Therapeutically active compositions and their methods of use
Provided are piperazine compounds of Formula I useful for treating cancer and methods of treating cancer comprising administering to a subject in need thereof a compound described here.
1. A compound of Structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Y is —N(R 5 );
R 1a is hydrogen, —C 1 -C 4 alkyl, —N(R 7 )(C 1 -C 4 alkylene)-N(R 7 )(C 1 -C 4 alkyl), aryl, heterocyclyl, —C(O)N(R 7 )-aryl, —N(R 7 )C(O)-aryl, —(C 1 -C 4 alkylene)-aryl, —(C 1 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-aryl, —O—(C 0 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-heterocyclyl, —O—(C 0 -C 4 alkylene)-carbocyclyl, —N(R 7 )-aryl, N(R 7 )-heteroaryl, —N(R 9 )-aryl, —N(R 9 )-heteroaryl, —O—(C 1 -C 4 alkeylene)-N(R 7 )C(O)O—(C 1 -C 4 alkylene)-aryl, or —N(R 9 )—C(O)—(C 2 -C 4 alkenyl);
R 1b is hydrogen, —C 1 -C 4 alkyl, —N(R 7 )(C 1 -C 4 alkylene)-N(R 7 )(C 1 -C 4 alkyl), aryl, heteroaryl, heterocyclyl, —C(O)N(R 7 )-aryl, —N(R 7 )C(O)-aryl, —(C 1 -C 4 alkylene)-aryl, —(C 1 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-aryl, —O—(C 0 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-heterocyclyl, —O—(C 0 -C 4 alkylene)-carbocyclyl, —N(R 7 )-aryl, N(R 7 )-heteroaryl, —N(R 9 )-aryl, —N(R 9 )-heteroaryl, —O—(C 1 -C 4 alkylene)-N(R 7 )C(O)O—(C 1 -C 4 alkylene)-aryl, or —N(R 9 )—C(O)—(C 2 -C 4 alkenyl), wherein:
at least one of R 1a and R 1b is not hydrogen or methyl;
any alkylene moiety present in R 1a or R 1b is optionally substituted with OH or F;
each R 7 is independently selected from hydrogen and C 1 -C 4 alkyl; and
any aryl, heteroaryl, or heterocyclyl of R 1a or R 1b is optionally substituted with one or more substituents selected from -G-L-M, halo, —NO 2 , C 1 -C 6 alkyl, —C≡N, ═O, —CF 3 and —OCF 3 ;
G is a bond or a bivalent C 1 -C 6 saturated or unsaturated, straight or branched hydrocarbon chain wherein optionally one, two or three methylene units of the hydrocarbon chain are independently replaced by —NR 8 —, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR 8 )—, —N═N—, or —C(═N 2 )—;
L is a covalent bond or a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by cyclopropylene, —NR 8 —, —N(R 8 )C(O)—, —C(O)N(R 8 )—, —N(R 8 )SO 2 —, SO 2 N(R 8 )—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR 8 )—, —N═N—, or —C(═N 2 )—;
M is E, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with at 1-4 groups independently selected from -D-E, oxo, NO 2 , halogen, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
D is a covalent bond or a bivalent C 1 -C 6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of D are optionally and independently replaced by —NR 8 —, —S—, —O—, —C(O)—, —SO—, or —SO 2 —;
E is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted with oxo, halogen, or CN; and
each R 8 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C 1 -C 6 alkoxy, —S(O) 2 —C 2 -C 4 alkenyl, or an optionally substituted group selected from phenyl, a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 2 is selected from phenyl, a 3-7 membered cycloalkyl, C 2 -C 4 alkyl, and CF 3 , wherein the phenyl or cycloalkyl is optionally substituted with a substituent selected from methyl or fluoro;
each R 3 is independently selected from halo, —(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —C 1 -C 4 fluoroalkyl, —C(O)—O—(C 1 -C 4 alkyl), -phenyl, -heteroaryl, C 3 -C 7 cycloalkyl, —CH 2 —N(C 1 -C 4 alkyl) 2 , C(O)—N—(C 1 -C 4 alkyl) 2 , —C(O)—NH—(C 1 -C 4 alkyl), and —C 1 -C 4 alkyl optionally substituted with one or more halo or —OH;
