WO2014174478A1 - Combinaisons pharmaceutiques d'un inhibiteur de la pkc et d'un inhibiteur du récepteur tyrosine-kinase c-met - Google Patents

Combinaisons pharmaceutiques d'un inhibiteur de la pkc et d'un inhibiteur du récepteur tyrosine-kinase c-met Download PDF

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WO2014174478A1
WO2014174478A1 PCT/IB2014/060976 IB2014060976W WO2014174478A1 WO 2014174478 A1 WO2014174478 A1 WO 2014174478A1 IB 2014060976 W IB2014060976 W IB 2014060976W WO 2014174478 A1 WO2014174478 A1 WO 2014174478A1
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methyl
pharmaceutically acceptable
compound
acceptable salt
inhibitor
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PCT/IB2014/060976
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Dale Porter
Caroline Emery
Lujian TAN
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Novartis Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical combination compri sing (a) a protein kinase C (PKC) inhibitor, or a pharmaceutical ly acceptable salt thereof, and (b) at least one c-MET receptor tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable carrier; the uses of such a combination in the treatment or prevention of proliferative diseases, such as cancer; and methods of treating a subject suffering from a proliferative disease, such as cancer,
  • PLC protein kinase C
  • the present invention also relates to a pharmaceutical combination
  • a pharmaceutical combination comprising (a) a protein kinase C (PKC) inhibitor which is 3 -(7.H. -indol-3 -yl)-4-[2-(4-methyl-piperazin-l -yl)- qumazolin-4-yl] ⁇ pyrrole-2,5-dione, or a pharmaceutically acceptable salt thereof, and (b) at least one c-MET receptor tyrosine kinase inhi bitor which is selected from the group
  • PLC protein kinase C
  • Uveal melanoma is a malignant neoplasm that arises in the pigmented portions of the eye, specifically in the iris, ciliary body or choroid.
  • Therapy for uveal melanoma includes local therapy with enucleation or brachy therapy.
  • a combination of a protein kinase C (PKC) inhibitor and a c-MET receptor tyrosine kinase inhibitor is effective for the delay of progression or treatment of a proliferative disease, especially uveal melanoma, metastatic uveal melanoma, and GNAQ or GNA1 1 mutant uveal melanoma.
  • PLC protein kinase C
  • PKC protein kinase C
  • a c-MET receptor tyrosine kinase inhibitor e.g (E)-2-(l -(3-((7-fluoroquinolin-6- yl)methyl)imidazo[l ,2-b]pyridazin-6-yl)ethylidene)hydrazine-carboxamide or 2-fluoro-N ⁇ methyl -4-[(7-quinolin-6-y] -methy])-imidazo[l ,2-b]triazir!-2-yl]benzamide, more preferably 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[l ,2-b]triazin-2-yl]benzamide, or a pharmaceutically acceptable salt thereof, e.g.
  • the dihydrochronic acid or dibenzenesulfoni c acid thereof results in unexpected improvement in the treatment of proliferative diseases, parti cularly cancer, and more particularly uveal melanoma, metastatic uveal melanoma, and GNAQ or GNA1 1 mutant uveal melanoma.
  • the preferred protein kinase C (PKC) inhibitor and the preferred c-MET receptor tyrosine kinase inhibitor interact in a synergistic manner to strongly inhibit cell proliferation and are surprisingly efficacious in uveal melanoma models. It is expected that the anti -proliferative effect of this combination is greater and more effective than the maximum effect that can be achieved with either type of therapeutic agent alone.
  • the invention provides pharmaceutical combinations and therapeutic methods which may be useful for inhibiting the cell growth of a tumor with a Ga mutation (GN Al 1 /GNAQ) and for treating proliferative diseases, particularly cancer, and more particularly uveal melanoma, metastatic uveal melanoma, and GNAQ or GNAl 1 mutant uveal melanoma.
  • GN Al 1 /GNAQ Ga mutation
  • proliferative diseases particularly cancer, and more particularly uveal melanoma, metastatic uveal melanoma, and GNAQ or GNAl 1 mutant uveal melanoma.
  • the present invention provides pharmaceutical combinations comprising: (a) a protein kinase C (PKC) inhibitor, or a pharmaceuti cally acceptable salt thereof, and (b) at least one c-MET receptor tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable carrier.
  • PKC protein kinase C
  • the present invention also provides pharmaceutical combinations consisting of: (a) a protein kinase C (PKC) inhibitor, or a pharmaceutically acceptable salt thereof, and (b) one c-MET receptor tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable carrier.
  • the PKC inhibitor may be selected from the group consisting of 3-(i.H. -indol-3 -yl)-4-[2-(4-methyl-piperazin-l -yl)-quinazolin-4-yl]-pyrrole-2,5- dione;
  • the c-MET receptor tyrosine kinase inhibitor may be independently selected from the PKC inhibitor, and may be independently chosen from the compounds described below.
  • MET tyrosine kinase inhi bitors also referred to as "c-MET receptor tyrosine kinase inhibitors"
  • those disclosed in WO 2011/018454 are a particular embodiment, especially those of the formula
  • Y is C or N
  • B is CH or N
  • R 1 is a group selected from i, ii and iii:
  • R " is heteroaryl
  • R 6 is hydrogen, deuterium, OH, methyl or halo
  • R' is hydrogen, deuterium, halo, or (Ci-C3)alkyl, wherein said (Ci-Cj)alkyl is optionally substituted by one or more substituents independently selected from OH and halo;
  • n 0, 1 or 2;
  • R 2 is hydrogen, NH 2 , or (Ci-C4)alkyi, wherein said (Ci-C4)alkyl is optionally substituted by one or more substituents independently selected from OH, NH 2 and halo;
  • R j is hydrogen, -CONH 2 , -CONH(C f -C 4 )alkyl, -CONHphenyl, wherein the phenyl of said CONHphenyl is optionally substituted by one or more halo, -(CrC ⁇ alkyl, ⁇ CO(Ci -C4)alkyl, - C0 2 (C] -C 4 )alkyl, phenyl, heteroaryl, -COheteroaryl, -CSNH 2 , -CSNH(C!
  • R 4 is hydrogen or (Ci ⁇ C 3 )alkyl
  • A is N or CR 3 :
  • Cy ! is aryl, heteroaryl, cycioalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 -W-X-Y-Z;
  • Cy 2 is aryl, heteroaryl, cycioalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 -W'-X'-Y'-Z';
  • L 1 is (CR 4 R 5 ) m , (CR 4 R 5 ) p -(cycloalkylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -(aiy-lene)-(CR 4 R 5 ) q , (CR R 5 )p-(heterocycloalkylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -(heteroaiylene)-(CR R 5 ) q ,
  • L 2 is (CR 7 R 8 ) r , (CR 7 R 8 ) s -(cycloalkyiene)-(CR 7 R 8 )t, (CR 7 R 8 ) s -(aiy1ene)-(CR 7 R 8 )t, (CR 7 R 8 ) s -(heterocycloalkyiene)-(CR 7 R s ) t , (CR 7 R 8 ) s -(heteroaiylene)-(CR 7 R 8 ) t ,
  • R 2 is H, halo, C 1-6 alkyl, C 2 . 6 alkenyl, C 2 ⁇ e alkynyl, C 1-6 haloalkyl, ,CN, NO?, OR A , SR A , C(0)R B , C(0)NR c R D , C(0)OR A , OC(0)R B , OC(0)NR c R D , NR C R D , NR c C(0)R B , NR c C(0)NR c R D , NR c C(0)OR A , S(0)R B , S(())NR C R D , S(()) 2 R B , NR c S(0) 2 R B , or
  • R 3 is H, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, halo, C3 ⁇ 4 -6 alkyl, C 2-6 alkenyl, C 2 .6 alkynyl, Ci.
  • R 2 and -L 2 -Cy 2 are linked together to form a group of formula:
  • ring B is a fused aryl or fused heteroaryl ring, each optionally substituted with 1, 2, or 3 -W'-X'-Y'-Z' ;
  • R 4 and R 5 are independently selected from H, halo, OH, C-.-c, alkyl, C 2 -6 alkenyl, C 2 -e alkynyl, Ci_6 alkoxy, alkoxy alkyl, cyanoaikyl, heterocycloalkyl, cycloalkyl, C 1-6 haloalkyl, CN, and N0 2 ;
  • R 4 and R 3 together with the C atom to which they are attached form a 3, 4, 5, 6, or 7-membered cycloalkyl or heterocycloalkyl ring, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, Ci_s alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -6 alkoxy, alkoxyalkyl, cyanoaikyl, heterocycloalkyl, cycloalkyl, Ci-6 haloalkyl, CN, and N0 2 ;
  • R 6 is H, d-6 alkyl, C 2-6 alkenyl, or C 2 .e alkynyl;
  • R' and R 8 are independently selected from H, halo, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C , haloalkyl, CN, and N0 2 ;
  • R 7 and R 8 together with the C atom to which they are attached form a 3, 4, 5, 6, or 7-membered cycloalkyl or heterocycloalkyl ring, each optionally substituted by 1 , 2, or 3 substituent independently selected from halo, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, Ci-e haloalkyl, CN, and NO?;
  • R 9 is H, Ci-6 alkyl, C 2 .e alkenyl, or C 2-6 alkynyl;
  • W, W, and W" are independently absent or independently selected from Cj.e alkylene, C 2 .. 6 alkenyl ene, C 2 .. 6 alkynyl ene, O, S, ⁇ R h . CO, COO, CONR h , SO, S0 2 , SONR h and NR a CQNR', wherein each of the C 1-6 alkyiene, C 2- 6 alkenylene, and C 2-6 alkynylene is optionally substituted by 1 , 2 or 3 substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyi, OH, C 1 -6 alkoxy, C 1-6 haloalkoxy, amino, C j -e alkylamino, and C 2-8 dialkylamino;
  • X, X', and X" are independently absent or independently selected from C 1 -6 alkyiene
  • each of the d-6 alkyiene, C2-6 alkenylene, C2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycioalkylene is optionally substituted by 1 , 2 or 3 substituents independently selected from halo, CN, NO 2 , OH, C 1-6 alkyl, C 1-6 haloalkyi, C2-8 alkoxyalkyl, Ci-e alkoxy, Ci-6 haloalkoxy, C2-8 alkoxyalkoxy, cycloalkyl,
  • Y, Y', and Y" are independently absent or independently selected from C i-6 alkyiene, C2..6 alkenylene, C 2 - 6 alkynylene, O, S, NR h , CO, COO, CONR h , SO, S0 2 , SONR h , and NR h CONR', wherein each of the C 1-6 alkyiene, C 2-6 alkenyl ene, and C 2 -6 alkynylene is optionally substituted by 1 , 2 or 3 substituents independently selected from halo, C 1.6 alkyl, Ci-6 haloalkyi , OH, Ci-6 alkoxy, C 1-6 haloalkoxy, amino, Ci -6 alkylamino, and C 2-8 dialkylamino;
  • Z, Z', and Z" are independently selected from H, halo, C i-6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, C w haloalkyi, halosulfanyl, CN, N0 2 , N 3 , OR 32 , SR a2 , C(0)R b2 , C(0)NR c2 R d2 , C(0)OR a2 , 0C(())R b2 , OC(0)NR c2 R d2 , NR c2 R d2 , NR c2 C(0)R b2 , NR c2 C(0)NR c2 R d2 ,
  • Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heierocycloalkyl are optionally substituted by 1 , 2, 3, 4 or 5 substituents independently selected from halo, (>.
  • two adjacent -W-X-Y-Z together with the atoms to which they are attached, optionally form a fused 4-20 membered cycloalkyl ring or a fused 4-20 membered heterocycioaikyl ring, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, C-.
  • R A is H, Ci-4 aikyl, C 2-4 alkenyl, C 2-4 aikynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein said C 1 -4 aikyl, C 2-4 alkenyl, C 2-4 aikynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently sel ected from OH, CN, amino, halo, and C 1-4 aikyl;
  • R b is H, C aikyl, C 2-4 alkenyl, C 2-4 aikynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein said C 1 -4 aikyl, C 2-4 alkenyl, or C 2-4 aikynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with I , 2, or 3 substituents independently selected from OH, CN, amino, halo, and C 1-4 aikyl;
  • R c and R D are independently selected from H, C 1 -4 aikyl, C 2-4 alkenyl, or C 2-4 aikynyl, wherein said Ci -4 aikyl, C 2-4 alkenyl, or C 2-4 aikynyl, is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, ammo, halo, and Ci . 4 aikyl;
  • R a , R al , R a2 , R 3 , and R a4 are independently selected from H, C 1 -6 aikyl, Ci. 6 haloalkyl, C 2- 6 alkenyl, C 2-6 aikynyl, aiyl, cycloalkyl, heteroaiyl, heterocycloalkyl, aryl aikyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycioaikyi, aiyialkyi, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN
  • R B , R l , R B2 , R 3 , and R 4 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, -e alkynyl, aryl, cycloalkyl, heteroaryl, heterocycioaikyi, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said d-6 alkyl, d -6 haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycioaikyi, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, d-6 al
  • R C and R a are independently selected from H, C MO alkyl, d -6 haloalkyl, C 2 . 6 alkenyl, C2-6 alkynyl , aryl, heteroaryl, cycloalkyl, heterocycioaikyi, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C O alkyl, d-6 haloalkyl, C2-6 alkenyl, C 2 -6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycioaikyi , arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, C-.-e alkyl, d-6 alkoxy, C
  • R c and R A together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycioaikyi group or heteroaryl group, each optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, d-6 alkyl, d-6 alkoxy, Ci- & haloalkyl, and Ci-e haloalkoxy;
  • R C L and R DL are independently selected from H, CMO alkyl, d-6 haloalkyl, C 2 -6 alkenyl, C 2-6 alkynyl, aryl , heteroaryl, cycloalkyl, heterocycioaikyi, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C O alkyl, d-6 haloalkyl, C?-6 alkenyl, C 2 _6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycioaikyi, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with I , 2, or 3 substituents independently selected from OH, CN, ammo, halo, C 1-6 alkyl, d-6 alkoxy, C 1-6
  • R cl and R dl together with the N atom to which they are attached form a 4 -, 5-, 6- or 7-membered heterocycioaikyi group or heteroaryl group, each optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci _6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and Cj -f, haioalkoxy;
  • R 1""' and R 02 are independently selected from H, C I -JO alkyl, C3 ⁇ 4 .6 haloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloaikyl, arylalkyi, heteroarylalkyl, cycloalkylalkyl, heterocycloalkvlalkyl, aiyl cycloalkyl, arylhetero
  • heteroarylheteroeycloaikyl , heteroarylaryl, and biheteroaryl are each optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, C i-6 alkyl, Cj .e alkoxy, Ci-6 haloalkyl, C 1-6 haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl,
  • R c and R d2 together with the N atom to which they are attached form a 4 -, 5-, 6- or 7-membered heterocycloaikyl group or heteroaryl group, each optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, ammo, halo, C 1-6 alkyl, Ci_ alkoxy, Ci-6 haloalkyl, C 1-6 haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, C(0)OR a4 , C(0)R° 4 , S(O)2R 0J , alkoxyalkyl, and alkoxyalkoxy;
  • R 1"3 and R dj are independently selected from H, Ci-10 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloaikyl, arylalkyi, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-10 alkyl, C: _6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloaikyl, arylalkyi, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, C ⁇ e alkyl, d-e alkoxy, C 1-5 haloalkyl, and
  • R 3 and R d" ' together with the N atom to which they are attached form a 4 -, 5-, 6- or 7-membered heterocycloaikyl group or heteroaryl group, each optionally substituted with 1 ,
  • R° 4 and R d4 are independently selected from H, CMO alkyl, Cj -e haloalkyl, C 2 -6 alkenyl, C 2- 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloaikyl, arylalkyi, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C O alkyl, C 1-6 haloalkyl, C2-6 alkenyl, C 2- 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloaikyl, arylalkyi, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, ammo, halo, C 1-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, and
  • Ci-6 haloalkoxy or R c and R l together with the N atom to wiiich they are attached form a 4 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 aikyl, Cj.6 alkoxy, Cj .e haloalkyl, and Ci-e haloalkoxy;
  • R e , R e ! , R e2 , and R e4 are independently selected from H, C i_s aikyl, Ci constitutional6 haloalkyl, Ci-e alkenyl, (Cj .e alkoxy) -C 1-6 aikyl, C 2- 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, aiylaikyl, cycloalkylalkyl, heteroaiylalkyi, and heterocycloalkylaikyl;
  • R f , R 11 , R", and R f4 are independently selected from H, Ci-e aikyl, Cj .e haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl;
  • R h and R 1 are independently selected from H and C 1-6 aikyl
  • R J is H, Ci-6 aikyl, C 1-6 haloalkyl, C 2 _ & alkenyl, C 2- 6 alkynyl, aryl, cycloalkyl, heteroaryl , heterocycloalkyl, arylalkyl, heteroarvlalkvl, cycloalkylalkyl, or heterocycloalkylaikyl ;
  • n 0, 1 , 2, 3, 4, 5, or 6;
  • p 0, 1 , 2, 3 , or 4;
  • q 0, 1 , 2, 3, or 4;
  • r is 0, 1 . 2, 3, 4, 5, or 6;
  • s is 0, 1 , 2, 3, or 4;
  • t 0, 1 , 2, 3, or 4.
  • the compounds of formula III useful according to the invention have Formula IIIA:
  • A is CH or N, especially N;
  • L l is (CR 4 R 3 ) ra wherein each of R 4 and R 5 , independently of the other, is H or d-6-alkyl and m is 0, I or 2,
  • L 2 is (CR 'R 8 )r wherein each of R 7 and R 8 , independently of the other, is H or Ci-6-alkyl and r is 0, 1 or 2,
  • R 1 is H, halo or Ci-e-alkyl
  • R 2 is H, halo or Cj .6 ⁇ alkyl
  • MET tyrosine kinase inhibitor See WO 2008/064157, Example 7. This is the most preferred MET tyrosine kinase inhibitor.
  • Whi le the two MET (or c-MET) inhibitors (COMPOUND B and COMPOUND C) mentioned above are of particular interest, other MET inhibitors are also included in the scope of the present invention.
  • Such other MET (or c-MET) inhibitors are, for example, selected from the following (including their pharmaceutically acceptable salts, and prodrugs thereof):
  • MGCD-265 Metal Gene
  • JNJ-38877605 (Johnson & Johnson) (aka BVT051) (see also WO 2007/075567) which has the formula
  • HM-5016504 Human Medipharma
  • ficlatuzumab (AVEO) monoclonal antibody against HGF (preferred); onartuzumab (Roche) monoclonal antibody against MET (preferred); rilotuzumab (Amgen) monoclonal antibody against HGF (preferred); Tak-701 (Takeda) monoclonal antibody against HGF); LA-480 (Eli Lilly) monoclonal antibody against MET; and/or LY.2875358 (Eli Lilly) monoclonal antibody against MET.
