Pyrrolo[2, 3-b]Pyrazine-Based Bifunctional Compounds as HPK1 Degraders and the Use Thereof
Disclosed herein are novel pyrrolo[2,3-b]pyrazine-based bifunctional compounds formed by conjugating HPK1 inhibitor moieties with E3 ligase Ligand moieties, which function to recruit targeted proteins to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
wherein
Z is selected from N or CR za ;
R za is selected from hydrogen, —C 1-8 alkyl, cycloalkyl;
R 1 and R 2 are each independently hydrogen, deuterium, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituents R 1a ; or
R 1 and R 2 together with the atom to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s), said ring is optionally substituted with at least one substituents R 1b ;
R 1a and R 1b are each independently —D (deutrium), halogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO 2 , —OR 1c , —SO 2 R 1c , —SO 2 NR 1c R 1d , —COR 1c , —CO 2 R 1c , —CONR 1c R 1d , —C(═NR 1c )NR 1d R 1e , —NR 1c R 1d , —NR 1c COR 1d , —NR 1c CONR 1d R 1e , —NR 1c CO 2 R 1c , —NR 1c SONR 1d R 1e , —NR 1c SO 2 NR 1d R 1e , or —NR 1c SO 2 R 1d , each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituents selected from halogen, —C 1-8 alkyl, —OR 1f , —NR 1f R 1g , cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 1c , R 1d , R 1e , R 1f , and R 1g are each independently hydrogen, —C 1-8 alkyl, C 1-8 alkoxy—C 1-8 alkyl-, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
n1 is 0, 1, 2, 3 or 4;
n2 is 0, 1, 2 or 3;
R 3 , at each of its occurrence, are independently halogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, —C 1-8 alkyl-heterocyclyl, —C 1-8 alkyl-cycloalkyl, aryl, heteroaryl, oxo, —CN, —NO 2 , —OR 3a , —SO 2 R 3a , —SO 2 NR 3a R 3b , —COR 3a , —CO 2 R 3a , —CONR 3a R 3b , —C(═NR 3a )NR 3b R 3c , —NR 3a R 3b , —NR 3a COR 3b , —NR 3a CONR 3b R 3c , —NR 3a CO 2 R 3b , —NR 3a SONR 3b R 3c , —NR 3a SO 2 NR 3b R 3c , or —NR 3a SO 2 R 3b , each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, —C 1-8 alkyl-heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituents R 3d ; or
or when n1=2, two R 3 , when on adjacent carbon atoms of the phenyl ring, together with the two intervening carbon atoms to which they are attached, form a 5- to 8-membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s);
R 3a , R 3b , and R 3c are each independently hydrogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituents R 3e ; or (R 3a and R 3b ), (R 3b and R 3c ), or (R 3c and R 3a ), together with the atom (s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s), said ring is optionally substituted with at least one substituents R 3e ;
R 3d and R 3e are each independently halogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO 2 , —OR 3f , —SO 2 R 3f , —SO 2 NR 3f R 3g , —COR 3f , —CO 2 R 3f , —CONR 3f R 3g , —C(═NR 3f )NR 3g R 3h , —NR 3f R 3g , —NR 3f COR 3g , —NR 3f CONR 3g R 3h , —NR 3a CO 2 R 3f , —NR 3f SONR 3f R 3g , —NR 3f SO 2 NR 3g R 3h , or —NR 3f SO 2 R 3g , each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituents selected from halogen, —C 1-8 alkyl, —OR 3i , —NR 3i R 3j , cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 3f , R 3g , R 3h , R 3i , and R 3j are each independently hydrogen, —C 1-8 alkyl, C 1-8 alkoxy—C 1-8 alkyl-, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 4 , R 5 and R 6 are each independently hydrogen, halogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO 2 , —OR 4a , —SO 2 R 4a , —COR 4a , —CO 2 R 4a , —CONR 4a R 4b , —C(═NR 4a )NR 4b R 4c , —NR 4a R 4b , —NR 4a COR 4b , —NR 4a CONR 4b R 4c , —NR 4a CO 2 R 4b , —NR 4a SONR 4b R 4c , —NR 4a SO 2 NR 4b R 4c , or —NR 4a SO 2 R 4b , each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, —C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 4a , R 4b , and R 4c are each independently hydrogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
X 1 and X 2 are each independently a single bond, —CR X1 R X2 , —CR X1 R X2 CR X3 R X4 , or —CR X1 R X2 CR X3 R X4 CR X5 R X6 ;
wherein R X1 , R X2 , R X3 , R X4 , R X5 and R X6 , at each of its occurrence, are independently selected from hydrogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, 5- to 12-membered heteroaryl, each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R Xa ;
each of said R Xa is independently oxo, halogen, hydroxy, —C 1-8 alkyl, —C 1-8 alkoxy, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, —C 1-8 haloalkyl, —C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl or 5- to 12-membered heteroaryl;
the Linker is a bond or a divalent linking group, and
the Degron is an E3 Ubiquitin ligase moiety.
