Bifunctional pyrrolo[2,3-b]pyrazine compounds as HPK1 degradation inducers and their use

Abstract

Disclosed herein are novel pyrrolo[2,3-b]pyrazine-based bifunctional compounds formed by combining an HPK1 inhibitor moiety and an E3 ligase ligand moiety, which function to recruit target proteins to E3 ubiquitin ligase for degradation, as well as methods for their preparation and use.

Description

[Technical field]

[0001] Disclosure herein provides pyrrolo[2,3-b]pyrazine-based bifunctional compounds, as well as compositions and methods of use thereof. The compounds disclosed herein have the activity of degrading hematopoietic progenitor kinase 1 (HPK1) protein, thereby reducing or inhibiting the function of HPK1. The disclosed compounds are useful in the treatment of various HPK1-mediated diseases, including cancer. [Background technology]

[0002] HPK1 regulates various functions of various immune cells, and its kinase activity is involved in the regulation of the T cell receptor (TCR) [Liou J.,et al.,Immunity,2000.12(4):pp.399-408], B cell receptor (BCR) [Liou J.,et al.,Immunity,2000.12(4):pp.399-408], transforming growth factor receptor (TGF-βR) [Wang,W.,et al.,J Biol Chem,1997.272(36):pp.22771-5, Zhou,G.,et al.,J Biol Chem,1999.274(19):pp.13133-8], and Gs-coupled PGE2 receptors (EP2 and EP4) [Ikegami,R.,et al.,J It has been shown that HPK1 is induced by activation of the TCR-induced IL-2 gene [Immunol,2001.166(7):pp.4689-96]. Overexpression of HPK1 suppresses TCR-induced activation of AP-1-dependent gene transcription in a kinase-dependent manner, suggesting that HPK1 is required to inhibit the Erk MAPK pathway [Liou J.,et al.,Immunity,2000.12(4):pp.399-408], and this blockade is thought to be the inhibitory mechanism that negatively regulates TCR-induced IL-2 gene transcription [Sawasdikosol,S.,et al.,Immunol Res,2012.54:pp.262-5].

[0003] In vitro HPK1- / - T cells have a lower TCR activation threshold, proliferate robustly, produce enhanced amounts of Th1 cytokines, and HPK1- / - mice experience more severe autoimmune symptoms [Sawasdikosol, S., et al., Immunol Res, 2012.54:pp.262-5]. In humans, HPK1 is downregulated in peripheral blood mononuclear cells of psoriatic arthritis patients or T cells of systemic lupus erythematosus (SLE) patients [Batliwalla FM, et al., Mol Med, 2005.11(1-12):pp.21-9], indicating that attenuation of HPK1 activity may contribute to autoimmunity in patients. Furthermore, HPK1 may regulate antitumor immunity through a T cell-dependent mechanism. In a PGE2-producing Lewis lung carcinoma tumor model, tumors developed more slowly in HPK1 knockout mice compared to wild-type mice [US Patent Application No. 2007 / 0087988]. HPK1-deficient T cells were more effective at controlling tumor growth and metastasis than wild-type T cells [Alzabin, S., et al., Cancer Immunol Immunother, 2010. 59(3): pp. 419-29]. Similarly, BMDCs from HPK1 knockout mice were more efficient at mounting T cell responses to eradicate Lewis lung carcinoma compared to wild-type BMDCs [Alzabin, S., et al., J Immunol, 2009. 182(10): pp. 6187-94].

[0004] HPK1 is thought to negatively regulate T cell activation by phosphorylating the Ser376 position of the SH2 domain-containing leukocyte protein of 76 kDa (SLP76), which recruits 14-3-3 proteins that lead to the proteolysis of SLP76 [Shui, JW., et al., Nat Immunol, 2007.8(1):pp.84-91]. In addition to kinase activity, HPK1 protein may also have a scaffolding function. For example, HPK1 may compete with degranulation-promoting adaptor protein (ADAP) to bind to SLP76, which inhibits T cell adhesion [Patzak, IM, et al., Eur J Immunol, 2010.40(11):pp.3220-5]. Degrading HPK1 protein may serve both the purpose of inhibiting the kinase function and the scaffolding function of HPK1 to enhance T cell activity. Moreover, the mode of proteolysis is predicted to overcome potential resistance due to genetic mutations and / or overexpression.

[0005] Proteolysis-inducing chimeric molecules (PROTACs) are a novel strategy for selective knockdown of target proteins by small molecules (Sakamoto KM et al., Proc Natl Acad Sci 2001,98:pp.8554-9.; Sakamoto KM et al., Methods Enzymol.2005;399:pp.833-47). PROTACs utilize the ubiquitin-protease system to target specific proteins and induce their cellular degradation (Zhou P.et al., Mol Cell.2000;6(3):pp.751-6; Neklesa TKet al., Pharmacol Ther.2017;174:138-144; Lu M.et al., Eur J Med Chem.2018;146:pp.251-9).

[0006] WO2020227325 discloses several bivalent compounds as HPK1 degradation inducers. However, there is a need for new HPK1 protein degradation inducers for treating HPK1-mediated diseases, particularly cancer. Summary of the Invention [Means for solving the problem]

[0007] It is an object of the present invention to provide a series of proteolysis targeting chimeric molecules (PROTAC) compounds combining HPK1 inhibitors and E3 ligase ligands, which function to recruit target proteins to E3 ubiquitin ligase for degradation, and to provide methods for their preparation and use. In particular, the present disclosure provides PROTAC compounds having formula (I):

[0008] Aspect 1: A compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, During the ceremony, Z is N or CR za Selected from; R za is hydrogen, -C 1-8 alkyl, cycloalkyl; R 1 and R 2 are independently hydrogen, deuterium, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may have at least one substituent R 1a optionally substituted with; or R 1 and R 2together with the atoms to which they are attached form a 3-12 membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring containing at least one substituent R 1b optionally substituted with; R 1a and R 1b are each independently -D (deuterium), halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 1c , -SO2R 1c , -SO2NR 1c R 1d , -COR 1c , -CO2R 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 CO2R 1c , -NR 1c SONR 1d R 1e , -NR 1c SO2NR 1d R 1e , or -NR 1c SO2R 1d and said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from halogen, -C 1-8 Alkyl, -OR 1f , -NR 1f R 1g, optionally substituted with at least one substituent selected from 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 is, in each occurrence, independently, a 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, -NO2, -OR 3a , -SO2R 3a , -SO2NR 3a R 3b , -COR 3a , -CO2R 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 CO2R 3b , -NR 3a SONR 3b R 3c , -NR 3a SO2NR 3b R3c , or -NR 3a SO2R 3b and said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, -C 1-8 Each of the alkyl-heterocyclyl, aryl, or heteroaryl may contain at least one substituent R 3d optionally substituted with; or Or, when n1=2, two R on adjacent carbon atoms of a phenyl ring 3 form, together with the two intervening carbon atoms to which they are attached, a 5-8 membered ring containing as ring member(s) 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; 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, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may have at least one substituent R 3e optionally substituted with; 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 3-12 membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring containing at least one substituent R 3e optionally substituted with; R 3d and R 3e are each independently a halogen, -C1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 3f , -SO2R 3f , -SO2NR 3f R 3g , -COR 3f , -CO2R 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 CO2R 3f , -NR 3f SONR 3f R 3g , -NR 3f SO2NR 3g R 3h , or -NR 3f SO2R 3g and said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from halogen, -C 1-8 Alkyl, -OR 3i , -NR 3i R 3j , optionally substituted with at least one substituent selected from 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, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 4 , R 5 and R 6 are each independently hydrogen, halogen, or -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 4a , -SO2R 4a , -COR 4a , -CO2R 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 CO2R 4b , -NR 4a SONR 4b R 4c , -NR 4a SO2NR 4b R 4c , or -NR 4a SO2R 4b and said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from halogen, hydroxy, -C 1-8 optionally substituted with 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 2-8alkynyl, 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 and; In the formula, R X1 , R X2 , R X3 , R X4 , R X5 , and R X6 represents, in each occurrence, hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, and 5- to 12-membered heteroaryl; 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl has at least one substituent R Xa optionally substituted with; R Xa each independently represents 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, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl; the linker is a linking group or a divalent linking group; The compound, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, wherein the degron is an E3 ubiquitin ligase site.

