JPWO2021138498A5 - - Google Patents

Description

Other Embodiments Although the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate rather than limit the scope of the invention, and the scope of the invention is as defined in the claims. Other aspects, advantages, and modifications are within the scope of the following claims.
The present application also includes the following embodiments.
[Aspect 1]
A method of treating cancer in a human subject in need of treatment comprising administering to the human subject an effective amount of a human CD73 inhibitor and an inhibitor of A2A adenosine receptor and/or A2B adenosine receptor, said method comprising:
(1) The human CD73 inhibitor is:
(a) includes a VH domain including variable heavy chain (VH) complementarity determining region (CDR) 1, VH CDR2, and VH CDR3;
(The VH CDR1 comprises the amino acid sequence GYTFTSYG (SEQ ID NO: 1);
said VH CDR2 comprises the amino acid sequence IYPGSGNT (SEQ ID NO: 2); and
the VH CDR3 comprises the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 3); and
Contains a variable light chain (VL) domain that includes CDR1, VL CDR2, and VL CDR3
(The VL CDR1 comprises the amino acid sequence QDVSTA (SEQ ID NO: 4);
said VL CDR2 comprises the amino acid sequence SAS (SEQ ID NO: 5); and
an antibody in which the VL CDR3 comprises the amino acid sequence QQHYNTPYT (SEQ ID NO: 6);
(b) an antibody that binds to human CD73 at an epitope within amino acids 40-53 of SEQ ID NO: 70;
(c) an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 24 and a light chain comprising the amino acid sequence of SEQ ID NO: 25; or
(d) Antibodies comprising VH domains including VH CDR1, VH CDR2, and VH CDR3
(The VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34);
the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and
the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36); and
Antibodies containing VL domains including VL CDR1, VL CDR2, and VL CDR3
(The VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37);
said VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); and
the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39);
(e) an antibody that binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70;
(f) an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 31;
(g) an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31;
(h) an antibody selected from the group consisting of 11E1, Medi9447, CPI-006, and BMS-986179; or
(i) an inhibitor selected from the group consisting of CB-708 and AB680; and
(2) The inhibitor of the A2A adenosine receptor and/or A2B adenosine receptor (A2A/A2B) is the following compound:
(a) Formula (I):
or a pharmaceutically acceptable salt thereof (wherein
Cy ¹ is phenyl, substituted with one or two substituents independently selected from halo and CN;
Cy ² is 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, and the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl of Cy ² is C _1-3 alkyl, C _1- each optionally substituted with 1, 2, or 3 groups each independently selected from 3 _- alkoxy, NH ₂ , NH(C _1-3 alkyl) and N(C _1-3 alkyl) ₂ ;
R ² is phenyl-C _1-3 alkyl-, C _3-7 cycloalkyl-C _1-3 alkyl-, (5-7 membered heteroaryl)-C _1-3 alkyl-, (4-7 membered heterocyclo alkyl)-C _1-3 alkyl-, and OR ^a2 , and the phenyl-C _1-3 alkyl- of R ² , C _3-7 cycloalkyl-C _1-3 alkyl-, 1, 2, or 3 R ^C aryl)-C _1-3 alkyl-, and (4-7 membered heterocycloalkyl)-C _1-3 alkyl- are each optionally independently selected. substituted with a substituent;
R ^a2 is (5-7 membered heteroaryl)-C _1-3 alkyl-, optionally substituted with one or two independently selected R ^C substituents;
Each R ^C is from halo, C _1-6 alkyl, C ₆ aryl, 5-7 membered heteroaryl, (4-7 membered heterocycloalkyl)-C _1-3 alkyl-, OR ^a4 , and NR ^c4 R ^d4 independently selected; and
each R ^a4 , R ^c4 , and R ^d4 is independently selected from H and C _1-6 alkyl);
(b) Formula (II):
or a pharmaceutically acceptable salt thereof (wherein
R ² is selected from H and CN;
Cy ¹ is phenyl, substituted with one or two substituents independently selected from halo and CN;
L is C _1-3 alkylene, said alkylene optionally substituted with 1, 2, or 3 independently selected R ^8D substituents;
Cy ⁴ is selected from phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl, each of which is optionally independently selected from R ^8D and R ⁸ 1 , 2, or 3 substituents;
Each R ⁸ is halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, phenyl, C _3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 Member heterocycloalkyl, phenyl-C _1-3 alkyl, C _3-7 cycloalkyl-C _1-3 alkyl, (5-6 membered heteroaryl)-C _1-3 alkyl, and (4-7 membered heterocycloalkyl) ) _{-C 1-3} alkyl _, wherein _R ⁸ is selected _from _ _ Aryl, 4-7 membered heterocycloalkyl, phenyl-C _1-3 alkyl, C _3-7 cycloalkyl-C _1-3 alkyl, (5-6 membered heteroaryl)-C _1-3 alkyl, and (4- each 7-membered heterocycloalkyl)-C _1-3 alkyl is optionally substituted with 1, 2, or 3 independently selected R ^8A substituents;
Each R ^8A is independently selected from halo, C _1-6 alkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, OR ^a81 , and NR ^c81 R ^d81 , and the C of R ^8A _1-3 alkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 independently selected R ^8B substituents;
each R ^a81 , R ^c81 , and R ^d81 is independently selected from H ^, _C 1-6 _alkyl , and ^{4-7 membered} heterocycloalkyl ; alkyl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 independently selected R ^8B substituents;
each R ^8B is independently selected from halo and C _1-3 alkyl; and
each R ^8D is independently selected from OH, CN, halo, C _1-6 alkyl, and C _1-6 haloalkyl);
(c) Formula (III):
or a pharmaceutically acceptable salt thereof (wherein
Cy ¹ is phenyl, substituted with one or two substituents independently selected from halo and CN;
R ² is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, and said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of R ² are each optionally 1, substituted with 2, or 3 independently selected R ^2A substituents;
each R ^2A is independently selected from D, halo, C _1-6 alkyl, and C _1-6 haloalkyl;
R ⁴ is phenyl-C _1-3 alkyl-, C _3-7 cycloalkyl-C _1-3 alkyl-, (5-6 membered heteroaryl)-C _1-3 alkyl-, and (4-7 member heteroaryl) ⁽ _5-6 membered heteroaryl ₎ -C _ _{_} _ _{_} _ _1-3 alkyl-, and (4-7 membered heterocycloalkyl)-C _1-3 alkyl-, each optionally with 1, 2, or 3 independently selected R ^4A substituents. replaced;
each R ^4A is independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl, CN, OR ^a41 , and NR ^c41 R ^d41 ; and
each R ^a41 , R ^c41 , and R ^d41 is independently selected from H and C _1-6 alkyl); or
(d) Formula (IV):
or a pharmaceutically acceptable salt thereof (wherein
Cy ¹ is phenyl, substituted with one or two substituents independently selected from halo and CN;
Cy ² is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of Cy 2 are each optionally 1 ^, substituted with 2, or 3 independently selected R ⁶ substituents;
each R ⁶ is independently selected from halo, C _1-6 alkyl, and C _1-6 haloalkyl;
R ² is phenyl-C _{1-3 alkyl-} or (5-6 membered heteroaryl) -C _1-3 alkyl- ^; each (aryl) -C _1-3 alkyl- is optionally substituted with 1, 2, or 3 independently selected R ^2A substituents; and
each R ^2A is independently selected from halo, C _1-6 alkyl, and C _1-6 haloalkyl);
or a pharmaceutically acceptable salt thereof.
