present invention and the indicated formula.

Examples

The synthesis of the compounds of the invention may be according to known procedures. The following examples and references are provided to aid in the understanding of the present invention. However, the examples are not intended to limit the invention, the true scope of which is set forth in the appended claims. The generation of the reactant and end product names in the examples was performed using AutoNom 2000Add-in v4.0 SP2 (function in ISIS Draw, Elsevier/MDL), or available functions in AutoNom 2000TT v4.01.305(Elsevier/MDL), or ChemDrawPro Control 11.0.2(cambridge soft Corp.), or the structure of an electronic notebook (name characteristics), or Accelrys Draw 4.0.

Examples

Preparation of intermediates

Intermediate 1

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

Step 1: mixing Cs₂CO₃(1.56g, 4.8mmol) was added to a solution of 3-methylindazole (0.634g, 4.8mmol) and 2-fluorocyanobenzene (1mL, 9.6mmol) in DMF (20 mL). After 12h with saturated NH₄The mixture was diluted with Cl and a precipitate formed. Filtering the solid with H₂O, hexane were washed and dried in vacuo to give 2- (3-methyl-1H-indazol-1-yl) cyanobenzene (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) cyanobenzene (1g, 4.29mmol) in CCl₄(20mL) and the mixture was heated to reflux for 2 h. The mixture was concentrated and the residue was purified by silica gel chromatography to give the title compound as an off-white solid (1.25g, 93%).

Intermediate 2

((S) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b)][1,4]Diaza derivatives-3-Yl) -carbamic acid tert-butyl ester

Step 1: to a solution of (S) -3-amino-2-tert-butoxycarbonylamino-propionic acid (Aldrich) (5g, 24.48mmol) in DMF (75mL) at Room Temperature (RT) was added 1-fluoro-2-nitrobenzene (2.92mL, 26.93mmol) and sodium bicarbonate (6.17g, 73.44mmol) and the resulting mixture was heated at 80 ℃ under nitrogen for 18 h. Water was added and the aqueous layer was washed with ethyl acetate. The aqueous solution was adjusted to pH 3 by adding 10% aqueous sodium hydrogensulfate solution and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (Na)₂SO₄) And concentrated under reduced pressure to give a crude block, which was triturated with hexane to give (S) -2-tert-butoxycarbonylamino-3- (2-nitro-phenylamino) -propionic acid as an orange solid (5g, 63%). LC-MS:326.2(M + H).

Step 2: a solution of (S) -2-tert-butoxycarbonylamino-3- (2-nitro-phenylamino) -propionic acid (Aldrich) (10g, 30.76mmol) in MeOH (100mL) was purged with argon for 30min and 10% Pd-C (1g) was added to the solution. The resulting mixture was hydrogenated using a balloon at room temperature for 18 h. The mixture was filtered through celite and the filtrate was concentrated, and the resulting material was triturated with hexanes to give (S) -3- (2-amino-phenylamino) -2-tert-butoxycarbonylamino-propionic acid as a brown solid (8.5g, 93%). LC-MS:296(M + H).

And step 3: to an ice-cooled solution of (S) -3- (2-amino-phenylamino) -2-tert-butoxycarbonylamino-propionic acid (4g, 13.54mmol) in DMF (40mL) were added EDCI. HCl (2.86g, 14.89mmol), HOBT (2.01g, 14.89mmol) and DIPEA (7.19mL, 40.63 mmol). The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was concentrated and the resulting material was purified by silica gel chromatography to give the title compound as an off white solid (2.9g, 77%). LC-MS:278(M + H).

Intermediate 3

((S) -7-cyano-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b)][1,4]Diaza derivatives-3-Yl) -carbamic acid tert-butyl ester

Step 1: to a solution of (S) -3-amino-2-tert-butoxycarbonylamino-propionic acid (Aldrich) (3g, 14.706mmol) in DMF (60mL) was added cesium carbonate (14.34g, 44.118mmol) and 3-fluoro-4-nitro-cyanobenzene (2.685mL, 16.176mmol) at room temperature and the resulting mixture was stirred at room temperature under nitrogen for 3 h. The reaction mixture was diluted with ethyl acetate, washed with ice-cold water, brine, dried and concentrated to give a material which was purified by silica gel chromatography to afford (S) -2-tert-butoxycarbonylamino-3- (5-cyano-2-nitro-phenylamino) -propionic acid (4.4g, 85.4%) as an orange solid. LC-MS:350.8(M + H).

Step 2: a solution of (S) -2-tert-butoxycarbonylamino-3- (5-cyano-2-nitro-phenylamino) -propionic acid (4.4g, 12.57mmol) in ethyl acetate (70mL) was purged with argon for 15min and 10% Pd-C (1g) was added. The resulting mixture was hydrogenated using a balloon at room temperature for 16 h. The mixture was filtered through celite and the filtrate was concentrated to give the material which was triturated with hexanes to give (S) -3- (2-amino-5-cyano-phenylamino) -2-tert-butoxycarbonylamino-propionic acid as a brown solid (4.16g, 94.69%). LC-MS:321.0(M + H).

And step 3: to an ice-cooled solution of (S) -3- (2-amino-5-cyano-phenylamino) -2-tert-butoxycarbonylamino-propionic acid (4.1g, 12.812mmol) in DMF (40mL) were added EDCI. HCl (2.89g, 15.125mmol), HOBT (2.05g, 15.125mmol) and DIPEA (7.1mL, 41.25 mmol). The resulting mixture was stirred at room temperature for 16h and the mixture was diluted with ethyl acetate, washed with water, brine and the organic solution was concentrated to give the material which was purified by silica gel chromatography to give the title compound as a pale pink solid (1.4g, 36.26%). LC-MS:303.2(M + H).

Intermediate 4

[ (S) -1- (6-bromo-2-methyl)Oxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b][1,4]Diaza derivatives-3-yl]-carbamic acid tert-butyl ester

To ((S) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b) at-78 ℃][1,4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester (intermediate 2) (6.5g, 23.48mmol) to a solution in THF (100mL) was added 1M LiHMDS (4.7g, 28mL, 28 mmol). The cold bath was removed and the mixture was stirred at room temperature for 1 h. The mixture was cooled to-78 ℃ and a mixture of 6-bromo-1-chloromethyl-2-methoxy-naphthalene (8.0g, 28.12mmol) and NaI (4.2g, 28.12mmol) in dry THF (30mL) was added dropwise. The cold bath was removed and the mixture was stirred at room temperature for 18 h. With saturated NH₄The mixture was diluted with Cl, extracted with ethyl acetate and the organic layer was washed with water, brine and dried (Na)₂SO₄) And concentrated to give the material which was purified by silica gel chromatography to give the title compound as a yellow solid (9g, 72%). LC-MS:528.0(M + H).

Intermediate 5

[ (S) -1- (5-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-yl]-carbamic acid tert-butyl ester

5min at-78 ℃ to ((S) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b)][1,4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester (intermediate 2) (500mg, 1.805mmol) to a stirred solution in THF (10mL) was added LiHMDS (1M in THF, 2.3mL, 2.3mmol) dropwise. The mixture was stirred at-78 ℃ for 20min and a mixture of sodium iodide (295.8mg, 1.986mmol) and 5-bromo-1-chloromethyl-2-methoxy-naphthalene (617.3mg, 2.166mmol) in THF (5mL) was added dropwise over 5 min. The mixture was stirred at-78 ℃ for 50min and the cold bath was removed. After 16h, aqueous citric acid solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium carbonate solution, dried and concentrated to give a material which was purified by silica gel chromatography to provide the title compound as a white solid (780mg, 82%). LC-MS:528(M + H).

Intermediate 6

[ (S) -1- (2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-yl]-carbamic acid tert-butyl ester

To prepare [ (S) -1- (5-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-yl]-carbamic acid tert-butyl ester (intermediate 5) in a similar manner as described for ((S) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b)][1,4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester (intermediate 4) (400mg, 1.44mmol) and 1-bromomethyl-2-methoxy-naphthalene (435.15mg, 1.733mmol) were converted to the title compound obtained as a white solid (450mg, 69.6%). LC-MS448(M + H).