[0009] Aspect 2. The degron site is: [ka] is selected from During the ceremony, Y1 and Y2 are each independently -CH2-, -NH-, or -C(O)-; Y3, Y4, Y5, and Y6 are each independently CH or N; Y7 is CH or N; L is selected from a bond, -CH2-, -O-, -NH-, and -S-; n5 is 0, 1, 2, 3 or 4; n6 is 0, 1, or 2; R 8 are each independently hydrogen, halogen, or -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR 8a , -SO2R 8a , -COR 8a , -CO2R 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 CO2R 8b , -NR 8a SONR 8b R 8c , -NR 8a SO2NR 8b R 8c , or -NR8a SO2R 8b and said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from halogen, hydroxy, -C 1-8 optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 8a , R 8b , and R 8c are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 The compound according to embodiment 1, which is alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0010] Aspect 3. The degron site is: [ka] is selected from In the formula, R 8 and n5 is as defined above.

[0011] Aspect 4. The degron site is: [ka] 3. The compound according to embodiment 2, selected from:

[0012] Aspect 5. The degron site is: [ka] is selected from In the formula, R 8 and n5 is as defined above.

[0013] Aspect 6. The degron site is: [ka] 3. The compound according to embodiment 2, selected from:

[0014] Aspect 7.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, -NO2, -OR 8a , -SO2R 8a , -COR 8a , -CO2R 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 CO2R 8b , -NR 8a SONR 8b R 8c , -NR 8a SO2NR 8b R 8c , or -NR 8a SO2R 8band 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 selected from the group consisting of -F, -Cl, - optionally substituted with Br, -I, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, 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 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.

[0015] Aspect 8.R8 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.

[0016] Aspect 9.R 8 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0017] Aspect 10. Site [ka] but, [ka] and In the formula, * LN is the part [ka] and ** LN is the part [ka] refers to the position at which the Z 1 and Z 2 are each independently selected from CH or N; n7 is 0 or 1; L 1is a single bond, -O-, -SO2-, -C(O)-, -NR L1a -, -C3-C8 cycloalkylene-, * L1 -OC 1-8 Alkylene-** L1 , * L1 -C 1-8 Alkylene-O-** L1 , * L1 -SO2-C 1-8 Alkylene-** L1 , * L1 -C 1-8 Alkylene-SO2-** 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 Alkylene NR 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 wherein the -C3-C8 cycloalkylene-, L1 -OC 1-8 Alkylene-** L1 , * L1 -C 1-8 Alkylene-O-** L1 , * L1 -SO2-C 1-8 Alkylene-** L1 , * L1 -C 1-8 Alkylene-SO2-** 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 Alkylene NR 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 Each alkynylene- is selected from the group consisting of at least one R L1c optionally substituted with; u1 and v1 are each independently selected from 1, 2, 3, 4, 5, 6, 7, or 8; In the formula, * L1 is the part [ka] and ** L1 is the part [ka] refers to the position at which the L 2 is a single bond, -O-, -SO2-, -CO-, -NR L2a -, -C3-C8 cycloalkylene-, * L2 -OC 1-8 Alkylene-** L2 , * L2 -C 1-8 Alkylene-O-** L2 , * L2 -SO2-C 1-8 Alkylene-** L2 , * L2 -C 1-8 Alkylene-SO2-** 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 Alkylene NR 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 selected from the group consisting of -C3-C8 cycloalkylene-, L2 -OC 1-8 Alkylene-** L2 , * L2 -C 1-8 Alkylene-O-** L2 , * L2 -SO2-C 1-8 Alkylene-** L2 , * L2 -C 1-8 Alkylene-SO2-** L2 , * L2 -CO-C 1-8 Alkylene-** L2 , * L2 -C 1-8Alkylene-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 Alkylene NR 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 Each alkynylene- has at least one substituent R L2c optionally substituted with; u2 and v2 are each independently selected from 1, 2, 3, 4, 5, 6, 7, or 8; In the formula, * L2 is the part [ka] and ** L2 is the part [ka] refers to the position at which the L3 is a single bond, -O-, -SO2-, -CO-, -NR L3a -, -C3-C8 cycloalkylene-, * L3 -OC 1-8 Alkylene-** L3 , * L3 -C 1-8 Alkylene-O-** L3 , *L3 -SO2-C 1-8 Alkylene-** L3 , * L3 -C 1-8 Alkylene-SO2-** 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 Alkylene NR 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 selected from the group consisting of -C3-C8 cycloalkylene-, L3 -OC 1-8 Alkylene-** L3 , * L3 -C 1-8 Alkylene-O-** L3 , * L3 -SO2-C 1-8 Alkylene-** L3 , * L3 -C 1-8 Alkylene-SO2-** 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)C 1-8 Alkylene-** L3 , * L3 -C(O)NR L3a C 1-8 Alkylene-** L3 , * L3 -C 1-8 Alkylene NR L3a C(O)-** L3 , * L3 -C 1-8 AlkyleneC(O)NR L3a -** L3 , -C 1-8 Alkylene-, -C 2-8 Alkenylene-, -C 2-8 Each alkynylene- has at least one substituent R L3c optionally substituted with; u3 and v3 are each independently selected from 1, 2, 3, 4, 5, 6, 7, or 8; In the formula, * L3 is the part [ka] and ** L3 is the part [ka] refers to the position at which the R L1a , R L1b , R L1c , R L2a , R L2b , R L2c , R L3a , R L3b and R L3c are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may have at least one substituent R L3d optionally substituted with; R L3d is halogen, hydroxy, -C 1-8 Alkyl, -HaloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 The compound according to embodiment 1, which is alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0018] Aspect 11.L 1 is a single bond, -O-, -SO2-, -C(O)-, -NH-, -N(CH3)-, -N(C2H5)-, -N(C3H7)-, * L1 -O-CH2-** L1 , *<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -O-C2H4-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -O-C3H6-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -O-C4H8-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -CH2-O-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -C2H4-O-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -C3H6-O-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -C4H8-O-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -SO2-CH2-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -SO2-C2H4-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -SO2-C3H6-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -SO2-C4H8-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -CH2-SO2-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -C2H4-SO2-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -C3H6-SO2-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -C4H8-SO2-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -C(O)-CH2-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -C(O)-C2H4-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -C(O)-C3H6-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -C(O)-C4H8-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -CH2-C(O)-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -C2H4-C(O)-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -C3H6-C(O)-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -C4H8-C(O)-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -NH-CH2-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> -NH-C2H4-**<h2 style=";text-align:left;direction:ltr"> L1 <h2 style=";text-align:left;direction:ltr"> 、*<h2 style=";text-align:left;direction:ltr"> L1-NH-C3H6-** L1 、* L1 -NH-C4H8-** L1 、* L1 -CH2-NH-** L1 、* L1 -C2H4-NH-** L1 、* L1 -C3H6-NH-** L1 、* L1 -C4H8-NH-** L1 、* L1 -NHC(O)-** L1 、* L1 -C(O)NH-** L1 、* L1 -N(CH3)C(O)-** L1 、* L1 -C(O)N(CH3)-** L1 、* L1 -N(C2H5)C(O)-** L1 、* L1 -C(O)N(C2H5)-** L1 、* L1 -N(C3H7)C(O)-** L1 * L1 -C(O)N(C3H7)-** L1 、* L1 -NHC(O)CH2-** L1 、* L1 -NHC(O)C2H4-** L1 、* L1 -NHC(O)C3H6-** L1 、* L1 -NHC(O)C4H8-** L1 * L1 -C(O)NHCH2-** L1 、* L1 -C(O)NHC2H4-** L1 * L1 -C(O)NHC3H6-** L1 * L1 -C(O)NHC4H8-** L1 、* L1 -CH2NHC(O)-** L1 * L1 -C2H4NHC(O)-** L1 * L1 -C3H6NHC(O)-**L1 , * L1 -C4H8NHC(O)-** L1 , * L1 -CH2C(O)NH-** L1 , * L1 -C2H4C(O)NH-** L1 , * L1 -C3H6C(O)NH-** L1 , * L1 -C4H8C(O)NH-** L1 , -CH2-, -C2H4-, -C3H6-, -C4H8-, -O(CH2)2-, -[O(CH2)2]2-, -[O(CH2)2]3-, -[O(CH2)2]4- or -[O(CH2)2]5-.

[0019] Aspect 12.L 1 teeth,* L1 -CH2-C(O)-** L1 , * L1 -CH2CH2-C(O)-** L1 , * L1 -CH2CH2CH2-C(O)-** L1 , * L1 -CH2-NH-** L1 , * L1 -CH2CH2-NH-** L1 , * L1 -CH2CH2CH2-NH-** L1 , * L1 -CH2NHC(O)-** L1 , * L1 -CH2CH2NHC(O)-** L1 , * L1 -CH2CH2CH2NHC(O)-** L1 , * L1 -CH2C(O)NH-** L1 , * L1 -CH2CH2C(O)NH-** L1 , * L1 -CH2CH2CH2C(O)NH-** L1 , -CH2-, -CH2CH2-, -CH2CH2CH2-.