[Aspect 2]
The A2A/A2B inhibitor is a compound of formula (I):
or a pharmaceutically acceptable salt thereof, in which:
Cy ¹ is phenyl, substituted with one or two substituents independently selected from halo and CN;
Cy ² is 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, and the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl of Cy ² is each independently C _1- each optionally substituted with 1, 2, or 3 groups selected from ₃ alkyl, C _1-3 alkoxy, NH ₂ , NH(C _1-3 alkyl) and N(C _1-3 alkyl) ₂ is;
R ² is phenyl-C _1-3 alkyl-, C _3-7 cycloalkyl-C _1-3 alkyl-, (5-7 membered heteroaryl)-C _1-3 alkyl-, (4-7 membered heterocyclo alkyl)-C _1-3 alkyl-, and OR ^a2 , and the phenyl-C _1-3 alkyl- of R ² , C _3-7 cycloalkyl-C _1-3 alkyl-, (aryl) -C _1-3 alkyl-, and (4-7 membered heterocycloalkyl) -C _1-3 alkyl- are each optionally 1, 2, or 3 independently selected R substituted with a ^C substituent;
R ^a2 is (5-7 membered heteroaryl)-C _1-3 alkyl-, optionally substituted with one or two independently selected R ^C substituents;
Each R ^C is from halo, C _1-6 alkyl, C ₆ aryl, 5-7 membered heteroaryl, (4-7 membered heterocycloalkyl)-C _1-3 alkyl-, OR ^a4 , and NR ^c4 R ^d4 independently selected; and
each R ^a4 , R ^c4 , and R ^d4 is independently selected from H and C _1-6 alkyl;
The method according to aspect 1.
[Aspect 3]
The A2A/A2B inhibitor is:
3-(5-amino-2-(pyridin-2-ylmethyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile , or a pharmaceutically acceptable salt thereof;
3-(5-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine -7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof;
3-(5-amino-2-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo [1,5-c]pyrimidin-7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof;
3-(5-amino-2-((3-methylpyridin-2-yl)methoxy)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine- 7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof; and
3-(2-((5-(1H-pyrazol-1-yl)-1H-tetrazol-1-yl)methyl)-5-amino-8-(pyrimidin-4-yl)-[1,2,4 ] triazolo[1,5-c]pyrimidin-7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof
The method according to aspect 2, selected from:
[Aspect 4]
The A2A/A2B inhibitor is a compound of formula (II):
or a pharmaceutically acceptable salt thereof, in which:
R ² is selected from H and CN;
Cy ¹ is phenyl, substituted with one or two substituents independently selected from halo and CN;
L is C _1-3 alkylene, said alkylene is optionally substituted with 1, 2, or 3 independently selected R ^8D substituents;
Cy ⁴ is selected from phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl, each of which is optionally independently selected from R ^8D and R ⁸ 1 , 2, or 3 substituents;
Each R ⁸ is halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, phenyl, C _3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 Member heterocycloalkyl, phenyl-C _1-3 alkyl, C _3-7 cycloalkyl-C _1-3 alkyl, (5-6 membered heteroaryl)-C _1-3 alkyl, and (4-7 membered heterocycloalkyl) ) _{-C 1-3} alkyl _, wherein _R ⁸ is selected _from _ _ Aryl, 4-7 membered heterocycloalkyl, phenyl-C _1-3 alkyl, C _3-7 cycloalkyl-C _1-3 alkyl, (5-6 membered heteroaryl)-C _1-3 alkyl, and (4- each 7-membered heterocycloalkyl)-C _1-3 alkyl is optionally substituted with 1, 2, or 3 independently selected R ^8A substituents;
Each R ^8A is independently selected from halo, C _1-6 alkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, OR ^a81 , and NR ^c81 R ^d81 , and the C of R ^8A _1-3 alkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 independently selected R ^8B substituents;
each R ^a81 , R ^c81 , and R ^d81 is independently selected from H ^, _C 1-6 _alkyl , and ^{4-7 membered} heterocycloalkyl ; alkyl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 independently selected R ^8B substituents;
each R ^8B is independently selected from halo and C _1-3 alkyl; and
each R ^8D is independently selected from OH, CN, halo, C _1-6 alkyl, and C _1-6 haloalkyl;
The method according to aspect 1.