Intermediate 7

{ (S) -1- [1- (2-cyano-phenyl) -1H-indazol-3-ylmethyl]-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b][1,4]Diaza derivatives-3-yl } -carbamic acid tert-butyl ester

To prepare [ (S) -1- (5-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-yl]-carbamic acid tert-butyl ester (intermediate 5) in a similar manner as described for ((S) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b)][1,4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester (intermediate 2) (500mg, 1.8mmol) and 2- (3-bromomethyl-indazol-1-yl) -cyanobenzene (intermediate 1) (676.18mg, 2.16mmol) were converted to the title compound obtained as a light yellow solid (670mg, 72.9%). LC-MS:509(M + H).

Intermediate 8

[ (S) -1- (2-methyl-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-yl]-carbamic acid tert-butyl ester

To 3.0g (10.83mmol) ((S) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] b) at-78 deg.C][1,4]Diaza derivativesTo a solution of tert-butyl (3-yl) -carbamate (intermediate 2) in 55mL of anhydrous tetrahydrofuran was slowly added a solution of 1M lithium bis (trimethylsilyl) amide in tetrahydrofuran (24mL, 24 mmol). The solution was stirred at-78 ℃ for 30 min. A solution of 5.35g (28.2mmol) 1-chloromethyl-2-methyl-naphthalene in 15mL tetrahydrofuran was slowly added. The reaction mixture was stirred at-78 ℃ for 10min, the cold bath was removed and the mixture was stirred overnight. Potassium iodide (1.8g, 10.83mmol) was added to the mixture. After 2h, water and ethyl acetate were added to the mixture, the organic layer was washed with 10% aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography to give the title compound (3.2g) as a light yellow solid. LC-MS:432(M + H).

Intermediate 9

[ (S) -7-cyano-1- (2-methyl-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-yl]-carbamic acid tert-butyl ester

To (S) -7-cyano-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] at-78 ℃][1,4]Diaza derivativesTo a stirred solution of (intermediate 3) (300mg, 0.993mmol) of tert-butyl (3-yl) -carbamate in THF (10mL) was added LiHMDS (1M in THF, 1.19mL, 1.19 mmol). After 20min, 1-chloromethyl-2-methyl-naphthalene (227.289mg, 1.192mmol) and NaI (178.677mg, 1.192mmol) in THF (5mL) were added to the mixture. After 1h the cooling bath was removed and the mixture was stirred for 16h, diluted with citric acid solution (1N) and extracted with ethyl acetate. The combined extracts were washed with water, brine, and Na₂SO₄Dried and concentrated. The residue was purified by silica gel chromatography to give the title compound as an off-white solid (400mg, 88.2%). LC-MS:457.2(M + H).

Intermediate 10

[ (S) -1- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -7-cyano-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-yl]-carbamic acid tert-butyl ester

To (S) -7-cyano-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] at-78 ℃][1,4]Diaza derivativesTo a solution of (3-yl) -carbamic acid tert-butyl ester (intermediate 3) (500mg, 1.656mmol) in THF was added LiHMDS (1.98mL, 1.987 mmol). After 20min, a mixture of 6-bromo-1-chloromethyl-2-methoxy-naphthalene (519mg, 1.821mmol) and NaI (297.8mg, 1.987mmol) in THF (10mL) was added. After 1h, the cold bath was removed and the mixture was stirred for 16h, diluted with citric acid solution (1N) and extracted with ethyl acetate. The combined extracts were washed with water, brine, and Na₂SO₄Dried and concentrated. The combined extracts were washed with water, brine, and Na₂SO₄Dried and concentrated. The residue was purified by silica gel chromatography to give the title compound as an off-white solid (638mg, 69.88%). LC-MS:550.9(M + H).

Intermediate 11

{ (S) -1- [ (S) -1- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-ylcarbamoyl]-ethyl } -methyl-carbamic acid tert-butyl ester

Step 1: to [ (S) -1- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] at 0 deg.C][1,4]Diaza derivatives-3-yl]To a stirred solution of tert-butyl carbamate (intermediate 4) (100mg, 0.19mmol) in DCM (2mL) was added 50% TFA in DCM (4mL) dropwise. After 2h the mixture was evaporated and the residue washed with diethyl ether to give (S) -3-amino-1- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -1,3,4, 5-tetrahydro-benzo [ b][1,4]Diaza derivatives-2-keto trifluoroacetate salt (72mg, 70.58%). LC-MS:426(M + H).

Step 2: Boc-N-Me-Ala-OH (650mg, 3.19mmol), HATU (1.32g, 3.48mmol) and DIPEA (1.52mL, 8.72mmol) were added to (S) -3-amino-1- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -1,3,4, 5-tetrahydro-benzo [ b][1,4]Diaza derivatives-2-keto trifluoroacetate salt (1.6g, 2.90mmol) in DMF (10 mL). After 18 the mixture was evaporated and the mixture was diluted with ethyl acetate. The mixture was washed with water, brine and dried (Na)₂SO₄) And concentrated. The residue was purified by silica gel chromatography to give the title compound as a yellow solid (1.6g, 88%). LC-MS:611(M + H).

Intermediate 12

{ (S) -1- [ (S) -1- (5-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-ylcarbamoyl]-ethyl } -methyl-carbamic acid tert-butyl ester

Step 1: to [ (S) -1- (5-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] at 0 deg.C][1,4]Diaza derivatives-3-yl]A solution of tert-butyl carbamate (intermediate 5) (480mg, 0.913mmol) in DCM (8mL) was added TFA (1.9mL) dropwise. The mixture was stirred at room temperature for 2h and evaporated. The residue was triturated with hexanes to give (S) -3-amino-1- (5-bromo-2-methoxy-naphthalen-1-ylmethyl) -1,3,4, 5-tetrahydro-benzo [ b ] as a brown solid][1,4]Diaza derivatives-2-keto trifluoroacetate salt (260 mg). LC-MS:428(M + H).

Step 2: Boc-N-Me-Ala-OH (107.91mg, 0.532mmol), DIPEA (0.251mL, 1.45mmol) and HATU (220.37mg, 0.58mmol) was added to (S) -3-amino-1- (5-bromo-2-methoxy-naphthalen-1-ylmethyl) -1,3,4, 5-tetrahydro-benzo [ b ] at 0 deg.C][1,4]Diaza derivatives-2-Ketone trifluoroacetate salt (260mg) in DMF (4 mL). After 3h the mixture was diluted with water and extracted with ethyl acetate. The extract was washed with 1M aqueous citric acid, brine, saturated aqueous sodium carbonate, dried and concentrated. The residue was purified by silica gel chromatography to give the title compound as an off-white solid (282mg, 51%). LC-MS:613.2(M + H).

Intermediate 13

{ (S) -1- [ (S) -1- (2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-ylcarbamoyl]-ethyl radical} -methyl-carbamic acid tert-butyl ester

Step 1: to prepare (S) -3-amino-1- (5-bromo-2-methoxy-naphthalen-1-ylmethyl) -1,3,4, 5-tetrahydro-benzo [ b][1,4]Diaza derivatives-2-Ketone trifluoroacetate salt (intermediate 12, step 1) in a similar manner as described for [ (S) -1- (2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b][1,4]Diaza derivatives-3-yl]-tert-butyl carbamate (intermediate 6) (450mg, 1.007mmol) was converted to (S) -3-amino-1- (2-methoxy-naphthalen-1-ylmethyl) -1,3,4, 5-tetrahydro-benzo [ b ] obtained as a brown solid][1,4]Diaza derivatives-2-keto trifluoroacetate salt (460mg, crude). LC-MS:348.2(M + H).

Step 2: to prepare { (S) -1- [ (S) -1- (5-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b { (S) -1- [ (S) -1- (5-bromo-2-methoxy-naphthalen-1-ylmethyl) - ] -][1,4]Diaza derivatives-3-ylcarbamoyl]-Ethyl } -methyl-carbamic acid tert-butyl ester (intermediate 12) in a similar manner as described for (S) -3-amino-1- (2-methoxy-naphthalen-1-ylmethyl) -1,3,4, 5-tetrahydro-benzo [ b][1,4]Diaza derivatives-2-Keto trifluoroacetate (step 1 above) (460mg) and Boc-N-Me-Ala-OH (223.3mg, 1.1mmol) were converted to the title compound obtained as a white solid (390mg, 73.2%). LC-MS:533(M + H).

Intermediate 14

((S) -1- { (S) -1- [1- (2-cyano-phenyl) -1H-indazol-3-ylmethyl]-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b][1,4]Diaza derivatives-3-ylcarbamoyl } -ethyl) -methyl-carbamic acid tert-butyl ester

Step 1: to prepare (S) -3-amino-1- (5-bromo-2-methoxy-naphthalen-1-ylmethyl) -1,3,4, 5-tetrahydro-benzo [ b][1,4]Diaza derivatives-2-keto trifluoroacetate salt (intermediate 12, step 1) in a similar manner as described for { (S) -1- [1- (2-cyano-phenyl) -1H-indazol-3-ylmethyl]-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b][1,4]Diaza derivatives-3-yl } -carbamic acid tert-butyl ester (intermediate 7) (670mg, 1.319mmol) was converted to 2- [3- ((S) -3-amino-2-oxo-2, 3,4, 5-tetrahydro-benzo [ b ] obtained as a yellow solid][1,4]Diaza derivatives-1-ylmethyl) -indazol-1-yl]Cyanophenyl trifluoroacetate (680 mg). LC-MS:408.8(M + H).

Step 2: to prepare { (S) -1- [ (S) -1- (5-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b { (S) -1- [ (S) -1- (5-bromo-2-methoxy-naphthalen-1-ylmethyl) - ] -][1,4]Diaza derivatives-3-ylcarbamoyl]-Ethyl } -methyl-carbamic acid tert-butyl ester (intermediate 12) in a similar manner to that described for 2- [3- ((S) -3-amino-2-oxo-2, 3,4, 5-tetrahydro-benzo [ b ]][1,4]Diaza derivatives-1-ylmethyl) -indazol-1-yl]Cyanobenzene trifluoroacetate (step 1 above) (680mg, 1.30mmol) and Boc-N-Me-Ala-OH (290.88mg, 1.43mmol) were converted to the title compound obtained as a white solid (570mg, 72.8%). LC-MS:594(M + H).

Intermediate 15

Methyl- { (S) -1- [ (S) -1- (2-methyl-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b [ -b ]][1,4]Diaza derivatives-3-ylcarbamoyl]-Ethyl } -carbamic acid tert-butyl ester

Step 1: stirring 20mL of [ (S) -1- (2-methyl-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] in 4.0M HCl in 1,4-dioxane (1,4-dioxane) at room temperature][1,4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester (intermediate 8) (1.29g, 3.0mmol) overnight. Removing the solvent and lyophilizing the residue to give (S) -3-amino-1- (2-methyl-naphthalen-1-ylmethyl) -1,3,4, 5-tetrahydro-benzo [ [ b ] as a white solid][1,4]Diaza derivatives2-keto hydrochloride (1.10g), which was used without purification.

Step 2: to (S) -3-amino-1- (2-methyl-naphthalen-1-ylmethyl) -1,3,4, 5-tetrahydro-benzo [ [ b ] at 0 deg.C][1,4]Diaza derivatives-2-keto hydrochloride (1.10g, 3mmol), 1-hydroxybenzotriazole hydrate (0.50g, 3.3mmol), Boc-N-Me-Ala-OH (0.64g, 3.15mmol), diisopropylEthylamine (2.1mL, 12.0mmol) in dimethylformamide (18mL) was added to O- (benzotriazol-1-yl) -N, N' -bis (tetramethylene) urea hexafluorophosphate (1.25g, 3.3 mmol). The mixture was stirred at room temperature for 4h, diluted with ethyl acetate, washed with aqueous sodium carbonate, brine, 1M citric acid, brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated. The residue was purified by silica gel chromatography to afford the title compound as a white solid. LC-MS:517(M + H).

Intermediate 16

{ (S) -1- [ (S) -7-cyano-1- (2-methyl-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-ylcarbamoyl]-ethyl } -methyl-carbamic acid tert-butyl ester

Step 1: to [ (S) -7-cyano-1- (2-methyl-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] at 0 deg.C][1,4]Diaza derivatives-3-yl]To a solution of tert-butyl carbamate (intermediate 9) (400mg, 0.877mmol) in 1,4 dioxane (3mL) was added dropwise a 4N HCl dioxane solution (0.7 mL). The mixture was stirred at room temperature for 16 h. The mixture was concentrated and the residue triturated with diethyl ether to give (S) -3-amino-1- (2-methyl-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] as an off-white solid][1,4]Diaza derivatives7-carbonitrile hydrochloride (310mg, 90.15%). LC-MS:357.2(M + H).

Step 2: to (S) -3-amino-1- (2-methyl-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivativesTo a stirred solution of-7-carbonitrile hydrochloride (305mg, 0.778mmol) in DMF (10mL) were added Boc-N-Me-Ala-OH (173.912mg, 0.856mmol), HOBT (115.645mg, 0.856mmol) and DIPEA (0.67mL, 3.89 mmol). After 10min, the mixture was cooled to 0 ℃ and HBTU (324.63mg, 0.856mmol) was added. After 2h, the mixture was diluted with ethyl acetate, washed with water, brine and Na₂SO₄Dried and concentrated. The residue was purified by silica gel chromatography to give the title compound as an off-white solid (390mg, 92.54%). LC-MS:542.0(M + H).

Intermediate 17

{ (S) -1- [ (S) -1- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -7-cyano-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-ylcarbamoyl]-ethyl } -methyl-carbamic acid tert-butyl ester

Step 1: except that the mixture was triturated with ether then hexane, to prepare (S) -3-amino-1- (2-methyl-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b][1,4]Diaza derivatives-7-carbonitrile hydrochloride (intermediate 16, step 1) in a similar manner as described for [ (S) -1- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -7-cyano-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] b][1,4]Diaza derivatives-3-yl]-tert-butyl carbamate (intermediate 10) (630mg, 1.143mmol) was converted to (S) -3-amino-1- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzene obtained as a white solidAnd [ b ]][1,4]Diaza derivatives7-carbonitrile hydrochloride (510mg, 91.53%). LC-MS:450.8(M + H).

Step 2: to (S) -3-amino-1- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivativesTo a solution of-7-carbonitrile hydrochloride (510mg, 1.047mmol) in DMF (10mL) were added Boc-N-Me-Ala-OH (234mg, 1.15mmol), HOBT (155.62mg, 1.15mmol) and DIPEA (0.943mL, 5.236 mmol). After 10min, the mixture was cooled to 0 ℃ and HBTU (436.7mg, 1.152mmol) was added in portions. The resulting mixture was stirred for 2 h. The mixture was diluted with water and extracted with EtOAc. Washing the extract with 1M aqueous citric acid, brine, saturated aqueous sodium carbonate, and Na₂SO₄Dried and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (570mg, 85.58%) as an off-white solid. LC-MS:636.0(M + H).

Intermediate 18a

Trans-1, 4-cyclohexane-dicarbonyl dichloride

To trans-1, 4-cyclohexane-dicarboxylic acid (500mg, 2.9mmol) was added SOCl at 0 deg.C₂(8mL) followed by addition of a catalytic amount of DMF. The resulting mixture was refluxed for 3h and concentrated under an inert atmosphere to give trans-1, 4-cyclohexane-dicarbonyl dichloride (510mg), which was used without purification.

The compounds shown in table 1 were prepared following the procedure described for the preparation of trans-1, 4-cyclohexane-dicarbonyl dichloride.

TABLE 1

Intermediate 19

4- { (S) -5- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -3- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino]-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Diaza derivatives-1-carbonyl } -benzoic acid methyl ester

To { (S) -1- [ (S) -1- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] at 0 deg.C][1,4]Diaza derivatives-3-ylcarbamoyl]To a solution of-ethyl } -methyl-carbamic acid tert-butyl ester (intermediate 11) (1.5g, 2.455mmol) in pyridine (20mL) was added monomethyl terephthalate (884mg, 4.91 mmol). The mixture was stirred at 0 ℃ for 10min and POCl was added slowly₃(0.472mL, 5.155mmol), remove the cold bath and stir the mixture at room temperature. After 16h the mixture was evaporated and the residue was diluted with ice water and extracted with ethyl acetate. The combined extracts were washed with water, brine, and Na₂SO₄Dried and concentrated. The residue was purified by silica gel chromatography to give the title compound. This sequence was repeated to provide a total of 4.2g of the title compound as an off-white solid. LC-MS:773(M + H).

Intermediate 20

4- { (S) -5- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -3- [ (S) -2- (tert-butoxy)Aminocarbonyl-methyl-amino) -propionylamino]-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Diaza derivatives-1-carbonyl } -benzoic acid

To 4- { (S) -5- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -3- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino]-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Diaza derivativesTo a solution of-1-carbonyl } -benzoic acid methyl ester (intermediate 19) (4g, 5.175mmol) in THF-MeOH-water 1:1:1(90mL) was slowly added LiOH. H₂Solution of O (574mg, 13.6m mol) in water. After 4h the mixture was concentrated, the residue diluted with water and acidified to pH-3 with 1N HCl. The mixture was extracted with ethyl acetate, the extracts were dried over sodium sulfate and evaporated. The residue was triturated with hexanes to give the title compound as an off-white solid (3.6g, 91.58%). LC-MS:759(M + H).

Intermediate 21

(2S,4S) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -2- [ (R) - (1,2,3, 4-tetrahydro-naphthalen-1-yl) carbamoyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of (2S,4S) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-1, 2-dicarboxylic acid 1-tert-butyl ester (Aldrich) (7.5g, 16.593mmol) in DMF (100mL) was added HATU (6.93g, 18.252mmol) and DIPEA (14.36mL, 82.965mmol) and the mixture was cooled to 0 ℃. (R) - (1,2,3, 4-tetrahydro-naphthalen-1-yl) amine (2.44g, 16.593mmol) was added dropwise and the cold bath removed. After 4h the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated to give the title compound (9.6g) as an off white solid which was used without purification. LC-MS:582(M + H).

Intermediate 22

({ (3S,5S) -5- [ (R) - (1,2,3, 4-tetrahydro-naphthalen-1-yl) carbamoyl ] -pyrrolidin-3-yl } -carbamic acid 9H-fluoren-9-ylmethyl ester trifluoroacetate salt

To a solution of (2S,4S) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -2- [ (R) - (1,2,3, 4-tetrahydro-naphthalen-1-yl) carbamoyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 21) (9.5g, 16.35mmol) in DCM (50mL) was added TFA (49mL, 654.045mmol) dropwise at 0 ℃ and the cold bath was removed. After 16h the mixture was concentrated and the residue was triturated with ether to give the title compound as an off-white solid (9.55 g). LC-MS:482(M + H).

Intermediate 23

{ (3S,5S) -1- ((S) -2-tert-Butoxycarbonylamino-2-cyclohexyl-acetyl) -5- [ (R) - (1,2,3, 4-tetrahydro-naphthalen-1-yl) carbamoyl ] -pyrrolidin-3-yl } -carbamic acid 9H-fluoren-9-ylmethyl ester

Add HATU (6.7g, 17.622mmol) followed by DIPEA (13.87mL, 80.101mmol) to a solution of (S) -tert-butoxycarbonylamino-cyclohexyl-acetic acid (Aldrich) (4.529g, 17.622mmol) in DMF (100 mL). The mixture was cooled to 0 ℃, and ({ (3S,5S) -5- [ (R) - (1,2,3, 4-tetrahydro-naphthalen-1-yl) carbamoyl ] -pyrrolidin-3-yl } -carbamic acid 9H-fluoren-9-ylmethyl ester trifluoroacetate (intermediate 22) (9.5g, 16.02mmol) in DMF (50mL) was added dropwise and then the cold bath was removed after 4H the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated to give the title compound (10g) as an off-white solid which was used without purification LC-MS:721(M + H).

Intermediate 24

{ (3S,5S) -1- ((S) -2-amino-2-cyclohexyl-acetyl) -5- [ (R) - (1,2,3, 4-tetrahydro-naphthalen-1-yl) carbamoyl ] -pyrrolidin-3-yl } -carbamic acid 9H-fluoren-9-ylmethyl ester hydrochloride

To a stirred solution of { (3S,5S) -1- ((S) -2-tert-butoxycarbonylamino-2-cyclohexyl-acetyl) -5- [ (R) - (1,2,3, 4-tetrahydro-naphthalen-1-yl) carbamoyl ] -pyrrolidin-3-yl } -carbamic acid 9H-fluoren-9-ylmethyl ester (intermediate 23) (6.5g, 9.03mmol) in dioxane (25mL) was added dropwise 4M HCl in dioxane (50mL) at 0 deg.C and the cold bath was then removed. After 6h the mixture was evaporated and the residue was triturated with ether to give the title compound as a white solid (5.58 g). LC-MS:621(M + H).

Intermediate 25

{ (3S,5S) -1- { (S) -2- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino ] -2-cyclohexyl-acetyl } -5- [ (R) - (1,2,3, 4-tetrahydro-naphthalen-1-yl) carbamoyl ] -pyrrolidin-3-yl } -carbamic acid 9H-fluoren-9-ylmethyl ester

To a stirred solution of Boc-N-Me-Ala-OH (2.55g, 12.57mmol) in DMF (30mL) was added HATU (4.78g, 12.57mmol) and DIPEA (9.9mL, 57.16 mmol). After 30min, the mixture was cooled to 0 ℃, { (3S,5S) -1- ((S) -2-amino-2-cyclohexyl-acetyl) -5- [ (R) - (1,2,3, 4-tetrahydro-naphthalen-1-yl) carbamoyl ] -pyrrolidin-3-yl } -carbamic acid 9H-fluoren-9-ylmethyl ester (intermediate 24) (7.5g, 11.43mmol) in DMF (50mL) was added and the cold bath was removed. After 4h the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography to give the title compound (5.32g) LC-MS:806(M + H) as an off-white solid.

Intermediate 26

[ (S) -1- ((S) -2- { (2S,4S) -4-amino-2- [ (R) - (1,2,3, 4-tetrahydro-naphthalen-1-yl) carbamoyl ] -pyrrolidin-1-yl } -1-cyclohexyl-2-oxo-ethylcarbamoyl) -ethyl ] -methyl-carbamic acid tert-butyl ester

{ (3S,5S) -1- { (S) -2- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino ] -2-cyclohexyl-acetyl } -5- [ (R) - (1,2,3, 4-tetrahydro-naphthalen-1-yl) carbamoyl ] -pyrrolidin-3-yl } -carbamic acid 9H-fluoren-9-ylmethyl ester (intermediate 25) (100mg, 124. mu.M) was dissolved in DMF (0.9mL) at room temperature and piperidine (0.1mL) was added. The mixture was stirred at room temperature for 30min, concentrated and the residue was purified by silica gel chromatography to give the title compound as a white foam (56.7mg, 78%). LC-MS:585(M + H).

Intermediate 27

(2S,4S) -1- { (S) -2- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino ] -2-cyclohexyl-acetyl } -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-2-carboxylic acid

Step 1: to a suspension of (2S,4S) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-1, 2-dicarboxylic acid 1-tert-butyl ester (Aldrich) (1g, 2.21mmol) in methanol (6mL) was added dropwise a solution of potassium carbonate (153mg, 1.1mmol) in water (6 mL). The mixture was stirred at room temperature for 1 hour, concentrated, and the residue was slurried in toluene and evaporated to dryness 3 times, and once from diethyl ether, to give a white solid. The solid and DMF (6mL) were mixed and bromomethyl-benzene (289. mu.L, 2.43mmol) was added dropwise at room temperature. After 16h, the mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography to give (2S,4S) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-1, 2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester as a foam (0.92g, 77%).

Step 2: 20mL of a TFA/DCM (1:1) mixture was added to 0 deg.C (2S,4S) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-1, 2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (0.92g, 0.17mmol), the cooling bath was removed and the mixture was stirred for 2H. The mixture was concentrated and triturated with diethyl ether to give (2S,4S) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-2-carboxylic acid benzyl ester trifluoroacetate (0.94g) as a white solid.

And step 3: add DIPEA (1.18mL, 6.76mmol) and HATU (674mg, 1.77mmol) to a solution of (S) -tert-butoxycarbonylamino-cyclohexyl-acetic acid (Aldrich) (435mg, 1.69mmol) in DMF at 0 deg.C. After 30min (2S,4S) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-2-carboxylic acid benzyl ester trifluoroacetate (0.94g, 1.69mmol) was added in one portion. The cold bath was removed and the mixture was stirred for 1H, diluted with water and the resulting white precipitate was collected, washed with water and air dried to give benzyl (2S,4S) -1- ((S) -2-tert-butoxycarbonylamino-2-cyclohexyl-acetyl) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-2-carboxylate (1.07g, 93%).

And 4, step 4: benzyl (2S,4S) -1- ((S) -2-tert-butoxycarbonylamino-2-cyclohexyl-acetyl) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-2-carboxylate (1.07g, 1.77mmol) was dissolved in 4M HCl in 1,4-dioxane (6mL) at 0 deg.C and stirred for 1H, the cold bath was removed and the reaction stirred for 1H. The mixture was concentrated and the residue triturated with diethyl ether to give (2S,4S) -1- ((S) -2-amino-2-cyclohexyl-acetyl) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-2-carboxylic acid benzyl ester hydrochloride as a light yellow solid (0.97g), which was used without further purification or characterization.