R 4 is selected from hydrogen, —CN, halo, C 1 -C 4 alkoxy, —CH 2 NH(C 1 -C 4 alkyl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), C 1 -C 4 fluoroalkyl, C(O)—N—(C 1 -C 4 alkyl) 2 , —C(O)—NH—(C 1 -C 4 alkyl), —C(O)—O—(C 1 -C 4 alkyl), —C(O)—OH, —S(O) 2 —(C 1 -C 4 alkyl), and a 5-membered heteroaryl;
R 5 is selected from: —C(O)—(C 1 -C 5 alkyl), —C(O)—(C 2 -C 6 alkenyl), —C(O)—(C 0 -C 2 alkylene)-Q, —C(O)—(C 1 -C 4 alkenylene)-Q, —C(O)—O—(C 0 -C 2 alkylene)-Q, —C(O)—(C 1 -C 2 alkylene)-O—(C 0 -C 2 alkylene)-Q, —C(O)—C(O)-Q, —S(O) 2 -Q, —C(O)—(C 1 -C 4 alkylene)-O—C(O)—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkylene)-C(O)—O—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 2 alkylene)-O—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 2 alkylene)-C(O)C(O)N(R)(C 1 -C 4 alkyl), —C(O)—O—(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —(C 0 -C 4 alkylene)-O—C(O)—(C 1 -C 4 alkyl), —(C 0 -C 4 alkylene)-C(O)—O—(C 1 -C 4 alkyl), —(C 0 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 2 alkylene)-S(O) 0-2 —(C 1 -C 4 alkyl), —S(O) 2 —(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkylene)-C(O)C(O)N(R 6 ) (C 1 -C 6 alkyl), —C(O)—(C 1 -C 4 alkylene)-N(R 6 )S(O) 2 —(C 1 -C 6 alkyl), and —C(O)—(C 1 -C 4 alkylene)-N(R 6 )S(O) 2 Q, wherein:
any alkylene moiety present in R 5 is optionally substituted with OCH 3 , OH or F;
any terminal methyl moiety present in R 5 is optionally replaced with —CH 2 OH, CF 3 , —CH 2 F, —CH 2 Cl, C(O)CH 3 , C(O)CF 3 , CN, —OCH 3 , —C(O)H, —OP(O)(OH) 2 , —OP(O)(C 1 -C 4 alkoxy) 2 or CO 2 H;
each R 6 is independently selected from hydrogen and methyl;
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, wherein Q is optionally substituted with up to 3 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —C(O)O—(C 1 -C 4 alkyl)-, —(C 1 -C 4 alkylene)-(C 1 -C 4 alkoxy), —CN, —OH, fluoro, chloro, and bromo, wherein each C 1 -C 4 alkyl is optionally substituted with OH;
R 9 is selected from aryl and heteroaryl, wherein each aryl or heteroaryl is optionally substituted with one or more substituents selected from -G-L-M, halo, C 1 -C 6 alkyl, —C≡N, ═O, —CF 3 and —OCF 3 ; and
m is 0, 1, 2 or 3.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
Y is —N(R 5 );
R 1a is hydrogen, —C 1 -C 4 alkyl, —N(R 7 )(C 1 -C 4 alkylene)-N(R 7 )(C 1 -C 4 alkyl), aryl, heterocyclyl, —C(O)N(R 7 )-aryl, —N(R 7 )C(O)-aryl, —(C 1 -C 4 alkylene)-aryl, —(C 1 -C 4 alkylene)-heteroaryl, —O—(C 1 -C 4 alkylene)-aryl, —O—(C 1 -C 4 alkylene)-heteroaryl, —O—(C 1 -C 4 alkylene)-heterocyclyl, —N(R 7 )-aryl, or —N(R 7 )-heteroaryl;
R 1b is hydrogen, —C 1 -C 4 alkyl, —N(R 7 )(C 1 -C 4 alkylene)-N(R 7 )(C 1 -C 4 alkyl), aryl, heteroaryl, heterocyclyl, —C(O)N(R 7 )-aryl, —N(R 7 )C(O)-aryl, —(C 1 -C 4 alkylene)-aryl, —(C 1 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-aryl, —O—(C 0 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-heterocyclyl, —O—(C 0 -C 4 alkylene)-carbocyclyl, —N(R 7 )-aryl, N(R 7 )-heteroaryl, —N(R 9 )-aryl, —N(R 9 )-heteroaryl, —O—(C 1 -C 4 alkeylene)-N(R 7 )C(O)O—(C 1 -C 4 alkylene)-aryl, or —N(R 9 )—C(O)—(C 2 -C 4 alkenyl), wherein:
at least one of R 1a and R 1b is not hydrogen or methyl;
any alkylene moiety present in R 1a or R 1b is optionally substituted with OH or F;
each R 7 is independently selected from hydrogen and C 1 -C 4 alkyl; and
any aryl, heteroaryl, or heterocylyl of R 1a or R 1b is optionally substituted with one or more substituents selected from -G-L-M, halo, C 1 -C 6 alkyl, —C≡N, ═O, —CF 3 and —OCF 3 ;
G is a bond or a bivalent C 1 -C 6 saturated or unsaturated, straight or branched hydrocarbon chain wherein optionally one, two or three methylene units of the hydrocarbon chain are independently replaced by —NR 8 —, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR 8 )—, —N═N—, or —C(═N 2 )—;