[Aspect 5]
The A2A/A2B inhibitor is:
3-(5-amino-2-(hydroxy(phenyl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile or a pharmaceutically acceptable salt thereof ;
3-(5-Amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzo Nitrile, or a pharmaceutically acceptable salt thereof;
5-amino-7-(3-cyano-2-fluorophenyl)-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-c]pyrimidine -8-carbonitrile or a pharmaceutically acceptable salt thereof; and
3-(5-amino-2-((2-fluoro-6-(((1-methyl-2-oxopyrrolidin-3-yl)amino)methyl)phenyl)(hydroxy)methyl)-[1,2, 4] Triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof
The method according to aspect 4, selected from:
[Aspect 6]
The A2A/A2B inhibitor is a compound of formula (III):
or a pharmaceutically acceptable salt thereof, in which:
Cy ¹ is phenyl, substituted with one or two substituents independently selected from halo and CN;
R ² is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, and said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of R ² are each optionally 1, substituted with 2, or 3 independently selected R ^2A substituents;
each R ^2A is independently selected from D, halo, C _1-6 alkyl, and C _1-6 haloalkyl;
R ⁴ is phenyl-C _1-3 alkyl-, C _3-7 cycloalkyl-C _1-3 alkyl-, (5-6 membered heteroaryl)-C _1-3 alkyl-, and (4-7 member heteroaryl) ⁽ _5-6 membered heteroaryl ₎ -C _ _{_} _ _{_} _ _1-3 alkyl-, and (4-7 membered heterocycloalkyl)-C _1-3 alkyl-, each optionally with 1, 2, or 3 independently selected R ^4A substituents. replaced;
each R ^4A is independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl, CN, OR ^a41 , and NR ^c41 R ^d41 ; and
each R ^a41 , R ^c41 , and R ^d41 is independently selected from H and C _1-6 alkyl;
The method according to aspect 1.
[Aspect 7]
The A2A/A2B inhibitor is:
3-(8-Amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1 ,5-a]pyrazin-6-yl)benzonitrile;
3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine -6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof;
3-(8-amino-2-(amino(2,6-difluorophenyl)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a] pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof; and
3-(8-Amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1, 5-a] pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof;
The method according to aspect 6.
[Aspect 8]
The A2A/A2B inhibitor is a compound of formula (IV):
or a pharmaceutically acceptable salt thereof, in which:
Cy ¹ is phenyl, substituted with one or two substituents independently selected from halo and CN;
Cy ² is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of Cy 2 are each optionally 1 ^, substituted with 2, or 3 independently selected R ⁶ substituents;
each R ⁶ is independently selected from halo, C _1-6 alkyl, and C _1-6 haloalkyl;
R ² is phenyl-C _{1-3 alkyl-} or (5-6 membered heteroaryl) -C _1-3 alkyl- ^; each (aryl) -C _1-3 alkyl- is optionally substituted with 1, 2, or 3 independently selected R ^2A substituents; and
each R ^2A is independently selected from halo, C _1-6 alkyl, and C _1-6 haloalkyl;
or a pharmaceutically acceptable salt thereof.
[Aspect 9]
The A2A/A2B inhibitor is:
3-(4-amino-2-(pyridin-2-ylmethyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl) Benzonitrile or a pharmaceutically acceptable salt thereof;
3-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c] pyridin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof;
3-(4-Amino-2-((3-fluoropyridin-2-yl)methyl)-7-(pyridin-4-yl)-2H-[1,2,3]triazolo[4,5-c] pyridin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof; and
3-(4-Amino-7-(1-methyl-1H-pyrazol-5-yl)-2-(pyridin-2-ylmethyl)-2H-[1,2,3]triazolo[4,5-c] pyridin-6-yl)-2-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof;
The method according to aspect 8.
[Aspect 10]
The A2A/A2B inhibitor is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1 , 2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
[Aspect 11]
The A2A/A2B inhibitor is 3-(5-amino-2-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)-8-(pyrimidin-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof, the method according to aspect 1.
[Aspect 12]
The human CD73 inhibitor is:
VH domain including VH CDR1, VH CDR2, and VH CDR3
(The VH CDR1 comprises the amino acid sequence GYTFTSYG (SEQ ID NO: 1);
said VH CDR2 comprises the amino acid sequence IYPGSGNT (SEQ ID NO: 2); and
the VH CDR3 comprises the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 3); and
VL domain including VL CDR1, VL CDR2, and VL CDR3
(The VL CDR1 comprises the amino acid sequence QDVSTA (SEQ ID NO: 4);
said VL CDR2 comprises the amino acid sequence SAS (SEQ ID NO: 5); and
the VL CDR3 comprises the amino acid sequence QQHYNTPYT (SEQ ID NO: 6))
The method according to any one of aspects 1 to 11, comprising an antibody comprising an antibody comprising:
[Aspect 13]
12. The method of any one of aspects 1-11, wherein said human CD73 inhibitor comprises an antibody that binds human CD73 at an epitope within amino acids 40-53 of SEQ ID NO:70.
[Aspect 14]
The human CD73 inhibitor comprises an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 24 and a light chain comprising the amino acid sequence of SEQ ID NO: 25. , the method according to any one of aspects 1 to 11.
[Aspect 15]
The human CD73 inhibitor is:
VH domain including VH CDR1, VH CDR2, and VH CDR3
(The VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34);
the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and
the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36); and
VL domain including VL CDR1, VL CDR2, and VL CDR3
(The VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37);
said VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); and
the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39))
The method according to any one of aspects 1 to 11, comprising an antibody comprising an antibody comprising:
[Aspect 16]
12. The method of any one of aspects 1-11, wherein said human CD73 inhibitor comprises an antibody that binds human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70.
[Aspect 17]
The human CD73 inhibitor comprises an antibody that binds to human CD73 and competes with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 31 for binding to human CD73. , the method according to any one of aspects 1 to 11.
[Aspect 18]
The human CD73 inhibitor comprises an antibody that binds to human CD73 and competes with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31 for binding to human CD73. , the method according to any one of aspects 1 to 11.
[Aspect 19]
The method according to any one of aspects 1 to 11, wherein the human CD73 inhibitor comprises an antibody selected from the group consisting of 11E1, Medi9447, CPI-006, and BMS-986179.
[Aspect 20]
The method according to any one of aspects 1 to 11, wherein said human CD73 inhibitor is selected from the group consisting of CB-708 and AB680.
[Aspect 21]
The VH domain comprises the amino acid sequence set forth in SEQ ID NO: 22, the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 23, and the compound comprises 3-(8-amino-5-(1-methyl- 6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile 13. The method according to aspect 12, comprising:
[Aspect 22]
The antibody comprises a heavy chain and a light chain, the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 24, the light chain comprises the amino acid sequence set forth in SEQ ID NO: 25, and the compound comprises 3- (8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5 -a] pyrazin-6-yl)benzonitrile.
[Aspect 23]
The VH domain comprises the amino acid sequence set forth in SEQ ID NO: 62, the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 61, and the compound comprises 3-(8-amino-5-(1-methyl- 6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile 16. The method according to aspect 15, comprising:
[Aspect 24]
The antibody comprises a heavy chain and a light chain, the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 30, the light chain comprises the amino acid sequence set forth in SEQ ID NO: 31, and the compound comprises 3- (8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5 -a] pyrazin-6-yl)benzonitrile.
[Aspect 25]
The VH domain comprises the amino acid sequence set forth in SEQ ID NO: 63, the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 61, and the compound comprises 3-(8-amino-5-(1-methyl- 6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile 16. The method according to aspect 15, comprising:
[Aspect 26]
The antibody comprises a heavy chain and a light chain, the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 33, the light chain comprises the amino acid sequence set forth in SEQ ID NO: 31, and the compound comprises 3- (8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5 -a] pyrazin-6-yl)benzonitrile.
[Aspect 27]
A method of treating cancer in a human subject in need of treatment comprising administering to the human subject an effective amount of an antibody that binds to human CD73 and an inhibitor of A2A adenosine receptor and/or A2B adenosine receptor. Then, the antibody:
(a) VH domain comprising variable heavy chain (VH) complementarity determining region (CDR) 1, VH CDR2, and VH CDR3
(The VH CDR1 comprises the amino acid sequence GYTFTSYG (SEQ ID NO: 1);
said VH CDR2 comprises the amino acid sequence IYPGSGNT (SEQ ID NO: 2); and
the VH CDR3 comprises the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 3); and
VL domain comprising variable light chain (VL) CDR1, VL CDR2, and VL CDR3
(The VL CDR1 comprises the amino acid sequence QDVSTA (SEQ ID NO: 4);
said VL CDR2 comprises the amino acid sequence SAS (SEQ ID NO: 5); and
the VL CDR3 comprises the amino acid sequence QQHYNTPYT (SEQ ID NO: 6);
(b) binds to human CD73 at an epitope within amino acids 40-53 of SEQ ID NO: 70;
(c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 24 and a light chain comprising the amino acid sequence of SEQ ID NO: 25;
(d) VH domain including VH CDR1, VH CDR2, and VH CDR3
(The VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34);
the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and
the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36); and
VL domain including VL CDR1, VL CDR2, and VL CDR3
(The VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37);
said VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); and
the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39);
(e) binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70;
(f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; or
(g) binding to human CD73 and competing for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31.
[Aspect 28]
The antibody has a VH domain comprising VH CDR1, VH CDR2, and VH CDR3.
(The VH CDR1 comprises the amino acid sequence GYTFTSYG (SEQ ID NO: 1);
said VH CDR2 comprises the amino acid sequence IYPGSGNT (SEQ ID NO: 2); and
the VH CDR3 comprises the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 3); and
VL domain including VL CDR1, VL CDR2, and VL CDR3
(The VL CDR1 comprises the amino acid sequence QDVSTA (SEQ ID NO: 4);
said VL CDR2 comprises the amino acid sequence SAS (SEQ ID NO: 5); and
28. The method of embodiment 27, wherein the VL CDR3 comprises the amino acid sequence QQHYNTPYT (SEQ ID NO: 6).
[Aspect 29]
29. The method of embodiment 28, wherein the VH domain comprises the amino acid sequence set forth in SEQ ID NO: 22.
[Aspect 30]
29. The method of embodiment 28, wherein the antibody comprises a heavy chain, and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 24.
[Aspect 31]
29. The method of aspect 28, wherein the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 23.
[Aspect 32]
29. The method of embodiment 28, wherein the antibody comprises a light chain, and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 25.
[Aspect 33]
29. The method of embodiment 28, wherein the VH domain is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 22 and the VL domain is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 23.
[Aspect 34]
29. The method of aspect 28, wherein the VH domain comprises the amino acid sequence set forth in SEQ ID NO: 22 and the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 23.
[Aspect 35]
29. The method of aspect 28, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 24, and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 25. .
[Aspect 36]
28. The method of embodiment 27, wherein the antibody binds human CD73 at an epitope within amino acids 40-53 of SEQ ID NO: 70.
[Aspect 37]
28. The antibody according to aspect 27, wherein the antibody binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 24 and a light chain comprising the amino acid sequence of SEQ ID NO: 25. Method.
[Aspect 38]
The antibody comprises a VH domain including VH CDR1, VH CDR2, and VH CDR3:
the VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34);
the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and
said VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36); and
The antibody comprises a VL domain including VL CDR1, VL CDR2, and VL CDR3:
the VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37);
the VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38);
28. The method of embodiment 27, wherein said VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39).
[Aspect 39]
the VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34);
the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35);
said VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36); and
the VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37);
said VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); and
39. The method of aspect 38, wherein said VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39).
[Aspect 40]
40. The method of aspect 39, wherein the VH domain comprises the amino acid sequence set forth in SEQ ID NO: 62.
[Aspect 41]
40. The method of embodiment 39, wherein the antibody comprises a heavy chain, and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 30.
