PHARMACEUTICAL COMBINATION COMPRISING AN ALK INHIBITOR AND A SHP2 INHIBITOR

1 . A pharmaceutical combination comprising:

(i) an ALK inhibitor or a pharmaceutically acceptable salt thereof, and

(ii) a SHP2 inhibitor, or a pharmaceutically acceptable salt thereof.

2 . The pharmaceutical combination of claim 1 , further comprising at least one pharmaceutically acceptable carrier.

3 . A pharmaceutical composition comprising a pharmaceutical combination of claim 1 and at least one pharmaceutically acceptable carrier.

4 . The pharmaceutical combination of claim 1 , wherein the ALK inhibitor or pharmaceutically acceptable salt thereof and the SHP2 inhibitor or pharmaceutically acceptable salt thereof are provided in jointly therapeutically effective amounts for use in the treatment of cancer.

5 . The pharmaceutical combination of claim 4 , wherein the ALK inhibitor or pharmaceutically acceptable salt thereof and the SHP2 inhibitor or pharmaceutically acceptable salt thereof are provided in synergistically effective amounts for use in the treatment of cancer.

6 . (canceled)

7 . (canceled)

8 . The pharmaceutical combination claim 4 , wherein the cancer is an ALK-positive cancer selected from anaplastic large-cell lymphoma, gastric cancer, breast cancers, oesophageal cancer, colorectal cancer, neuroblastoma, inflammatory myofibroblastic tumor, renal cancer, pancreatic cancer and lung cancer.

9 . (canceled)

10 . (canceled)

11 . The pharmaceutical combination of claim 4 , wherein the cancer is an ALK-positive cancer resistant to an ALK inhibitor.

12 . (canceled)

13 . The pharmaceutical combination of claim 4 , wherein the cancer is an ALK-positive cancer characterized by ALK-independent resistance to an ALK inhibitor.

14 . (canceled)

15 . (canceled)

16 . (canceled)

17 . A method of treating a cancer in a subject, comprising administering to said subject a therapeutically effective amount of:

(i) an ALK inhibitor or a pharmaceutically acceptable salt thereof, and

(ii) a SHP2 inhibitor or a pharmaceutically acceptable salt thereof.

18 . (canceled)

19 . The method of claim 17 , wherein the cancer is an ALK-positive cancer selected from anaplastic large-cell lymphoma, gastric cancer, breast cancers, oesophageal cancer, colorectal cancer, neuroblastoma, inflammatory myofibroblastic tumor, renal cancer, pancreatic cancer and lung cancer.

20 . (canceled)

21 . (canceled)

22 . (canceled)

23 . (canceled)

24 . (canceled)

25 . The pharmaceutical combination of claim 1 , wherein the ALK inhibitor is selected from 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N4-[2-(isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine (ceritinib), (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (lorlatinib; PF-06463922),

26 . The pharmaceutical combination of claim 1 , wherein the ALK inhibitor is 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N4-[2-(isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine (ceritinib).

27 . The pharmaceutical combination of claim 1 , wherein the SHP2 inhibitor is selected from:

6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine;

6-(4-(aminomethyl)-4-phenylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine;

6-(4-(aminomethyl)-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine;

6-(4-(aminomethyl)-4-methylpiperidin-1-yl)-3-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazin-2-amine;

(R)-8-(6-amino-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine;

(R)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine;

(3S,4S)-8-(6-amino-5-(2,3-dichlorophenyl)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine;

3-(2,3-dichlorophenyl)-6-(1,8-diazaspiro[4.5]decan-8-yl)pyrazin-2-amine;

(R)-8-(6-amino-5-(2,3-dichlorophenyl)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine;

(S)-8-(6-amino-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine;

(S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine;

(1R,3R)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine;

(2S,4R)-4-amino-8-(6-amino-5-((2,3-dichloropyridin-4-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-2-ol;

(2R,4R)-4-amino-8-(6-amino-5-((2,3-dichloropyridin-4-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-2-ol;

(1R)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-2-methyl-8-azaspiro[4.5]decan-1-amine;

(3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine;

(3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-y)thio)pyrazin-2-yl)-3-ethyl-2-oxa-8-azaspiro[4.5]decan-4-amine;

(2R,4R)-4-amino-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-2-ol;

(1R,3R)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-8-azaspiro[4.5]decan-1-amine;

(1R)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-2-methyl-8-azaspiro[4.5]decan-1-amine;

(3S,4S)-8-(5-((6-amino-2,3-dichloropyridin-4-y)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine;

(3S,4S)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine;

(R)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine;

(S)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine;

6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-y)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one;

6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-y)-5-((3-chloro-2-methylpyridin-4-yl)thio)-3-methylpyrimidin-4(3H)-one;

6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-y)-5-((2,3-dichlorophenyl)thio)-3-methylpyrimidin-4(3-)-one;

6-amino-2-((1R,3R)-1-amino-3-methyl-8-azaspiro[4.5]decan-8-y)-3-methyl-5-((3-(trifluoromethyl)pyridin-4-yl)thio)pyrimidin-4(3H)-one;

6-amino-2-((1R,3R)-1-amino-3-methyl-8-azaspiro[4.5]decan-8-y)-5-(2,3-dichlorophenyl)-3-methylpyrimidin-4(31-)-one;

6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-y)-5-((2-chloro-3-methoxyphenyl)thio)-3-methylpyrimidin-4(31-)-one;

6-amino-2-((3S,4S)-4-amino-3-ethyl-2-oxa-8-azaspiro[4.5]decan-8-y)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one;

6-amino-5-((3-amino-2-(trifluoromethyl)phenyl)thio)-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4 0.5]decan-8-yl)-3-methylpyrimidin-4(3H)-one;

(R)-6-amino-2-(1-amino-3,3-difluoro-8-azaspiro[4.5]decan-8-yl)-5-((2-amino-3-chloropyridin-4-yl)thio)-3-methylpyrimidin-4(31-)-one;

6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-y)-3-methyl-5-((3-(trifluoromethyl)pyridin-4-yl)thio)pyrimidin-4(3H)-one;

6-amino-2-((1R,3R)-1-amino-3-methyl-8-azaspiro[4.5]decan-8-y)-5-(4-chlorophenyl)-3-methylpyrimidin-4(31-)-one;

6-amino-2-((1R,3R)-1-amino-3-methyl-8-azaspiro[4.5]decan-8-y)-3-methyl-5-phenylpyrimidin-4(31-)-one;

(R)-6-(1-amino-8-azaspiro[4.5]decan-8-y)-3-(2,3-dichlorophenyl)-5-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one;

2-(4-(aminomethyl)-4-methylpiperidin-1-yl)-5-(2,3-dichlorophenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one;

(3S,4S)-8-(3-(2,3-dichloropyridin-4-y)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine;

3-(6-amino-2-methylpyridin-3-y)-6-((1R,3R)-1-amino-3-methyl-8-azaspiro[4.5]decan-8-yl)-5-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one;

(R)-3-(6-amino-2-methylpyridin-3-yl)-6-(1-amino-3,3-difluoro-8-azaspiro[4.5]decan-8-yl)-5-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one;

6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(3-chloro-2-(cyclopropylamino)pyridin-4-yl)-5-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one;

2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-(3-chloro-2-methoxypyridin-4-yl)-3-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one;

N-(3-((3-amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;

N-(3-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;

N-(3-((3-amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-4-hydroxy-2-oxo-1-phenyl-2,5-dihydro-1H-pyrrole-3-carboxamide;

(R)-N-(3-((3-amino-5-(1-amino-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;

N-(3-((3-amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;

(R)-N-(3-((3-amino-5-(1-amino-3,3-difluoro-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;

N-(3-((3-amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;

N-(3-((3-amino-5-(4-amino-4-(fluoromethyl)piperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;

N-(3-((3-amino-5-(4-amino-4-(fluoromethyl)piperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide;

(S)-N-(3-((3-amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide, and

N-(3-((3-amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-5-benzyl-4-hydroxy-1-methyl-2-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide.