# US 10,478,423 B2 · Substituted indazole derivatives active as kinase inhibitiors

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- Number: US 10,478,423 B2
- Document ID: US10478423B2
- Status: Granted
- Kind: B2
- Application number: 16/013,019
- Filed: 2018-06-20
- Published: 2018-10-11
- Granted: 2019-11-19
- Earliest claimed: 2011-05-12
- Assignees: Nerviano Medical Sciences S.R.L.
- Applicants: Nerviano Medical Sciences S.R.L.
- Inventors: Andrea Lombardi Borgia; Marina Ciomei; Daniele Donati; Marcella Nesi
- Web page: https://patentgrep.com/patent/US10478423B2

## CPC

- A61K 31/416: condensed with carbocyclic ring systems, e.g. indazole
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 295/155: with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 295/185: from aliphatic carboxylic acids
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C12N 9/12: transferring phosphorus containing groups, e.g. kinases (2.7)
- C12Y 207/10001: Receptor protein-tyrosine kinase (2.7.10.1)
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

The present invention relates to substituted indazole compounds which modulate the activity of protein kinases and are therefore useful in treating diseases caused by degulated protein kinase activity, like cancer. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing such these compounds or the pharmaceutical compositions containing them.

## Claims

### Claim 1

A compound of formula (I):
wherein:
Ar is a group selected from
wherein:
R1 is A, NR6R7, OR8, SOnR9, COR10, nitro, cyano or an optionally substituted group selected from C3-C6 cycloalkyl and heteroaryl;
R2, R3, R4 and R5 are independently hydrogen, halogen, nitro, cyano, SOnR9, COR10, NR11R12, OR13 or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C6 cycloalkyl and heterocyclyl wherein:
A is a straight or branched C1-C6 alkyl substituted with a group selected from an optionally substituted heterocyclyl, an optionally substituted heteroaryl, SOnR9, COR10, NR11R12 and OR13;
R6 is hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C6 cycloalkyl, heterocyclyl, aryl and heteroaryl;
R7 is hydrogen, SOnR9, COR10, a substituted straight or branched C1-C6 alkyl or an optionally substituted group selected from straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C6 cycloalkyl, heterocyclyl, aryl and heteroaryl or
R6 and R7, taken together with the nitrogen atom to which they are bound, may form an optionally substituted heterocyclyl group;
R8 is hydrogen, A, COR10 or an optionally substituted group selected from straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C6 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein A is as defined above;
R9 is NR11R12 or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C6 cycloalkyl, heterocyclyl, aryl and heteroaryl;
R10 is hydrogen, NR11R12, OR13 or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C6 cycloalkyl, heterocyclyl, aryl and heteroaryl;
R11 and R12 are independently hydrogen, SOnR9, COR10 or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C6 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein R9 and R10 are as defined above, or
R11 and R12, taken together with the nitrogen atom to which they are bound, may form an optionally substituted heterocyclyl group;
R13 is hydrogen, COR10 or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C6 cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein R10 is as defined above;
n is 0, 1 or 2;
X is an optionally substituted straight or branched C1-C6 alkyl;
Y is oxygen;
Z is an optionally substituted straight or branched C1-C6 alkyl;
Ar′ is an optionally substituted aryl or an optionally substituted heteroaryl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of formula (I) as defined in claim 1 wherein:
R1 is A, NR6R7, OR8 or an optionally substituted heterocyclyl, wherein A, R6, R7 and R8 are as defined in claim 1.

### Claim 3 (depends on 1)

The compound of formula (I) as defined in claim 1 wherein:
Ar is Ar1 or Ar2; and R2, R3, R4, and R5 are each independently hydrogen, halogen, NR11R12 or OR13, wherein R11, R12 and R13 are as defined in claim 1.

### Claim 4 (depends on 1)

A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 which is selected from the group consisting of:
N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-benzamide,
N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-benzamide,
N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(1-methyl-piperidin-4-ylamino)-benzamide,
N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-dimethylaminomethyl-benzamide,
N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(1-methyl-piperidin-4-yloxy)-benzamide,
N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-benzamide,
N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(2-morpholin-4-yl-ethylamino)-benzamide,
N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(tetrahydro-pyran-4-ylamino)-benzamide,
N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[(1-methyl-piperidin-4-ylmethyl)-amino]-benzamide,
N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[methyl-(1-methyl-1-oxy-piperidin-4-yl)-amino]-benzamide, and
N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-2,4-bis-(4-methyl-piperazin-1-yl)-benzamide.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, and at least one pharmaceutically acceptable excipient, carrier and/or diluent.

### Claim 6 (depends on 5)

A pharmaceutical composition according to claim 5 further comprising one or more chemotherapeutic agents.

### Claim 7 (depends on 1)

A product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.

### Claim 8 (depends on 1)

The compound of formula (I) as defined in claim 1 wherein said substituted straight or branched C1-C6 alkyl under R7 is a straight or branched C1-C6 alkyl containing one to three substituents independently selected from the group consisting of halogen, cyano, nitro, SOnR9, COR10, NR11R12, OR13, R11R12N—(C1-C6)-alkyl, R13O—(C1-C6)-alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and optionally substituted heterocyclyl, aryl and heteroaryl.

### Claim 9 (depends on 1)

The compound of formula (I) as defined in claim 1 wherein R1 is NR6R7.

### Claim 10 (depends on 9)

The compound of formula (I) as defined in claim 9 wherein the substituted straight or branched C1-C6 alkyl under R7 is a straight or branched C1-C6 alkyl containing one to three substituents independently selected from the group consisting of halogen, cyano, nitro, SOnR9, COR10, NR11R12, OR13, R11R12N—(C1-C6)-alkyl, R13O—(C1-C6)-alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and optionally substituted heterocyclyl, aryl and heteroaryl.

### Claim 11 (depends on 9)

The compound of formula (I) as defined in claim 9 wherein R7 is an optionally substituted heterocyclyl, aryl, or heteroaryl.

### Claim 12 (depends on 9)

The compound of formula (I) as defined in claim 9 wherein R7 is an optionally substituted heterocyclyl.

### Claim 13 (depends on 9)

The compound of formula (I) as defined in claim 9 wherein R7 is an optionally substituted piperidinyl.

### Claim 14 (depends on 9)

The compound of formula (I) as defined in claim 9 wherein R7 is N-methyl-piperidinyl.