[0020] Aspect 13.L 2is a single bond, -O-, -SO2-, -C(O)-, -NH-, -N(CH3)-, -N(C2H5)-, -N(C3H7)-, * L2 -O-CH2-** L2 、* L2 -O-C2H4-** L2 、* L2 -O-C3H6-** L2 、* L2 -O-C4H8-** L2 、* L2 -CH2-O-** L2 、* L2 -C2H4-O-** L2 、* L2 -C3H6-O-** L2 、* L2 -C4H8-O-** L2 、* L2 -SO2-CH2-** L2 、* L2 -SO2-C2H4-** L2 、* L2 -SO2-C3H6-** L2 、* L2 -SO2-C4H8-** L2 、* L2 -CH2-SO2-** L2 、* L2 -C2H4-SO2-** L2 、* L2 -C3H6-SO2-** L2 、* L2 -C4H8-SO2-** L2 、* L2 -C(O)-CH2-** L2 、* L2 -C(O)-C2H4-** L2 、* L2 -C(O)-C3H6-** L2 、* L2 -C(O)-C4H8-** L2 、* L2 -CH2-C(O)-** L2 、* L2 -C2H4-C(O)-** L2 、* L2 -C3H6-C(O)-** L2 、* L2 -C4H8-C(O)-** L2* L2 -NH-CH2-** L2 * L2 -NH-C2H4-** L2 * L2 -NH-C3H6-** L2 * L2 -NH-C4H8-** L2 * L2 -CH2-NH-** L2 * L2 -C2H4-NH-** L2 * L2 -C3H6-NH-** L2 * L2 -C4H8-NH-** L2 * L2 -NHC(O)-** L2 * L2 -C(O)NH-** L2 * L2 -N(CH3)C(O)-** L2 * L2 -C(O)N(CH3)-** L2 * L2 -N(C2H5)C(O)-** L2 * L2 -C(O)N(C2H5)-** L2 * L2 -N(C3H7)C(O)-** L2 * L2 -C(O)N(C3H7)-** L2 * L2 -NHC(O)CH2-** L2 * L2 -NHC(O)C2H4-** L2 * L2 -NHC(O)C3H6-** L2 * L2 -NHC(O)C4H8-** L2 * L2 -C(O)NHCH2-** L2 * L2 -C(O)NHC2H4-** L2 * L2 -C(O)NHC3H6-** L2 * L2 -C(O)NHC4H8-** L2 * L2-CH2NHC(O)-** L2 , * L2 -C2H4NHC(O)-** L2 , * L2 -C3H6NHC(O)-** L2 , * L2 -C4H8NHC(O)-** L2 , * L2 -CH2C(O)NH-** L2 , * L2 -C2H4C(O)NH-** L2 , * L2 -C3H6C(O)NH-** L2 , * L2 -C4H8C(O)NH-** L2 , -CH2-, -C2H4-, -C3H6-, -C4H8-, -O(CH2)2-, -[O(CH2)2]2-, -[O(CH2)2]3-, -[O(CH2)2]4- or -[O(CH2)2]5-.

[0021] Aspect 14.L 2 is a single bond, -C(O)-, -NH-, * L2 -NHC(O)-** L2 , * L2 -C(O)NH-** L2 , * L2 -NH-CH2-** L2 , * L2 -NH-CH2CH2-** L2 , * L2 -NH-CH2CH2CH2-** L2 , * L2 -C(O)-CH2-** L2 , * L2 -C(O)-CH2CH2-** L2 , * L2 -C(O)-CH2CH2CH2-** L2 , * L2 -NHC(O)CH2-** L2 , * L2 -NHC(O)CH2CH2-** L2 , * L2 -NHC(O)CH2CH2CH2-** L2 , * L2 -C(O)NHCH2-** L2, * L2 -C(O)NHCH2CH2-** L2 ,or* L2 -C(O)NHCH2CH2CH2-** L2 11. The compound according to embodiment 10, wherein

[0022] Aspect 15.L 3 is a single bond, -O-, -SO2-, -C(O)-, -NH-, -N(CH3)-, -N(C2H5)-, -N(C3H7)-, * L3 -O-CH2-** L3 , * L3 -O-C2H4-** L3 , * L3 -O-C3H6-** L3 , * L3 -O-C4H8-** L3 , * L3 -CH2-O-** L3 , * L3 -C2H4-O-** L3 , * L3 -C3H6-O-** L3 , * L3 -C4H8-O-** L3 , * L3 -SO2-CH2-** L3 , * L3 -SO2-C2H4-** L3 , * L3 -SO2-C3H6-** L3 , * L3 -SO2-C4H8-** L3 , * L3 -CH2-SO2-** L3 , * L3 -C2H4-SO2-** L3 , * L3 -C3H6-SO2-** L3 , * L3 -C4H8-SO2-** L3 , * L3 -C(O)-CH2-** L3 , * L3 -C(O)-C2H4-** L3 , * L3 -C(O)-C3H6-** L3 , * L3 -C(O)-C4H8-**L3 、* L3 -CH2-C(O)-** L3 、* L3 -C2H4-C(O)-** L3 、* L3 -C3H6-C(O)-** L3 、* L3 -C4H8-C(O)-** L3 * L3 -NH-CH2-** L3 、* L3 -NH-C2H4-** L3 * L3 -NH-C3H6-** L3 * L3 -NH-C4H8-** L3 * L3 -CH2-NH-** L3 * L3 -C2H4-NH-** L3 、* L3 -C3H6-NH-** L3 * L3 -C4H8-NH-** L3 、* L3 -NHC(O)-** L3 * L3 -C(O)NH-** L3 * L3 -N(CH3)C(O)-** L3 、* L3 -C(O)N(CH3)-** L3 、* L3 -N(C2H5)C(O)-** L3 、* L3 -C(O)N(C2H5)-** L3 、* L3 -N(C3H7)C(O)-** L3 、* L3 -C(O)N(C3H7)-** L3 、* L3 -NHC(O)CH2-** L3 、* L3 -NHC(O)C2H4-** L3 、* L3 -NHC(O)C3H6-** L3 、* L3 -NHC(O)C4H8-** L3 、* L3-C(O)NHCH2-** L3 , * L3 -C(O)NHC2H4-** L3 , * L3 -C(O)NHC3H6-** L3 , * L3 -C(O)NHC4H8-** L3 , * L3 -CH2NHC(O)-** L3 , * L3 -C2H4NHC(O)-** L3 , * L3 -C3H6NHC(O)-** L3 , * L3 -C4H8NHC(O)-** L3 , * L3 -CH2C(O)NH-** L3 , * L3 -C2H4C(O)NH-** L3 , * L3 -C3H6C(O)NH-** L3 , * L3 -C4H8C(O)NH-** L3 , -CH2-, -C2H4-, -C3H6-, -C4H8-, -O(CH2)2-, -[O(CH2)2]2-, -[O(CH2)2]3-, -[O(CH2)2]4- or -[O(CH2)2]5-.

[0023] Aspect 16.L 3 is a single bond.

[0024] 17. Location [ka] [ka] where: LN is the part [ka] and ** LN is the part [ka] The compound according to embodiment 10, wherein the compound is bonded to

[0025] 18. Location [ka] [ka] and In the formula, * LN is the part [ka] and ** LN is the part [ka] The compound according to embodiment 1, wherein the compound is bonded to

[0026] Aspect 19.R 1 and R 2are 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; wherein 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 may be selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, and pyrazinyl. 1a optionally substituted with; or R 1 and R 2 together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring containing at least one substituent R 1b optionally substituted with; R 1a and R 1beach independently represents -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, -NO2, -OR 1c , -SO2R 1c , -SO2NR 1c R 1d , -COR 1c , -CO2R 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 CO2R 1c , -NR 1c SONR 1c R 1d , -NR 1c SO2NR 1d R 1e , or -NR 1c SO2R 1dand 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 -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 1-8The compound according to embodiment 1, which is 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.

[0027] Aspect 20.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 aryl, 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

[0036] The compound of embodiment 1, wherein:

[0028] Aspect 21.R 1 and R 2 are each independently hydrogen, -CD3, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2-hydroxypropyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, or 4-hydroxybutyl.

