IP Library › Granted Patent US 9,073,892

Granted Patent B2

US 9,073,892 · App. 13/995,803 · Granted Jul 7, 2015

Indazolyl triazol derivatives

Inventors: Catherine Jorand-Lebrun (Contamine-Sarzin, FR); Stefano Crosignani (St Genis-Pouilly, FR); Jerome Dorbais (Annecy, FR); Tania Grippi-Vallotton (Puplinge, CH); Adeline Pretre (Viry, FR)

Assignee: Merck Serono S.A.

C07D403/04 A61K31/4192 A61K45/06 C07D401/14 C07D403/14 A61K31/454 A61K31/537 A61K31/551

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Quick Facts

Patent No.: US 9,073,892
App. No.: 13/995,803
Granted: Jul 7, 2015
Kind: B2

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Abstract

Compounds of Formula (I) are used for the treatment of inflammation and autoimmune disorders.

Claims (412)

1. A compound of Formula (I)

wherein

Q denotes Ar or Het;

E denotes —(CH 2 ) m CO—, —(CH 2 ) m SO 2 , —(CH 2 ) q —, —(CH 2 ) m NHCO—, or a single bond;

R 1 denotes H, OH, NH—C 1 -C 6 -alkyl, OC 1 -C 6 -alkyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, Cyc, Hal, Het 1 , O-Het 1 , CO-Het 1 , NH-Het 1 , CO—Ar 1 , O—Ar 1 , Ar 1 , NH—Ar 1 , —(CH 2 ) q Het 1 , —CONH—(CH 2 ) q Het 1 , —CONH-Het 1 , —(CH 2 ) q O-Het 1 , —(CH 2 ) q O—Ar 1 , —(CH 2 ) q Ar 1 , —CONH—(CH 2 ) q Ar 1 , —CONH—Ar 1 , —CONHC 3 -C 6 -cycloalkyl, —(CH 2 ) q Hal, —(CH 2 ) q Cyc, CF 3 , —(CH 2 ) s NH—(CH 2 ) q -Het 1 , or —(CH 2 ) s NH—(CH 2 ) q —Ar 1 , wherein NH—C 1 -C 6 -alkyl, OC 1 -C 6 -alkyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl may be substituted by 1 to 3 groups independently selected from OC 1 -C 3 -alkyl, OH, CONH 2 , and NH 2 ;

R 2 denotes H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, Hal, or CF 3 ;

R 3 denotes Het 1 , Ar 1 , NR a R b , COOH, —(CH 2 ) q Het 1 , —(CH 2 ) q Ar 1 , —(CH 2 ) q NR a R b , —(CH 2 ) q COOH, or C 1 -C 6 -alkyl wherein 1 to 3 hydrogen atoms may each be independently replaced by OH or CF 3 ;

R 4 denotes H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, or Hal;

R a denotes H, linear, branched or cyclic C 1 -C 6 -alkyl;

R b denotes H, Het b , Ar b , —CO-Het b , —CO—Ar b , a C 3 -C 8 -cycloalkyl or a linear or branched alkyl having 1 to 6 carbon atoms, wherein 1 to 3 hydrogen atoms may each be replaced by Het b , Ar b , NH 2 , N(C 1 -C 6 -alkyl) 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl)(C 3 -C 8 -cycloalkyl), NH(C 3 -C 8 -cycloalkyl), O(C 1 -C 6 -alkyl), CN, OH, CF 3 , or Hal;

n is 0, 1, 2, 3 or 4;

m is 0, 1, 2, 3 or 4;

q is 1, 2, or 3;

s is 0, 1, 2 or 3;

Hal denotes Cl, Br, I, F;

Ar denotes a divalent monocyclic or fused bicyclic arylene group having 6 to 14 carbon atoms, which may be further substituted with 1 to 4 substituents selected from Hal, C 1 -C 6 -alkyl, —(CH 2 ) m OC 1 -C 6 -alkyl, CN, OH, NO 2 , CF 3 , —(CH 2 ) m COOH, and —(CH 2 ) m COOC 1 -C 6 -alkyl;

Het denotes a divalent monocyclic or fused bicyclic unsaturated, saturated or aromatic heterocyclic group having 1 to 5 heteroatoms independently selected from N, O, S and/or a group —C═O, which may be further substituted with 1 to 4 substituent selected from Hal, C 1 -C 6 -alkyl, —(CH 2 ) m OC 1 -C 6 -alkyl, CN, OH, NO 2 , CF 3 , —(CH 2 ) m COOH, and —(CH 2 ) m COOC 1 -C 6 -alkyl;

Ar 1 denotes a monocyclic or bicyclic, aromatic carbocyclic ring having 6 to 14 carbon atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, —CF 3 , —OCF 3 , —NO 2 , —CN, perfluoroalkyl, Hal, —CF 3 , —OCF 3 , —NO 2 , —CN, perfluoroalkyl, linear or branched C 1 -C 6 -alkyl, cycloalkyl, —OH, —OC 1 -C 6 -alkyl, —COC 1 -C 6 -alkyl, —NH 2 , —COH, —COOH, —CONH 2 , a group R b , —SO 2 NR a R b or SO 2 (C 1 -C 6 alkyl);

Het 1 denotes a monocyclic or bicyclic saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 heteroatom independently selected from N, O, S and/or a CO group, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, —CF 3 , —OCF 3 , —NO 2 , —CN, perfluoroalkyl, linear or branched C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, —OH, —OC 1 -C 6 -alkyl, —NH 2 , —N(C 1 -C 6 -alkyl) 2 , —COH, —COOH, —CONH 2 , —COC 1 -C 6 -alkyl, —NHCO(C 3 -C 6 cycloalkyl), a group R b , —SO 2 NR a R b or SO 2 (C 1 -C 6 alkyl), wherein the bicyclic heterocyclic ring can be fused, bridged or spiro;

Het b denotes a monocyclic or bicyclic saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 heteroatom independently selected from N, O, S and/or a CO group, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, —CF 3 , —OCF 3 , —NO 2 , —CN, perfluoroalkyl, —OH, —OC 1 -C 6 -alkyl, —NH 2 , —COH, —COOH, —CONH 2 , or by a linear or branched C 1 -C 6 -alkyl wherein 1 to 3 hydrogen atoms may each be replaced by NH 2 , N(C 1 -C 6 -alkyl) 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl)(C 3 -C 8 -cycloalkyl), NH(C 3 -C 8 -cycloalkyl), O(C 1 -C 6 -alkyl), CN, OH, CF 3 , Hal, C 3 -C 8 -cycloalkyl, or by a 4 to 8-membered heterocyclic ring containing a heteroatom selected from O, S and N, wherein the bicyclic heterocyclic ring can be fused or spiro;

Ar b denotes a monocyclic or bicyclic, aromatic carbocyclic ring having 6 to 14 carbon atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, —CF 3 , —OCF 3 , —NO 2 , —CN, perfluoroalkyl, Hal, —CF 3 , —OCF 3 , —NO 2 , —CN, perfluoroalkyl, —OH, —OC 1 -C 6 -alkyl, —NH 2 , —COH, —COOH, —CONH 2 , or by a linear or branched C 1 -C 6 -alkyl wherein 1 to 3 hydrogen atoms may each be replaced by NH 2 , N(C 1 -C 6 -alkyl) 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl)(C 3 -C 8 -cycloalkyl), NH(C 3 -C 8 -cycloalkyl), O(C 1 -C 6 -alkyl), CN, OH, CF 3 , Hal, C 3 -C 8 -cycloalkyl, or by a 4 to 8-membered heterocyclic ring containing an heteroatom selected from O, S and N; and

Cyc denotes a saturated or unsaturated carbocyclic ring having 3 to 8 carbon atoms, wherein 1 to 5 H atoms are replaced by Hal, —CF 3 , —OCF 3 , —NO 2 , —CN, perfluoroalkyl, Hal, —CF 3 , —OCF 3 , —NO 2 , —CN, perfluoroalkyl, linear or branched C 1 -C 6 -alkyl, cycloalkyl, —OH, —OC 1 -C 6 -alkyl, —COC 1 -C 6 -alkyl, —NH 2 , —COH, —COOH, —CONH 2 , a group R b such as —CH 2 O(C 1 -C 6 -alkyl), —SO 2 NR a R b or SO 2 (C 1 -C 6 alkyl);

or a pharmaceutically acceptable solvate, tautomer, salt, hydrate, or stereoisomer-thereof, including mixtures thereof in all ratios.