2 . The compound according to claim 1 , wherein the Degron moiety is selected from:
wherein
Y 1 and Y 2 are each independently —CH 2 —, —NH— or —C(O)—;
Y 3 , Y 4 , Y 5 and Y 6 are each independently CH or N;
Y 7 is CH or N;
L is selected from a bond, —CH 2 —, —O—, —NH— and —S—;
n5 is 0, 1, 2, 3, or 4;
n6 is 0, 1, or 2;
R 8 is each independently hydrogen, halogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO 2 , —OR 8a , —SO 2 R 8a , —COR 8a , —CO 2 R 8a , —CONR 8a R 8b , —C(═NR 8a )NR 8a R 8c , —NR 8a R 8b , —NR 8a COR 8b , —NR 8a CONR 8b R 8c , —NR 8a CO 2 R 8b , —NR 8a SONR 8b R 8c , —NR 8a SO 2 NR 8b R 8c , or —NR 8a SO 2 R 8b , each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, —C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and
R 8a , R 8b , and R 8c are each independently hydrogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
3 . The compound according to claim 2 , wherein Degron moiety is selected from
wherein R 8 and n5 are defined as above.
4 . The compound according to claim 2 , wherein Degron moiety is selected from
5 . The compound according to claim 2 , wherein Degron moiety is selected from
wherein R 8 and n5 are defined as above.
6 . The compound according to claim 2 , wherein Degron moiety is selected from
7 . The compound according to claim 2 , wherein R 8 is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, —CN, —NO 2 , —OR 8a , —SO 2 R 8a , —COR 8a , —CO 2 R 8a , —CONR 8a R 8b , —C(═NR 8a )NR 8b R 8c , —NR 8a R 8b , —NR 8a COR 8b , —NR 8a CONR 8b R 8c , —NR 8a CO 2 R 8b , —NR 8a SONR 8b R 8c , —NR 8a SO 2 NR 8b R 8c , or —NR 8a SO 2 R 8b , each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl is optionally substituted with —F, —Cl, —Br, —I, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, hepthoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl; and
R 8a , R 8b , and R 8c are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl.
8 . The compound according to claim 2 , wherein R 8 is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl or —CN.
9 . The compound according to claim 2 , wherein R 8 is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
10 . The compound according to claim 1 , wherein the
moiety is
wherein * LN refers to the position attached to the
moiety, and ** LN refers to the position attached to the
moiety;
Z 1 and Z 2 are each independently selected from CH or N;
n7 is 0 or 1;
L 1 is a single bond, —O—, —SO 2 —, —C(O)—, —NR L1a , —C 3 -C 8 cycloalkylene-, * L1 —O—C 1-8 alkylene-** L1 , * L1 —C 1-8 alkylene-O—** L1 , * L1 —SO 2 —C 1-8 alkylene-** L1 , * L1 —C 1-8 alkylene-SO 2 —** L1 , * L1 —C(O)—C 1-8 alkylene-** L1 , * L1 —C 1-8 alkylene-C(O)—** L1 , * L1 —NR L1a —C 1-8 alkylene-** L1 , * L1 —C 1-8 alkylene-NR L1a —** L1 , * L1 —NR L1a C(O)—** L1 , * L1 —C(O)NR L1a —** L1 , * L1 —NR L1a C(O)C 1-8 alkylene-** L1 , * L1 —C(O)NR L1a C 1-8 alkylene-** L1 , * L1 —C 1-8 alkyleneNR L1a C(O)—** L1 , * L1 —C 1-8 alkyleneC(O)NR L1a —** L1 , —C 1-8 alkylene-, —C 2-8 alkenylene-, —C 2-8 alkynylene-, —[O(CR L1a R L1b ) u1 ] v1 —, * L1 —CO—(CR L1a R L1b ) u1 —** L1 , * L1 —(CR L1a R L1b ) u1 —CO—** L1 , * L1 —(CR L1a R L1b ) u1 —** L1 ; each of said —C 3 -C 8 cycloalkylene-, * L1 —O—C 1-8 alkylene-** L1 , * L1 —C 1-8 alkylene-O—** L1 , * L1 —SO 2 —C 1-8 alkylene-** L1 , * L1 —C 1-8 alkylene-SO 2 —** L1 , * L1 —C(O)—C 1-8 alkylene-** L1 , * L1 —C 1-8 alkylene-C(O)—** L1 , * L1 —NR L1a —C 1-8 alkylene-** L1 , * L1 —C 1-8 alkylene-NR L1a —** L1 , * L1 —NR L1a C(O)C 1-8 alkylene-** L1 , * L1 —C(O)NR L1a C 1-8 alkylene-** L1 , * L1 —C 1-8 alkyleneNR L1a C(O)—** L1 , * L1 —C 1-8 alkyleneC(O)NR L1a —** L1 , —C 1-8 alkylene-, —C 2-8 alkenylene or —C 2-8 alkynylene- are optionally substituted with at least one RLIc;
u1 and v1 are each independently selected from 1, 2, 3, 4, 5, 6, 7 or 8;
wherein * L1 refers to the position attached to the
moiety, and
** L1 refers to the position attached to the
moiety;
L 2 is selected from a single bond, —O—, —SO 2 —, —CO—, —NR L2a —, —C 3 -C 8 cycloalkylene-, * L2 —O—C 1-8 alkylene-** L2 , * L2 —C 1-8 alkylene-O—** L2 , * L2 —SO 2 —C 1-8 alkylene-** L2 , * L2 —C 1-8 alkylene-SO 2 —** L2 , * L2 —CO—C 1-8 alkylene-** L2 , * L2 —C 1-8 alkylene-CO—** L2 , * L2 —NR L2a —C 1-8 alkylene-** L2 , * L2 —C 1-8 alkylene-NR L2a —** L2 , * L2 —NR L2a C(O)—** L2 , * L2 —C(O)NR L2a —** L2 , * L2 —NR L2a C(O)C 1-8 alkylene-** L2 , * L2 —C(O)NR L2a C 1-8 alkylene-** L2 , * L2 —C 1-8 alkyleneNR L2a C(O)—** L2 , * L2 —C 1-8 alkyleneC(O)NR L2a —** L2 , —C 1-8 alkylene-, —C 2-8 alkenylene-, —C 2-8 alkynylene- , —[O(CR L2a R L2b ) u2 ] v2 —, * L2 —CO—(CR L2a R L2b ) u2 —** L2 , * L2 —(CR L2a R L2b ) u2 —CO—** L2 , * L2 —(CR L2a R L2b ) u2 —** L2 ; each of said —C 3 -C 8 cycloalkylene-, * L2 —O—C 1-8 alkylene-** L2 , * L2 —C 1-8 alkylene-O—** L2 , * L2 —SO 2 —C 1-8 alkylene-** L2 , * L2 —C 1-8 alkylene-SO 2 —** L2 , * L2 —CO—C 1-8 alkylene-** L2 , * L2 —C 1-8 alkylene-CO—** L2 , * L2 —NR L2a —C 1-8 alkylene-** L2 , * L2 —C 1-8 alkylene-NR L2a —** L2 , * L2 —NR L2a C(O)C 1-8 alkylene-** L2 , * L2 —C(O)NR L2a C 1-8 alkylene-** L2 , * L2 —C 1-8 alkyleneNR L2a C(O)—** L2 , * L2 —C 1-8 alkyleneC(O)NR L2a —** L2 , —C 1-8 alkylene-, —C 2-8 alkenylene or —C 2-8 alkynylene- are optionally substituted with at least one substituent R L2c ;
u2 and v2 are each independently selected from 1, 2, 3, 4, 5, 6, 7 or 8;
wherein * L2 refers to the position attached to the
moiety, and
** L2 refers to the position attached to the
moiety;
L 3 is selected from a single bond, —O—, —SO 2 —, —CO—, —NR L3a —, —C 3 -C 8 cycloalkylene-, * L3 —O—C 1-8 alkylene-** L3 , * L3 —C 1-8 alkylene-O—** L3 , * L3 —SO 2 —C 1-8 alkylene-** L3 , * L3 —C 1-8 alkylene-SO 2 —** L3 , * L3 —CO—C 1-8 alkylene-** L3 , * L3 —C 1-8 alkylene-CO—** L3 , * L3 —NR L3a —C 1-8 alkylene-** L3 , * L3 —C 1-8 alkylene-NR L3a —** L3 , * L3 —NR L3a C(O)—** L3 , * L3 —C(O)NR L3a —** L3 , * L3 —NR L3a C(O)C 1-8 alkylene-** L3 , * L3 —C(O)NR L3a C 1-8 alkylene-** L3 , * L3 —C 1-8 alkyleneNR L3a C(O)—** L3 , * L3 —C 1-8 alkyleneC(O)NR L3a —** L3 , —C 1-8 alkylene-, —C 2-8 alkenylene-, —C 2-8 alkynylene-, —[O(CR L3a R L3b ) u3 ] v3 —, —* L3 —CO—(CR L3a R L3b ) u3 —** L3 , * L3 —(CR L3a R L3b ) u3 —CO—** L3 , * L3 —(CR L3a R L3b ) u3 —** L3 ; each of said —C 3 -C 8 cycloalkylene-, * L3 —O—C 1-8 alkylene-** L3 , * L3 —C 1-8 alkylene-O—** L3 , * L3 —SO 2 —C 1-8 alkylene-** L3 , * L3 —C 1-8 alkylene-SO 2 —** L3 , * L3 —CO—C 1-8 alkylene-** L3 , * L3 —C 1-8 alkylene-CO—** L3 , * L —NR L3a —C 1-8 alkylene-** L3 , * L3 —C 1-8 alkylene-NR L3a —** L3 , * L3 —NR L3a C(O)C 1-8 alkylene-** L3 , * L3 —C(O)NR L3a C 1-8 alkylene-** L3 , * L3 —C 1-8 alkyleneNR L3a C(O)—** L3 , * L3 —C 1-8 alkyleneC(O)NR L3a —** L3 , —C 1-8 alkylene-, —C 2-8 alkenylene-, —C 2-8 alkynylene-, are optionally substituted with at least one substituent R L3c ;