  • the present invention also provides a pharmaceutical combination comprising: (a) a protem kinase C (PKC) inhibitor which is 3-(7.H. -indol-3-yl)-4-[2-(4-methyl-piperazin-l -yl)- qumazolin-4-yi]-pyrroie-2,5-dione (COMPOUND A) or a pharmaceutically acceptable salt thereof!, and (b) at least one c-MET receptor tyrosine kinase inhibitor which is selected from the group consisting of 2 ⁇ fluoro-N-methyl-4-[(7-quinoiin-6-yl-niethyl)-imidazo[l ,2-b]triazin- 2-yi]benzamide (COMPOUND B); (E)-2-(l -(3 -((7-fiuoroqiunolin-6-yl)methyl)imidazo[l,2- b]pyridazin-6-yl)ethylidene
  • cabozantmib tivatinib; foretmib; MGCD-265; AMG-208; AMG-337; JNJ-38877605 (BVT051); MK-8033; E ⁇ 7050; EMD-1204831 ; EMD-1214063 ; amuvatinib (MP-470); LY- 2875358; BMS-817378; DP-3590; ASP-08001; ⁇ -5016504; PF-4217903; SGX523 (SGX), or a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable carrier.
  • the combination partners are (a) a PKC inhibitor which is 3-(7.H. -indol-3-yl)-4-[2-(4-methyl-piperazin-l-yl)-quinazolin-4-yl]- pyrrole-2,5-dione (COMPOUND A), or a pharmaceutically acceptable salt thereof, and (b) at least one c-MET compound which is selected from the group consisting of 2-fluoro-N- methyl ⁇ -[(7-quinolin-6-y]-methy])-irnidazo[l,2-b]triazin-2-yl]benzamide (COMPOUND B), (E)-2-(l -(3 -((7-fluoroquinolin-6-yl)methyl)imidazo[ 1 ,2-b jpyridazin- ⁇ - yl)ethylidene)hydrazine-carboxamide (COMPOUND C), or a pharmaceutically
  • the combination partners are (a) a PKC inhibitor which is 3-(7.H. -indol-3 -yl)-4-[2-(4-methyl-piperazin-l -yl)- quinazolin-4-yl]-pyrrole-2,5-dione (COMPOUND A), or a pharmaceutically acceptable salt thereof, and (b) a c-MET receptor tyrosine kinase inhibitor which is 2-fluoro-N-methyl-4- [(7-quinolin-6-yl-methyl)-imidazo[l,2-b]triazin-2-yl]benzamide (COMPOUND B), or a pharmaceutically acceptable salt thereof.
  • the present invention further relates to a combined preparation or a pharmaceutical composition
  • a PKC inhibitor which is 3 -(7.H. -indol-3-yl)-4-[2-(4-methyl- piperazin-l -yl)-quinazolin-4-yl]-pyrrole-2,5-dione (COMPOUND A), or a pharmaceutically acceptable salt thereof, and (b) at least one c-MET receptor tyrosine kinase inhibitor which is selected from the group consisting of 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)- imidazo[l,2-b]triazin-2-yl]benzamide (COMPOUND B): (E)-2-(l -(3-((7-fluoroqumolin-6- yl)methyl)imidazo[l,2-b]pyridazin-6-yl)ethylidene)hydrazine-carboxamide (COMPOUND C
  • SGX523 (SGX), or a pharmaceutically acceptable salt thereof, and mixtures thereof, and optionally at least one pharmaceutically acceptable carrier.
  • the present invention relates to a combined preparation which comprises: (i) one or more unit dosage forms of combination partner (a), and (ii) one or more unit dosage forms of combination partner (b).
  • the present invention particularly pertains to a pharmaceutical combination comprising (a) a PKC inhibitor which is 3 -(7.H.-indol-3 -yl)-4- [2-(4-methyl-piperazin-l -yl)-quinazolin-4-yl]-pyrrole-2,5-dione (COMPOUND A), or a pharmaceutically acceptable salt thereof, and (b) at least one c-MET receptor tyrosine kinase inhibitor which is selected from the group consisting of 2-fluoro-N-methyl-4-[(7-quinolin-6- yl-methyl)-imidazo[ 1 ,2-b]tnazin-2-yl]benzamide (COMPOUND B); (E)-2-( 1 -(3 -((7- fluoro quino!
  • the present invention also pertains to a pharmaceutical combination
  • a pharmaceutical combination comprising (a) a PKC inhibitor which is 3-(i.H. -indol-3-yl)-4-f2-(4-methyl-piperazin-l-yl)-quinazolin-4-yl]- pyrrol e-2, 5 -di one (COMPOUND A), or a pharmaceutically acceptable salt thereof, and (b) at least one c-MET receptor tyrosine kinase inhibitor which is selected from the group consisting of 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[l ,2-b]triazin-2- yljbenzamide (COMPOUND B); (E)-2-(l -(3 -((7-fluoroquinolin-6-yl)methyl)imidazo[ ' l ,2- b]pyridazin-6-yl)ethylidene)hydrazme-
  • cabozantimb tivatimb; foretmib; MGCD-265; AMG-208; AMG-337; JNJ-38877605
  • the present invention also pertains to a pharmaceutical combination
  • a pharmaceutical combination comprising (a) a PKC inhibitor which is 3 ⁇ (1.H, -indol-3 -yl)-4-[2-(4-methyl-piperazin-l -yl)-quinazolin-4-yl]- pyrrole-2,5-dione (COMPOUND A), or a pharmaceutically acceptable salt thereof , and (b) the c-MET receptor tyrosine kinase inhibitor which is 2-fluoro-N-methyl-4-[(7-quinolin-6-yl- niethyl)-imidazo[l ,2 ⁇ b]triaziii"2 ⁇ yl]benzamide (COMPOUND B), or a pharmaceutically acceptable salt thereof, e.g. the dihydrochronic acid or dibenzenesulfonic aci d thereof.
  • the present invention further pertains to the use of a PKC inhibitor which is -( / // ⁇ indol-3 -yl)-4-[2-(4-methyl-piperazin-l -yl)-quinazolin-4-yl]-pyrrole-2,5-dione (COMPOUND A), or a pharmaceutically acceptable salt thereof, in combination with at least one c-MET receptor tyrosine kinase inhibitor which is selected from the group consisting of 2-fluoro-N- methyl-4-[(7-quinolin-6-yl -methyl)-im (COMPOUND B);
  • the present invention relates to a method of treating a subject having a proliferative disease comprising administered to said subject a combination comprising (a) a PKC inhibitor which is 3 ⁇ (l.H. -indoi-3 -yl)-4-[2-(4-methyl-piperazin-l -yl)-quinazoiin-4-yl] - pyrrol e-2, 5 -di one (COMPOUND A), or a pharmaceutically acceptable salt thereof, and (b) a c-MET receptor tyrosine kinase inhibitor which is selected from the group consisting of 2- fluoi -N-methyl ⁇ 4-[(7-quinoiin-6tyl-methyi) midazo[l ,2-b]triazin-2-yl]benzamide
  • the present invention further provides a commercial package comprising as therapeutic agents a combination comprising (a) a PKC inhibitor selected from the group consisting of 3-(7.H. -indol-3 -yl)-4-[2-(4-methyl-piperazin-l -yl)-quinazolin-4-yl]-pyrrole-2,5- dio e;
  • the present invention further provides a commercial package comprising as therapeutic agents a combination comprising (a) a PKC inhibitor which is 3 -(I.H. -indoi-3 - yl)-4-[2-(4-methyl-piperazin-l -yl)-quinazolin-4-yl]-pyrrole-2,5-dione (COMPOUND A) or a pharmaceutically acceptable salt thereof, and (b) a c-MET receptor tyrosine kinase inhibitor which is selected from the group consisting of 2-fluoro-N-methyl-4-[(7-quinolin-6-yl- methyl)-imidazo[l ,2-b]triazin-2 ⁇ yllbenzaniide (COMPOUND B); (E)-2-(l -(3-((7- fluoroquinolin-6-yi)methyi)iniidazo[l ,2-b]pyridazin-6"yl)ethylidene)hydrazine-car
  • Figure 1 HGF-R expression +/- AEB071 treatment in 92.1 uveal melanoma cell line.
  • Figures 2, 3 and 4 c-MET inhibtion prevents HGF attenuation of PKC pharmacological inhibtion in vitro in uveal melanoma cell line 92.1.
  • FIGURES Figure 1 : HGF-R expression +/- AEB071 treatment in 92.1 uveal melanoma cell line.
  • Figure 1 shows the effect of 3 -(I.H. -indol-3 -yl)-4-[2-(4-methyl-piperazin-l -yl)-quinazolin-4-yl]- pyrrole-2,5-dione (COMPOUND A) on the Ivel of phosphor -HGF-R (c-MET) in the 92.1 uveal melanoma cel l line.
  • AEB071 decreases the level of phospho- HGF-R (c-MET), as measured by phospho -receptor tyrosine kinase array.
  • Figures 2, 3 and 4 c-MET inhibtion prevents HGF attenuation of PKC pharmacological inhibtion in vitro in uveal melanoma cell line 92.1.