2. A compound according to claim 1 , wherein the group Q-E-R 3 denotes one of the following groups:

3. A compound according to claim 1 , wherein R 1 denotes H, Hal, Methyl, trifluoromethyl, methoxy, hydroxy or one of the following groups:

4. A compound according to claim 1 , wherein the compound is selected from the following group:

compounds

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5. A method for treating a patient suffering from human melanoma or colon cancer comprising administering to said patient an effective amount of a compound of Formula (I):

wherein

Q denotes Ar or Het,

E denotes —(CH 2 ) m CO—, —(CH 2 ) m SO 2 , —(CH 2 ) q —, —(CH 2 ) m NHCO—, or a single bond;

R 1 denotes H, OH, NH—C 1 -C 6 -alkyl, OC 1 -C 6 -alkyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, Cyc, Hal, Het 1 , O-Het 1 , CO-Het 1 , NH-Het 1 , CO—Ar 1 , O—Ar 1 , Ar 1 , NH—Ar 1 , —(CH 2 ) q Het 1 , —CONH—(CH 2 ) q Het 1 , —CONH-Het 1 , —(CH 2 ) q O-Het 1 , —(CH 2 ) q —Ar 1 , —(CH 2 ) q Ar 1 , —CONH—(CH 2 ) q Ar 1 , —CONH—Ar 1 , —CONHC 3 -C 6 -cycloalkyl, —(CH 2 ) q Hal, —(CH 2 ) q Cyc, CF 3 , —(CH 2 ) q NH—(CH 2 ) q -Het 1 , or —(CH 2 ) q NH—(CH 2 ) q —Ar 1 , wherein NH—C 1 -C 6 -alkyl, OC 1 -C 6 -alkyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl may be further substituted by 1 to 3 groups independently selected from OC 1 -C 3 -alkyl, OH, CONH 2 , and NH 2 ;

R 2 denotes H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, Hal, or CF 3 ;

R 4 denotes H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, or Hal;

R a denotes H, linear, branched or cyclic C 1 -C 6 -alkyl,

n is 0, 1, 2, 3 or 4;

m is 0, 1, 2, 3 or 4;

q is 1, 2, or 3;

s is 0, 1, 2 or 3;

Hal denotes Cl, Br, I, F;

Het b denotes a monocyclic or bicyclic (fused or spiro) saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 heteroatom independently selected from N, O, S and/or a CO group, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, —CF 3 , —OCF 3 , —NO 2 , —CN, perfluoroalkyl, —OH, —OC 1 -C 6 -alkyl, —NH 2 , —COH, —COOH, —CONH 2 , or by a linear or branched C 1 -C 6 -alkyl wherein 1 to 3 hydrogen atoms may each be replaced by NH 2 , N(C 1 -C 6 -alkyl) 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl)(C 3 -C 8 -cycloalkyl), NH(C 3 -C 8 -cycloalkyl), O(C 1 -C 6 -alkyl), CN, OH, CF 3 , Hal, C 3 -C 8 -cycloalkyl, or by a 4 to 8-membered heterocyclic ring containing a heteroatom selected from O, S and N, wherein the bicyclic heterocyclic ring can be fused or spiro;

or a pharmaceutically acceptable solvate, tautomer, salt, hydrate or stereoisomer thereof, including mixtures thereof in all ratios.

6. A method according to claim 5 , wherein said patient is suffering from human melanoma.

7. A method according to claim 5 , wherein said patient is suffering from colon cancer.

8. A kit consisting of separate packs of:

(a) an effective amount of a compound according to claim 1 , and

(b) an effective amount of at least one immunomodulating agent.

9. A pharmaceutical composition comprising at least one compound according to claim 1 .

10. A pharmaceutical composition according to claim 9 , wherein said composition further comprises a suitable carrier.

11. A pharmaceutical composition according to claim 9 , wherein said composition further comprises at least one immunomodulating agent.

12. A process for the production of a compound according to claim 1 , said process comprising:

reacting a compound of Formula II

wherein R 1 , R 2 , R 4 and n are as defined in claim 1 , and PG 1 denotes H or a nitrogen protecting group,

with a compound of Formula (III)

wherein Q, E and R 3 are as defined in claim 1 .

13. A compound according to claim 1 , wherein said compound is of sub-Formula (Ia) or sub-Formula (Ib)

14. A compound according to claim 1 , wherein

Q denotes Ar,

E denotes —(CH 2 ) m CO—,

R 1 denotes H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, Cyc, Hal, Het 1 , O-Het 1 , O—Ar 1 , Ar 1 , —(CH 2 ) q Het 1 , —(CH 2 ) q O-Het 1 , —(CH 2 ) q O—Ar 1 , —(CH 2 ) q Ar 1 , —(CH 2 ) q Hal, —(CH 2 ) q Cyc, CF 3 ,

R 2 denotes H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, Hal, CF 3 ,

R 3 denotes Het 1 or NR a R b , and

R 4 denotes H.