[Aspect 42]
40. The method of aspect 39, wherein the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 61.
[Aspect 43]
40. The method of embodiment 39, wherein the antibody comprises a light chain, and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 31.
[Aspect 44]
40. The method of embodiment 39, wherein the VH domain is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 62 and the VL domain is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 61.
[Aspect 45]
40. The method of aspect 39, wherein the VH domain comprises the amino acid sequence set forth in SEQ ID NO: 62 and the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 61.
[Aspect 46]
The method of aspect 39, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 30, and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 31. .
[Aspect 47]
the VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34);
the VH CDR2 comprises the amino acid sequence MSYEGSNK (SEQ ID NO: 40);
said VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36);
the VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37);
said VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); and
39. The method of aspect 38, wherein said VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39).
[Aspect 48]
48. The method of embodiment 47, wherein the VH domain comprises the amino acid sequence set forth in SEQ ID NO: 63.
[Aspect 49]
48. The method of aspect 47, wherein the antibody comprises a heavy chain, and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 33.
[Aspect 50]
48. The method of aspect 47, wherein the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 61.
[Aspect 51]
48. The method of embodiment 47, wherein the antibody comprises a light chain, and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 31.
[Aspect 52]
48. The method of embodiment 47, wherein said VH domain is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 63 and said VL domain is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 61.
[Aspect 53]
48. The method of aspect 47, wherein the VH domain comprises the amino acid sequence set forth in SEQ ID NO: 63 and the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 61.
[Aspect 54]
48. The method of embodiment 47, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 33, and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 31.
[Aspect 55]
28. The method of embodiment 27, wherein the antibody binds human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70.
[Aspect 56]
28. The antibody according to aspect 27, wherein the antibody binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 31. Method.
[Aspect 57]
28. The antibody according to aspect 27, wherein the antibody binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31. Method.
[Aspect 58]
The inhibitor:
7-(5-methylfuran-2-yl)-3-[[6-[[(3S)-oxolan-3-yl]oxymethyl]pyridin-2-yl]methyl]triazolo[4,5-d] Pyrimidine-5-amine;
3-(5-amino-2-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo [1,5-c]pyrimidin-7-yl)benzonitrile;
3-[2-amino-6-[1-[[6-(2-hydroxypropan-2-yl)pyridin-2-yl]methyl]triazol-4-yl]pyrimidin-4-yl]-2-methyl Benzonitrile;
6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine, 5-bromo-2,6-di(1H- pyrazol-1-yl)pyrimidin-4-amine; and
58. The method according to any one of aspects 27-57, selected from the group consisting of EOS100850.
[Aspect 59]
59. The method according to any one of aspects 1 to 58, wherein said cancer has a high adenosine signature.
[Aspect 60]
60. The method according to any one of aspects 1 to 59, wherein the cancer is head and neck cancer, colorectal cancer, lung cancer, melanoma, ovarian cancer, bladder cancer, liver cancer, or renal cell cancer.

Claims (35)

(1) A human subject in need of cancer treatment comprising a pharmaceutical composition comprising a human CD73 inhibitor and a pharmaceutical composition comprising an inhibitor of A2A adenosine receptor and/or A2B adenosine receptor A combination drug for use in the treatment of cancer, comprising :
(1) The human CD73 inhibitor is:
(a) a variable heavy chain (VH) comprising a VH domain comprising complementarity determining region (CDR) 1, VH CDR2, and VH CDR3 , where:
The VH CDR1 comprises the amino acid sequence GYTFTSYG (SEQ ID NO: 1);
said VH CDR2 comprises the amino acid sequence IYPGSGNT (SEQ ID NO: 2); and said VH CDR3 comprises the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 3); and
A variable light chain (VL) comprising a VL domain comprising CDR1, VL CDR2, and VL CDR3 (wherein
The VL CDR1 comprises the amino acid sequence QDVSTA (SEQ ID NO: 4);
The VL CDR2 comprises the amino acid sequence SAS (SEQ ID NO: 5); and the VL CDR3 comprises the amino acid sequence QQHYNTPYT (SEQ ID NO: 6).