  • Figures 2, 3 and 4 show a closer look at the pattern of synergy between the AEB071 (COMPOUND A) and COMPOUND B in the 92.1 uveal melanoma cell line, and displays the synergistic effect between the two agent.
  • the dose matrix between the two agents is shown; the effect on cell growth relative to untreated cells is shown in the panel (i), the excess inhibition (HAS) in the panel (ii) and the growth inhibition relative to day zero normalization is shown in panel (iii).
  • the present invention provides pharmaceutical combinations comprising: (a) a protein kinase C (PKC) inhibitor, or a pharmaceutically acceptable salt thereof, and (b) at least one c- MET receptor tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable carrier.
  • PLC protein kinase C
  • the present invention relates to such pharmaceutical combinations for simultaneous, separate or sequential administration, in particular for use in the treatment or prevention of a proliferative disease.
  • the term “combination” or “pharmaceutical combination” is defined herein to refer to either a fixed combination in one dosage unit form, a non-fixed combination or a kit of parts for the combined administration where the PKC inhibitor, e.g. COMPOUND A, or a pharmaceutically acceptable salt thereof, and at least one c-MET receptor tyrosine kinase inhibitor, e.g. COMPOUND B or COMPOUND C, or a pharmaceutically acceptable salt thereof, may be administered simultaneously, independently at the same time or separately within time intervals that allow that the combination partners to show a cooperative, e.g. synergistic, effect.
  • the term "fixed combination” means that the active ingredients, e.g.
  • non-fixed combination means that the active ingredients, e.g. COMPOUND A, or a pharmaceutically acceptable salt thereof, and a combination partner, e.g. COMPOUND B, or a
  • a protein kinase C inhibitor is defined herein to refer to a compound which targets, decreases or inhibits protein kinase C.
  • PKC generally refers to the entire family of isoforms: conventional iso forms; alpha, beta ( ⁇ and ⁇ 2) and gamma, novel isoforrns; delta, epsilon, eta, and theta, and atypical isoforms; zeta, and tau/lambda.
  • Suitable PKC inhibitors include maleimide derivatives, such as compounds described in US Patent Nos. 5,545,636; 5,668,152; 5,672,681; 5,698,578; 5,710,145; 6,645,970; 7,220,774; 7,235,555; US Publication No. 2008/0318975; European Patent Nos. 0776895 Bl ; 0817627 B l ; 1449529 B 1 ; 1337527 B l ; and PCT Publication Nos. WO03/082859; and
  • PKC inhibitors of interest include sotrastaurin (also known as AEB071 and described in US Patent No. 6,645,970),
  • PKC inhibitors may be sel ected from the group consi sting of AD 198, aprinocarsen, balanol, bryostatin 1 , balphostin, cedefingol, CGP 53353, chelerythrine chloride, cycloplatam, delcasertib, enzastaunn, EP 70905, GF 1 09203X, gnidimacrm, GO 6976, GO 7716, GO 7775, GO 7852, HO 0303, ingenol mebutate, ISI 641 , JTV 519, KAI 1678, LY 290181 , LY 317644, midostaurin, NA 0345, NPC 15437, NSC 639365, NSC 639366, NSC 646958, p XSC, RD 65071 , RO 31 7549, RO 31 8220, RO 318425, RO 31 8830, RO 320432, Safingol
  • a c-MET receptor tyrosine kinase inhibitor is defined herein to refer to a compound which targets, decreases or inhibits the c-MET pathway.
  • composition is defined herein to refer to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human, in order to prevent or treat a particular disease or condition affecting the mammal or human.
  • pharmaceutically acceptable is defined herein to refer to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues a subject, e.g., a mammal or human, without excessive toxicity, irritation allergic response and other problem
  • co-administration or “combined administration” as used herein is defined to encompass the administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • treating comprises a treatment relieving, reducing or alleviating at least one symptom in a subject or effecting a delay of progression of a disease.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradi cation of a disorder, such as cancer.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
  • protection is used herein to mean prevent delay or treat, or all, as appropriate, development or continuance or aggravation of a disease in a subj ect, e.g., a mammal or human.
  • prevent comprises the prevention of at least one symptom associated with or caused by the state, disease or disorder being prevented.
  • jointly therapeutically active or “joint therapeutic effect” as used herein means that the therapeutic agents may be given separately (in a chronologically staggered manner, especially a sequence-specific manner) in such time intervals that they prefer, in the warm-blooded animal, especially human, to be treated, still show a (preferably synergistic) interaction (joint therapeutic effect). Whether this is the case can, inter alia, be determined by following the blood levels, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals.
  • pharmaceutically effective amount or “clinically effective amount” of a combination of therapeutic agents is an amount sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the disorder treated with the combination.
  • synergistic effect refers to action of two therapeutic agents such as, for example, a compound of formula (I), e.g.. Compound A, and a c-MET inhibitor compound of the present invention, e.g., Compound B, producing an effect for example, slowing the symptomatic progression of a proliferative disease, particularly cancer, or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves.
  • a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet.
  • subject or “patient” as used herein includes animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer.
  • subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits rats and transgenic non-human animals.
  • the subj ect is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from cancers.
  • compositions of the present invention may include compound 3 - (7.H -indol-3 -yl)-4-f2-(4-methyl-piperazin-l -yl)-quinazolin-4-yl]-pyrfole-2,5-dione
  • COMPOUND A is a protein kinase C (PKC) inhibitor of Formula I
  • COMPOUND A is described in WO02/38561 and US Patent No. 6,645,970, The synthesis of COMPOUND A and its acetate salt is described at Example 56 of WO WOG2/38561 , which is hereby incorporated by reference in its entirety.
  • salts or “salts” is understood to be a salt of COMPOUND A that can be present alone or in mixture with the free compound of Formula (I) and are preferably pharmaceutically acceptable salts.
  • Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from the compound of Formula (I) with a basic nitrogen atom, especially the pharmaceutically acceptable salts.
  • Suitable inorganic acids are, for example, halogen acids, such as
  • hydrochloric acid sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, e.g., carboxylic acids or sulfonic acids, such as acetic acid, fumaric acid or methansulfonic acid.
  • pharmaceutically unacceptable salts for example picrates or perchlorates.
  • pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
  • any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.
  • the salts of COMPOUND A are preferably pharmaceutically acceptable salts; suitable counter -ions forming pharmaceutically acceptable salts are known in the field.
  • a most preferred salt of the COMPOUND A is the acetate salt.
  • compositions of the present invention may include a c-MET receptor tyrosine kinase inhibitor which is selected from the group consisting of the MET tyrosine kinase inhibitors disclosed in WO 2011/018454 (incorporated herein by reference especially with regard to the classes of compoounds and compounds disclosed therein) are a particular embodiment, especially those of the formula (I),
  • Y is C or N
  • X is CH or N
  • B is CH or N
  • A is a ring
  • R 1 is a roup selected from i, ii and iii:
  • R ' is heteroaryl
  • R 6 is hydrogen, deuterium, OH, methyl or halo
  • R' is hydrogen, deuterium, halo, or (C 1 -C-3)alkyl, wherein said (C 1 -C3)alkyl is optionally substituted by one or more substituents independently selected from OH and halo;
  • n 0, 1 or 2;
  • R 2 is hydrogen, NH 2 , or (C] -C4)alkyi, wherein said (C 1 -C4)alkyl is optionally substituted by one or more substituents independently selected from OH, NH 2 and halo;
  • R' IS hydrogen, -CONH 2 , -CONH(C 1 -C4)alkyl, -CONHphenyl, wherein the phenyl of said CONHphenyl is optionally substituted by one or more halo, -(Ci -C4)alkyl, -CO(Ci -C4)aikyl, C0 2 (Ci -C 4 )alkyl, phenyl, heteroaryl, -CGheteroaryi, -CSNH 2 , -CSNH(Ci-C 4 )alkyl, - CSNHbenzyl, -S02(Ci-C 4 )alkyl or -COCH 2 heterocyclyl, said heterocyclyl being optionally substituted by (C3 ⁇ 4 -C3)alkyi;
  • A is N or CR 3 ;
  • Cy 1 is ary!, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1 , 2, 3, 4, or 5 --W-X-Y-Z;
  • Cy 2 is ary!, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 -W'-X'-Y'-Z';
  • L 1 is (CR 4 R 5 ) ffl , (CR 4 R 5 )p-(c cloalkylene)-(CR 4 R 5 ) q , (CR 4 R'V(arylene
  • L 2 is (CR 7 R 8 ) r , (CR 7 R 8 ) s -(cycloalkyiene)-(CR 7 R s ) t , (CR 7 R 8 ) s -(arylene)-(CR 7 R 8 ) t , (CR 7 R 8 ) s -(heterocycloalkylene)-(CR 7 R 8 ) t , (CR 7 R 8 ) s -(heieroarylene)-(CR 7 R 8 ) t ,
  • R 2 is H, halo, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C w haloalkyi, ,CN, N0 2 , ()R A , SR A , C(0)R B C(())NR C R D , C(0)()R A , OC(0)R B , OC(0)NR c R D , NR C R D , NR c C(0)R B , NR c C(0)NR c R D , NR c C(0)()R A , S(())R B , S(0)NR c R D , S(0) 2 R B , NR c S(0) 2 R B , or
  • R 3 is H, cycloalkyl, aryl, heterocycloalkyl, heieroaryl, halo, Ci-6 alkyl, C 2 -6 alkenyl, C 2 . 6 alkynyl, Ci_ 6 haloalkyi, ,CN, N0 2 , OR A , SR A , C(0)R B , C(())NR C R D , C(0)OR A ,
  • cycloalkyl, aryl, heterocycloalkyl, heieroaryl, or C ⁇ _6 alkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from Cy 5 , halo, Ci-6 alkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, Ci-6 haloalkyi, halosulfanyi, CN, N0 2 , N 3 , OR ai , SR ai , C(0)R b3 ⁇ 4 , C(0)NR c3 ⁇ 4 R d3 ⁇ 4
  • R 2 and -L 2 ⁇ Cy z are linked together to form a group of formula:
  • ring B is a fused aryl or fused heteroaryl ring, each optionally substituted with 1 , 2, or 3 -W' -X'-Y' -Z' ;
  • R 4 and R 5 are independently selected from H, halo, OH, Ci-e alkyl, C 2 -e> alkenyl, C 2 -6 alkynyl, Ci_6 alkoxy, alkoxyalkyl, cyanoalkyl, heterocycloalkyl, cycloalkyl, Ci_6 haloalkyl, CN, and N0 2 ;
  • R 4 and R "' together with the C atom to which they are attached form a 3, 4, 5, 6, or 7-membered cycloalkyl or heterocycloalkyl ring, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, OH, C 1 -6 alkyl, C 2 _ & alkenyl, C 2-6 alkynyl, C 1 -6 alkoxy, alkoxyalkyl, cyanoalkyl, heterocycloalkyl, cycloalkyl, C 1-6 haloalkyl, CN, and N0 2 ;
  • R 6 is H, Ci_6 alkyl, C 2- 6 alkenyl, or C 2-6 alkynyl;
  • R 7 and R 8 are independently selected from H, halo, OH, C ⁇ alkyl, C 2-6 alkenyl, C 2 _6 alkynyl, Ci_ 6 alkoxy, C 1-6 haloalkyl, CN, and N0 2 ;
  • R 9 is H, d-6 alkyl, C 2-6 alkenyl, or C2.6 alkynyl;
  • W, W, and W" are independently absent or independently selected from C 1 -6 alkylene, C 2 . 6 alkenylene, C 2 . 6 alkynylene, O, S, NR h , CO, COO, CONR h , SO, S0 2 , SONR h and NR h CONR l , wherein each of the Cj-6 alkylene, Ci-e alkenylene, and C 2-6 alkynylene is optionally substituted by 1 , 2 or 3 substituents independently selected from halo, C i .6 alkyl, Cj-6 haloalkyl, OH, haloalkoxy, amino, C 1 -6 alkylamino, and C 2-8 dialkylamino;
  • X, X', and X" are independently absent or independently selected from C i-6 alkylene, C 2 ..6 alkenylene, C 2 . 6 alkynylene, arylene, cycloalkylene, heteroaryl ene, and
  • heterocycloalkylene wherein each of the Ci-6 alkylene, C?..e alkenylene, C?-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkyl ene is optionally substituted by 1 , 2 or 3 substituents independently selected from halo, CN, N0 2 , OH, Cj .6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C ⁇ alkoxy, C i ⁇ haloalkoxy, C 2- 8 alkoxyalkoxy, cycloalkyl,
  • Y, Y', and Y" are independently absent or independently selected from C 1 -6 alkylene
  • Ci.e alkylene, C 2 .. 6 alkynylene O, S, NR h , CO, COO, CONR h , SO, S0 2 , SONR h , and NR h CONR l , wherein each of the Ci.e alkylene, C 2-6 alkenylene, and C 2 ..6 alkynylene is optionally substituted by 1 , 2 or 3 substituents independently selected from halo, C 1-6 alkyl, Ci geometry6 haloalkyl, OH, Ci-e alkoxy, Ci. 6 haloalkoxy, amino, Ci.e alkylamino, and C 2 .g dialkylamino;
  • Z, Z' , and Z" are independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyi, CN, N0 2 , N 3 , OR 32 , SR a2 , C(0)R 2 , C(())NR c2 R d2 , C(0)OR a2 , OC(0)R 2 , OC(0)NR c2 R d2 , NR c R d2 , NR c2 C(0)R 2 , NR c2 C(0)NR c2 R d2 ,
  • two adjacent -W-X-Y-Z together with the atoms to which they are attached, optionally form a fused 4-20 membered cycloalkyl ring or a fused 4-20 membered heterocycloalkyl ring, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci_6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyi, CN, N0 2 , OR 33 , SR 33 , C(0)R 3 , C(0)NR c3 R d3 , C(0)OR a3 , ()C(0)R 3 , ()C(0)NR c3 R d3 , NR c R d3 , N - ; C(() ⁇ h ; .
  • R A is H, Ci-4 alkyl, C 2- 4 alkenyl, CM aikynyl, cycloalkyl, heterocycloalkvl, aryl, or heteroaryl wherein said Cj .4 alkyl, C 2 .4 alkenyl, C 2 .4 aikynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optional ly substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, and C 1 .4 alkyl;
  • R B is H, Ci-4 alkyl, C 2 _4 alkenyl, C 2- 4 aikynyl, cycloalkyl, heterocycloalkyl , aryl, or heteroaryl wherein said Ci-4 alkyl, C 2 -4 alkenyl, or CM aikynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, ammo, halo, and C alkyl;
  • R c and R D are independently selected from H, C alkyl, C 2- 4 alkenyl, or C 2 -4 aikynyl, wherein said C alkyl, C 2- 4 alkenyl, or C 2- 4 aikynyl, is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, and C alkyl;
  • R c and R D together with the N atom to which they are attached form a 4 -, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, ammo, halo, and C i-4 alkyl;
  • R A , R A! , R a2 , R a3 , and R A4 are independently selected from H, Ci- 6 alkyl, C 5 . 6 haloalkyl, C 2 -6 alkenyl, C 2 . 6 aikynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, aryl alkyl, heieroarylalkyi, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said Cj -6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 aikynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heieroarylalkyi, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN
  • R b , R bl , R B Z , R 3 , and R 4 are independently selected from H, C i. 6 alkyl, Ci. 6 haloalkyl, C 2-6 alkenyl, C 2-6 aikynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said d-6 alkyl, d-6 haloalkyl, C 2 -6 alkenyl, -6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycioalkyi, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, d-6 al
  • R c and R d are independently selected from H, C MO alkyl, d-6 haloalkyl, C 2-6 alkenyl , C 2- 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycioalkyi, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Cwo alkyl, Ci .6 haloalkyl, C 2 ⁇ alkenyl, C 2 .6 alkynyl, aryl , heteroaryl, cycloalkyl, heterocycioalkyi, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, d-6 alkyl, d-6 alkoxy, d-6
  • R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycioalkyi group or heteroaryl group, each optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, d-6 alkyl, d -6 alkoxy, C 1-6 haloalkyl, and C 1-6 haioalkoxy;
  • R cl and d! are independently selected from H, CMO alkyl, -6 haloalkyl, d-6 alkenyl, -6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycioalkyi, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci-10 alkyl, -6 haloalkyl, d-6 alkenyl, d-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycioalkyi, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, d-6 alkyl, d-6 alkoxy, d-6 haloalkyl, and Ci-
  • R l and R dl together with the N atom to which they are attached form a 4 -, 5-, 6- or 7-membered heterocycioalkyi group or heteroaryl group, each optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, d-6 alkyl, d-6 alkoxy, d-6 haloalkyl, and d-6 haioalkoxy;
  • R c2 and R d2 are independently selected from H, C O alkyl, d _6 haloalkyl, -6 alkenyl, d-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycioalkyi, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aiyl cycloalkyl, aryiheterocycloalkyi, arylheteroaryi, biaryl, heteroaiylcycloalkyi, heteroaryiheterocycloalkyi, heteroarylaryl, and biheteroaryl, wherein said C O alkyl, Ci- haloalkyl, d-6 alkenyl, d-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycioalkyi, arylalkyl, heteroarylalkyl
  • R CJ and R d3 are independently selected from H, Ci-io alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C 2 .6 alkynyl, aryl , heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloal kylalkyl, wherein said C w alkyl, C 1-6 haloalkyl, C 2 _& alkenyl, C 2 .6 alkynyl, aryl , heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkyl alkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1 ..6 alkoxy, C
  • R c3 and R d3 together with the N atom to which they are attached form a 4 -, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, C i-6 alkyl, Ci_6 alkoxy, Ci-6 haloalky l, and C 1 -6 haloalkoxy;
  • R a and d4 are independently selected from H, CMO alkyl, Ci- ⁇ haloalkyl, C 2 -6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said Ci- 10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaiyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci-6 alkyl, C 1-6 alkoxy, C 1 -5 haloalkyl, and Ci
  • R 4 and R d4 together with the N atom to which they are attached form a 4 -, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, Cj-6 alkoxy, Ci-6 haloalkyl, and C 1-6 haloalkoxy;
  • R e , R e ! , R e2 , and R e4 are independently selected from H, C i_s alkyl, Ci equally6 haloalkyl, C 2 -6 alkenyl, (Ci _ 6 alkoxy)-C 1 - 6 alkyl, C 2 -6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl; R f , R f!