15. A compound according to claim 13 , wherein

Q denotes Ar,

E denotes —(CH 2 ) m CO—,

R 2 denotes H, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, Hal, CF 3 ,

R 3 denotes Het 1 or NR a R b , and

R 4 denotes H.

16. A compound according to claim 1 , wherein

Q denotes Ar,

E denotes —(CH 2 ) m CO—,

R 1 , R 2 are both H,

R 3 denotes Het 1 or NR a R b , and

R 4 denotes H.

17. A compound according to claim 13 , wherein

Q denotes Ar,

E denotes —(CH 2 ) m CO—,

R 1 , R 2 are both H,

R 3 denotes Het 1 or NR a R b , and

R 4 denotes H.

18. A compound according to claim 1 , wherein said compound is of sub-Formulae (Ic), (Id) or (Ie):

19. A compound according to claim 1 , wherein said compound is of sub-Formula (If):

20. A compound according to claim 1 , wherein E denotes —(CH 2 ) m CO— or —(CH 2 ) m NHCO—.

21. A compound according to claim 20 ,

wherein m is 0, 1 or 2.

22. A compound according to claim 1 , wherein E denotes —(CH 2 ) q — or a single bond.

23. A compound according to claim 22 , wherein q is 1.

24. A compound according to claim 19 , wherein

Q is Ar,

E is —CO—, —(CH 2 )— or a bond,

R 3 is Het 1 , and

R 1 is H, F, —CH 3 , Het 1 , —(CH 2 ) q -Het 1 , —NH-Het 1 , —CONH—(CH 2 ) q Het 1 , —CONH-Het 1 , —CONH—Ar 1 , or a C 2 -C 6 -alkenyl which may be substituted by 1 to 3 groups independently selected from OC 1 -C 3 -alkyl, OH, CONH 2 , and NH 2 .

25. A compound according to claim 1 , wherein

Het 1 denotes a monocyclic or bicyclic, fused or spiro, saturated, unsaturated or aromatic 5-12-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from N and a CO group, which is unsubstituted or monosubstituted, or disubstituted by C 3 -C 8 -cycloalkyl, —OH, —OC 1 -C 6 -alkyl, —NH 2 , —N(C 1 -C 6 -alkyl) 2 , —COHet b , Het b , Ar b or a linear or branched alkyl having 1 to 6 carbon atoms wherein 1 to 3 hydrogen atoms may each be independently replaced by Het b , Ar b , OH, CF 3 ,

Het b denotes a saturated or aromatic 5- or 6-membered ring having 1 nitrogen atom, optionally substituted with 1 to 3 substituent selected from C 1 -C 6 -alkyl, OH, or Hal, and

Ar b denotes a phenyl ring optionally substituted by 1 to 3 substituents selected from Hal and OH.

26. A compound according to claim 1 , wherein Q is phenylene wherein 1 H atom may be replaced by C 1 -C 6 -alkyl, O—C 1 -C 6 -alkyl or CF 3 .

27. A compound according to claim 1 , wherein Q is a divalent monocyclic unsaturated or aromatic 5- or 6-membered heterocyclic group having 1 or 2 nitrogen atoms.

28. A compound according to claim 1 , wherein only one of R a and R b denotes H.

Assignments (2)

CORRECTIVE ASSIGNMENT TO CORRECT THE NAME OF THE ASSIGNEE PREVIOUSLY RECORDED AT REEL: 030839 FRAME: 0971. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Apr 30, 2015

From: JORAND-LEBRUN, CATHERINE; CROSIGNANI, STEFANO; DORBAIS, JEROME; GRIPPI-VALLOTTON, TANIA; PRETRE, ADELINE

To: MERCK SERONO S.A.

Reel/Frame 035553/0728 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 19, 2013

From: JORAND-LEBRUN, CATHERINE; CROSIGNANI, STEFANO; DORBAIS, JEROME; GRIPPI-VALLOTTON, TANIA; PRETRE, ADELINE

To: MERCK PATENT GMBH

Reel/Frame 030839/0971 →

Priority Claims (1)

EP 10195867 · Dec 20, 2010 · regional

Continuity (2)

Provisional Application 61424890 · Dec 20, 2010

Related Publication 20130274241A1 · Oct 17, 2013