antibody;
(b) an antibody that binds to human CD73 at an epitope within amino acids 40-53 of SEQ ID NO: 70;
(c) an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 24 and a light chain comprising the amino acid sequence of SEQ ID NO: 25; or (d) VH comprises a VH domain including CDR1, VH CDR2, and VH CDR3 (wherein
The VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34);
the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36); and
Contains a VL domain including VL CDR1, VL CDR2, and VL CDR3 (wherein
The VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37);
the VL CDR2 comprises the amino acid sequence AAS ( SEQ ID NO: 38); and the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39);
(e) an antibody that binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70;
(f) an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 31;
(g) an antibody that binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31;
(h) an antibody selected from the group consisting of 11E1, Medi9447, CPI-006, and BMS-986179; or (i) an inhibitor selected from the group consisting of CB-708 and AB680; and (2) said Inhibitors of A2A adenosine receptor and/or A2B adenosine receptor (A2A/A2B) are the following compounds:
(a) Formula (I):
or a pharmaceutically acceptable salt thereof (wherein
Cy ¹ is phenyl, substituted with one or two substituents independently selected from halo and CN;
Cy ² is 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl, and the 5-6 membered heteroaryl or 4-7 membered heterocycloalkyl of Cy ² is C _1-3 alkyl, C _1- each optionally substituted with 1, 2, or 3 groups each independently selected from 3 _- alkoxy, NH ₂ , NH(C _1-3 alkyl) and N(C _1-3 alkyl) ₂ ;
R ² is phenyl-C _1-3 alkyl-, C _3-7 cycloalkyl-C _1-3 alkyl-, (5-7 membered heteroaryl)-C _1-3 alkyl-, (4-7 membered heterocyclo alkyl)-C _1-3 alkyl-, and OR ^a2 , and the phenyl-C _1-3 alkyl- of R ² , C _3-7 cycloalkyl-C _1-3 alkyl-, (aryl)-C _1-3 alkyl-, and (4-7 membered heterocycloalkyl)-C _1-3 alkyl- optionally represent 1, 2, or 3 R ^C substituted with a substituent;
R ^a2 is (5-7 membered heteroaryl)-C _1-3 alkyl-, optionally substituted with one or two independently selected R ^C substituents;
Each R ^C is from halo, C _1-6 alkyl, C ₆ aryl, 5-7 membered heteroaryl, (4-7 membered heterocycloalkyl)-C _1-3 alkyl-, OR ^a4 , and NR ^c4 R ^d4 and each R ^a4 , R ^c4 , and R ^d4 are independently selected from H and C _1-6 alkyl);
(b) Formula (II):
or a pharmaceutically acceptable salt thereof (wherein
^R2 is selected from H and CN;
Cy ¹ is phenyl, substituted with one or two substituents independently selected from halo and CN;
L is C _1-3 alkylene, said alkylene optionally substituted with 1, 2, or 3 independently selected R ^8D substituents;
Cy ⁴ is selected from phenyl, cyclohexyl, pyridyl, pyrrolidinonyl, and imidazolyl, each of which is optionally independently selected from R ^8D and R ⁸ , 2, or 3 substituents;
Each R ⁸ is halo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, phenyl, C _3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 Member heterocycloalkyl, phenyl-C _1-3 alkyl, C _3-7 cycloalkyl-C _1-3 alkyl, (5-6 membered heteroaryl)-C _1-3 alkyl, and (4-7 membered heterocycloalkyl) )-C _1-3 alkyl, _{wherein R} ⁸ is _{selected from} Aryl, 4-7 membered heterocycloalkyl, phenyl-C _1-3 alkyl, C _3-7 cycloalkyl-C _1-3 alkyl, (5-6 membered heteroaryl)-C _1-3 alkyl, and (4- each 7-membered heterocycloalkyl)-C _1-3 alkyl is optionally substituted with 1, 2, or 3 independently selected R ^8A substituents;
Each R ^8A is independently selected from halo, C _1-6 alkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, OR ^a81 , and NR ^c81 R ^d81 , wherein said C of R ^8A _1-3 alkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 independently selected R ^8B substituents;
Each R ^a81 , R ^c81 , and R ^d81 is independently selected from ^H , C _1-6 alkyl, and ^{4-7 membered} heterocycloalkyl _; alkyl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 independently selected R ^8B substituents;
Each R ^8B is independently selected from halo and C _1-3 alkyl; and each R ^8D is independently selected from OH, CN, halo, C _1-6 alkyl, and C _1-6 haloalkyl. );
(c) Formula (III):
or a pharmaceutically acceptable salt thereof (wherein
Cy ¹ is phenyl, substituted with one or two substituents independently selected from halo and CN;
R ² is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of R ² are each optionally 1, substituted with 2, or 3 independently selected R ^2A substituents;
each R ^2A is independently selected from D, halo, C _1-6 alkyl, and C _1-6 haloalkyl;
R ⁴ is phenyl-C _1-3 alkyl-, C _3-7 cycloalkyl-C _1-3 alkyl-, (5-6 membered heteroaryl)-C _1-3 alkyl-, and (4-7 member heteroaryl) _{( 5-6 membered} heteroaryl ₎ ^-C _1-3 alkyl-, and (4-7 membered heterocycloalkyl)-C _1-3 alkyl-, each optionally with 1, 2, or 3 independently selected R ^4A substituents. replaced;
Each R ^4A is independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl, CN, OR ^a41 , and NR ^c41 R ^d41 ; and each R ^a41 , R ^c41 , and R ^d41 is H and C _1-6 alkyl); or (d) formula (IV):
or a pharmaceutically acceptable salt thereof (wherein
Cy ¹ is phenyl, substituted with one or two substituents independently selected from halo and CN;
Cy ² is selected from 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl, said 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl of Cy ² are each optionally 1, substituted with 2, or 3 independently selected R ⁶ substituents;
each R ⁶ is independently selected from halo, C _1-6 alkyl, and C _1-6 haloalkyl;
R ² is phenyl _- C _1-3 alkyl- or (5-6 membered heteroaryl)-C _1-3 alkyl- ^; aryl) -C _1-3 alkyl- is each optionally substituted with 1, 2, or 3 independently selected R ^2A substituents; and each R ^2A is halo, C _{1- 6} alkyl, and C _1-6 haloalkyl) ;
including ,
The combination medicine . The A2A/A2B inhibitor is:
3-(5-amino-2-(pyridin-2-ylmethyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile , or a pharmaceutically acceptable salt thereof;
3-(5-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine -7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof;
3-(5-amino-2-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo [1,5-c]pyrimidin-7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof;
3-(5-amino-2-((3-methylpyridin-2-yl)methoxy)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine- 7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof;
3-(2-((5-(1H-pyrazol-1-yl)-1H-tetrazol-1-yl)methyl)-5-amino-8-(pyrimidin-4-yl)-[1,2,4 ] triazolo[1,5-c]pyrimidin-7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof;
3-(5-amino-2-(hydroxy(phenyl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile or a pharmaceutically acceptable salt thereof ;