[0029] Aspect 22.R 3 is, at each occurrence, independently selected from -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, pyrid ... nyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, -CH2-heterocyclyl, -CH2CH2-heterocyclyl, -CH2CH2CH2-heterocyclyl, -CH2CH2CH2CH2-heterocyclyl, -CH2-cycloalkyl, -CH2CH2-cycloalkyl, -CH2CH2CH2-cycloalkyl, -CH2CH2CH2CH2-cycloalkyl, oxo, -CN, -NO2, -OR 3a , -SO2R 3a , -SO2NR 3a R 3b , -COR 3a, -CO2R 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 CO2R 3b , -NR 3a SONR 3b R 3c , -NR 3a SO2NR 3b R 3c , or -NR 3a SO2R 3b and wherein the 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, Each of -aryl, -pyrazolyl, -thiazolyl, -oxazolyl, -triazolyl, -thiophenyl, -furanyl, -pyridyl, -pyrimidinyl, -pyrazinyl, -CH-heterocyclyl, -CHCH-heterocyclyl, -CHCHCH-heterocyclyl, -CHCHCH-cycloalkyl, -CHCH-cycloalkyl, -CHCHCH-cycloalkyl, or -CHCHCHCH-cycloalkyl may be selected from the group consisting of -aryl, -pyrazolyl, -thiazolyl, -oxazolyl, -triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, -pyrazinyl, -CH-heterocyclyl, -CHCH-heterocyclyl, -CHCH-cycloalkyl, -CHCH-cycloalkyl, -CHCH-cycloalkyl, or -CHCH-cycloalkyl. 3d optionally substituted with; or or two R on adjacent carbon atoms of a phenyl ring 3 form, together with the two intervening carbon atoms to which they are attached, a 5-8 membered ring containing as ring member(s) 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; 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 the 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 may be selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, and pyrazinyl. 3e optionally substituted with; 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 3-12 membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring containing at least one substituent R 3e optionally substituted with; R 3d and R 3eeach independently represents -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, -NO2, -OR 3f , -SO2R 3f , -SO2NR 3f R 3g , -COR 3f , -CO2R 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 CO2R 3f , -NR 3f SONR 3f R 3g , -NR 3f SO2NR 3g R 3h , or -NR 3f SO2R 3gand 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 -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 3jare 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 The compound according to embodiment 1, wherein said compound is alkyl-.

[0030] Aspect 23.R 3 is, at each occurrence, independently selected from -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, pyrid ... nyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, -CH2-heterocyclyl, -CH2CH2-heterocyclyl, -CH2CH2CH2-heterocyclyl, -CH2CH2CH2CH2-heterocyclyl, -CH2-cycloalkyl, -CH2CH2-cycloalkyl, -CH2CH2CH2-cycloalkyl, -CH2CH2CH2CH2-cycloalkyl, oxo, -CN, -NO2, -OR 3a , -SO2R 3a , -SO2NR 3a R 3b , -COR 3a , -CO2R 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 CO2R 3b , -NR 3a SONR 3b R 3c , -NR 3a SO2NR 3b R 3c , or -NR 3a SO2R 3b and wherein the 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, Each of -aryl, -pyrazolyl, -thiazolyl, -oxazolyl, -triazolyl, -thiophenyl, -furanyl, -pyridyl, -pyrimidinyl, -pyrazinyl, -CH-heterocyclyl, -CHCH-heterocyclyl, -CHCHCH-heterocyclyl, -CHCHCH-cycloalkyl, -CHCH-cycloalkyl, -CHCHCH-cycloalkyl, or -CHCHCHCH-cycloalkyl may be selected from the group consisting of -aryl, -pyrazolyl, -thiazolyl, -oxazolyl, -triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, -pyrazinyl, -CH-heterocyclyl, -CHCH-heterocyclyl, -CHCH-cycloalkyl, -CHCH-cycloalkyl, -CHCH-cycloalkyl, or -CHCH-cycloalkyl. 3d optionally substituted with; or Two R on adjacent carbon atoms of a phenyl ring 3 form, together with the two intervening carbon atoms to which they are attached, a 5-8 membered ring containing as ring member(s) 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; R 3a , R 3b , and R 3care 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 the 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 may be selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, and pyrazinyl. 3e optionally substituted with; 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 3-12 membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring containing at least one substituent R 3e optionally substituted with; R 3d and R 3eeach independently represents -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, -NO2, -OR 3f , -SO2R 3f , -SO2NR 3f R 3g , -COR 3f , -CO2R 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 CO2R 3f , -NR 3f SONR 3f R 3g , -NR 3f SO2NR 3g R 3h , or -NR 3f SO2R 3gand 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 -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 3jare 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 The compound according to embodiment 1, wherein said compound is alkyl.

[0031] Aspect 23.R 3 is, at each occurrence, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -F, -Cl, -Br, -I, -CN, OR 3a or -NR 3a CONR 3b R 3c selected from the group consisting of: 1-8 The alkyl group may have at least one substituent R 3d Optionally substituted with 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.

[0032] Aspect 24.R 3 is -F, -Cl, -Br, -I, OH, CN, -CH3, -C2H5, -CH2CH2CH3, -CH(CH3)CH3, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2F, -CHF2, -CF3, or -NHCOCH3.

[0033] 25. Location [ka] [ka] 2. The compound according to embodiment 1, wherein

[0034] 26. Location [ka] [ka] 2. The compound according to embodiment 1, wherein

[0035] Aspect 27.R 4 , R 5 , and R 6 each independently represents 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, -NO2, -OR 4a , -SO2R 4a , -COR 4a , -CO2R 4a , -CONR 4a R 4b , -C(=NR 4a )NR 4b R 4c , -NR 4a R 4b , -NR 4a COR 4b , -NR4a CONR 4b R 4c , -NR 4a CO2R 4b , -NR 4a SONR 4b R 4c , -NR 4a SO2NR 4b R 4c , or -NR 4a SO2R 4b and 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 selected from the group consisting of -F, -Cl, - optionally substituted with Br, -I, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, 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 4care 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.

[0036] Aspect 28.R 5 and R 6 are each independently hydrogen or -C 1-8 The compound according to embodiment 1, wherein the alkyl is hydrogen or methyl.

[0037] Aspect 29.R 4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -OR 4a or -NR 4a R 4b wherein said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl is optionally substituted with at least one substituent -OH, -F, -Cl, -Br, -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 -CH3, -OCH3, -NHCH3, -CHF2, or -C(CH3)2OH.

[0038] Aspect 30.X 1 and X 2is each independently a single bond, -CH2-, -CH2CH2-, or -CH2CH2CH2-.

[0039] Aspect 31.X 1 If -CH2-, then X 2 is -CH2CH2-; or X 1 If -CH2CH2-, then X 2 is -CH2-; or X 1 If is a single bond, X 2 is -CH2CH2CH2-; or X 1 If -CH2CH2CH2-, then X 2 is a single bond.

[0040] Aspect 32.R X1 , R X2 , R X3 , R X4 , R X5 and R X6are each 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, and pyrazinyl; Each of 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, and pyrazinyl may be selected from the group consisting of phenyl, ... Xa wherein R is optionally substituted with Xa is 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.

[0041] Aspect 33.R Xais 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.

[0042] Aspect 34.R Xa is selected from oxo, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl.

[0043] Aspect 35. The compound according to aspect 1, wherein the compound is selected from the following: [ka]

[0044] In a second aspect, disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier or excipient.

[0045] In a third aspect, disclosed herein is a method of reducing HPK1 activity by inhibition and / or proteolysis, the method comprising administering to an individual a compound disclosed herein, including a compound of formula (I) or the specific compounds exemplified herein, or a pharma- ceutically acceptable salt thereof.

[0046] In a fourth aspect, disclosed herein is a method of treating a disease or disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, as an HPK1 degradation inducer, the compound disclosed herein comprising a compound of formula (I) or a specific compound exemplified herein. In some embodiments, the disease or disorder is associated with inhibition of HPK1. Preferably, the disease or disorder is cancer. Detailed Description of the Invention

[0047] definition The following terms have the meanings indicated throughout this specification.

[0048] As used in this specification, including the appended claims, singular words such as "a," "an," and "the" include their corresponding plural references unless the context clearly dictates otherwise.

[0049] The term "or" means, and is used interchangeably with, the term "and / or," unless context clearly dictates otherwise.

[0050] The term "alkyl" refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups containing 1 to 18, for example 1 to 12, further 1 to 10, further 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C 1-6Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0051] The term "propyl" refers to 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0052] The term "butyl" refers to 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), and 1,1-dimethylethyl or t-butyl ("t-Bu").

