IMIDAZOLONYLQUINOLINES AND THE USE THEREOF AS ATM KINASE INHIBITORS

• US 20180072715A1
• Filed: 03/31/2016
• Published: 03/15/2018
• Est. Priority Date: 04/02/2015
• Status: Active Grant

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: FUCHSS, Thomas, SCHIEMANN, Kai
• Granted Patent: US 10,457,677 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

Compounds of the formula (I), which are ATM kinase inhibitors and can be employed, inter alia, for the treatment of cancer.

Claims

1. Compound of the formula (I)

2. Compound of the formula (I) according to claim 1 in which

Het¹ denotes mono- or bicyclic heteroaryl having 2, 3, 4, 5, 6, 7, 8 or 9 C atoms and 1, 2, 3 or 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or tri-substituted, independently of one another, by Hal, A, CN, —

(CY₂)_p—

OY, —

(CY₂)_p—

NYY, —

(CY₂)_p—

COOY, —

(CY₂)_p—

CO—

NYY, —

(CY₂)_p—

NY—

COY and/or —

SO₂-Het²,

HET denotes a 5- or 6-membered aromatic heterocycle having 1, 2 or 3 N atoms and optionally an O atom or S atom, where this heterocycle is linked to the N atom of the skeleton via a ring C atom and where this heterocycle may be unsubstituted or substituted by one, two or three substituents, which are selected, independently of one another, from the group consisting of;

Hal, A, Het², CN, —

(CY₂)_p—

OY, —

(CY₂)_p—

O—

(CY₂)_t—

OY, —

(CY₂)_p—

O—

(CY₂)_t—

POAA, —

(CY₂)_p—

NYY, —

(CY₂)_p—

COOY, —

(CY₂)_p—

CO—

NYY, —

(CY₂)_p—

NY—

COY or—

SO₂-Het²; and

may be part of a bicyclic 11- or 12-membered aromatic heterocycle, where this bicyclic aromatic heterocycle may overall be unsubstituted or substituted by one, two, three or more substituents, which are selected, independently of one another, from the group consisting of;

Hal, A, Het², —

CN, —

(CY₂)_p—

OY, —

(CY₂)_p—

O—

(CY₂)_t—

OY, —

(CY₂)_p—

O—

(CY₂)_t—

POAA, —

(CY₂)_p—

NYY, —

(CY₂)_p—

COOY, —

(CY₂)_p—

CO—

NYY, —

(CY₂)_p—

NY—

COY or —

SO₂-Het²,

Hal denotes F, Cl, Br or I,

p denotes, independently of one another, 0, 1, 2, 3, 4, 5 or 6 and

t denotes 1, 2, 3, 4, 5 or 6.

and/or pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios.

3. Compound of the formula (I) according to claim 1, where HET is selected from the following aromatic heterocycles, which may in each case be unsubstituted or substituted as defined for the compound of formula (I):

pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-ox a-3,4-diazolyl, 1-oxa-2,5-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-3,4-diazolyl, 1-thia-2,5-diazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, and tetrazolyl;

pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl;

indolyl, isoindolyl, benzimidazolyl, indazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo [2,3-c] pyridinyl, pyrrolo [3,2-11] pyridinyl, pyrrolo [3,2-c] pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, purinyl, indozilinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a[pyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phtalazinyl, 1,6-naphtyridinyl, 1,7-naphtyridinyl, 1,8-naphtyridinyl, 1,5-naphtyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]-pyrimidinyl, pyrido [4,3 -d] pyrimidinyl, pyrido [3,4-d]pyrimidinyl, pyrido [2,3 -d] pyrimidinyl, pyrido [2,3 -d] pyrazinyl, pyrido [3,4-11] pyrazinyl, pyrazino [2,3 -b] pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrimido[4,5-d]pyrimidinyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, furopyridinyl, and thienopyridinyl,

and/or pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios.

4. Compound of the formula (I) according to claim 1, of where HET is selected from the following 5- or 6-membered monocyclic aromatic heterocycles, which may in each case be unsubstituted or substituted as defined for the compound of formula (I):

pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl,

and/or pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios.

5. Compound of the formula (I) according to claim 1, where HET is selected from pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-b]pyridinyl and quinolinyl, which may in each case be unsubstituted or substituted as defined for the compound of formula (I):

preferably 1H- pyrrolo[3,2-c]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-6-yl or 5-fluoro-1H-pyrrolo[2,3-b]pyridin-6-yl,

and/or pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios.

6. Compound of the formula (I) according to claim 3, where the aromatic heterocycles HET may be substituted by one, two, three or more substituents which are selected, independently of one another, from the group consisting of:

F, Cl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, piperazinyl, tetrahydropyranyl, —

CN, 2-methoxyethoxy, 2-hydroxyethoxy, fluoromethoxy, difluoromethoxy, N-methylcarbamoyl (—

C(═

O)—

NH—

CH₃), 2-methylaminoethoxy, 1-methyl-azetidin-3-yl-methoxy, trideuteriomethoxy, trifluoromethoxy, methylsulfonylmethoxy, methylsulfonyl, cyclopropyl, allyloxy, piperazinyl, and azetidinyloxy,

and/or pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios.

7. Compound of the formula (I) according to claim 1 where HET is selected from the following 5- or 6-membered monocyclic aromatic heterocycles:

pyridin-2-yl, pyridin-4-yl, 5-allyloxy-3-fluoropyridin-2-yl, 5-(azetidin-3-yloxy)-3-fluoropyridin-2-yl, 5-chloro-3-fluoropyridin-2-yl, 3-cyclopropylpyridin-4-yl, 3-cyclopropyl-5-fluoropyridin-4-yl, 3,5-difluoropyridin-2-yl, 3,5-difluoropyridin-4-yl, 5-difluoromethoxy-3-fluoropyridin-2-yl, 3-difluoromethoxy-5-fluoropyridin-4-yl, 5-ethoxy-3 -fluoropyridin-2-yl, 3 -fluoro-5-(1-methylazetidin-3 -ylmethoxy)pyridin-2-yl, 3-fluoro-5-methoxypyridin-4-yl, 3-fluoro-5-methoxypyridin-2-yl, 3-fluoro-5-fluoromethoxypyridin-2-yl, 3-fluoro-5-fluoromethoxypyridin-4-yl, 3-fluoropyridin-2-yl, 3-fluoro-5-methyl-sulfonylmethoxypyridin-2-yl, 3-fluoro-5-methylsulfonylpyridin-2-yl 3-fluoro-5-(2-methylamino-ethoxy)pyridin-2-yl, 3-fluoro-5-methylpyridin-4-yl, 3-fluoro-5-methylpyridin-2-yl, 3-fluoropyridin-4-yl, 3-fluoropyridin-2-yl, 3-fluoro-5-piperazin-1-ylpyridin-2-yl, 3-chloro-pyridin-4-yl, 3-ethylpyridin-4-yl, 3-ethyl-5-fluoropyridin-4-yl, 3-ethyl-5-methylpyridin-4-yl, 5-fluoropyridin-2-yl, 3-methylpyridin-4-yl, 3-methoxy-pyridin-4-yl, 2-cyano-pyridin-4-yl, 3-cyanopyridin-4-yl, 3-cyanopyridin-6-yl, 3-cyano-5-fluoropyridin-4-yl, 3-fluoro-5-(2-methoxyethoxy)pyridin-2-yl, 3-fluoro-5-(2-hydroxy-ethoxy)pyridin-2-yl, 3-fluoro-5-(trideuteriomethoxy)pyridin-4-yl, 3-fluoro-5-(trideuterio-methoxy)pyridin-2-yl, 5-fluoro-3-(N-methylcarbamoyl)pyridin-6-yl, 5-fluoropyrimidin-2-yl, 5-fluoropyrimidin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, 1H-pyrazol-4-yl, 1-ethyl-3-methyl-1H-pyrazol-4-yl, 1,2-dimethyl-1H-pyrazol-4-yl, 1,3 -dimethyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl, 1-(tetrahydropyran-4-yl)-1H-pyrazol-4-yl, 2-methyl-2H-pyrazol-3-yl, 3-methyl-1H-pyrazol-4-yl, 2-methylthiazol-4-yl, 3,5-dimethyl-1H-pyrazol-4-yl, 3-fluoro-1-methylpyrazol-4-yl, thiazol-2-yl, and 1-methyl-1H-imidazolyl,

and/or pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios.

8. Compound of the formula (I) according to claim 1, where R1 is methyl, and/or pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios.

9. Compound of the formula (I) according to claim 1, where Het¹ is a monocyclic heteroaryl having 2, 3, or 4 C atoms and 1, 2, or 3 N atoms, which may be unsubstituted or substituted as defined for the compound of formula (I), and/or pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios.

10. Compound of the formula (I) according to claim 9, where Het¹ is selected from pyridinyl, pyrimidinyl, pyrazolyl, triazolyl and imidazolyl, which may be unsubstituted or substituted as defined for the compound of formula (I),

and/or pharmaceutically pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios.

11. Compound of the formula (I) according to claim 10, where Het¹ is pyrazolyl, which may be unsubstituted or substituted as defined for the compound of formula (I), and/or pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios.

12. Compound of the formula (I) according to claim 10, where Het¹ is triazolyl, preferably 1,2,3-triazolyl, which may be unsubstituted or substituted as defined for the compound of formula (I), and/or pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios.

13. Compound of the formula (I) according to claim 9, where Het¹ is unsubstituted or substituted by one or two substituents selected, independently of one another, from alkyl, which may be unsubstituted or mono- or polysubstituted by halogen, in particular F, or from —

OY, —

NYY, halogen, and -Het², particularly preferably methyl, ethyl, amino, methoxy, fluoromethyl, difluoromethyl, fluorine, azetidinyl, and/or pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios.