L is a covalent bond or a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by cyclopropylene, —NR 8 —, —N(R 8 )C(O)—, —C(O)N(R 8 )—, —N(R 8 )SO 2 —, SO 2 N(R 8 )—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR 8 )—, —N═N—, or —C(═N 2 )—;
M is E, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with at 1-4 groups independently selected from -D-E, oxo, NO 2 , halogen, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
D is a covalent bond or a bivalent C 1 -C 6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of D are optionally and independently replaced by —NR 8 —, —S—, —O—, —C(O)—, —SO—, or —SO 2 —;
E is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted with oxo, halogen, or CN; and
each R 8 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or an optionally substituted group selected from phenyl, a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 2 is selected from phenyl, a 3-7 membered cycloalkyl, and C 2 -C 4 alkyl, wherein the phenyl or cycloalkyl is optionally substituted with a substituent selected from methyl or fluoro;
each R 3 is independently selected from —C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —C 1 -C 4 fluoroalkyl, —C(O)—O—(C 1 -C 4 alkyl), -phenyl, -heteroaryl, C 3 -C 7 cycloalkyl, —CH 2 —N(C 1 -C 4 alkyl) 2 , C(O)—N—(C 1 -C 4 alkyl) 2 , and —C(O)—NH—(C 1 -C 4 alkyl);
R 4 is selected from hydrogen, —CN, halo, C 1 -C 4 alkoxy, —CH 2 NH(C 1 -C 4 alkyl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), C 1 -C 4 fluoroalkyl, C(O)—N—(C 1 -C 4 alkyl) 2 , —C(O)—NH—(C 1 -C 4 alkyl), —C(O)—O—(C 1 -C 4 alkyl), —C(O)—OH, —S(O) 2 —(C 1 -C 4 alkyl), and a 5-membered heteroaryl;
R 5 is selected from: —C(O)—(C 1 -C 4 alkyl), —C(O)—(CH 2 ) 0-2 -Q, —C(O)—O—(CH 2 ) 1-2 -Q, —C(O)—(CH 2 ) 1-2 —O—(CH 2 ) 0-2 -Q, —C(O)—C(O)-Q, —S(O) 2 -Q, —C(O)—(C 1 -C 4 alkylene)-O—C(O)—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkylene)-C(O)—O—(C 1 -C 4 alkyl), —C(O)—(CH 2 ) 1-2 —O—(C 1 -C 4 alkyl), —C(O)—O—(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —(CH 2 ) 0-4 —O—C(O)—(C 1 -C 4 alkyl), —(CH 2 ) 0-4 —C(O)—O—(C 1 -C 4 alkyl), —(CH 2 ) 0-4 —O—(C 1 -C 4 alkyl), —C(O)—(CH 2 ) 1-2 —S—(C 1 -C 4 alkyl), —S(O) 2 —(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkylene)-C(O)C(O)N(R 6 ) (C 1 -C 6 alkyl), —C(O)—(C 1 -C 4 alkylene)-N(R 6 )S(O) 2 —(C 1 -C 6 alkyl), and —C(O)—(C 1 -C 4 alkylene)-N(R 6 )S(O) 2 Q, wherein:
any alkylene moiety present in R 5 is optionally substituted with OH or F; any terminal methyl moiety present in R 5 is optionally replaced with —CH 2 OH, CF 3 , —CH 2 F, —CH 2 Cl, C(O)CH 3 , or C(O)CF 3 ;
each R 6 is independently selected from hydrogen and methyl;
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, wherein Q is optionally substituted with up to 3 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —CN, fluoro, chloro, and bromo, wherein each C 1 -C 4 alkyl is optionally substituted with OH; and
m is 0, 1,2 or 3.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is —CN or C(O)—O—C 1 -C 4 alkyl.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 is —C(O)—(C 1 -C 3 alkyl)-O—(C 1 -C 2 alkyl), —C(O)-Q, —C(O)—(C 1 -C 5 alkyl), —C(O)—(C 1 -C 2 alkylene)-Q, —C(O)—(C 2 -C 4 alkenyl), —C(O)O—(C 1 -C 4 alkyl), or —C(O)—(C 1 -C 4 alkenylene)-Q; wherein: any alkylene moiety present in R 5 is optionally substituted with OH; any terminal methyl moiety present in R 5 is optionally replaced with —OH, CF 3 , OCH 3 , —C(O)H, OP(O)(C 1 -C 4 alkoxy) 2 , or —OP(O)(OH) 2 (or a salt of —OP(O)(OH) 2 ).