  • R n , and R f4 are independently selected from H, alkyl, C 1-6 haloalkyl, i- alkenyi C'2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkvl;
  • R g isH, CN,andN0 2 ;
  • R h and R 1 are independently selected from H and Cj.e alkyl
  • R J isH, Ci-6 alkyl, C 1-6 haloalkyl, C 2 _3 ⁇ 4 alkenyi, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkvl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • p 0, 1, 2, 3, or 4;
  • r is 0, I, 2, 3, 4, 5, or 6;
  • s 0, i, 2, 3, or 4;
  • the compounds of formula III useful according to the invention have Formula IIIA:
  • the compounds of formula III useful according to the invention have Formula ⁇ :
  • A is CH or N, especially N;
  • L 1 is (CR 4 R 3 ) ra wherein each of R 4 and R 5 , independently of the other, is H or Ci-e-alkyl and m is 0.1 or 2.
  • L 2 is (CR 'R 8 ) r wherein each of R 7 and R 8 , independently of the other, is H or Ci-6-alkyl and r is 0, 1 or 2,
  • R ! is H, halo or C 1 -6 -alkyl
  • R 2 is H, halo or Ci-6-alkyl
  • Such other MET inhibitors are, for example, selected from the following (including their pharmaceutically acceptable salts, and prodrugs thereof):
  • cabozantinib (Exelixis) (aka XL-184) (a highly preferred compound) which has the formula
  • tivatinib (ArQu!e, daiichi, Kyovva) (aka ARQ-197) (a highly preferred compound) which has the formula
  • MGCD-265 (MethylGene) (a highly preferred compound) which has the formula
  • AMG-208 (Amgen) (see also WO 2008/008539) which has the formula
  • JNJ-38877605 (Johnson & Johnson) (aka BVT051 ) (see also WO 2007/075567) which has the formula
  • EMD-1214063 (Merck Serono) (see also WO 2007/019933) which has the formula
  • amuvatinib (SuperGen) (ak -470) which has the formula
  • HM-5016504 Human Medipharma
  • ficlatuzumab (AVEO) monoclonal antibody against HGF (preferred); onartuzumab (Roche) monoclonal antibody against MET (preferred); rilotuzumab (Amgen) monoclonal antibody against HGF (preferred); Tak-701 (Takeda) monoclonal antibody against HGF); LA-480 (Eli Lilly) monoclonal antibody against MET; and/or LY.2875358 (Eli Lilly) monoclonal antibody against MET.
  • the c-MET receptor tyrosine kinase inhibitor used in the combination of the present invention is selected from the group consisting of 2-fluoro-N-methyl-4-[(7- quinolin-6-yl-methyl)-imidazo[l,2-b]triazin-2-yl]benzamide (COMPOUND B),
  • the c-MET inhibitor used in the combination of the present invention is 2- fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[l ,2-b]triazin-2-yl]benzamide
  • salts As related to the c-MET receptor tyrosine kinase inhibitors, the term “salt” or “salts”, unless otherwise indicated, includes salts of acidic and basic groups which may be present in the compounds of the present invention.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiet' by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Prefered pharmaceutically acceptable salts of COMPOUND B suitable for the present invention include the salts disclosed in PCX Application No. WQ2009/143211 , which is hereby incorporated into the present application by reference Especially prefered
  • compositions of COMPOUND B suitable for the present invention include the dihydrochronic acid or dibenzenesulfonic acid salts.
  • reference to therapeutic agents useful in the pharmaceutical combination of the present invention includes both the free base of the compounds, and all pharmaceutically acceptable salts of the compounds.
  • a pharmaceutical combination which comprises (a) a PKC inhibitor, or a
  • This term is also taken to mean a pharmaceutical combination which consists of (a) a PKC inhibitor, or a pharmaceutically acceptable salt thereof, and (b) one c-MET receptor tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier, wherein the PKC inhibitor and the c-MET receptor tyrosine kinase inhibitor are the sole therapeutic agents.
  • An example of a COMBINATION OF THE IN VENTION is a pharmaceutical combination which comprises (a) a PKC inhibitor which is 3 -(7.H. -indol-3-yl)-4-[2-(4-methyl-piperazin-l - yl)-quinazolin-4-yl]-pyrrole-2,5-dione (COMPOUND A), or a pharmaceutically acceptable salt thereof, and (b) at least one c-MET receptor tyrosine kinase inhibitor which is selected from the group consisting of 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[l,2- b]triazin-2 » yl]benzamide (COMPOUND B); (E)-2-(l -(3-((7-fluoroquinolin-6- yl)niethyl)imidazo[l,2-b]pyridazin-6-yl)ethylidene)hydr
  • SGX523 (SGX), or a pharmaceutically acceptable salt thereof, and optionally a
  • the combination partners are (a) a PKC inhibitor which is 3-(7.H. -indol-3-yl)-4-[2-(4-methyl-piperazin-l-yl)-quinazolin-4-yl]- pyrrole-2,5-dione (COMPOUND A), or a pharmaceutically acceptable salt thereof, and (b) a c-MET receptor tyrosine kinase inhibitor which is selected from the group consisting of 2- fluoro-N-methyl ⁇ 4 (7 -quinolin-6 tyl -m
  • the combination partners are (a) a PKC inhibitor which is 3 -(7.H. -indol-3 -yl)-4-[2-(4-methyl-piperazin-l -yl)- quinazolin-4-yl]-pyrrole-2,5-dione (COMPOUND A), or a pharmaceutically acceptable salt thereof, and (b) a c-MET receptor tyrosine kinase inhibitor (E) ⁇ 2 ⁇ (l -(3-((7-fluoroquinolin-6- yl)methyl)imidazo[l,2-b]pyridaan-6-yl)ethy (COMPOUND C), or a pharmaceutically acceptable salt thereof.
  • a PKC inhibitor which is 3 -(7.H. -indol-3 -yl)-4-[2-(4-methyl-piperazin-l -yl)- quinazolin-4-yl]-pyrrole-2,5-dione
  • the combination partners are (a) a PKC inhibitor which is 3-(7.H. -indol-3-yl)-4-[2-(4-methyl-piperazin-l-yl)-quinazolin-4-yl]- pyrrol e-2, 5 ⁇ di one (COMPOUND A), or a pharmaceutically acceptable salt thereof, and (b) a c-MET receptor tyrosine kinase inhibitor 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)- imidazo[l,2 ⁇ b]triaziii"2 ⁇ yl]benzaniide (COMPOUND B), or a pharmaceutically acceptable salt thereof,
  • the present invention also pertains to a combined preparation or a pharmaceutical composition
  • a PKC inhibitor e.g. 3-(i.H. -indol-3-yl)-4-[2-(4-methyl- piperazin-l -yl)-quinazolin-4-yl]-pyiTole-2,5-dione (COMPOUND A), or a pharmaceutically acceptable salt thereof
  • a c-MET receptor tyrosine kinase inhibitor which is selected from the group consisting of 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[l,2- b]triazm-2-yl]benzamide
  • COMPOUND B 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[l,2- b]triazm-2-yl]benzamide
  • E -2-(l ⁇ (3-((7-fluoroqumolm-6-
  • SGX523 (SGX), or a pharmaceutically acceptable salt thereof, and mixtures thereof, and optionally a pharmaceutically acceptable carrier.
  • the present invention relates to a combined preparation which comprises: (i) one or more unit dosage forms of combination partner (a), and (ii) one or more unit dosage forms of combination partner (b).
  • the present invention particularly pertains to a COMBINATION OF THE
  • INVENTION is used for the treatment or prevention of a proliferative disease comprising administering to the subject a combination therapy, comprising an effective amount of a PKC inhibitor, e.g. 3-(7.H. -indol-3-yl)-4-[2-(4-methyl-piperazin-l -yl)-quinazolin-4-yl]-pyrrole- 2,5-dione (COMPOUND A), or a pharmaceutically acceptable salt thereof, and a c-MET receptor tyrosine kinase inhibitor, which is selected from the group consisting of 2-fiuoro-N- methyl -4-[(7-quinolin-6-yl-methyl)-imidazo[l,2-b]triazin-2-yl]benzamide (COMPOUND B); (E) ⁇ 2-(l -(3 -((7-fluoroquinolin-6-yl)methyl)imidazo[l ,2 ⁇ b]pyridazm-6- y
  • the proliferative disease is a melanoma, e.g. uveal melanoma, metastatic uveal melanoma, and GNAQ or GNA11 mutant uveal melanoma. It will be understood that the COMBINATION OF THE INVENTION may be used solely for the treatment of a proliferative disease in accordance with the present invention.
  • the combination therapy comprising the COMBINATION OF THE INVENTION results in unexpected improvement in the treatment or prevention of proliferative diseases as compared to the monotherapy.
  • a pharmaceutical combination of the invention may result not only in a beneficial effect, e.g. a synergistic therapeutic effect, e.g. with regard to alleviating, delaying progression of or inhibiting the symptoms, but also in further surprising benefi cial effects, e.g. fewer side-effects, an improved quality of life or a decreased morbidity, compared with a monotherapy applying only one of the pharmaceutically therapeutic agents used in the combination of the invention.
  • a further benefit is that lower doses of the therapeutic agents of the COMBINATION OF THE INVENTION can be used, for example, that the dosages need not only often be smaller, but are also applied less frequently, or can be used in order to diminish the incidence of side-effects observed with one of the combination partners alone. This is in accordance with the desires and requirements of the patients to be treated.
  • Suitable clinical studies are in particular, for example, open label, dose escalation studies in patients with a proliferative diseases. Such studies prove in particular the synergism of the therapeutic agents of the COMBINATION OF THE INVENTION.