And 5: add DIPEA (1.27mL, 8.85mmol) and HATU (626mg, 1.65mmol) to a solution of Boc-N-Me-Ala-OH (351mg, 1.73mmol) in DMF at 0 deg.C. After 30min, (2S,4S) -1- ((S) -2-amino-2-cyclohexyl-acetyl) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-2-carboxylic acid benzyl ester hydrochloride (0.97g, 1.57mmol) was added, the cold bath removed and the reaction stirred for 1H. The mixture was diluted with ethyl acetate, washed with a saturated ammonium chloride solution, a saturated sodium bicarbonate solution, water and brine, and dried over anhydrous magnesium sulfate. Concentration gave benzyl (2S,4S) -1- { (S) -2- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino ] -2-cyclohexyl-acetyl } -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-2-carboxylate (1.2g) as an oil, which was used without further purification or characterization.

Step 6: benzyl (2S,4S) -1- { (S) -2- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino ] -2-cyclohexyl-acetyl } -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-2-carboxylate (1.2g, 1.56mmol) was dissolved in methanol (15mL) and 10% Pd-C (200mg) was added. The reaction was stirred under hydrogen (1atm) for 1h, filtered through celite and concentrated to give the title compound as a colourless oil (800mg, 76%) which solidified on standing and was used without purification.

Intermediate 28

{ (S) -1- [ (S) -2- ((2S,4S) -4-amino-2-benzylcarbamoyl-pyrrolidin-1-yl) -1-cyclohexyl-2-oxo-ethylcarbamoyl ] -ethyl } -methyl-carbamic acid tert-butyl ester

Step 1: to (2S,4S) -1- { (S) -2- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino ] -2-cyclohexyl-acetyl } -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-2-carboxylic acid (intermediate 27) in DMF was added DIPEA (116. mu.L, 0.66mmol) and HATU (93mg, 0.24mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 15min and then benzylamine (26.1mg, 0.24mmol) in DMF (0.5mL) was added dropwise, the cold bath was removed and the reaction stirred for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined extracts were washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution, water and brine and dried over anhydrous magnesium sulfate. Concentration afforded ((3S,5S) -5-benzylcarbamoyl-1- { (S) -2- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino ] -2-cyclohexyl-acetyl } -pyrrolidin-3-yl) -carbamic acid 9H-fluoren-9-ylmethyl ester as a foam, which was used without purification.

Step 2: ((3S,5S) -5-Benzylcarbamoyl-1- { (S) -2- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino ] -2-cyclohexyl-acetyl } -pyrrolidin-3-yl) -carbamic acid 9H-fluoren-9-ylmethyl ester (100mg, 0.13mmol) was dissolved in DMF (0.9mL) at room temperature and piperidine (0.1mL) was added. The mixture was stirred at room temperature for 30min, concentrated and the residue was purified by silica gel chromatography to give the title compound as a white foam (71mg, 52%).

Intermediate 29

[ (S) -1- ((S) -2- { (2S,4S) -4-amino-2- [ (S) - (1,2,3, 4-tetrahydro-naphthalen-1-yl) carbamoyl ] -pyrrolidin-1-yl } -1-cyclohexyl-2-oxo-ethylcarbamoyl) -ethyl ] -methyl-carbamic acid tert-butyl ester

In a similar manner to that described for tert-butyl { (S) -1- [ (S) -2- ((2S,4S) -4-amino-2-benzylcarbamoyl-pyrrolidin-1-yl) -1-cyclohexyl-2-oxo-ethylcarbamoyl ] -ethyl } -methyl-carbamate (intermediate 28), the (2S,4S) -1- { (S) -2- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino ] -2-cyclohexyl-acetyl } -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-2-carboxylic acid (intermediate 27) (150mg, 0.22mmol) and (S) - (1,2,3, 4-tetrahydro-naphthalen-1-yl) amine (Aldrich) (33mg, 0.22mmol) were converted to the title compound (48mg, foam).

Intermediate 30

[ (S) -1- ((S) -2- { (2S,4S) -4-amino-2- [ (R) - (1,2,3, 4-tetrahydro-naphthalen-1-yl) carbamoyl ] -pyrrolidin-1-yl } -1-cyclohexyl-2-oxo-ethylcarbamoyl) -ethyl ] -methyl-carbamic acid tert-butyl ester, alternative preparation

In a similar manner to that described for { (S) -1- [ (S) -2- ((2S,4S) -4-amino-2-benzylcarbamoyl-pyrrolidin-1-yl) -1-cyclohexyl-2-oxo-ethylcarbamoyl ] -ethyl } -methyl-carbamic acid tert-butyl ester (intermediate 28, step 2), { (3S,5S) -1- { (S) -2- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino ] -2-cyclohexyl-acetyl } -5- [ (R) - (1,2,3, 4-tetrahydro-naphthalen-1-yl) carbamoyl ] -pyrrolidin-3-yl } -amino Formic acid 9H-fluoren-9-ylmethyl ester (intermediate 25) (500mg, 0.62mmol) was converted to the title compound (360mg, foam).

Intermediate 31

{ (S) -1- [ (S) -2- ((2S,4S) -4-amino-2-cyclohexylcarbamoyl-pyrrolidin-1-yl) -1-cyclohexyl-2-oxo-ethylcarbamoyl ] -ethyl } -methyl-carbamic acid tert-butyl ester

In a similar manner to that described for tert-butyl { (S) -1- [ (S) -2- ((2S,4S) -4-amino-2-benzylcarbamoyl-pyrrolidin-1-yl) -1-cyclohexyl-2-oxo-ethylcarbamoyl ] -ethyl } -methyl-carbamate (intermediate 28), the (2S,4S) -1- { (S) -2- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino ] -2-cyclohexyl-acetyl } -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-2-carboxylic acid (intermediate 27) (50mg, 0.074mmol) and cyclohexylamine (15mg, 0.15mmol) were converted to the title compound (74mg, foam).

Intermediate 32

{ (S) -1- [ (S) -2- ((2S,4S) -4-amino-2-isopropylcarbamoyl-pyrrolidin-1-yl) -1-cyclohexyl-2-oxo-ethylcarbamoyl ] -ethyl } -methyl-carbamic acid tert-butyl ester

To (2S,4S) -1- { (S) -2- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino ] -2-cyclohexyl-acetyl } -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-2-carboxylic acid (intermediate 27) (50mg, 73.9. mu. mol) in DMF was added DIPEA (29mg, 222. mu. mol) and HATU (31mg, 81.3. mu. mol) at 0 ℃ and the mixture was stirred at 0 ℃ for 15 minutes. Isopropylamine (0.10mL) was added, the cold bath removed and the mixture stirred at room temperature for 1 h. The mixture was evaporated to give the title compound, which was used without purification.

Example 1

(2S,4S) -N-benzyl-4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]Pyrrolidine-2-carboxamide dihydrochloride

Step 1: 4- { (S) -5- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -3- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino ] in DMF (3mL) at 0 ℃]-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Diaza derivatives-1-carbonyl } -benzoic acid (intermediate 20) (53mg, 0.07mmol) DIPEA and HATU were added. The mixture was stirred at 0 ℃ for 30 minutes and { (S) -1- [ (S) -2- ((2S,4S) -4-amino-2-benzylamine was added in one portionCarbamoyl-pyrrolidin-1-yl) -1-cyclohexyl-2-oxo-ethylcarbamoyl]-ethyl } -methyl-carbamic acid tert-butyl ester (intermediate 28) (38mg, 0.07 mmol). The cooling bath was removed and the mixture was stirred for 1h, diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution, water and brine and dried over anhydrous magnesium sulfate. Concentrating to obtain oily solid, and purifying with silica gel chromatography to obtain oily solid N- [ (1S) -2- [ [ (1S) -2- [ (2S,4S) -2- (benzylcarbamoyl) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-3- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino]Propionyl group]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]Pyrrolidin-1-yl radical]-1-cyclohexyl-2-oxo-ethyl]Amino group]-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl ester (45mg, 50%).

Step 2: n- [ (1S) -2- [ [ (1S) -2- [ (2S,4S) -2- (benzylcarbamoyl) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl ] in methanol (2mL) at room temperature]-3- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino]Propionyl group]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]Pyrrolidin-1-yl radical]-1-cyclohexyl-2-oxo-ethyl]Amino group]-1-methyl-2-oxo-ethyl]tert-butyl-N-methyl-carbamate (45mg, 0.035mmol) acetyl chloride (25. mu.L, 0.035mmol) was added dropwise. The mixture was allowed to stand at room temperature. After 16h the mixture was concentrated and the residue was triturated with acetonitrile to give the title compound as a tan solid (40mg, 98%). MS m/z 1085 (MH)⁺)

Examples 2 to 5

Following the procedure described above for the preparation of example 1,4- { (S) -5- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -3- [ (S) -2- (tert-butoxycarbonyl-methyl-amino) -propionylamino]-4-oxo-2, 3,4, 5-tetrahydro-benzo [ b][1,4]Diaza derivatives-1-carbonyl } -benzoic acid (intermediate 20) and the indicated amine were converted to the compound shown in table 2, which was obtained as the dihydrochloride salt.

TABLE 2

Example 6

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [3- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide dihydrochloride

Step 1: to { (S) -1- [ (S) -1- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] at room temperature][1,4]Diaza derivatives-3-ylcarbamoyl]-ethyl-To a stirred solution of methyl-carbamic acid tert-butyl ester (intermediate 11) (300mg, 0.49mmol) in THF (10.0mL) was added Cs₂CO₃(320mg, 0.98mmol) and stirred for 3 h. The mixture was cooled to 0 ℃, isophthaloyl dichloride (49mg, 0.24mmol) was added, the cold bath was removed and the mixture was stirred at room temperature. After 18h, the mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was evaporated and the residue was purified by preparative reverse phase HPLC to give N- [ (1S) -2- [ [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [3- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino]Propionyl group]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Amino group]-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl ester (18mg, 3%). LC-MS 1353.8(M + H), 1370.8(M + NH)₄)。

Step 2: to N- [ (1S) -2- [ [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group at 0 deg.C]-1- [3- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino]Propionyl group]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Amino group]-1-methyl-2-oxo-ethyl]To a stirred solution of-N-methyl-carbamic acid tert-butyl ester (15mg, 0.01mmol) in dioxane (0.2mL) was added 4N HCl in dioxane (0.2mL), the cold bath was removed and the mixture was stirred at room temperature. After 2h, the mixture was evaporated to give the title compound as an off-white solid (8mg, 58.9%). LC-MS:1153.6(M + H).

Examples 7 to 18

Following the procedure described for the preparation of example 6, { (S) -1- [ (S) -1- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b][1,4]Diaza derivatives-3-ylcarbamoyl]-ethyl } -methyl-carbamic acid tert-butyl ester (intermediate 11) and the dicarbonyl chloride indicated were converted to the compound shown in table 3, which was obtained as the dihydrochloride salt.

TABLE 3

Example 19

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [5- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Pyrazine-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide dihydrochloride

Step 1: to { (S) -1- [ (S) -1- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] at 0 deg.C][1,4]Diaza derivatives-3-ylcarbamoyl](ii) -Ethyl } -methyl-carbamic acid tert-butyl ester (intermediate 11) (300mg, 0.49mmol) and pyrazine-2, 5-dicarboxylic acid (41.2mg, 0.24mmol) in pyridine (5mL) was added POCl₃(46. mu.L, 0.49mmol) and the cooling bath removed. After 5h, the mixture was diluted with dichloromethane, washed with water and dried (Na)₂SO₄) And concentrated. The residue was purified by preparative reverse phase HPLC to give N- [ (1S) -2- [ [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl ] as an off-white solid]-1- [5- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino]Propionyl group]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine1-carbonyl group]Pyrazine-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Amino group]-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl ester (52mg, 7.82%). LC-MS:1355.0(M + H).

Step 2: in a similar manner as described for step 2 of example 6, N- [ (1S) -2- [ [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-1- [5- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino]Propionyl group]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Pyrazine-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Amino group]-1-methyl-2-oxo-ethyl]Tert-butyl (50mg, 0.04mmol) of-N-methyl-carbamate was converted to the title compound (32mg, 71%) as a white solid. LC-MS:1155.6(M + H).

Example 20

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [7- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Naphthalene-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide dihydrochloride

In a similar manner as described for example 19, { (S) -1- [ (S) -1- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-ylcarbamoyl]-Ethyl } -methyl-carbamic acid tert-butyl ester (intermediate 11) (300mg, 0.49mmol) and naphthalene-2, 7-dicarboxylic acid (54mg, 0.24mmol) were converted to the title compound obtained as an off-white solid (31 mg). LC-MS:1203.6(M + H).

Example 21

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [2- [3- [2- [ (3S) -5- [ (6-bromo)-2-methoxy-1-naphthyl) methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-2-oxo-ethyl]Phenyl radical]Acetyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide dihydrochloride

In a similar manner as described for example 19, { (S) -1- [ (S) -1- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-ylcarbamoyl]-ethyl } -methyl-carbamic acid tert-butyl ester (intermediate 11) (300mg, 0.49mmol) and (3-carboxymethyl-phenyl) -acetic acid (47.62mg, 0.24mmol) were converted to the title compound obtained as an off-white solid (86 mg). LC-MS:1381.2(M + H).

Example 22

(2S) -N- [ (3S) -5- [ (5-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [ (3S) -5- [ (5-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide dihydrochloride

Step 1: to a stirred solution of terephthaloyl chloride (124.591mg, 0.614mmol) in dry THF (5mL) was added triethylamine (0.428mL, 3.069mmol) and { (S) -1- [ (S) -1- (5-bromo-2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b][1,4]Diaza derivatives-3-ylcarbamoyl]-ethyl } -methyl-carbamic acid tert-butyl ester (intermediate 12) (750mg, 1.227 mmol). After 18h, the mixture was evaporated and the residue was purified by silica gel chromatography to give N- [ (1S) -2- [ [ (3S) -5- [ (5-bromo-2-methoxy-1-naphthyl) methyl ] as a white solid]-1- [4- [ (3S) -5- [ (5-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino]Propionyl group]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Amino group]-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl ester (170mg, 20.47%).

Step 2: to N- [ (1S) -2- [ [ (3S) -5- [ (5-bromo-2-methoxy-1-naphthyl) methyl group at 0 deg.C]-1- [4- [ (3S) -5- [ (5-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino]Propionyl group]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Amino group]-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl esterA solution of the ester (50mg, 0.037mmol) in dioxane (1mL) was added dropwise 4M HCl in dioxane (0.6mL) and the cold bath removed. After 3h the mixture was evaporated and the residue triturated with hexanes to give the title compound as a white solid (35mg, 77.2%). LC-MS:1153.2(M + H).

Example 23

(2S) -2- (methylamino) -N- [ (3S) -1- [4- [ (3S) -3- [ [ (2S) -2- (methylamino) propanoyl group]Amino group]-5- [ (2-methyl-1-naphthyl) methyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-5- [ (2-methyl-1-naphthyl) methyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Propionamide dihydrochloride

Terephthaloyl chloride (60mg, 0.296mmol) and methyl- { (S) -1- [ (S) -1- (2-methyl-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] are reacted in a similar manner as described for example 22][1,4]Diaza derivatives-3-ylcarbamoyl]-Ethyl } -carbamic acid tert-butyl ester (intermediate 15) (305.37mg, 0.591mmol) was converted to the title compound (50mg) as an off-white solid. LC-MS:963.6(M + H).

Example 24

(2S) -N- [ (3S) -5- [ [1- (2-cyanophenyl) indazol-3-yl]Methyl radical]-1- [4- [ (3S) -5- [ [1- (2-cyanophenyl) indazol-3-yl]Methyl radical]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide dihydrochloride

In a similar manner as described for example 22, ((S) -1- { (S) -1- [1- (2-cyano-phenyl) -1H-indazol-3-ylmethyl]-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b][1,4]Diaza derivatives-3-ylcarbamoyl } -ethyl) -methyl-carbamic acid tert-butyl ester (intermediate 14) (262.9mg, 0.443mmol) and terephthaloyl chloride (45mg, 0.222mmol) were converted to the title compound (13mg) as a white solid. LC-MS:1118(M + H).

Example 25

(2S) -N- [ (3S) -5- [ (2-methoxy-1-naphthyl) methyl group]-1- [4- [ (3S) -5- [ (2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide dihydrochloride

Step 1: to (S) -1- [ (S) -1- (2-methoxy-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-ylcarbamoyl]To a stirred solution of-ethyl } -methyl-carbamic acid tert-butyl ester (51.89mg, 0.098mmol) in dry THF (4mL) was added cesium carbonate (65mg, 0.2 mmol). After 2h terephthaloyl chloride (9mg, 0.044mmol)1.227mmol) was added and the mixture was stirred for 18 h. The mixture was evaporated and the residue was purified by silica gel chromatography to give N- [ (1S) -2- [ [ (3S) -1- [4- [ (3S) -3- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino ] as a white solid]Propionyl group]Amino group]-5- [ (2-methoxy-1-naphthyl) methyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-5- [ (2-methoxy-1-naphthyl) methyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Amino group]-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl ester (45mg, 84.9%). LC-MS:1195.8(M + H).

Step 2: in a similar manner to that described for step 2 of example 6, N- [ (1S) -2- [ [ (3S) -1- [4- [ (3S) -3- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino group]Propionyl group]Amino group]-5- [ (2-methoxy-1-naphthyl) methyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-5- [ (2-methoxy-1-naphthyl) methyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Amino group]-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl ester (40mg, 0.33mmol) converted to the title compound as a white solidSubstance (30mg, 84%). LC-MS:996(M + H).

Example 26

(2S) -N- [ (3S) -7-cyano-5- [4- [ (3S) -7-cyano-3- [ [ (2S) -2- (methylamino) propanoyl group]Amino group]-1- [ (2-methyl-1-naphthyl) methyl group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-5-carbonyl group]Benzoyl radical]-1- [ (2-methyl-1-naphthyl) methyl group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide dihydrochloride

Step 1: to { (S) -1- [ (S) -7-cyano-1- (2-methyl-naphthalen-1-ylmethyl) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-ylcarbamoyl]To a solution of tert-butyl-ethyl } -methyl-carbamate (intermediate 16) (90mg, 0.166mmol) in pyridine (1mL) was added terephthalic acid (13.808mg, 0.083 mmol). After 10min the mixture was cooled to 0 ℃ and POCl was added₃(0.017mL, 0.183mmol) and the cold bath removed. After 1h, the mixture was concentrated, the residue was dissolved in ethyl acetate and washed with water, NaHCO₃The mixture was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by preparative reverse phase HPLC to give N- [ (1S) -2- [ [ (3S) -5- [4- [ (3S) -3- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino ] as a white solid]Propionyl group]Amino group]-7-cyano-1- [ (2-methyl-1-naphthyl) methyl group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-5-carbonyl group]Benzoyl radical]-7-cyano-1- [ (2-methyl-1-naphthyl) methyl group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-3-yl]Amino group]-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl ester (5mg, 5.32%). LC-MS:1213.6(M + H).

Step 2: to N- [ (1S) -2- [ [ (3S) -5- [4- [ (3S) -3- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino group at 0 deg.C]Propionyl group]Amino group]-7-cyano-1- [ (2-methyl-1-naphthyl) methyl group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-5-carbonyl group]Benzoyl radical]-7-cyano-1- [ (2-methyl-1-naphthyl) methyl group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-3-yl]Amino group]-1-methyl-2-oxo-ethyl]To a solution of tert-butyl-N-methyl-carbamate (27mg, 0.022mmol) in dioxane (3mL) was added 4M HCl in dioxane (2 mL). The mixture was stirred at 0 ℃ for 10min and the cold bath was removed. After 16h, the mixture was concentrated and the residue triturated with diethyl ether to give the title compound as a white solid (19mg, 78.69%). LC-MS:1013.8(M + H).

Example 27

(2S) -N- [ (3S) -1- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-5- [4- [ (3S) -1- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-7-cyano-3- [ [ (2S) -2- (methylamino) propanoyl]Amino group]-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-5-carbonyl group]Benzoyl radical]-7-cyano-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylammonium)Mesityl) propionamide dihydrochloride

Step 1: to { (S) -1- [ (S) -1- (6-bromo-2-methoxy-naphthalen-1-ylmethyl) -7-cyano-2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ]][1,4]Diaza derivatives-3-ylcarbamoyl]To a solution of-ethyl } -methyl-carbamic acid tert-butyl ester (intermediate 4) (120mg, 0.189mmol) in pyridine (2mL) was added terephthalic acid (20.604mg, 0.113 mmol). After 10min, the mixture was cooled to 0 ℃ and POCl was added₃(0.036mL, 0.396mmol) and the cold bath removed. After 1h, the mixture was concentrated, the residue was diluted with ethyl acetate and filtered. The filtrate was concentrated and the residue was purified by preparative HPLC to afford N- [ (1S) -2- [ [ (3S) -1- [ (6-bromo-2-methoxy-1-naphthyl) methyl as an off-white solid]-5- [4- [ (3S) -1- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino]Propionyl group]Amino group]-7-cyano-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-5-carbonyl group]Benzoyl radical]-7-cyano-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-3-yl]Amino group]-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl ester (6mg, 1%). LC-MS:1403.2(M + H).

Step 2: in a similar manner to that described for step 2 of example 26, N- [ (1S) -2- [ [ (3S) -1- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-5- [4- [ (3S) -1- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino]Propionyl group]Amino group]-7-cyano-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-5-carbonyl group]Benzoyl radical]-7-cyano-2-oxo-3, 4-dihydro-1, 5-benzodiazepine-3-yl]Amino group]-1-methyl-2-oxo-ethyl]Tert-butyl (6mg, 0.0042mmol) of (E) -N-methyl-carbamate was converted to the title compound as a white solid (4.5mg, 76.6%). LC-MS:1203.2(M + H).

Example 28

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide dihydrochloride

Step 1: ((S) -2-oxo-2, 3,4, 5-tetrahydro-1H-benzo [ b ] in anhydrous THF (1mL)][1,4]Diaza derivatives-3-yl) -carbamic acid tert-butyl ester (intermediate 2) (57.9mg, 0.209mmol) and triethylamine (29.1. mu.L, 0.209mmol) was added to terephthaloyl dichloride (21.2mg, 0.104 mmol). The resulting suspension was stirred at room temperature for 4 h. The mixture was concentrated and the residue was triturated with water. The solid was collected, washed with water and purified by silica gel chromatography to afford N- [ (3S) -5- [4- [ (3S) -3- (tert-butoxycarbonylamino) -2-oxo-3, 4-dihydro-1H-1, 5-benzodiazepine as a white solid-5-carbonyl group]Benzoyl radical]-2-oxo-3, 4-dihydro-1H-1, 5-benzodiazepine-3-yl]Tert-butyl carbamate (27.6mg, 39%).

Step 2: combining N- [ (3S) -5- [4- [ (3S) -3- (tert-Butoxycarbonylamino) -2-oxo-3, 4-dihydro-1H-1, 5-benzodiazepine in DMF (2mL)-5-carbonyl group]Benzoyl radical]-2-oxo-3, 4-dihydro-1H-1, 5-benzodiazepine-3-yl]Tert-butyl carbamate (27.6mg, 0.0403mmol), 6-bromo-1- (chloromethyl) -2-methoxynaphthalene (25.3mg, 0.0887mmol) and cesium carbonate (39.4mg, 0.121mmol) and stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate, washed with water, brine, and dried over anhydrous magnesium sulfate. Concentrating to obtain oil, and subjecting to silica gel chromatography to obtain white foam N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- (tert-Butoxycarbonylamino) -4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Tert-butyl carbamate (31mg, 65%).

And step 3: combine N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl in MeOH (2mL)]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- (tert-Butoxycarbonylamino) -4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Tert-butyl carbamate (31mg, 0.026mmol) and acetyl chloride (9.3. mu.L, 0.131mmol) and stirred at room temperature for 16 h. The mixture was concentrated to give (3S) -3-amino-1- [4- [ (3S) -3-amino-5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group as a white solid]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-2, 3-dihydro-1, 5-benzodiazepine-4-keto dihydrochloride (27mg, 98%), which was used without further purification.

Step 4 in CH₂Cl₂(2mL) to (3S) -3-amino-1- [4- [ (3S) -3-amino-5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-2, 3-dihydro-1, 5-benzodiazepine-4-keto dihydrochloride (27mg, 0.026mmol), Boc-N-Me-Ala-OH (10.9mg, 0.0537mmol), N-diisopropylethylamine (44.7. mu.L, 0.256mmol) and HATU (20.4mg, 0.0537mmol) and stirred at room temperature for 5 days. The mixture was partitioned between saturated ammonium chloride solution and dichloromethane. The organic layer was separated and washed with water, saturated sodium bicarbonate solution, brine, and dried over anhydrous magnesium sulfate. Concentrating to obtain oily substance, and performing silica gel chromatography to obtain oily N- [ (1S) -2- [ [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino]Propionyl radicalBase of]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Amino group]-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl ester (24.5mg, 71%).

And 5: combine N- [ (1S) -2- [ [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group in MeOH (2mL)]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino]Propionyl group]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]Amino group]-1-methyl-2-oxo-ethyl]-N-methyl-carbamic acid tert-butyl ester (24mg, 0.018mmol) and acetyl chloride (6.3 μ L, 0.089mmol) and stirred at room temperature overnight. The mixture was concentrated and the residue was triturated with acetonitrile to give the title compound as a solid (18.3mg, 84%). LC-MS 1149[ M-H ]]。

Example 29

Biochemical analysis

TR-FRET analysis of BIR2 and BIR3

The ability of the test compounds to inhibit binding of peptide a (an SMAC-derived peptide described below) by BIR2 and/or BIR3 domains of XIAP proteins indicates that the test compounds act as SMAC-mimetics, resulting in reactivation of the apoptotic pathway.

The peptide AVPIAQKSEK- (-biotin) -OH 1:2TFA ("peptide a") was confirmed to be a substrate for TR-FRET analysis by screening the 6x histidine-tagged BIR2 domain and BIR3 domain of XIAP against a panel of 29 peptides synthesized based on the sequences reported by Sweeny et al (Biochemistry, 2006, 45, 1474014748). The peptides were labeled with a fluorescent label FITC or TAMRA and Kd values were determined by fluorescence polarization analysis. The sequence AVPIAQKSEK was confirmed to be optimal for analytical use. The peptide sequences were derivatized with biotin to provide AVPIAQKSEK- (-biotin) -OH 1:2TFA as a substrate for TR-FRET assay.

XIAP protein sequences were obtained from the SWISS-PROT protein sequence database and from which BIR2 and BIR3 domains were derived. The sequence of the BIR2 domain used in the TR-FRET assay was MRHHHHHHRDHFALDRPSETHADYLLRTGQVVDISDTIYPRNPAMYSEEARLKSFQNWPDYAHLTPRELASAGLYYTGIGDQVQCFACGGKLKNWEPGDRAWSEHRRHFPNCFFVLGRNLNIRSE.

The BIR3 domain sequence used for TR-FRET analysis was MRHHHHHHRSDAVSSDRNFPNSTNLPRNPSMADYEARIFTFGTWIYSVNKEQLARAGFYALGEGDKVKCFHCGGGLTDWKPSEDPWEQHAKWYPGCKYLLEQKGQEYINNIHLTHSLEECLVRTT.

10 nanomoles 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) were mixed with 20nM of the peptide PIAVAQEKKSK- (-biotin) -OH 1:2TFA in the presence of 50mM Tris-Cl, pH 7.5, 100mM NaCl, 1mM Dithiothreitol (DTT) and 0.1mg/mL Bovine Serum Albumin (BSA). After incubation at 37 ℃ for 45 min, europium-streptavidin and allophycocyanin, which bound the anti-histidine antibody, were added to final concentrations of 1.5nM and 15nM, respectively. Time resolved fluorescence resonance energy transfer (TR-FRET) signals were measured after 1 hour at room temperature. Test compound titers were evaluated at 10 serial dilution concentrations. Determining percent inhibition at each concentration to generate IC for each test compound₅₀The value is obtained.

These values are listed in table 4 below.

TABLE 4

Claims

1. A compound of formula I

Wherein

Z is selected from the following groups:

a) optionally is OR³Halogen and C_1-6-alkyl-substituted aryl, and

x is selected from the following groups:

a)C_1-6-an alkyl group,

b)C_1-6-alkyl-aryl-C_1-6-alkyl radical

c) Optionally is covered with C_1-6Aryl substituted by-alkyl and-O-aryl, and

d) a heteroaryl group;

q is selected from

R¹Selected from the group H and cyano;

R²selected from the following groups:

a) c optionally substituted by aryl_1-6-an alkyl group,

b) optionally phenyl-fused C_3-7-a cycloalkyl group,

c) phenyl, and

d)C_3-7-a cycloalkylaryl group; and is

R³Is C_1-6-an alkyl group;

wherein said aryl group refers to a monovalent aromatic carbocyclic mono-, bi-, or tricyclic ring system containing 6 to 19 carbon ring atoms; and said heteroaryl means an heteroaromatic ring system containing up to two rings, wherein at least one ring contains 1,2 or 3 heteroatoms, the remaining ring atoms being carbon, said heteroatoms referring to atoms selected from N, O or S;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein

Z is selected from the following groups:

b) heteroaryl optionally substituted with cyano-phenyl;

x is selected from the following groups:

a)C_1-6-an alkyl group,

b)C_1-6-alkyl-aryl-C_1-6-alkyl radical

c) Optionally is covered with C_1-6Aryl substituted by-alkyl and-O-aryl, and

d) a heteroaryl group;

q is selected from

R¹Selected from the group H and cyano;

R²selected from the following groups:

a) c optionally substituted by aryl_1-6-an alkyl group,

b)C_3-7-a cycloalkyl group,

c) phenyl, and

d) tetrahydronaphthyl (tetralinyl), and

or a pharmaceutically acceptable salt thereof.

3. The compound of any one of claims 1-2, wherein Z is optionally substituted with O-C_1-6Alkyl, halogen and C_1-6-alkyl substituted aryl.

4. The compound according to any one of claims 1-2, wherein Z is naphthyl optionally substituted with bromo, methoxy and methyl.

5. The compound according to any one of claims 1-2, wherein Z is 6-bromo-2-methoxy-1-naphthyl.

6. The compound of any one of claims 1-2, wherein X is C_1-6Alkyl, heteroaryl, aryl, or C_1-6Alkyl-substituted aryl, C_1-6-alkyl-phenyl-C_1-6-alkyl or phenyl-O-phenyl.

7. The compound according to any one of claims 1-2, wherein X is phenyl or naphthyl.

8. A compound according to any one of claims 1-2, wherein X is pyrazinyl or pyridinyl.

9. The compound of any one of claims 1-2, wherein Q is a.

10. The compound of any one of claims 1-2, wherein R¹Is H.

11. The compound of any one of claims 1-2, wherein Q is B.

12. The compound of any one of claims 1-2, wherein R²Is tetrahydronaphthyl.

13. A compound selected from the group consisting of:

(2S) -2-amino-N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-1- [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]-2, 5-dimethyl-benzoyl]-4-oxo-2, 3-bisHydrogen-1, 5-benzodiazepines-3-yl]The amino acid sequence of the amino acid is shown as propionamide,

(2S) -N- [ (3S) -5- [ (6-bromo)-2-methoxy-1-naphthyl) methyl]-1- [2- [3- [2- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-2-oxo-ethyl]Phenyl radical]Acetyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [3- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-3-oxo-propionyl group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [5- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Pyrazine-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [6- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthalene)Radical) methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-yl]-6-oxo-hexanoyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl]-1- [6- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Pyridine-2-carbonyl]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (methylamino) propanamide,

(2S) -N- [ (3S) -5- [ [1- (2-cyanophenyl) indazol-3-yl]Methyl radical]-1- [4- [ (3S) -5- [ [1- (2-cyanophenyl) indazol-3-yl]Methyl radical]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-3-yl]-2- (A)A alkylamino group) a propionamide,

(2S,4S) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl ] methyl]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]-N- [ (1R) -tetrahydronaphthalen-1-yl]The pyrrolidine-2-carboxylic acid amide is a compound of formula (I),

(2s,4S) -4- [ [4- [ (3S) -5- [ (6-bromo-2-methoxy-1-naphthyl) methyl group]-3- [ [ (2S) -2- (methylamino) propanoyl ] amino]Amino group]-4-oxo-2, 3-dihydro-1, 5-benzodiazepine-1-carbonyl group]Benzoyl radical]Amino group]-1- [ (2S) -2-cyclohexyl-2- [ [ (2S) -2- (methylamino) propanoyl]Amino group]Acetyl group]-N-isopropyl-pyrrolidine-2-carboxamide, and

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising as an active ingredient a compound according to any of claims 1-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

15. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of cancer.