6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Q is cyclopropyl, cyclobutyl, oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl, wherein each member of Q is optionally substituted with one substituent independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —(C 1 -C 4 alkylene)-(C 1 -C 4 alkoxy), and —OH, wherein each C 1 -C 4 alkyl is optionally substituted with OH.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1a is H and R 1b is aryl, heteroaryl, heterocyclyl, —(C 1 -C 4 alkylene)-aryl, —(C 1 -C 4 alkylene)-heteroaryl, —O—(C 0 -C 4 alkylene)-aryl, —O—(C 0 -C 4 alkylene)-heteroaryl, —N(R 7 )-aryl, —N(R 7 )heteroaryl, —N(R 9 )-aryl, or —N(R 9 )-heteroaryl; wherein said aryl or heteroaryl is substituted with -G-L-M, CH 3 , or CN.
8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein any aryl in R 1b is phenyl.
9. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein any heteroaryl in R 1b is pyridyl, pyrimidinyl, naphthyridinyl, quinolyl, isoquinolyl, isoxazolyl, benzoxazolyl, imidazopyrazinyl, benzothiazolyl, benzimidazolyl, pyrollopyridinyl, pyrazolopyridinyl, indolyl, indazolyl, imidazopyridinyl, quinoxalinyl, quinazolinyl, pyridazinyl or pyrazolyl.
10. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein any heterocyclyl in R 1b is benzodioxole, pyridazinone, benzoxazolone, indolinone, N-methylindolinone, piperazinyl, N-methylisoquinolinone, tetrahydropyridinyl, dihydropyrrolyl and said phenyl, pyridyl, pyrimidinyl, naphthyridinyl, quinolyl, isoquinolyl, isoxazolyl, benzoxazolyl, imidazopyrazinyl, benzothiazolyl, benzimidazolyl, pyrollopyridinyl, pyrazolopyridinyl, indolyl, indazolyl, imidazopyridinyl, quinoxalinyl, quinazolinyl, pyridazinyl, pyrazolyl, benzodioxole, pyridazinone, benzoxazolone, indolinone, N-methylindolinone, piperazinyl, N-methylisoquinolinone, tetrahydropyridinyl, or dihydropyrrolyl.
11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1a is methyl and R 1b is aryl, heteroaryl, heterocyclyl, —O—(C 0 -C 4 alkylene)-aryl, or —O—(C 0 -C 4 alkylene)-heteroaryl.
12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R 1a is methyl and R 1b is aryl, heteroaryl, heterocyclyl, —O—(CH 2 )-aryl, —O—CH(CH 3 )-aryl, —O—(CH 2 )-heteroaryl or —O—CH(CH 3 )-heteroaryl.
13. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein any aryl in R 1b is phenyl or naphthyl.
14. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein any heteroaryl in R 1b is quinolinyl, pyrazolyl, isoquinolinyl, pyridyl, pyrimidinyl, indolyl, or pyrazolyl.
15. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein any heterocyclyl in R 1b is tetrahydropyridinyl.
16. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein any aryl, heteroaryl or heterocyclyl in R 1b is substituted with -G-L-M, halo, CH 3 , or CN.
17. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein -G-L-M is:
C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, tetrazolyl, morpholino, piperazinyl, pyrrolidinone, pyrazolyl, benzyl, —(CH 2 ) 1-4 —SH, —(CH 2 ) 1-4 —NH 2 , —NH 2 , —(CH 2 ) 1-4 —OH, —N(H)C(O)OCH(CH 3 ) 3 , —(CH 2 ) 1-4 —OCH 3 , —NH—(CH 2 ) 1-4 —OH, —C(O)—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkenyl), —O—(CH 2 ) 1-4 —C(O)—O—(C 1 -C 4 alkyl), —C(O)NH 2 , —(CH 2 ) 1-4 C(O)CH 3 , —N(CH 3 )(CH 3 ), —NHC(O)(C 2 -C 4 alkenyl), —NHC(O)(C 2 -C 4 alkyl), —SO 2 (CH 2 ) 1-4 , —(CH 2 ) 1-4 —NHSO 2 Me, —NHSO 2 (CH 2 ) 1-4 , —O—SO 2 CF 3 , —SO 2 NH—(C 1 -C 4 alkyl), —SO 2 NH—(C 2 -C 4 alkenyl), SO 2 —NH 2 or —NHSO 2 Me.
18. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
19. The composition of claim 18 , further comprising a second cancer therapeutic agent.
20. The compound according to claim 1 or a pharmaceutically acceptable salt thereof which is:
21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof which is:
22. The compound according to claim 1 or a pharmaceutically acceptable salt thereof which is:
23. The compound according to claim 1 or a pharmaceutically acceptable salt thereof which is:
24. A compound or a pharmaceutically acceptable salt thereof which is:
25. The compound according to claim 1 or a pharmaceutically acceptable salt thereof which is:
26. The compound according to claim 1 or a pharmaceutically acceptable salt thereof which is: