# US 9,493,455 B2 · Azaindole derivatives as inhibitors of protein kinases

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- Number: US 9,493,455 B2
- Document ID: US9493455B2
- Status: Granted
- Kind: B2
- Application number: 14/655,613
- Filed: 2013-12-30
- Published: 2015-12-10
- Granted: 2016-11-15
- Earliest claimed: 2012-12-28
- Assignees: Oribase Pharma
- Applicants: Oribase Pharma
- Inventors: Gwénaël Cheve; Bénédicte Dayde-Cazals; Bénédicte Fauvel; Cédric Bories; Abdelaziz Yasri
- Web page: https://patentgrep.com/patent/US9493455B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12Q 1/485: {involving kinase}
- G01N 33/5758: {involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites}
- G01N 2333/91215: with a definite EC number (2.7.1.-)
- G01N 2500/04: Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
- G01N 2500/10: involving cells
- G01N 2500/20: cell-free systems
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention relates to compounds of the following formula (I) and/or the pharmaceutically acceptable addition salts, solvates, enantiomers, diastereoisomers thereof, as well as mixtures thereof. The subject matter of the present invention thus also includes the preparation of compounds of formula (I), their uses, in particular in the inhibition of protein kinases which are implicated for example in numerous diseases such as cancers or immune system disorders.

## Claims

### Claim 1

Compound of the following formula (I):
characterized in that,
R1 is a C1-C6 alkyl group,
X is CH2 or C═O,
R2 is hydrogen atom, an alkyl group or a halogen atom,
Y is chosen from a group consisting of HNC(O), HNC(S), HNSO2, HNC(O)CH2, HNC(O)NH, HNC(S)NH, C(O)NH, C(O)NHCH2, CH2NHC(O) and CH2NHC(S), and
R3 is chosen from a group consisting of:
a phenyl group mono or polysubstituted with:
a hydroxyl,
a halogen,
a C1-C6 alkyl-amine,
a C1-C6 alkoxy,
a C1-C6 trifluoroalkoxy,
a C1-C6 alkyl,
a C1-C6 trifluoroalkyl,
a heteroaryl fragment optionally substituted with a C1-C6 alkyl, a C1-C6 trifluoroalkyl, a halogen and/or a hydroxyl, wherein said heteroaryl fragment is chosen from a group consisting of dihydrobenzofuran, indol, benzodioxol, benzotriazol, pyridine or a thiazol,
an imidazole, with the proviso that Y is HNC(S), HNSO2, HNC(O)CH2, HNC(O)NH, HNC(S)NH, C(O)NHCH2, CH2NHC(O), CH2NHC(S) or C(O)NH wherein NH is directly linked to R3,
a heteroaryl group,
non aromatic monosubstituted cyclic group, and
a fragment chosen from a group consisting of:
and/or the pharmaceutically acceptable addition salts, solvates, enantiomers, diastereoisomers thereof, as well as mixtures thereof.

### Claim 2 (depends on 1)

Compound according to claim 1, characterized in that,
X is CH2, and
R2 is an alkyl or a halogen.

### Claim 3 (depends on 1)

Compound according to claim 1, characterized in that,
R1 is C1-C6 alkyl,
X is CH2,
R2 is a methyl or a chloride atom,
Y is chosen from a group consisting of HNC(O), HNC(O)CH2, HNC(O)NH, HNC(S)NH, C(O)NH, C(O)NHCH2, and CH2NHC(O),
R3 is chosen from a group consisting of:
a phenyl group mono substituted with a C1-C6 trifluoroalkyl group, a C1-C6 trifluoroalkoxy group, a C1-C6 alkyl group, a halogen, or a thiazol group optionally monosubstituted by a CF3 and/or a methyl group,
a phenyl group polysubstituted with a C1-C6 trifluoroalkyl, a C1-C6 alkyl-amine, and/or a hydroxyl group,
a pyridine group, optionally substituted with a C1-C6 alkyl or a C1-C6 trifluoroalkyl,
non aromatic cyclic group chosen between a cyclic C3-C10 alkyl, monosubstituted with a C1-C6 alkyl and/or a C1-C6 trifluoroalkyl, and
a fragment chosen from a group consisting of:

### Claim 4 (depends on 1)

Compound according to claim 1, characterized in that,
R1 is a C1-C6 alkyl group,
X is a CH2,
R2 is methyl,
Y is HNC*(O), wherein C* is linked to R3 and
R3 is chosen from a group consisting of:

### Claim 5 (depends on 1)

Compound according to claim 1 of general formula (II):
characterized in that,
R1 is a methyl,
X is a CH2,
R2 is methyl,
Y is HNC*(O), wherein C* is linked to R3 and
R3 is chosen from a group consisting of:

### Claim 6 (depends on 1)

Compound according to claim 1, characterized in that X is C═O and R2 is an alkyl or a halogen.

### Claim 7 (depends on 1)

Method of preparation of the compounds according to claim 1, characterized in that it comprises at least one of the following steps:
a. in the case of X being CO, forming the NH—CO bond by means of peptide coupling techniques with an aromatic carboxylic acid substituted with an NO2 group, or if X is CH2, forming the NH—CH2 bond by a reductive amination with an aromatic aldehyde substituted with an NO2 group, and
b. reducing the NO2 group into NH2.