14. Compound of the formula (I) according to claim 10, where Het¹ is selected from:

1H-pyrazol-4-yl, 2H-pyrazol-3-yl, 1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, 3-methyl-1H-pyrazol-4-yl, 5-methyl-1H-pyrazol-3-yl, 4-methyl-1H-pyrazol-3-yl, 1-fluoro-methyl-1H-pyrazol-4-yl, 1-difluoromethyl-1H-pyrazol-4-yl, 1,3 -dimethyl-1H-pyrazol-4-yl, 1-ethyl-1H-pyrazol-4-yl, 1-ethyl-3-methyl-1H-pyrazolyl, 3 -fluoro-l-methyl-1H-pyrazol-4-yl, 3 - amino-1H-pyrazol-5-yl, 2H-1,2,3 -triazol-4-yl, 3H-1,2,3 -triazol-4-yl-, 1-methyl-1H-1,2,3-triazol-4-yl, 2-methyl-2H-1,2,3-triazol-4-yl, 2-amino-1H-imidazol-4-yl, 6-methoxypyridin-3-yl, and 1-(azetidin-3 -yl)-3 -methyl-1H-pyrazol-4-yl,

and/or pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios.

15. Compound of the formula (I) according to claim 1, where Het¹ is a bicyclic heteroaryl having 6, 7 or 8 C atoms and 1, 2, or 3 N atoms, which may be unsubstituted or substituted as defined for the compound of formula (I),

and/or pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios.

16. Compound of the formula (I) according to claim 15, where Het¹ is selected from bezimidazolyl, imidazo[4,5-b]pyridinyl, benzodiazolyl, which may be unsubstituted or substituted for the compound of formula (I), preferably 2-methyl-3H-benzimidazol-5-yl, 2-methyl-1H-imidazo[4,5-b]pyridin-6-yl, and/or pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios

17. Compound of the formula (I) according to claim 1, where R3 denotes unbranched or branched alkyl having 1, 2, or 3 C atoms, where 1, 2, 3, 4, or 5 H atoms may be replaced, independently of one another, by Hal, and particularly preferably denotes methyl,

and/or pharmaceutically usable derivative, salt, solvate, tautomer, stereoisomer thereof, including mixtures thereof in all ratios.

18. Compound according to claim 1, selected from:

20. A method for the treatment of diseases in which the inhibition/regulation and/or modulation of ATM kinase signal transduction plays a role or for use in the treatment of diseases which are influenced by inhibition of ATM kinase, comprising administering a compound of claim 1 to a subject in need thereof in an effective amount.

21. A method for the treatment of cancer, tumours and/or metastases, comprising adiministering a compound of claim 1 to a subject in need thereof in an effective amount.

22. A method for the treatment of cancer, tumours and/or metastases in combination with radiotherapy, comprising administering a compound of claim 1 to a subject in need thereof in an effective amount.

23. A method for the treatment of cancer, tumours and/or metastases in combination with at least one anticancer agent, comprising administering a compound of claim 1 to a subject in need thereof in an effective amount.

24. A method for the sensitisation of cancer cells to an anticancer agent and/or ionising radiation, comprising administering a compound of claim 1 to a subject in need thereof in an effective amount.

25. A method for the treatment a tumor selected from the group of diseases of squamous epithelium, bladder, stomach, kidneys, head, neck, oesophagus, cervix, thyroid, intestine, bone, liver, brain, prostate, urogenital tract, lymphatic system, larynx, lung, skin, blood and immune system, and/or the cancer is selected from the group of monocytic leukaemia, lung adenocarcinoma, small-cell lung carcinoma, pancreatic cancer, glio-blastoma, intestinal carcinoma, breast carcinoma, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia, chronic lymphatic leukaemia, Hodgkin'"'"'s lymphoma and non-Hodgkin'"'"'s lymphoma, comprising administering a compound of claim 1 to a subject in need thereof in an effective amount.

26. Pharmaceutical composition comprising an effective amount of at least one compound according to claim 1 and/or a pharmaceutically usable derivative, salt, solvate, tautomer, or stereoisomer thereof, optionally together with at least one pharmaceutically tolerated excipient.

27. Pharmaceutical composition according to claim 26, furthermore comprising at least one further medicament active compound, preferably at least one anticancer agent.

28. Kit comprising separate packs of

(a) an effective amount of a compound according to claim 1 and/or pharmaceutically usable derivative, salt, solvate, tautomer, or stereoisomer thereof, and

(b) an effective amount of a further medicament active compound, preferably an anticancer agent.

29. A method for the inhibition of a protein kinase, preferably ATM kinase in vitro, comprising bringing together a compound of claim 1 with said protein kinase.

30. Process for the preparation of a medicament, preferably for use in the treatment of cancer and/or tumours, comprising:

i. determination that a concentration at which a compound according to claim 1 and/or pharmaceutically usable derivative, salt, solvate, tautomer, or stereoisomer thereof, achieves 50% inhibition of the activity of ATM kinase is 500 nM or less, preferably 100 nM or less, and

ii. preparation of a pharmaceutical composition which comprises the compound.

19. (canceled)

31. (canceled)