u3 and v3 are each independently selected from 1, 2, 3, 4, 5, 6, 7 or 8;
wherein * L3 refers to the position attached to the
moiety, and ** L3 referes to the position attached to the
moiety;
R L1a , R L1b , R L1c , RL 2a , R L2b , R L2c , R L3a , R L3b , R L3c are each independently selected from hydrogen, —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or membered heteroaryl is optionally substituted with at least one substituent R L3d ; R L3d is halogen, hydroxy, —C 1-8 alkyl, -haloC 1-8 alkyl, —C 1-8 alkoxy, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
11 . The compound according to claims 10 , wherein L 1 is a single bond, —O—, —SO 2 —, —C(O)—, —NH—, —N(CH 3 )—, —N(C 2 H 5 )—, —N(C 3 H 7 )—, * L1 —O—CH 2 —** L1 , * L1 —O—C 2 H 4 —** L1 , * L1 —O—C 3 H 6 —** L1 , * L1 —O—C 4 H 8 —** L1 , * L1 —CH 2 —O—** L1 , * L1 —C 2 H 4 —O—** L1 , * L1 —C 3 H 6 —O—** L1 , * L1 —C 4 H 8 —O—** L1 , * L1 —SO 2 —CH 2 —** L1 , * L1 13 SO 2 —C 2 H 4 —** L1 , * L1 —SO 2 —C 3 H 6 —** L1 , * L1 —SO 2 —C 4 H 8 —** L1 , * L1 —CH 2 —SO 2 —** L1 , * L1 —C 2 H 4 —SO 2 —** L1 , * L1 —C 3 H 6 —SO 2 —** L1 , * L1 —C 4 H 8 —SO 2 —** L1 , * L1 —C(O)—CH 2 —** L1 , * L1 —C(O)—C 2 H 4 —** L1 , * L1 —C(O)—C 3 H 6 —** L1 , * L1 —C(O)—C 4 H 8 —** L1 , * L1 —CH 2 —C(O)—** L1 , * L1 —C 2 H 4 —C(O)—** L1 , * L1 —C 3 H 6 —C(O)—** L1 , * L1 —C 4 H 8 —C(O)—** L1 , * L1 —NH—CH 2 —** L1 , * L1 —NH—C 2 H 4 —** L1 , * L1 —NH—C 3 H 6 —** L1 , * L1 —NH—C 4 H 8 —** L1 , * L1 —CH 2 —NH—** L1 , * L1 —C 2 H 4 —NH—** L1 , * L1 —C 3 H 6 —NH—** L1 , * L1 —C 4 H 8 —NH—** L1 , * L1 —NHC(O)—** L1 , * L1 —C(O)NH—** L1 , * L1 —N(CH 3 )C(O)—** L1 , * L1 —C(O)N(CH 3 )—** L1 , * L1 —N(C 2 H 5 )C(O)—** L1 , * L1 —C(O)N(C 2 H 5 )—** L1 , * L1 —N(C 3 H 7 )C(O)—** L1 , * L1 —C(O)N(C 3 H 7 )—** L1 , * L1 —NHC(O)CH 2 —** L1 , * L1 —NHC(O)C 2 H 4 —** L1 , * L1 —NHC(O)C 3 H 6 —** L1 , * L1 —NHC(O)C 4 H 8 —** L1 , * L1 —C(O)NHCH 2 —** L1 , * L1 —C(O)NHC 2 H 4 —** L1 , * L1 —C(O)NHC 3 H 6 —** L1 , * L1 —C(O)NHC 4 H 8 —** L1 , * L1 —CH 2 NHC(O)—** L1 , * L1 —C 2 H 4 NHC(O)—** L1 , * L1 —C 3 H 6 NHC(O)—** L1 , * L1 —C 4 H 8 NHC(O)—** L1 , * L1 —CH 2 C(O)NH—** L1 , * L1 —C 2 H 4 C(O)NH—** L1 , * L1 —C 3 H 6 C(O)NH—** L1 , * L1 —C 4 H 8 C(O)NH—** L1 , —CH 2 —, —C 2 H 4 —, —C 3 H 6 —, —C 4 H 8 —, —O(CH 2 ) 2 —, —[O(CH 2 ) 2 ] 2 —, —[O(CH 2 ) 2 ] 3 —, —[O(CH 2 ) 2 ] 4 — or —[O(CH 2 ) 2 ] 5 —.
12 . The compound according to claims 10 , wherein L 1 is * L1 —CH 2 —C(O)—** L1 , * L1 —CH 2 CH 2 —C(O)—** L1 , * L1 —CH 2 CH 2 CH 2 —C(O)—** L1 , * L1 —CH 2 —NH—** L1 , * L1 —CH 2 CH 2 —NH—** L1 , * L1 —CH 2 CH 2 CH 2 —NH—** L1 , * L1 —CH 2 NHC(O)—** L1 , * L1 —CH 2 CH 2 NHC(O)—** L1 , * L1 —CH 2 CH 2 CH 2 NHC(O)—** L1 , * L1 —CH 2 C(O)NH—** L1 , * L1 —CH 2 CH 2 C(O)NH—** L1 , * L1 —CH 2 CH 2 CH 2 C(O)NH—** L1 , —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —.
13 . The compound according to claims 10 , wherein L 2 is a single bond, —O—, —SO 2 —, —C(O)—, —NH—, —N(CH 3 )—, —N(C 2 H 5 )—, —N(C 3 H 7 )—, * L2 —O—CH 2 —** L2 , * L2 —O—C 2 H 4 —** L2 , * L2 —O—C 3 H 6 —** L2 , * L2 —O—C 4 H 8 —** L2 , * L2 —CH 2 —O—** L2 , * L2 —C 2 H 4 —O—** L2 , * L2 —C 3 H 6 —O—** L2 , * L2 —C 4 H 8 —O—** L2 , * L2 —SO 2 —CH 2 —** L2 , * L2 —SO 2 —C 2 H 4 —** L2 , * L2 —SO 2 —C 3 H 6 —** L2 , * L2 —SO 2 —C 4 H 8 —** L2 , * L2 —CH 2 —SO 2 —** L2 , * L2 —C 2 H 4 —SO 2 —** L2 , * L2 —C 3 H 6 —SO 2 —** L2 , * L2 —C 4 H 8 —SO 2 —** L2 , * L2 —C(O)—CH 2 —** L2 , * L2 —C(O)—C 2 H 4 —** L2 , * L2 —C(O)—C 3 H 6 —** L2 , * L2 —C(O)—C 4 H 8 —** L2 , * L2 —CH 2 —C(O)—** L2 , * L2 —C 2 H 4 —C(O)—** L2 , * L2 —C 3 H 6 —C(O)—** L2 , * L2 —C 4 H8—C(O)—** L2 , * L2 —NH—CH 2 —** L2 , * L2 —NH—C 2 H 4 —** L2 , * L2 —NH—C 3 H 6 —** L2 , * L2 —NH—C 4 H 8 —** L2 , * L2 —CH 2 —NH—** L2 , * L2 —C 2 H 4 —NH—** L2 , * L2 —C 3 H 6 —NH—** L2 , * L2 —C 4 H 8 —NH—** L2 , * L2 —NHC(O)—** L2 , * L2 —C(O)NH—** L2 , * L2 —N(CH 3 )C(O)—** L2 , * L2 —C(O)N(CH 3 )—** L2 , * L2 —N(C 2 H 5 )C(O)—** L2 , * L2 —C(O)N(C 2 H 5 )—** L2 , * L2 —N(C 3 H 7 )C(O)—** L2 , * L2 —C(O)N(C 3 H 7 )—** L2 , * L2 —NHC(O)CH 2 —** L2 , * L2 —NHC(O)C 2 H 4 —** L2 , * L2 —NHC(O)C 3 H 6 —** L2 , * L2 —NHC(O)C 4 H 8 —** L2 , * L2 —C(O)NHCH 2 —** L2 , * L2 —C(O)NHC 2 H 4 —** L2 , * L2 —C(O)NHC 3 H 6 —** L2 , * L2 —C(O)NHC 4 H 8 —** L2 , * L2 —CH 2 NHC(O)—** L2 , * L2 —C 2 H 4 NHC(O)—** L2 , * L2 —C 3 H(NHC(O)—** L2 , * L2 —C 4 H 8 NHC(O)—** L2 , * L2 —CH 2 C(O)NH—** L2 , * L2 —C 2 H 4 C(O)NH—** L2 , * L2 —C 3 H 6 C(O)NH—** L2 , * L2 —C 4 H 8 C(O)NH—** L2 , —CH 2 —, —C 2 H 4 —, —C 3 H 6 —, —C 4 H 8 —, —O(CH 2 ) 2 —, —[O(CH 2 ) 2 ] 2 —, —[O(CH 2 ) 2 ] 3 —, —[O(CH 2 ) 2 ] 4 —or —[O(CH 2 ) 2 ] 5 —.
14 . The compound according to claims 10 , wherein L 2 is a single bond, —C(O)—, —NH—, * L2 —NHC(O)—** L2 , * L2 —C(O)NH—** L2 , * L2 —NH—CH 2 —** L2 , * L2 —NH—CH 2 CH 2 —** L2 , * L2 —NH—CH 2 CH 2 CH 2 —** L2 , * L2 —C(O)—CH 2 —** L2 , * L2 —C(O)—CH 2 CH 2 —** L2 , * L2 —C(O)—CH 2 CH 2 CH 2 —** L2 , * L2 —NHC(O)CH 2 —** L2 , * L2 —NHC(O)CH 2 CH 2 —** L2 , * L2 —NHC(O)CH 2 CH 2 CH 2 —** L2 , * L2 —C(O)NHCH 2 —** L2 , * L2 —C(O)NHCH 2 CH 2 —** L2 , or * L2 —C(O)NHCH 2 CH 2 CH 2 —** L2 .