### Claim 8 (depends on 7)

Method of preparation according to claim 7, characterized in that the method comprises one of the following steps:
c1) forming a urea in the case of Y being HNC(O)NH, by reacting the compound obtained after step b) with an isocyanate,
c2) forming a thiourea in the case of Y being HNC(S)NH, by reacting the compound obtained after step b) with an isothiocyanate,
c3) forming a sulfonamide in the case of Y being HNSO2, by reacting the compound obtained after step b) with a halogen sulfonyl
c4) forming an amide in the case of Y being HNCO, by reacting the compound obtained after step b) with an activated carboxylic acid, or
c5) forming a thioamide in the case of Y being HNCS, by reacting the compound obtained after step c4) with the Lawesson's reagent, and
d) optionally saponifying the obtained product.

### Claim 9 (depends on 1)

Pharmaceutical composition, characterized in that it contains, as active principle, a compound according to claim 1 and a pharmaceutical acceptable excipient.

### Claim 10 (depends on 1)

Method for treating a human or animal disease selected from the group consisting of liver cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer, leukemias, renal cancer, endometrial cancer, colorectal cancer, chemoresistant cancers, and macular degeneration comprising administering a compound according to claim 1 to a patient in need thereof.

### Claim 11 (depends on 1)

Method for inhibiting protein kinases selected from the group consisting of BRAF, EGFR, FGFR2, KDR, PDGFRA, SRC, ABL, FGFR1, VEGFR1, PDGFRB, ABL2, BLK, BMX, BTK, CSK, EPHA1, EPHA2, EPHA4, EPHB2, EPHB4, HER2, ERBB4, FES, FGR, FLT3, FMS, FRK, FYN, HCK, LCK, LYN, MAPK14, ERK2, PKC theta, RET, VEGFR3 and YES in diseases comprising administering a compound according to claim 1 to a patient in need thereof.

### Claim 12 (depends on 1)

An in vitro method for predicting whether a patient in need thereof is likely to respond to at least one of the compounds according to claim 1, which method comprises determining the expression levels, gene modifications, activation state or appearance of a mutated form of the protein kinase in a sample of said patient, wherein said protein kinase is selected from the following list of kinases BRAF, EGFR, FGFR2, KDR, PDGFRA, SRC, ABL, FGFR1, VEGFR1, PDGFRB, ABL2, BLK, BMX, BTK, CSK, EPHA1, EPHA2, EPHA4, EPHB2, EPHB4, HER2, ERBB4, FES, FGR, FLT3, FMS, FRK, FYN, HCK, LCK, LYN, MAPK14, ERK2, PKC theta, RET, VEGFR3 and YES.

### Claim 13 (depends on 1)

An In vitro method for predicting whether a patient in need thereof is likely to respond to at least one of the compounds according to claim 1, which method comprises the following steps:
a) putting into contact said compound(s) with a sample of human tissue or cells,
b) determination of the activity of the compound(s) on the sample via for example IC50 and/or via a compared activity of the protein kinases present, which can for example be chosen from the following list of kinases BRAF, EGFR, EGFR T790M L858R, FGFR2, KDR PDGFRA, SRC, ABL, ABL T3151, FGFR1, VEGFR1, PDGFRB, ABL E255K, ABL G250E, ABL Y253F, ABL2, BLK, BMX, BRAF V600E, BTK, CSK, EPHA1, EPHA2, EPHA4, EPHB2, EPHB4, HER2, ERBB4, FES, FGR, FLT3, FMS, FRK, FYN, HCK, LCK, LYN, MAPK14, ERK2, PKC theta, RET, VEGFR3 and YES;
c) optionally conducting the same test as step e) with healthy cells of said patient to determine the toxicity of the compound according to claim 1 to healthy cells;
d) selecting the compound according to claim 1 presenting the best activity, and/or eventually lowest toxicity, to be administered to the patient in need thereof.

### Claim 14 (depends on 1)

Compound according to claim 1, characterized in that,
R1 is a C1-C6 alkyl group,
X is a C═O,
R2 is methyl,
Y is HNC*(O), wherein C* is linked to R3 and
R3 is chosen from a group consisting of:

### Claim 15 (depends on 11)

Method for inhibiting protein kinases in diseases according to claim 11, wherein the disease is selected from the group consisting of cancers, immune disorders, inflammatory diseases, thrombotic diseases, neurodegenerative diseases, bone diseases, macular degeneration, fibrosis, cystogenesis, hyperproliferative diseases.

### Claim 16 (depends on 9)

Method for inhibiting cellular proliferation and/or angiogenesis involved in treating a human or animal disease selected from the group consisting of liver cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer, leukemias, renal cancer, endometrial cancer, colorectal cancer, chemoresistant cancers, and macular degeneration comprising administering a composition according to claim 9 to a patient in need thereof.

### Claim 17 (depends on 9)

Method for inhibiting protein kinases selected from the group consisting of BRAF, EGFR, FGFR2, KDR, PDGFRA, SRC, ABL, FGFR1, VEGFR1, PDGFRB, ABL2, BLK, BMX, BTK, CSK, EPHA1, EPHA2, EPHA4, EPHB2, EPHB4, HER2, ERBB4, FES, FGR, FLT3, FMS, FRK, FYN, HCK, LCK, LYN, MAPK14, ERK2, PKC theta, RET, VEGFR3 and YES in diseases comprising administering a composition according to claim 9 to a patient in need thereof.

### Claim 18 (depends on 17)

Method for inhibiting protein kinases in diseases according to claim 17, wherein the disease is selected from the group consisting of cancers, immune disorders, inflammatory diseases, thrombotic diseases, neurodegenerative diseases, bone diseases, macular degeneration, fibrosis, cystogenesis, hyperproliferative diseases.