3-(5-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzo Nitrile, or a pharmaceutically acceptable salt thereof;
5-Amino-7-(3-cyano-2-fluorophenyl)-2-((2,6-difluorophenyl)(hydroxy)methyl)-[1,2,4]triazolo[1,5-c]pyrimidine -8-carbonitrile or a pharmaceutically acceptable salt thereof;
3-(5-amino-2-((2-fluoro-6-(((1-methyl-2-oxopyrrolidin-3-yl)amino)methyl)phenyl)(hydroxy)methyl)-[1,2, 4] triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof;
3-(8-Amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1 , 5-a] pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof;
3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine -6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof;
3-(8-amino-2-(amino(2,6-difluorophenyl)methyl)-5-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-a] pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof;
3-(8-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1, 5-a] pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof;
3-(4-amino-2-(pyridin-2-ylmethyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl) Benzonitrile or a pharmaceutically acceptable salt thereof;
3-(4-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(pyrimidin-4-yl)-2H-[1,2,3]triazolo[4,5-c] pyridin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof;
3-(4-Amino-2-((3-fluoropyridin-2-yl)methyl)-7-(pyridin-4-yl)-2H-[1,2,3]triazolo[4,5-c] pyridin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof; and 3-(4-amino-7-(1-methyl-1H-pyrazol-5-yl)-2-(pyridin-2- ylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof;
The pharmaceutical combination according to claim 1 . The A2A/A2B inhibitor is 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1 , 2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. The A2A/A2B inhibitor is 3-(5-amino-2-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)-8-(pyrimidin-4-yl)- The pharmaceutical combination according to claim 1, which is [1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. The human CD73 inhibitor is:
A VH domain comprising VH CDR1, VH CDR2, and VH CDR3 (wherein
The VH CDR1 comprises the amino acid sequence GYTFTSYG (SEQ ID NO: 1);
the VH CDR2 comprises the amino acid sequence IYPGSGNT (SEQ ID NO: 2); and the VH CDR3 comprises the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 3); and the VL domain comprising VL CDR1, VL CDR2, and VL CDR3 (wherein in,
The VL CDR1 comprises the amino acid sequence QDVSTA (SEQ ID NO: 4);
The VL CDR2 comprises the amino acid sequence SAS (SEQ ID NO: 5); and the VL CDR3 comprises the amino acid sequence QQHYNTPYT (SEQ ID NO: 6).
including antibodies containing;
The pharmaceutical combination according to any one of claims 1 to 5 . The human CD73 inhibitor is:
A VH domain comprising VH CDR1, VH CDR2, and VH CDR3 (wherein
The VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34);
the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36); and VL CDR1, VL CDR2, and VL VL domain containing CDR3 (where:
The VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37);
said VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); and said VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39).
including antibodies containing;
The pharmaceutical combination according to any one of claims 1 to 4 . The VH domain comprises the amino acid sequence set forth in SEQ ID NO: 22, the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 23, and the compound comprises 3-(8-amino-5-(1-methyl- 6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)benzonitrile The pharmaceutical combination according to claim 5 , comprising: The antibody comprises a heavy chain and a light chain, the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 24, the light chain comprises the amino acid sequence set forth in SEQ ID NO: 25, and the compound comprises 3- (8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5 -a] pyrazin-6-yl)benzonitrile. The pharmaceutical combination according to claim 5 . (a) the VH domain comprises the amino acid sequence set forth in SEQ ID NO: 62, the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 61, and the compound comprises 3-(8-amino-5-(1 -methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl) Does it contain benzonitrile?
(b) the antibody comprises a heavy chain and a light chain, the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 30, the light chain comprises the amino acid sequence set forth in SEQ ID NO: 31, and the compound , 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[ 1,5-a]pyrazin-6-yl)benzonitrile;
(c) the VH domain comprises the amino acid sequence set forth in SEQ ID NO: 63, the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 61, and the compound comprises 3-(8-amino-5-(1 -methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl) Contains benzonitrile; or
(d) the antibody comprises a heavy chain and a light chain, the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 33, the light chain comprises the amino acid sequence set forth in SEQ ID NO: 31, and the compound , 3-(8-amino-5-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[ 1,5-a]pyrazin-6-yl)benzonitrile,
The pharmaceutical combination according to claim 6 . A human in need of cancer treatment comprising a pharmaceutical composition comprising an antibody that binds to human CD73 and a pharmaceutical composition comprising an inhibitor of A2A adenosine receptor and/or A2B adenosine receptor. A medicament combination for use in the treatment of cancer in a subject, wherein said antibody is:
(a) A VH domain comprising variable heavy chain (VH) complementarity determining region (CDR) 1, VH CDR2, and VH CDR3 , where:
The VH CDR1 comprises the amino acid sequence GYTFTSYG (SEQ ID NO: 1);
The VH CDR2 comprises the amino acid sequence IYPGSGNT (SEQ ID NO: 2); and the VH CDR3 comprises the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 3).
including ; and
a variable light chain (VL) domain comprising CDR1, VL CDR2, and VL CDR3 , where:
The VL CDR1 comprises the amino acid sequence QDVSTA (SEQ ID NO: 4);
The VL CDR2 comprises the amino acid sequence SAS (SEQ ID NO: 5); and the VL CDR3 comprises the amino acid sequence QQHYNTPYT (SEQ ID NO: 6).
Does it include ;
(b) binds to human CD73 with an epitope within amino acids 40-53 of SEQ ID NO: 70;
(c) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 24 and a light chain comprising the amino acid sequence of SEQ ID NO: 25;
(d) a VH domain comprising VH CDR1, VH CDR2, and VH CDR3 , where:
The VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34);
The VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36).
including ; and
A VL domain comprising VL CDR1, VL CDR2, and VL CDR3 (wherein
The VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37);
said VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); and said VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39).