15 . The compound according to claims 10 , wherein L 3 is a single bond, —O—, —SO 2 —, —C(O)—, —NH—, —N(CH 3 )—, —N(C 2 H 5 )—, —N(C 3 H 7 )—, * L3 —O—CH 2 —** L3 , * L3 —O—C 2 H 4 —** L3 , * L3 —O—C 3 H 6 —** L3 , * L3 —O—C 4 H 8 —** L3 , * L3 —CH 2 —O—** L3 , * L3 —C 2 H 4 —O—** L3 , * L3 —C 3 H 6 —O—** L3 , * L 3 —C 4 H 8 —O—** L3 , * L3 —SO 2 —CH 2 —** L3 , * L3 —SO 2 —C 2 H 4 —** L3 , * L3 —SO 2 —C 3 H 6 —** L3 , * L3 —SO 2 —C 4 H 8 —** L3 , * L3 —CH 2 —SO 2 —** L3 , * L3 —C 2 H 4 —SO 2 —** L3 , * L3 —C 3 H 6 —SO 2 —** L3 , * L3 —C 4 H 8 —SO 2 —** L3 , * L3 —C(O)—CH 2 —** L3 , * L3 —C(O)—C 2 H 4 —** L3 , * L3 —C(O)—C 3 H 6 —** L3 , * L3 —C(O)—C 4 H 8 —** L3 , * L3 —CH 2 —C(O)—** L3 , * L3 —C 2 H 4 —C(O)—** L3 , * L3 —C 3 H 6 —C(O)—** L3 , * L3 —C 4 H 8 —C(O)—** L3 , * L3 —NH—CH 2 —** L3 , * L3 —NH—C 2 H 4 —** L3 , * L3 —NH—C 3 H 6 —** L3 , * L3 —NH—C 4 H 8 —** L3 , * L3 —CH 2 —NH—** L3 , * L3 —C 2 H 4 —NH—** L3 , * L3 —C 3 H 6 —NH—** L3 , * L3 —C 4 H 8 —NH—** L3 , * L3 —NHC(O)—** L3 , * L3 —C(O)NH—** L3 , * L3 —N(CH 3 )C(O)—** L3 , * L3 —C(O)N(CH 3 )—** L3 , * L3 —N(C 2 H 5 )C(O)—** L3 , * L3 —C(O)N(C 2 H 5 )—** L3 , * L3 —N(C 3 H 7 )C(O)—** L3 , * L3 —C(O)N(C 3 H 7 )—** L3 , * L3 —NHC(O)CH 2 —** L3 , * L3 —NHC(O)C 2 H 4 —** L3 , * L3 —NHC(O)C 3 H 6 —** L3 , * L3 —NHC(O)C 4 H 8 —** L3 , * L3 —C(O)NHCH 2 —** L3 , * L3 —C(O)NHC 2 H 4 —** L3 , * L3 —C(O)NHC 3 H 6 —** L3 , * L3 —C(O)NHC 4 H 8 —** L3 , * L3 CH 2 NHC(O)—** L3 , * L3 —C 2 H 4 NHC(O)—** L3 , * L3 —C 3 H 6 NHC(O)—** L3 , * L3 —C 4 H 8 NHC(O)—** L3 , * L3 —CH 2 C(O)NH—** L3 , * L3 —C 2 H 4 C(O)NH—** L3 , * L3 —C 3 H 6 C(O)NH—** L3 , * L3 —C 4 H 8 C(O)NH—** L3 , —CH 2 —, —C 2 H 4 —, —C 3 H 6 —, —C 4 H 8 —, —O(CH 2 ) 2 —, —[O(CH 2 ) 2 ] 2 —, —[O(CH 2 ) 2 ] 3 —, —[O(CH 2 ) 2 ] 4 — or —[O(CH 2 ) 2 ] 5 —.
16 . The compound according to claims 10 , wherein L 3 is a single bond.
17 . The compound according to claims 10 , wherein
moiety is
wherein * LN refers to the position attached to the
moiety, and ** LN refers to the position attached to the
moiety.
18 . The compound according to claim 1 , wherein the
moiety is
wherein * LN refers to the position attached to the
moiety, and ** LN refers to the position attached to the
moiety.
19 . The compound according to claim 1 , wherein R 1 and R 2 are each independently hydrogen, deuterium, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl is optionally substituted with at least one substituents R 1a ; or
R 1 and R 2 together with the atom to which they are attached, form a 3-, 4-, 5-, 6-, 7- or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s), said ring is optionally substituted with at least one substituents R 1b .
R 1a and R 1b are each independently —D, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, oxo, —CN, —NO 2 , —OR 1c , —SO 2 R 1c , —SO 2 NR 1c R 1d , —COR 1c , —CO 2 R 1c , —CONR 1c R 1d , —C(═NR 1c )NR 1d R 1e , —NR 1c R 1d , —NR 1c COR 1d , —NR 1c CONR 1d R 1e , —NR 1c CO 2 R 1c , —NR 1c SONR 1c R 1d , —NR 1c SO 2 NR 1d R 1e , or —NR 1c SO 2 R 1d , each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl is optionally substituted with at least one substituents selected from —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —OR 1f , —NR 1f R 1g , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl;
R 1c , R 1d , R 1e , R 1f , and R 1g are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, C 1-8 alkoxy-C 1-8 alkyl-, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl.
20 . The compound according to claim 1 , wherein R 1 and R 2 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl is optionally substituted with at least one OH; or
R 1 and R 2 together with the atom to which they are attached, form a 3-, 4-, 5-, 6-, 7- or 8-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s).
21 . The compound according to claim 1 , wherein R 1 and R 2 are each independently hydrogen, —CD 3 , methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, 2-hydroxypropyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, or 4-hydroxybutyl.
22 . The compound according to claim 1 , wherein R 3 , at each of its occurrence, are independently —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, —CH 2 -heterocyclyl, —CH 2 CH 2 -heterocyclyl, —CH 2 CH 2 CH 2 -heterocyclyl, —CH 2 CH 2 CH 2 CH 2 -heterocyclyl, —CH 2 -cycloalkyl, —CH CH 2 -cycloalkyl, —CH CH 2 CH 2 -cycloalkyl, —CH 2 CH 2 CH 2 CH 2 -cycloalkyl, oxo, —CN, —NO 2 , —OR 3a , —SO 2 R 3a , —SO 2 NR 3a R 3b , —COR 3a , —CO 2 R 3a , —CONR 3a R 3b , —C(═NR 3a )NR 3b R 3c , —NR 3a R 3b , —NR 3a COR 3b , —NR 3a CONR 3b R 3c , —NR 3a CO 2 R 3b , —NR 3a SONR 3b R 3c , —NR 3a SO 2 NR 3b R 3c , or —NR 3a SO 2 R 3h , each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, —CH 2 -heterocyclyl, —CH 2 CH 2 -heterocyclyl, —CH 2 CH 2 CH 2 -heterocyclyl, —CH 2 CH 2 CH 2 CH 2 -heterocyclyl, —CH 2 -cycloalkyl, —CH 2 CH 2 -cycloalkyl, —CH 2 CH 2 CH 2 -cycloalkyl or —CH 2 CH 2 CH 2 CH 2 -cycloalkyl is optionally substituted with at least one substituents R 3d ; or
or two R 3 , when on adjacent carbon atoms of the phenyl ring, together with the two intervening carbon atoms to which they are attached, form a 5- to 8-membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s);
R 3a , R 3b , and R 3a are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl is optionally substituted with at least one substituents R 3e ; or
(R 3a and R 3b ), (R 3b and R 3c ), or (R 3c and R 3a ), together with the atom (s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s), said ring is optionally substituted with at least one substituents R 3e ;
R 3d and R 3e are each independently —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, oxo, —CN, —NO 2 , —OR 3f , —SO 2 R 3f , —SO 2 NR 3f R 3g , —COR 3f , —CO 2 R 3f , —CONR 3f R 3g , —C(═NR 3f )NRR 3g R 3h , —NR 3f R 3g , —NR 3f COR 3g , —NR 3f CONR 3g R 3h , —NR 3f CO 2 R 3f , —NR 3f SONR 3f R 3g , —NR 3f SO 2 NR 3g R 3h , or —NR 3f SO 2 R 3g , each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl is optionally substituted with at least one substituents selected from —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —OR 3i , —NR 3i R 3j , cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl;
R 3f , R 3g , R 3h , R 3i , and R 3j are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, C 1-8 alkoxy-C 1-8 alkyl-
23 . The compound according to claim 1 , wherein R 3 , at each of its occurrence, are independently —F, —Cl, —F, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, —CH 2 -heterocyclyl, —CH 2 CH 2 -heterocyclyl, —CH 2 CH 2 CH 2 -heterocyclyl, —CH 2 CH 2 CH 2 CH 2 -heterocyclyl, —CH 2 -cycloalkyl, —CH 2 CH 2 -cycloalkyl, —CH 2 CH 2 CH 2 -cycloalkyl, —CH 2 CH 2 CH 2 CH 2 -cycloalkyl, oxo, —CN, —NO 2 , —OR 3a , —SO 2 R 3a , —SO 2 NR 3a R 3b , —COR 3a , —CO 2 R 3a , —CONR 3a R 3b , —C(═NR 3a )NR 3b R 3c , —NR 3a R 3b , —NR 3a COR 3b , —NR 3a CONR 3b R 3c , —NR 3a CO 2 R 3b , —NR 3a SONR 3b R 3c , —NR 3a SO 2 NR 3b R 3c , or —NR 3a SO 2 R 3b , each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, —CH 2 -heterocyclyl, —CH 2 CH 2 -heterocyclyl, —CH 2 CH 2 CH 2 -heterocyclyl, —CH 2 CH 2 CH 2 CH 2 -heterocyclyl, —CH 2 -cycloalkyl, —CH 2 CH 2 -cycloalkyl, —CH 2 CH 2 CH 2 -cycloalkyl or —CH 2 CH 2 CH 2 CH 2 -cycloalkyl is optionally substituted with at least one substituents R 3d ; or
two R 3a , when on adjacent carbon atoms of the phenyl ring, together with the two intervening carbon atoms to which they are attached, form a 5- to 8-membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s);
R 3a , R 3b , and R 3c are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl is optionally substituted with at least one substituents R 3e ; or
(R 3a and R 3b ), (R 3b and R 3c ), or (R 3c and R 3a ), together with the atom (s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s), said ring is optionally substituted with at least one substituents R 3e ;
R 3d and R 3e are each independently —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, oxo, —CN, —NO 2 , —OR 3f , —SO 2 R 3f , —SO 2 NR 3f R 3g , —COR 3f , —CO 2 R 3f , —CONR 3f R 3g , —C(═NR 3f )NR 3g R 3h , —NR 3f R 3g , —NR 3f COR 3g , —NR 3f CONR 3g R 3h , —NR 3f CO 2 R 3f , —NR 3f SONR 3f R 3g , —NR 3f SO 2 NR 3g R 3h , or —NR 3f SO 2 R 3g , each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl is optionally substituted with at least one substituents selected from —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —OR 3i , —NR 3i R 3j , cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl;
R 3f , R 3g , R 3h , R 3i , and R 3j are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, C 1-8 alkoxy-C 1-8 alkyl.