  • the beneficial effects on proliferative diseases may be determined directly through the results of these studies which are known as such to a person skilled in the art.
  • Such studies may be, in particular, be suitable to compare the effects of a monotherapy using either therapeutic agent and a COMBINATION OF THE INVENTION.
  • the dose of the PKC inhibitor is escalated until the Maximum Tolerated Dosage is reached, and a c-MET receptor tyrosine kinase inhibitor of the present invention is administered with a fixed dose.
  • the PKC inhibitor e.g. COMPOUND A
  • the dose of the c- MET receptor tyrosine kinase inhibitor of the present invention may be escalated.
  • Each patient may receive doses of the PKC inhibitor and/or a c-MET receptor tyrosine kinase inhibitor of the present invention either daily or intermittently.
  • the efficacy of the treatment may be determined in such studies, e.g., after 12, 18 or 24 weeks by evaluation of symptom scores, e.g. every 6 weeks.
  • the c-MET receptor tyrosine kinase inhibitor is N-MET receptor tyrosine kinase inhibitor
  • the c-MET receptor tyrosine kinase inhibitor is COMPOUND B. In a preferred embodiment, the c-MET receptor tyrosine kinase inhibitor is
  • COMPOUND C or a pharmaceutically acceptable salt thereof.
  • the c-MET receptor tyrosine kinase inhibitor is COMPOUND C.
  • the optimum range for the effect and absolute dose ranges of each component for the effect may be definitively measured by administration of the components over different w/w ratio ranges and doses to patients in need of treatment.
  • INVENTION comprises a PKC inhibitor which is 3 -(i.H. -indol-3 -yl)-4-[2-(4-methyl- piperazin-l -yl)-quinazolin-4-yll-pyrrole-2,5-dione (COMPOUND A), or a pharmaceutically acceptable salt thereof, and a c-MET receptor tyrosine kinase inhibitor which is selected from the group consisting of 2-fiuoro-N-methyl-4- (7-quinoiin-6-yl-methyl)-irmdazo[l,2-b]triazin- 2-yi]benzamide (COMPOUND B); (E)-2-(l -(3-((7-fluoroquinolin-6-yl)methyl)imidazo[l,2- b]pyridazin-6-yl)ethylidene)hydrazine-carboxamide (COMPOUND C);
  • a proliferative disease e.g. uveal melanoma, metastatic uveal melanoma, and GNAQ or GNAl 1 mutant uveal melanoma, preferably uveal melanoma harboring mutations in either GNAQ or GNAl 1.
  • a proliferative disease e.g. uveal melanoma, metastatic uveal melanoma, and GNAQ or GNAl 1 mutant uveal melanoma, preferably uveal melanoma harboring mutations in either GNAQ or GNAl 1.
  • the present invention provides a synergistic combination for human administration comprising (a) a PKC inhibitor which is 3 -(7.H. -indol-3-yl)-4-[2-(4-methyl- piperazin-l -yl)-quinazolin-4-yl]-pyrrole-2,5-dione (COMPOUND A), or a pharmaceutically acceptable salt thereof!, and (b) a c-MET receptor tyrosine kinase inhibitor of the present invention, preferably COMPOUND B, or a pharmaceutically acceptable salt thereof, in a combination range (w/w) which corresponds to the ranges observed in a tumor model, e.g., as described in the Examples below, used to identity a synergistic interaction.
  • a PKC inhibitor which is 3 -(7.H. -indol-3-yl)-4-[2-(4-methyl- piperazin-l -yl)-quinazolin-4-yl]-pyrrol
  • the present invention provides a synergistic combination for human administration comprising (a) a PKC inhibitor which is 3 -(i.H. -indol-3-yl)-4-[2-(4-methyl- piperazm -yl)-quinazolin-4-yi]-pyrroie-2,5-dione (COMPOUND A), or a pharmaceutically acceptable salt thereof, and (b) a c-MET receptor tyrosine kinase inhibitor of the present invention, preferably COMPOUND B, or a pharmaceutically acceptable salt thereof, in a combination range (w/w) which corresponds to the ranges observed in a tumor model, e.g., as described in the Examples below, used to identify a synergistic interaction.
  • a PKC inhibitor which is 3 -(i.H. -indol-3-yl)-4-[2-(4-methyl- piperazm -yl)-quinazolin-4-yi]-pyrroie
  • the present invention provides a synergistic
  • a PKC inhibitor which is 3 -(i.H - indol-3-yl)-4-[2-(4-methyl-piperazin-l-yl)-quinazolin-4-yl]-pyrrole-2,5-dione (COMPOUND A), or a pharmaceutically acceptable salt thereof
  • a c-MET receptor tyrosine kinase inhibitor of the present invention preferably COMPOUND B, or a pharmaceutically acceptable salt thereof
  • the dose range of each component corresponds to the synergistic ranges observed in a suitable tumor model, e.g., the tumor models described in the Examples below, primarily used to identify a synergistic interaction.
  • It is one objective of this invention to provide a pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against a proliferative disease comprising the COMBINATION OF THE INVTiNTION.
  • the combination partners (a) and (b) can be either administered in a single formulation or unit dosage form, administered concurrently but separately, or administered sequentially by any suitable route.
  • the unit dosage form may also be a fixed combination.
  • compositions for separate administration of both combination partners, or for the administration in a fixed combination may be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including humans, comprising a therapeutically effective amount of at least one pharmacologically active combination partner alone, e.g. as indicated above, or in combination with one or more pharmaceutically acceptable earners, especially suitable for enteral or parenteral application.
  • the novel pharmaceutical composition contains may contain, from about 0.1 % to about 99.9%, preferably from about 1 % to about 60 %, of the therapeutic agent(s).
  • Suitable pharmaceutical compositions for the combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of various conventional mixing, comminution, direct compression, granulating, sugar-coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those skilled in the art. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount may be reached by administration of a plurality of dosage units.
  • a unit dosage form containing the combination of agents or indiv dual agents of the combination of agents may be in the form of micro-tablets enclosed inside a capsule, e.g. a gelatin capsule.
  • a gelatin capsule as is employed in pharmaceutical formulations can be used, such as the hard gelatin capsule known as CAPSUGEL, available from Pfizer.
  • the unit dosage forms of the present invention may optionally further comprise additional conventional carriers or excipients used for pharmaceuticals.
  • additional conventional carriers or excipients used for pharmaceuticals include, but are not limited to, disintegrants, binders, lubricants, glidants, stabilizers, and fillers, diluents, colorants, flavours and preservatives.
  • disintegrants include, but are not limited to, disintegrants, binders, lubricants, glidants, stabilizers, and fillers, diluents, colorants, flavours and preservatives.
  • One of ordinary skill in the art- may select one or more of the aforementioned carriers with respect to the particular desired properties of the dosage form by routine experimentation and without any undue burden.
  • the amount of each carriers used may vary within ranges conventional in the art.
  • the following references which are all hereby incorporated by reference disclose techniques and excipients used to formulate oral dosage forms.
  • These optional additional conventional carriers may be incorporated into the oral dosage form either by incorporating the one or more conventional carriers into the initial mixture before or during granulation or by combining the one or more conventional carriers with granules comprising the combination of agents or individual agents of the combination of agents in the oral dosage form.
  • the combined mixture may be further blended, e.g., through a V-blender, and subsequently compressed or molded into a tablet, for example a monolithic tablet, encapsulated by a capsule, or filled into a sachet.
  • dismtegrants examples include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, e.g., POLYPLASDONE XL from International Specialty Products (Wayne, NJ); cross-linked sodium carboxymethylcellulose or
  • croscarmellose sodium e.g., AC-DI-SOL from FMC; and cross-linked calcium
  • the disintegrant may be present in an amount from about 0% to about 10% by weight of the composition. In one embodiment, the disintegrant is present in an amount from about 0.1% to about 5% by weight of composition.
  • binders examples include, but are not limited to, starches; celluloses and derivatives thereof, for example, microcrystailine cellulose, e.g., A TCEL PH from FMC (Philadelphia, PA), hydroxypropyl cellulose hydroxy!ethy! cellulose and hydroxylpropylmethyl cellulose METHOCEL from Dow Chemical Corp. (Midland, MI); sucrose; dextrose; corn syrup; polysaccharides; and gelatin.
  • the binder may be present in an amount from about 0% to about 50%, e.g., 2-20% by weight of the composition.
  • Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium tnsilicate, starches, talc, tnbasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystailine cellulose.
  • the lubricant may be present in an amount from about 0% to about 10% by weight of the composition. In one embodiment, the lubricant may be present in an amount from about 0.1% to about 1.5% by weight of composition.
  • the glidant may be present in an amount from about 0.1 % to about 10% by weight.
  • Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystailine cellulose, powdered cellulose, sorbitol, sucrose and talc.
  • the filler and/or diluent e.g., may be present in an amount from about 0% to about 80% by weight of the composition.
  • the present invention also pertains to a COMBINATION OF
  • TFIE INVENTION for use in the preparation of a pharmaceutical composition or medicament for the treatment or prevention of a proliferative disease in a subject in need thereof.
  • the present invention pertains to the use of a PKC inhibitor which is 3 -(l.H.
  • a pharmaceutical composition or medicament for the preparation of a pharmaceutical composition or medicament for the treatment or prevention of a proliferative disease in a subject in need thereof.
  • Preferred is a c-MET receptor tyrosine kinase inhibitor which is 2- fluoro-N-methyl-4-[(7-quinolin-6-yl-m
  • a therapeutically effective amount of each of the combination partner of the COMBINATION OF THE INVENTION may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination.
  • the method of treating a proliferative disease according to the invention may comprise (i) administration of the first agent (a) in free or pharmaceutically acceptable salt form and (ii) administration of an agent (b) in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g. in daily or intermittently dosages corresponding to the amounts described herein.
  • the individual combination partners of the COMBINATION OF THE INVENTION may be administered separately at different times during the course of therapy or
  • administering also encompasses the use of a pro-drug of a combination partner that convert in vivo to the combination partner as such.
  • the instant invention is therefore to be understood as embracing all such regimens of simultaneous or alternating treatment and the term
  • administering is to be interpreted accordingly.
  • the effective dosage of each of the combination partners employed in the COMBINATION OF THE INVENTION may vary depending on the parti cular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, and the severity of the condition being treated.
  • the dosage regimen of the COMBINATION OF THE INVENTION is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient.
  • a clinician or physician of ordinary skill can readily determine and prescribe the effective amount of the single therapeutic agents required to alleviate, counter or arrest the progress of the condition.
  • the optimum ratios, individual and combined dosages, and concentrations of the combination partners (a) and (b) of the COMBIN ATION OF THE INVENTION that yield efficacy without toxicity are based on the kinetics of the therapeutic agents' availability to target sites, and may be determined using methods known to those of skill in the art.
  • packaged pharmaceutical products may contain one or more dosage forms that contain the combination of compounds, and one or more dosage forms that contain one of the combination of compounds, but not the other compound(s) of the combination.
  • THE INVENTION are applied in the form as marketed as single drugs, their dosage and mode of administration can be in accordance with the information provided on the package insert of the respective marketed drug, if not mentioned herein otherwi se.
  • the PKC inhibitor e.g. COMPOUND A
  • an effective dosage in the range of about 0.05 to about 50 mg per kg body weight per day, preferably about 0.1 -25 mg kg/day, more preferably from about 0.5 - 10 mg/kg ' 'day , in single or divided doses.
  • each combination partner for treatment of a proliferative disease can be determined empirically for each individual using known methods and will depend upon a variety of factors, including, though not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration: and other medications the individual is taking. Optimal dosages may be established using routine testing and procedures that are well known, in the art.
  • each combination partner that may be combined with the carrier materials to produce a single dosage form will vary depending upon the individual treated and the particular mode of administration.
  • the unit dosage forms containing the combination of agents as described herein will contain the amounts of each agent of the combination that are typically administered when the agents are administered alone.
  • Frequency of dosage may vary depending on the compound used and the particular condition to be treated or prevented. In general, the use of the minimum dosage that is sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those of ordinary skill in the art.
  • the present invention relates to a method of treating a subject having a proliferative disease comprising administered to said subject a COMBINATION OF THE INVENTION in a quantity, which is jointly therapeutically effective against a proliferative disease.
  • INVENTION is uveal melanoma, metastatic uveal melanoma, and GNAQ or GNAl 1 mutant uveal melanoma.
  • the present invention further relates to the COMBINATION OF THE INVENTION for use in the treatment of a proliferative disease, particularly cancer, such as uveal melanoma, metastatic uveal melanoma, and GNAQ or GNAl 1 mutant uveal melanoma.
  • a proliferative disease particularly cancer, such as uveal melanoma, metastatic uveal melanoma, and GNAQ or GNAl 1 mutant uveal melanoma.
  • the present invention further provides a commercial package comprising as therapeutic agents COMBINATION OF THE INVENTION, together with instructions for simultaneous, separate or sequential administration thereof for use in the delay of progression or treatment of a proliferative disease in a subject in need thereof.
  • a method for treating a proliferative disease comprising the simultaneous, separate or sequential administration of a therapeutically effective amount of a PKC inhibitor, or a pharmaceutically acceptable salt thereof, in a combination with at least one c-MET receptor tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, to a patient in need thereof having a proliferative disease.
  • a method for treating a proliferative disease comprising the simultaneous, separate or sequential administration of a therapeutically effective amount of the PKC inhibitor 3 - (l.H, -indol -3 -yl) -4 -[2 ⁇ (4 -methyl -pi perazin- 1 -yl) -quinazolin-4 -y 1] -pyrrol e-2, 5 -dione, or a pharmaceutically acceptable salt thereof, in combination with at least one c-MET receptor tyrosine kinase inhibitor selected from the groupgroup consisting of 2-fluoro ⁇ N-methy] -4-[(7-quinolin-6-yl-mei]tyl)-imidazo[l,2-b]triazin-2-yl]benzarnide, (E)-2-(l - (3 ⁇ ((7 ⁇ fluoroquinoiin ⁇ 6 ⁇ yl)methyi)i
  • ficlatuzumab monoclonal antibody against HGF onartuzumab monoclonal antibody against MET, rilotuzumab monoclonal antibody against HGF, Tak-701 monoclonal antibody against HGF, LA-480 monoclonal antibody against c-MET, and/or LY2875358 monoclonal antibody against c-MET, and mixtures thereof, to a patient in need thereof having a proliferative disease.
  • melanoma e.g. uveal melanoma, metastatic uveal melanoma, and GNAQ or GNA1 1 mutant uveal melanoma.
  • a combined preparation comprising (a) one or more unit dosage forms of the PKC inhibitor3 -(l.H. -indol-3 -yl )-4-f 2-(4-methyl-piperazin-l -y l)-quinazolin-4-yl] -pyrrole-
  • a combined preparation comprising (a) one or more unit dosage forms of the PKC inhibitor 3 -(7.H.
  • a commercial package comprising as therapeutic agents a pharmaceutical combination as defined above together with instructions for simultaneous, separate or sequential administration thereof for use in the delay of progression or treatment of a proliferative disease.
  • Uveal melanoma cell line 92.1 is cultured in RPMI 1640 media (ATCC #30-2001) suppl emented with 10% fetal bovine serum (Gibco #10099) and incubated at 37°C/5% C02. Cell proliferatiois in combination dose matrix
  • Cells are seeded at a density of 3000 cells per 100 ⁇ of medium per well in 96 -well plates (Costar #3904) and incubated overnight prior to compound addition. Compound stock is freshly prepared in the appropriate culture medium and manually added to the plates by electronic multichannel pipette in three replicates. Cells are treated with Compound alone or with a combination of COMPOUND A and COMPOUND B diluted 1 :2 for a ten point dilution ranging from 0.039 ⁇ to 10 ⁇ . Cells were also supplemented with lOOng/ml HGF for some experiments, as indicated.
  • the viability of cells is assessed at the time of compound addition and after 144 hours of treatment by quantification of cellular ATP levels via Cell Titer Glo (Promega #G7571) according to the manufacturer's protocol. Plates are read on a luminescence plate reader (Victor X4, Perkin Elmer). Fractional inhibition of growth is calculated using XLfit and normalized to no compound wells. For growth inhibition, day 0 values are subtracted before calculating inhibition. Data is analyzed by Chalice software (http:// chalice.zaii cus. com/documentation/anaiyzer/indexj sp) to calculate growth inhibition, inhibition and HSA excess using methods known in the art.
  • Uveal cells are seeded at 5x10 6 cells per 10 cm plate. After 24 hours, cells are untreated or treated with vehicle or 0.5 ⁇ . ⁇ COMPOUND A for 6 hours. Cells are lysed in M-PER mammalian protein extraction buffer containing PhosStop Phosphatase inhibitor cocktail tablet (Roche Diagnostics #04 906 837 001) and Complete Protease Inhibitor cocktail tablet (Roche Diagnostics # 11 836 145 001). For each sample, 300 micrograms of protein lysate is incubated with the phopho-RTK array and each array is assayed according to the

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Abstract

L'invention concerne une combinaison pharmaceutique à administrer de manière simultanée, distincte ou séquentielle, comprenant (a) un inhibiteur de la protéine kinase C (PKC) ou un sel pharmaceutiquement acceptable de celui-ci, et (b) au moins un inhibiteur du récepteur tyrosine-kinase c-MET ou un sel pharmaceutiquement acceptable de celui-ci, et éventuellement, un excipient pharmaceutiquement acceptable. L'invention concerne également les utilisations d'une telle combinaison pour le traitement de maladies prolifératives, ainsi que des méthodes permettant de traiter un patient atteint d'une maladie proliférative consistant à administrer une quantité thérapeutiquement efficace de ladite combinaison.
PCT/IB2014/060976 2013-04-26 2014-04-24 Combinaisons pharmaceutiques d'un inhibiteur de la pkc et d'un inhibiteur du récepteur tyrosine-kinase c-met WO2014174478A1 (fr)

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* Cited by examiner, † Cited by third party
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WO2022055893A1 (fr) * 2020-09-08 2022-03-17 Ideaya Biosciences Inc. Combinaison pharmaceutique et traitement antitumoral
WO2023107894A1 (fr) * 2021-12-06 2023-06-15 Ideaya Biosciences, Inc. Polythérapie comprenant un inhibiteur de pkc et un inhibiteur de c-met

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022055893A1 (fr) * 2020-09-08 2022-03-17 Ideaya Biosciences Inc. Combinaison pharmaceutique et traitement antitumoral
WO2023107894A1 (fr) * 2021-12-06 2023-06-15 Ideaya Biosciences, Inc. Polythérapie comprenant un inhibiteur de pkc et un inhibiteur de c-met

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