Does it include ;
(e) binds to human CD73 at an epitope within amino acids 386-399 and 470-489 of SEQ ID NO: 70;
(f) binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 and a light chain comprising the amino acid sequence of SEQ ID NO: 31; or (g) human binds to CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 31;
The combination medicine . The antibody is
A VH domain comprising VH CDR1, VH CDR2, and VH CDR3 (wherein
The VH CDR1 comprises the amino acid sequence GYTFTSYG (SEQ ID NO: 1);
the VH CDR2 comprises the amino acid sequence IYPGSGNT (SEQ ID NO: 2); and the VH CDR3 comprises the amino acid sequence ARYDYLGSSYGFDY (SEQ ID NO: 3); and the VL domain comprising VL CDR1, VL CDR2, and VL CDR3 (wherein in,
The VL CDR1 comprises the amino acid sequence QDVSTA (SEQ ID NO: 4);
The VL CDR2 comprises the amino acid sequence SAS (SEQ ID NO: 5); and the VL CDR3 comprises the amino acid sequence QQHYNTPYT (SEQ ID NO: 6).
The pharmaceutical combination according to claim 10 , comprising: 12. The pharmaceutical combination according to claim 11 , wherein the VH domain comprises the amino acid sequence set forth in SEQ ID NO:22. 12. The pharmaceutical combination according to claim 11 , wherein the antibody comprises a heavy chain, and the heavy chain comprises the amino acid sequence set forth in SEQ ID NO:24. 12. The medicament combination according to claim 11 , wherein the VL domain comprises the amino acid sequence set forth in SEQ ID NO:23. 12. The pharmaceutical combination according to claim 11 , wherein the antibody comprises a light chain, and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 25. 12. The pharmaceutical combination according to claim 11, wherein the VH domain is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 22 and the VL domain is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 23 . . 12. The pharmaceutical combination according to claim 11 , wherein the VH domain comprises the amino acid sequence set forth in SEQ ID NO: 22 and the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 23. 12. The antibody of claim 11, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 24, and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 25 . Combination medicine . 11. The pharmaceutical combination according to claim 10 , wherein the antibody binds human CD73 at an epitope within amino acids 40-53 of SEQ ID NO:70. 11. The antibody binds to human CD73 and competes for binding to human CD73 with an antibody having a heavy chain comprising the amino acid sequence of SEQ ID NO: 24 and a light chain comprising the amino acid sequence of SEQ ID NO: 25 . combination medicine . wherein the antibody comprises a VH domain including VH CDR1, VH CDR2, and VH CDR3 ;
the VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34);
the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35) or MSYEGSNK (SEQ ID NO: 40); and the VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36); and the antibody comprises VL CDR1, Contains a VL domain including VL CDR2, and VL CDR3 (wherein
the VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37);
the VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38);
the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39 ) ,
The pharmaceutical combination according to claim 10 . the VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34);
the VH CDR2 comprises the amino acid sequence MSYDGSNK (SEQ ID NO: 35);
said VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36) ;
the VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37);
the VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); and the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39).
The pharmaceutical combination according to claim 21 . 23. The pharmaceutical combination according to claim 22 , wherein the VH domain comprises the amino acid sequence set forth in SEQ ID NO: 62 and/or the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 61 . 22. The antibody comprises a heavy chain and a light chain, the heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 30, and/or the light chain comprising the amino acid sequence set forth in SEQ ID NO: 31. Combination medicine described in. 23. The pharmaceutical combination according to claim 22, wherein the VH domain is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 62 and the VL domain is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 61 . . 23. The pharmaceutical combination according to claim 22 , wherein the VH domain comprises the amino acid sequence set forth in SEQ ID NO: 62 and the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 61. 23. The antibody of claim 22, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 30, and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 31 . Combination medicine . the VH CDR1 comprises the amino acid sequence GFTFSSYD (SEQ ID NO: 34);
the VH CDR2 comprises the amino acid sequence MSYEGSNK (SEQ ID NO: 40);
said VH CDR3 comprises the amino acid sequence ATEIAAKGDY (SEQ ID NO: 36);
the VL CDR1 comprises the amino acid sequence QGISNY (SEQ ID NO: 37);
the VL CDR2 comprises the amino acid sequence AAS (SEQ ID NO: 38); and the VL CDR3 comprises the amino acid sequence QQSYSTPH (SEQ ID NO: 39).
The pharmaceutical combination according to claim 21 . 29. The medicament combination according to claim 28 , wherein the VH domain comprises the amino acid sequence according to SEQ ID NO: 63 and/or the VL domain comprises the amino acid sequence according to SEQ ID NO: 61 . 28. Said antibody comprises a heavy chain and a light chain, said heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 33 , and/or said light chain comprising the amino acid sequence set forth in SEQ ID NO: 31. Combination medicine described in. 29. The pharmaceutical combination according to claim 28, wherein the VH domain is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 63 and the VL domain is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 61 . . 29. The pharmaceutical combination according to claim 28 , wherein the VH domain comprises the amino acid sequence set forth in SEQ ID NO: 63 and the VL domain comprises the amino acid sequence set forth in SEQ ID NO: 61. 29. The combination of claim 28, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 33, and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 31 . Medicine . The inhibitor:
7-(5-methylfuran-2-yl)-3-[[6-[[(3S)-oxolan-3-yl]oxymethyl]pyridin-2-yl]methyl]triazolo[4,5-d] Pyrimidine-5-amine;
3-(5-amino-2-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo [1,5-c]pyrimidin-7-yl)benzonitrile;
3-[2-amino-6-[1-[[6-(2-hydroxypropan-2-yl)pyridin-2-yl]methyl]triazol-4-yl]pyrimidin-4-yl]-2-methyl Benzonitrile;
6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine, 5-bromo-2,6-di(1H- pyrazol-1-yl)pyrimidin-4-amine; and EOS100850
The pharmaceutical combination according to any one of claims 10 to 33 , selected from the group consisting of: The cancer has a high adenosine signature and/or the cancer is head and neck cancer, colorectal cancer, lung cancer, melanoma, ovarian cancer, bladder cancer, liver cancer, or renal cell cancer. Item 35. The pharmaceutical combination according to any one of Items 1 to 34 .