Substituted indole derivatives

1. A compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof,

Wherein

X is CH or N;

R is H or PO 3 H 2 ;

R1 is H; or C 1-4 alkyl;

R2 is H; or C 1-4 alkyl;

R3 is H; C 1-4 alkyl; CN; Hal; or OH; and

R4 and R5 are independently from each other H, or C 1-4 alkyl; or R4 and R5 form together with the carbon atom to which they are attached a 3-6 membered cycloalkyl group.

2. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt or hydrate thereof,

wherein X is CH;

R is H;

R1 is H;

R2 is H; or C 1-4 alkyl;

R3 is H; or C 1-4 alkyl; and

R4 and R5 are independently from each other H; or R4 and R5 form together with the carbon atom to which they are attached a 3-6 membered cycloalkyl group.

3. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt or hydrate thereof,

wherein X is N;

R is PO 3 H 2 ;

R1 is H;

R2 is H; or C 1-4 alkyl;

R3 is H; and

R4 and R5 are independently from each other H; or R4 and R5 form together with the carbon atom to which they are attached a 3-6 membered cycloalkyl group.

4. The compound according to claim 1 which is a compound of formula (III)

or a pharmaceutically acceptable salt or hydrate thereof.

5. The compound in accordance to claim 1 , which is phosphoric acid mono-[3-[3-(4,7-diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl]ester, mono-hydrate.

6. The compound in accordance to claim 1 , which is 3-[3-(4,7-diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-1-hydroxymethyl-4-(7-methyl-1H-indol-3-yl)-pyrrole-2,5-dione or a pharmaceutically acceptable salt thereof.

7. The compound in accordance to claim 1 , which is phosphoric acid mono-{3-(1H-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl} ester or a pharmaceutically acceptable salt thereof.

8. A crystalline form of phosphoric acid mono-[3-[3-(4,7-diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl]ester, which has an X-ray powder diffraction pattern with at least one of the following peaks at an angle of refraction 2 theta (θ) of 9.525, 16.356, 17.091, 18.005, 20.859, each ±0.2, especially as depicted in FIG. 1 and/or Table 1.

9. The crystalline form of phosphoric acid mono-[3-[3-(4,7-diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl]ester, according to claim 8 , in the form of the mono-hydrate, which has an X-ray powder diffraction pattern with at least one of the following peaks at an angle of refraction 2 theta (θ) of 9.525, 16.356, 17.091, 18.005, 20.859, each ±0.2, especially as depicted in FIG. 1 and/or Table 1.

10. The crystalline form of phosphoric acid mono-[3-[3-(4,7-diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl]ester, according to claim 8 , which has an X-ray powder diffraction pattern with at least three of the following peaks at an angle of refraction 2 theta (θ) of 9.525, 16.356, 17.091, 18.005, 20.859, each ±0.2, especially as depicted in FIG. 1 and/or Table 1.

11. The crystalline form of phosphoric acid mono-[3-[3-(4,7-diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl]ester, according to claim 8 , which has an X-ray powder diffraction pattern with all the following peaks at an angle of refraction 2 theta (θ) of 9.525, 16.356, 17.091, 18.005, 20.859, each ±0.2, especially as depicted in FIG. 1 and/or Table 1.

12. A combination, comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or hydrate thereof, and a second drug substance selected from selected from calcineurin inhibitor a mTOR inhibitor; an ascomycin having immuno-suppressive properties; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid or salt; mycophenolate mofetil; 15-deoxyspergualine or an immunosuppressive homologue, analogue or derivative thereof; a PKC inhibitor, a S1P receptor agonist or modulator, immunosuppressive monoclonal antibodies, other immunomodulatory compounds; adhesion molecule inhibitors, LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or antichemokine antibodies or antichemokine receptor antibodies, or low molecular weight chemokine receptor antagonists; or another antiproliferative agent selected from (i) aromatase inhibitors, (ii) antiestrogens, (iii) topoisomerase I inhibitors, (iv) topoisomerase II inhibitors; (v) microtubule active agents; (vi) alkylating agents; (vii) histone deacetylase inhibitors; (viii) farnesyl transferase inhibitors; (ix) COX-2 inhibitors; (x) MMP inhibitors; (xi) mTOR inhibitors; (xii) antineoplastic antimetabolites; (xiii) platin compounds; (xiv) compounds decreasing the protein kinase activity and further anti-angiogenic compounds; (xv) gonadorelin agonists; (xvi) anti-androgens; (xvii) bengamides; (xviii) bisphosphonates; (xix) antiproliferative antibodies; (xx) temozolomide (TEMODAL®); (xxi) Statins.

13. A method of manufacturing a compound of formula (I) as defined in claim 1 ,

wherein X is CH or N;

R is H or PO 3 H 2 ;

R1 is H; or C 1-4 alkyl;

R2 is H; or C 1-4 alkyl;

R3 is H; C 1-4 alkyl; CN; Hal; or OH; and

R4 and R5 are independently from each other H, or C 1-4 alkyl; or R4 and R5 form together with the carbon atom to which they are attached a 3-6 membered cycloalkyl group, comprising:

(a) optionally, for compounds wherein R1 and/or R2 are hydrogen, treating the maleimide of formula (Va) with di-tert-butyl dicarbonate in the presence or absence of a solvent such as THF or dichloromethane and/or a base such as triethyl amine, thereby yielding the maleimide of formula (Va) comprising tert-butoxycarbonyl groups instead of the hydrogens on R1 and/or R2 where appropriate;

(b) treating the optionally protected maleimide of formula (Va) with formaldehyde in the presence or absence of a solvent and/or a base, thereby yielding an alcohol of formula (Vb), wherein R=H;

(c) optionally treating the alcohol of formula (Vb) with trichloroacetonitrile typically in the presence of a base, to form a reactive ester, followed by the treatment with a phosphorylating agent, typically in the presence of a base, whereupon the resulting intermediate ester is treated with an appropriate acid, in the absence of presence of a solvent to yield the final product in accordance to general formula (I), or as an alternative step (c)

alcohol of formula (Vb) may be reacted directly with a phosphoric acid ester, under Mitsunobu reaction conditions to furnish the phosphoric acid ester, which may then be hydrolyzed, to furnish the final product of formula (I)