23 . The compound according to claim 1 , wherein R 3 , at each of its occurrence, is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —F, —Cl, —Br, —I, —CN, OR 3a or —NR 3a CONR 3b R 3c ; said—C 1-8 alkyl is optionally substituted with at least one substituents R 3d ; R 3a , R 3b and R 3c are each independently hydrogen, or —C 1-8 alkyl (preferably methyl); R 3d is each independently —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl.
24 . The compound according to claim 1 , wherein R 3 is —F, —Cl, —Br, —I, OH, CN, —CH 3 , —C 2 H 5 , —CH 2 CH 2 CH 3 , —CH(CH 3 )CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 )CH 3 , —C(CH 3 ) 3 , —CH 2 F, —CHF 2 , —CF 3 or —NHCOCH 3 .
25 . The compound according to claim 1 , wherein
26 . The compound according to claim 1 , wherein
moiety is
27 . The compound according to claim 1 , wherein R 4 , R 5 and R 6 are each independently hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, oxo, —CN, —NO 2 , —OR 4a , —SO 2 R 4a , —COR 4a , —CO 2 R 4a , —CONR 4a R 4b , —C(═NR 4a )NR 4b R 4c , —NR 4a R 4b , —NR 4a COR 4b , —NR 4a CONR 4b R 4c , —NR 4a CO 2 R 4b , —NR 4a SONR 4b R 4c , —NR 4a SO 2 NR 4b R 4c , or —NR 4a SO 2 R 4b , each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl is optionally substituted with —F, —Cl, —Br, —I, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, hepthoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyrazinyl;
R 4a , R 4b , and R 4c are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl or pyraziny.
28 . The compound according to claim 1 , wherein R 5 and R 6 are each independently hydrogen or —C 1-8 alkyl (preferably hydrogen or methyl).
29 . The compound according to claim 1 , wherein R 4 is from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —OR 4a or —NR 4a R 4b , said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl is optionally substituted with at least one substituents —OH, —F, —Cl, —F, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl;
R 4a and R 4b are each hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl; preferably R 4 is selected from —CH 3 , —OCH 3 , —NHCH 3 , —CHF 2 , or —C(CH 3 ) 2 OH.
30 . The compound according to claim 1 , wherein X 1 and X 2 are each independently a single bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —.
31 . The compound according to claim 30 , wherein when X 1 is —CH 2 —, X 2 is —CH 2 CH 2 —; or when X′ is —CH 2 CH 2 —, X 2 is —CH 2 —; or when X 1 is a single bond, X 2 is —CH 2 CH 2 CH 2 —; or when X 1 is —CH2CH 2 CH 2 —, X 2 is a single bond.
32 . The compound according to claim 1 , wherein R X1 , R X2 , R X3 , R X4 , R X5 and R X6 each is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl is optionally substituted with at least one substituent R Xa ; each of said R Xa are independently oxo, —F, - Cl, -Br. —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl.
33 . The compound according to claim 32 , wherein R Xa is selected from oxo, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl.
34 . The compound according to claim 33 , wherein R Xa is selected from oxo, —F, —Cl, —Br, —I, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl.
35 . The compound according to claim 1 , wherein the compound is selected from
36 . A pharmaceutical composition comprising the compound according to any one of claims 1-35 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
37 . A method of decreasing HPK1 activity by inhibition and/or protein degradation, which comprises administering to an individual the compound according to any one of claims 1-35 , or a pharmaceutically acceptable salt thereof.
38 . A method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof as an HPK1 degrader, wherein the compound disclosed herein includes the compound of claims 1-35 .