[0053] The term "pentyl" refers to 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl.

[0054] The term "hexyl" refers to 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0055] The term "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0056] The term "haloalkyl" refers to an alkyl group in which one or more hydrogens are replaced by one or more halogen atoms, such as fluoro, chloro, bromo, and iodo. Examples of haloalkyl include, but are not limited to, haloC 1-8 Alkyl, haloC 1-6 Alkyl or haloC 1-4 Alkyl, for example, -CF3, -CH2Cl, -CH2CF3, -CHCl2, -CF3.

[0057] The term "alkenyl" refers to a hydrocarbon group selected from linear and branched chain hydrocarbon groups containing at least one C=C double bond and 2 to 18, such as 2 to 8, further such as 2 to 6, carbon atoms. Alkenyl groups, such as C 2-6 Examples of alkenyl include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl groups.

[0058] The term "alkynyl" refers to a hydrocarbon group selected from linear and branched chain hydrocarbon groups containing at least one C≡C triple bond and 2 to 18, such as 2 to 8, further such as 2 to 6, carbon atoms. Alkynyl groups, such as C 2-6 Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0059] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyls.

[0060] For example, the cycloalkyl group may contain 3 to 12, such as 3 to 10, further 3 to 8, further 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Further, for example, the cycloalkyl group may be selected from monocyclic groups containing 3 to 12, such as 3 to 10, further 3 to 8, 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, saturated monocyclic cycloalkyl groups such as C 3-8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embodiment, cycloalkyl is an alkyl group having 3 to 6 carbon atoms (C), including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3-6 Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0061] The term "spirocycloalkyl" refers to a cyclic structure containing carbon atoms and formed by at least two rings that share one atom. The term "7-12 membered spirocycloalkyl" refers to a cyclic structure containing 7-12 carbon atoms and formed by at least two rings that share one atom.

[0062] The term "fused cycloalkyl" refers to a bicyclic cycloalkyl group, as defined herein, that is saturated and formed by two or more rings sharing two adjacent atoms.

[0063] The term "bridged cycloalkyl" refers to a cyclic structure containing carbon atoms and formed by two rings sharing two atoms that are not adjacent to each other. The term "7-10 membered bridged cycloalkyl" refers to a cyclic structure containing 7-12 carbon atoms and formed by two rings sharing two atoms that are not adjacent to each other.

[0064] The term "cycloalkenyl" refers to a non-aromatic cyclic alkyl group of 3 to 10 carbon atoms having a single or multiple rings and at least one double bond, preferably 1 to 2 double bonds. In one embodiment, cycloalkenyl is cyclopentenyl or cyclohexenyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, preferably cyclohexenyl.

[0065] The term "fused cycloalkenyl" refers to a bicyclic cycloalkyl group, as defined herein, that contains at least one double bond and is formed by two or more rings sharing two adjacent atoms.

[0066] The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group of from 5 to 10 carbon atoms having single or multiple rings and having at least one triple bond.

[0067] The term "fused cycloalkynyl" refers to a bicyclic cycloalkyl group, as defined herein, that contains at least one triple bond and is formed by two or more rings sharing two adjacent atoms.

[0068] The term "benzofused cycloalkyl" refers to a bicyclic fused cycloalkyl in which a 4- to 8-membered monocyclic cycloalkyl ring is fused to a benzene ring. For example, a benzofused cycloalkyl is [ka] where the wavy lines indicate the positions of the bonds.

[0069] The term "benzofused cycloalkenyl" refers to a bicyclic fused cycloalkenyl in which a 4- to 8-membered monocyclic cycloalkenyl ring is fused to a benzene ring.

[0070] The term "benzofused cycloalkynyl" refers to a bicyclic fused cycloalkynyl in which a 4- to 8-membered monocyclic cycloalkynyl ring is fused to a benzene ring.

[0071] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo 3-8 membered cycloalkyl, benzo C 4-6 Examples include, but are not limited to, cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8-9 membered fused rings, which refers to ring structures containing 8-9 ring atoms within the scope of the preceding examples.

[0072] The term "aryl", used alone or in combination with other terms, refers to a group selected from: a) 5- and 6-membered carbocyclic aromatic rings, for example phenyl, b) bicyclic ring systems, for example 7-12 membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example naphthyl and indanyl, and c) Tricyclic ring systems, for example 10-15 membered tricyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example fluorenyl.

[0073] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0074] Specifically, the term "bicyclic fused aryl" refers to a bicyclic aryl ring as defined herein. An exemplary bicyclic fused aryl is naphthalene.

[0075] The term "heteroaryl" refers to a group selected from: a) a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom, e.g., 1 to 4, or in some embodiments 1 to 3, and in some embodiments 1 to 2 heteroatoms, selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring atoms being carbon; b) 7-12 membered bicyclic rings containing at least one heteroatom selected from N, O, and S, e.g., 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom being in the aromatic ring; and c) 11-14 membered tricyclic rings containing at least one heteroatom, e.g., 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2 heteroatoms, selected from N, O, and S, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being in the aromatic ring.

[0076] When the total number of S and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in a heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is 1 or less. When a heteroaryl group contains two or more heteroatom ring members, the heteroatoms can be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group can be oxidized to form an N-oxide.

[0077] In particular, the term "bicyclic fused heteroaryl" refers to a 7-12 membered, preferably 7-10 membered, more preferably 9 or 10 membered fused bicyclic heteroaryl ring as defined herein. Typically, a bicyclic fused heteroaryl is a 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic. The group can be attached to the remainder of the molecule via either ring.

[0078] Representative examples of bicyclic fused heteroaryl include the following groups: benzisoxazolyl, benzodiazolyl, benzofuranyl, benzofurazanyl, benzofuryl, benzimidazolyl, benzisothiazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzoxadiazolyl, benzoxazolyl, furopyridinyl, furopyrrolyl, imidazopyridinyl, imidazopyridyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isobenzofuryl, isobenzophenyl ... These include, but are not limited to, isoindolyl, isoquinolinyl (or isoquinolyl), naphthyridinyl, phthalazinyl, pteridinyl, purinyl, pyrazinopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridyl, pyrazolotriazinyl, pyridazolopyridyl, pyrrolopyridinyl, quinazolinyl, quinolinyl (or quinolyl), quinoxalinyl, thiazolopyridyl, thienopyrazinyl, thienopyrazolyl, thienopyridyl, thienopyrrolyl, thienothienyl, or triazolopyridyl.

[0079] The term "benzofused heteroaryl" refers to a bicyclic fused heteroaryl in which a 5- to 7-membered (preferably 5- or 6-membered) monocyclic heteroaryl ring, as defined herein, is fused to a benzene ring.

[0080] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 ring members, including 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring members being carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring, including 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a monocyclic, 5-6 membered heteroaryl ring, including 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a bicyclic, 8-10 membered heteroaryl ring having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0081] Examples of heteroaryl groups or monocyclic or bicyclic aromatic heterocycles include (counting from the attachment position assigned priority 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl). diazolyl), tetrazolyl, thienyl (e.g., thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, or 1 ,3,4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3- These include, but are not limited to, diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), and indazolyl (e.g., 1H-indazol-5-yl).

[0082] "Heterocyclyl", "heterocycle", or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclyl group containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, and including monocyclic, fused, bridged, and spirocyclic rings, i.e., monocyclic, heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclic groups.

[0083] As used herein, the term "optionally oxidized sulfur" refers to S, SO, or SO2.

[0084] The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member (e.g., 1 to 3 heteroatoms, 1 or 2 heteroatom(s)) is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle may be saturated or partially saturated.

[0085] Exemplary monocyclic 4- to 9-membered heterocyclyl groups include pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, Aziridine-1-yl, aziridin-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidyl 1,4-Dithiepanyl, 1,4-Thiazepanyl, 1,4-Dithiepanyl, 1,4-Thiazepanyl, 1,4-Diazepanyl, 1,4-Dithianyl, 1,4-Azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofu ... Examples of pyrrolinyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1,1-dioxo-thiomorpholinyl.

[0086] The term "spiroheterocyclyl" refers to a 5-20 membered polycyclic heterocyclyl having rings connected through one common carbon atom (called a spiro atom) and containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of a spiroheterocyclyl group may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably, the spiroheterocyclyl is 6-14 membered, more preferably 7-12 membered. Depending on the number of common spiro atoms, the spiroheterocyclyl may be a monospiroheterocyclyl, a dispiroheterocyclyl, or a polyspiroheterocyclyl, preferably a monospiroheterocyclyl or a dispiroheterocyclyl, and more preferably a 4-membered / 3-membered, 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl. Representative examples of spiroheterocyclyl include the following groups: 2,3-dihydrospiro[indene-1,2'-pyrrolidine] (e.g., 2,3-dihydrospiro[indene-1,2'-pyrrolidine]-1'-yl), 1,3-dihydrospiro[indene-2,2'-pyrrolidine] (e.g., 1,3-dihydrospiro[indene-2,2'-pyrrolidine]-1'-yl), azaspiro[2.4]heptane (e.g., 5-azaspiro[2.4]heptane-5-yl), 2-oxa-6-azaspiro[3.3]heptane (e.g., 2-oxa-6-azaspiro[3.3]heptane-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro [3.4]octan-6-yl), 2-oxa-6-azaspiro[3.4]octane (e.g., 2-oxa-6-azaspiro[3.4]octan-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octan-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octan-6-yl), 1,7-dioxaspiro[4.5]decane, 2-oxa-7-aza-spiro[4.4]nonane (e.g., 2-oxa-7-aza-spiro[4.4]non-7-yl), 7-oxa-spiro[3.5]nonyl, and 5-oxa-spiro[2.4]heptyl.

[0087] The term "fused heterocyclyl" refers to a 5-20 membered polycyclic heterocyclyl group, in which each ring in the system contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members and shares adjacent atom pairs (carbon and carbon, or carbon and nitrogen) with another ring in which the remaining ring members are carbon. One or more rings of the fused heterocyclic group may contain one or more double bonds, but the fused heterocyclic group does not have a fully conjugated pi-electron system. Preferably, the fused heterocyclyl has 6 to 14 members, more preferably 7 to 12 members, or 7 to 10 members. Depending on the number of membered rings, the fused heterocyclyl may be a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl. The group may be attached to the rest of the molecule via either ring.

[0088] In particular, the term "bicyclic fused heterocyclyl" refers to a 7-12 membered, preferably 7-10 membered, more preferably 9 or 10 membered, fused heterocyclyl as defined herein containing two fused rings and containing 1 to 4 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members. Typically, the bicyclic fused heterocyclyl is a 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic fused heterocyclyl. Representative examples of (bicyclic) fused heterocycles include the following groups: octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindolinyl, octahydro-benzo[b][1,4]dioxine, indolinyl, isoindolinyl, benzopyranyl, dihydrothiazolopyrimidinyl, tetrahydroquinolyl, tetrahydroisoquinolyl (or tetrahydroisoquinolinyl), dihydrobenzofuranyl, dihydrobenzoxazinyl, dihydrobenzimidazolyl, tetrahydrobenzothienyl, tetra ... These include, but are not limited to, ranyl, benzodioxolyl, benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl, dihydrobenzodioxinyl, dihydrobenzoxedinyl, dihydrobenzodioxepinyl, dihydrothienodioxinyl, dihydrobenzoxazepinyl, tetrahydrobenzoxazepinyl, dihydrobenzazepinyl, tetrahydrobenzazepinyl, isochromanyl, chromanyl, or tetrahydropyrazolopyrimidinyl (e.g., 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl).

[0089] The term "benzofused heterocyclyl" refers to a bicyclic fused heterocyclyl, as defined herein, in which a monocyclic 4- to 9-membered heterocyclyl (preferably 5- or 6-membered) is fused to a benzene ring.

[0090] The term "bridged heterocyclyl" refers to a 5-14 membered polycyclic heterocyclic alkyl group, in which every two rings in the system contain one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and share two disconnected atoms, with the remaining ring members being carbon. One or more rings of the bridged heterocyclyl group may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably, the bridged heterocyclyl is 6-14 membered, more preferably 7-10 membered. Depending on the number of membered rings, the bridged heterocyclyl may be a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, preferably a bicyclic, tricyclic, or tetracyclic bridged heterocyclyl, and more preferably a bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocyclyls include, but are not limited to, the following groups: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0091] The term "at least one substituent" disclosed herein includes, for example, 1 to 4 substituents, such as 1 to 3, or even 1 or 2, as long as valence theory is satisfied. For example, "at least one substituent R 6d " is R 6d and 1 to 4, such as 1 to 3, further such as 1 or 2, substituents selected from the list of:

[0092] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. When the compounds disclosed herein have two or more asymmetric centers, they may further exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All such possible stereoisomers are intended to be included, such as substantially purely resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharma-ceutically acceptable salts are intended to be included. Unless otherwise specified, a reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is not specified, all possible isomers are included.

[0093] As used herein, the term "substantially pure" means that the target stereoisomer contains 35% by weight or less, such as 30% by weight or less, further such as 25% by weight or less, such as even further such as 20% by weight or less of any other stereoisomer(s). In some embodiments, the term "substantially pure" means that the target stereoisomer contains 10% by weight or less, such as 5% by weight or less, such as 1% by weight or less of any other stereoisomer(s).

[0094] When the compounds disclosed herein contain olefinic double bonds, unless otherwise specified, such double bonds are intended to include both E and Z geometric isomers.

[0095] When the compounds disclosed herein comprise a disubstituted cyclic ring system, the substituents found in such ring system can adopt cis and trans configuration.Cis configuration means that both substituents are found on the top side of the arrangement of two substituents on carbon, while trans means that they are on opposite sides.For example, disubstituted cyclic ring system can be cyclohexyl or cyclobutyl ring.

[0096] It may be advantageous to separate reaction products from each other and / or from starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter, separated) to the desired degree of homogeneity by techniques common in the art. Typically, such separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include any number of methods, including, for example, reverse and normal phase, size exclusion, ion exchange, high, medium, and low pressure liquid chromatography methods and apparatus, small scale analytical, simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as small scale thin layer and flash techniques. The skilled artisan will apply the technique most likely to achieve the desired separation.

[0097] "Diastereomers" refers to stereoisomers of a compound that have two or more chiral centers, but are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical or chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional recrystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers and diastereomers can also be separated by the use of chiral HPLC columns.

[0098] Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by resolution of racemic mixtures using methods such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H., et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3)(1975): pp. 283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods; (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of the diastereomers, and conversion to pure stereoisomers; and (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions. Reference: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0099] "Pharmaceutically acceptable salts" refers to salts that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, etc., and that correspond to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base functional group with a suitable organic acid, or by reacting an acidic group with a suitable base.

[0100] In addition, when the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, such as a pharma- ceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize a variety of synthetic methods that can be used without undue experimentation to prepare non-toxic pharma-ceutically acceptable addition salts.

[0101] As defined herein, "a pharma- ceutically acceptable salt thereof" includes at least one salt of a compound of formula (I), and salts of stereoisomers of a compound of formula (I), such as salts of enantiomers and / or salts of diastereomers.

[0102] The terms "administration," "administering," "treating," and "treatment," as used herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to the contact of an exogenous pharmaceutical, therapeutic, diagnostic, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent with the cell, as well as contact of a reagent with a fluid, where the fluid contacts the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment, e.g., of a cell with a reagent, diagnostic, binding compound, or with another cell. The term "subject" as used herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0103] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient, such as a compound, that, when administered to a subject to treat a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or condition. A "therapeutically effective amount" may vary with the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any given case may be apparent to one of ordinary skill in the art or may be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharma- ceutically acceptable salt thereof, which is effective in "treating" a disease or disorder in a subject, as defined herein. In the case of a combination therapy, a "therapeutically effective amount" refers to the total amount of the combination for effective treatment of a disease, disorder, or condition.

[0104] The pharmaceutical composition comprising the compound disclosed herein can be administered to a subject in need thereof via oral, inhalation, rectal, parenteral or topical route.For oral administration, the pharmaceutical composition can be a conventional solid formulation such as tablet, powder, granule, capsule, liquid formulation such as water or oil suspension, or other liquid formulation such as syrup, solution, suspension, etc., and for parenteral administration, the pharmaceutical composition can be a solution, aqueous solution, oil suspension concentrate, freeze-dried powder, etc.Preferably, the pharmaceutical composition formulation is selected from tablet, coated tablet, capsule, suppository, nasal spray, or injection, more preferably tablet or capsule.The pharmaceutical composition can be a single dose with a precise dosage.In addition, the pharmaceutical composition can further comprise additional active ingredients.

[0105] All formulations of pharmaceutical compositions disclosed herein can be manufactured by conventional methods in the pharmaceutical field. For example, active ingredients can be mixed with one or more excipients to produce a desired formulation. "Pharmaceutically acceptable excipient" refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as diluents, vehicles such as water, various organic solvents, excipients such as starch, sucrose, binders such as cellulose derivatives, alginates, gelatin, polyvinylpyrrolidone (PVP), wetting agents such as glycerol, disintegrants such as agar, calcium carbonate, sodium bicarbonate, absorption enhancers such as quaternary ammonium compounds, surfactants such as hexadecanolide, absorption carriers such as kaolin and soap clay, lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition may further comprise other pharma- ceutically acceptable excipients, such as dispersing agents, stabilizers, thickening agents, complexing agents, buffers, permeation enhancers, polymers, flavoring agents, sweeteners, dyes, and the like.

[0106] The term "disease" refers to any disease, ailment, disorder, symptom or indication, and may be interchangeable with the term "disorder" or "condition."

[0107] Throughout this specification and the claims that follow, unless the context otherwise requires, the term "comprise," as well as variations such as "comprises" and "comprising," are intended to specify the presence of the subsequent feature but do not exclude the presence or addition of one or more other features. As used herein, the term "comprising" can be substituted with the terms "containing," "including," or, in some cases, "having."

[0108] Throughout this specification and the following claims, "C n-m The term "inclusive" denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. Examples include1-8 , C 1-6 etc.

[0109] Unless specifically defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0110] Overall reaction scheme for compound preparation The subject compounds and their pharma- ceutically acceptable salts can be prepared from (a) commercially available starting materials, (b) known starting materials that can be prepared as described in literature procedures, and (c) new intermediates as described in the schemes and experimental procedures herein. In the preparation of the compounds of the present invention, the order of the synthetic steps may be altered to increase the yield of the desired product. Some of the compounds of the present invention can be produced by the methods as shown in the following reaction schemes and their descriptions.

[0111] The reaction for preparing the compounds disclosed herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.A suitable solvent can be substantially non-reactive with starting material, intermediate, or product at the temperature at which the reaction is carried out, for example, a temperature that can vary from room temperature to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of solvents.

[0112] The selection of an appropriate protecting group can be readily determined by one of skill in the art.

[0113] Reactions can be monitored according to any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. Compounds can be purified by a variety of methods, including HPLC and normal phase silica chromatography.

[0114] The compounds disclosed herein can be prepared according to Scheme I below.

[0115] Scheme I [ka]

[0116] For example, a compound of formula (I) can be synthesized as shown in Scheme I. Compound (i) can be reacted with compound (ii) using a transition metal catalyzed reaction, followed by deprotection to give compound (iii). Compound (iii) can be further reacted with compound (iv) using a transition metal catalyzed reaction to give compound (v). Compound (v) can be deprotected to give compound (vi). A linker can be attached to compound (vi) to give compound (vii). Compound (vii) can be attached to a degron to give compound (viii) [i.e., formula (I)]. Scheme A EXAMPLES

[0117] The following examples are intended to be merely illustrative and should not be considered as limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers Sigma-Aldrich, Alfa Aesar, or TCI and used without further purification unless otherwise indicated. Unless otherwise indicated, reactions described below were carried out in anhydrous solvents under a positive pressure of nitrogen or argon or with drying tubes, reaction flasks were fitted with rubber septa for introduction of substrates and reagents by syringe, and glassware was oven-dried and / or heat-dried.

[0118] Abbreviation In the examples below, the following abbreviations are used: [Table 1]

[0119] Example 1: N-(2-(6-(7-(4-(dimethylcarbamoyl)-3-methylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxamide [ka]

[0120] Step 1: 2-Bromo-7-iodo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine [ka]

[0121] To a solution of 2-bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine (162 g, 500 mmol) in anhydrous DMF (1500 mL) was added sodium hydride (30.0 g, 750 mmol) portionwise at 0° C. The resulting mixture was stirred at 0° C. for 15 min, then TsCl (124 g, 650 mmol) was added portionwise. The mixture was allowed to warm to room temperature with stirring. After 3 h, the reaction mixture was poured into ice water (2 L) and the precipitate was collected by filtration. The solid was rinsed with water (200 mL×5) and then dried under vacuum to give the title compound (239 g, 99%). LCMS (M+H) + = 479.9.

[0122] Step 2: 4-Bromo-N,N,2-trimethylbenzamide [ka]

[0123] A mixture of 4-bromo-2-methylbenzoic acid (25.0 g, 116 mmol) in SOCl2 (200 mL) was stirred at 60° C. for 3 h. The solvent was removed in vacuum. The residue was redissolved in anhydrous DCM (200 mL). Dimethylamine hydrochloride (14.0 g, 174.4 mmol) and TEA (80 mL, 581 mmol) were added at 0° C. The mixture was stirred at room temperature for 2 h. Water (200 mL) was added and the mixture was extracted with DCM (200 mL×3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, and concentrated under reduced pressure to give the title compound (28.0 g, 99%). LC-MS (M+H) + =242.0, 244.0.

[0124] Step 3: N,N,2-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka]

[0125] 4-Bromo-N,N,2-trimethylbenzamide (28.0 g, 115 mmol), BPD (44.0 g, 174 mmol), Pd(dppf)Cl2 (5.1 g, 6.94 mmol), and AcOK (22.7 g, 231 mmol) were added to dioxane (400 mL) under nitrogen. The reaction mixture was heated to reflux overnight and then cooled to room temperature. EtOAc (400 mL) was added and the mixture was washed with brine (300 mL x 2). The aqueous layer was extracted with EtOAc (400 mL). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1:5-2:1) to give the title compound (26.0 g, 73%). LC-MS (M+H) + =290.1.

[0126] Step 4: 4-(2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N,2-trimethylbenzamide [ka]

[0127] To a solution of 2-bromo-7-iodo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (16.5 g, 34.6 mmol) and N,N,2-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (10.0 g, 34.5 mmol) in dioxane (150 mL) and water (50 mL) was added K2CO3 (9.55 g, 69.2 mmol) and Pd(dppf)Cl2 (1.54 g, 2.07 mmol) under nitrogen atmosphere. After stirring at 50 °C for 5 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc / PE (1:2 to 2:1) to give the title compound (11.0 g, 62%). 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.68 (s, 1H), 8.09-8.01 (m, 4H), 7.49-7.44 (m, 2H), 7.29 (d, J = 7.8 Hz, 1H), 3.02 (s, 3H), 2.79 (s, 3H), 2.36 (s, 3H), 2.27 (s, 3H). LCMS (M+H) + = 513.0.

[0128] Step 5: tert-Butyl(pivaloyloxy)carbamate [ka]

[0129] To a stirred solution of pivaloyl anhydride (17.0 g, 86.7 mmol) in CHCl3 (300 mL) was added tert-butyl N-hydroxycarbamate (10.0 g, 71.3 mmol) dropwise at 0° C. The reaction mixture was heated at 70° C. for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc (500 mL) and water (500 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (7.2 g, 46%).

[0130] Step 6: O-Pivaloylhydroxylamine trifluoromethanesulfonate [ka]

[0131] TfOH (18.9 g, 125.7 mmol) was added to a solution of tert-butyl(pivaloyloxy)carbamate (24.8 g, 114.3 mmol) in MTBE (230 mL) at 0° C. and stirred at room temperature for 4 h. The volume of the solution was reduced to about 100 mL under reduced pressure and the precipitate was collected by filtration. The solid was dried under vacuum to give the title compound (26.0 g, 85%). LC-MS (M+H) + =118.0.

[0132] Step 7: 4-Bromo-2-methyl-N-(pivaloyloxy)benzamide [ka]

[0133] DIPEA (15.7 g, 121.6 mmol) was added to a solution of 4-bromo-2-methylbenzoic acid (8.82 g, 40.52 mmol) in THF (150 mL) at 0° C., followed by T3P (25.8 g, 81.1 mmol) and O-pivaloylhydroxylamine trifluoromethanesulfonate (26.0 g, 97.3 mmol). The reaction was stirred at room temperature overnight. Brine (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (7.5 g, 59%). LC-MS (M+H) + =314.0.

[0134] Step 8: 6-Bromo-8-methyl-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0135] KOAc (5.16 g, 52.5 mmol) and dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (737.7 mg, 1.19 mmol) were added to a solution of 4-bromo-2-methyl-N-(pivaloyloxy)benzamide (7.5 g, 23.9 mmol) in acetonitrile (150 mL). The solution was stirred overnight at room temperature under ethylene atmosphere (3 bar). The solvent was removed in vacuo and the residue was partitioned between water (20 mL) and ethyl acetate (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (4.67 g, 82%). LC-MS (M+H) + =240.0.

[0136] Step 9: 6-Bromo-8-methyl-1,2,3,4-tetrahydroisoquinoline [ka]

[0137] To 6-bromo-8-methyl-3,4-dihydroisoquinolin-1(2H)-one (4.67 g, 19.5 mmol) was added BH3 in THF (1.0 M, 77.8 mL, 77.8 mmol) and the reaction mixture was refluxed overnight. The mixture was cooled to 0° C. and MeOH (5 mL) was added followed by HCl (2 M, 25 mL). The solution was heated at 80° C. for 3 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in DCM (50 mL) and the solution was washed successively with saturated NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (3.79 g, 86%). LC-MS (M+H) + =226.0.

[0138] Step 10: tert-Butyl 6-bromo-8-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate [ka]

[0139] To a solution of 6-bromo-8-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (36.0 g, 137 mmol) in DCM (400 mL) at 0° C., triethylamine (34.7 g, 343 mmol), DMAP (1.67 g, 13.7 mmol), and Boc2O (74.8 g, 342.1 mmol) were added portionwise. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography eluting with EtOAc in PE (0% to 50% gradient) to give the title compound (23.3 g, 52%). LC-MS (Mt-Bu+H) + = 269.9.

[0140] Step 11: tert-Butyl 8-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate [ka]

[0141] To a solution of tert-butyl 6-bromo-8-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylate (20.0 g, 61.3 mmol) in dioxane (500 mL) was added BPD (23.4 g, 92.1 mmol), KOAc (18.0 g, 183.9 mmol) and Pd(dppf)Cl2.CH2Cl2 (5.0 g, 6.1 mmol) under nitrogen. The reaction was heated to 100 °C and stirred for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc in PE (0% to 50% gradient) to give the title compound (19.0 g, 83%). LC-MS (M-Boc+H) + = 274.1.

[0142] Step 12: tert-Butyl 6-(7-(4-(dimethylcarbamoyl)-3-methylphenyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka]

[0143] To a solution of 4-(2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N,2-trimethylbenzamide (20.0 g, 39 mmol) in dioxane (300 mL) and H2O (30 mL) was added tert-butyl 8-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (20.0 g, 51 mmol), K2CO3 (10.8 g, 78 mmol) and Pd(dppf)Cl2.CH2Cl2 (3.20 g, 3.9 mmol) under nitrogen. The mixture was heated to 100 °C and stirred for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH in DCM (0% to 10% gradient) to give the title compound (11.8 g, 45%). LC-MS (M+H) + = 680.4.

[0144] Step 13: tert-Butyl 6-(7-(4-(dimethylcarbamoyl)-3-methylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka]

[0145] To a solution of tert-butyl 6-(7-(4-(dimethylcarbamoyl)-3-methylphenyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (11.8 g, 18.7 mmol) in MeOH (400 mL) was added aqueous NaOH (2.0 M, 37 mL, 74 mmol) at room temperature. The mixture was heated to 60° C. and stirred for 20 min. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with MeOH in DCM (0% to 10% gradient) to give the title compound (6.3 g, 64%). LC-MS (M+H) + = 526.3.

[0146] Step 14: N,N,2-trimethyl-4-(2-(8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)benzamide hydrochloride [ka]

[0147] tert-Butyl 6-(7-(4-(dimethylcarbamoyl)-3-methylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (6.3 g, 12.2 mmol) was added slowly to HCl in dioxane (4.0 M, 100 mL, 0.40 mol) at room temperature. The mixture was stirred for 3 h and then concentrated in vacuo. The residue was triturated with ether (200 mL) and the solid was collected by filtration and then washed with ether (100 mL x 3) to give the title compound (5.47 g, 97%). 1 H NMR (300 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.76 (s, 2H), 8.91 (s, 1H), 8.48 (d, J = 3.0 Hz, 1H), 8.28-8.13 (m, 2H), 7.93 (d, J = 14.1 Hz, 2H), 7.23 (d, J = 8.1, 2.9 Hz, 1H), 4.22 (s, 2H), 3.42-3.32 (m, 2H), 3.15 (t, J = 5.9 Hz, 2H), 3.02 (s, 3H), 2.82 (s, 3H), 2.30 (d, J = 11.7, 3.0 Hz, 6H). LC-MS (M+H) + = 426.3.

[0148] Step 15: tert-Butyl (2-bromoethyl)carbamate [ka]

[0149] A solution of 2-bromoethan-1-amine hydrochloride (4.0 g, 19.6 mmol), (Boc)2O (4.7 g, 21.6 mmol), and triethylamine (13 mL, 98.0 mmol) in THF (80 mL) was stirred at room temperature overnight. The mixture was then partitioned between water (80 mL) and EtOAc (80 mL). The organic layer was washed with brine (80 mL), dried over Na2SO4, and filtered. The crude product was purified by silica gel column chromatography eluting with PE / EtOAc=10:1 to give the title compound (3.7 g, 84%). LC-MS (M+H) + = 224.0.

[0150] Step 16: tert-Butyl (2-(6-(7-(4-(dimethylcarbamoyl)-3-methylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)carbamate [ka]

[0151] A mixture of N,N,2-trimethyl-4-(2-(8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)benzamide hydrochloride (1.0 g, 2.2 mmol), tert-butyl (2-bromoethyl)carbamate (580 mg, 2.6 mmol) and Na2CO3 (460 mg, 4.3 mmol) in DMF (15 mL) was stirred at room temperature overnight. The mixture was diluted with water (60 mL) and then extracted with EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel preparative TLC developed with DCM / MeOH=10:1 to give the title compound (400 mg, 33%). LC-MS (M+H) + = 569.3.

[0152] Step 17: 4-(2-(2-(2-aminoethyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N,2-trimethylbenzamide dihydrochloride [ka]

[0153] To tert-butyl (2-(6-(7-(4-(dimethylcarbamoyl)-3-methylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)carbamate (400 mg, 0.79 mmol) was added HCl in dioxane (4.0 M, 10 mL). The reaction mixture was stirred at room temperature overnight. The precipitate was collected by filtration and washed with MTBE (2×10 mL) to give the title compound (400 mg, 96%). LC-MS (M+H) + = 469.6.

[0154] Step 18: N-(2-(6-(7-(4-(dimethylcarbamoyl)-3-methylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxamide

[0155] To a solution of 4-(2-(2-(2-aminoethyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N,2-trimethylbenzamide dihydrochloride (100 mg, 0.18 mmol), 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxylic acid (84 mg, 0.22 mmol) and HATU (79 mg, 0.21 mmol) in DMF (3 mL) was added triethylamine (0.14 mL, 1.0 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel preparative TLC developing with DCM / MeOH=8:1 to give Example 1 (10 mg, 7%). 1 H NMR (400 MHz, DMSO) δ 12.28 (d, J = 2.7 Hz, 1H), 11.02 (s, 1H), 8.82 (s, 1H), 8.40 (d, J = 2.6 Hz, 1H), 8.20 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.82 - 7.76 (m, 2H), 7.74 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.26 (s, 1H), 7.17 (d, J = 8.1 Hz, 2H), 5.02-4.97 (m, 1H), 4.01-3.98 (m, 2H), 3.51 (s, 2H), 3.25 (s, 3H), 2.96-2.93 (m, 5H), 2.91 - 2.82 (m, 3H), 2.76 (s, 3H), 2.66 (d, J = 5.1 Hz, 2H), 2.60 - 2.52 (m, 3H), 2.22 (s, 6H), 1.98 - 1.89 (m, 1H), 1.70 (d, J = 10.5 Hz, 2H), 1.59-1.51 (m, 2H). LC-MS (M+H) + = 836.9.

[0156] Example 2: 4-(2-(2-(3-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)amino)-3-oxopropyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N,2-trimethylbenzamide [ka]

[0157] Step 1: tert-Butyl 3-(6-(7-(4-(dimethylcarbamoyl)-3-methylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoate [ka]

[0158] To a mixture of N,N,2-trimethyl-4-(2-(8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)benzamide (1.0 g, 0.22 mmol) and tert-butyl 3-bromopropanoate (500 mg, 0.24 mmol) in DMF (15 mL) was added K2CO3 (0.60 g, 0.65 mmol). The mixture was stirred at room temperature overnight and then diluted with water (50 mL). The mixture was extracted with EtOAc (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel preparative TLC developed with DCM / MeOH=10:1 to give the title compound (700 mg, 53%). LC-MS (M+H) + = 554.3.

[0159] Step 2: 3-(6-(7-(4-(dimethylcarbamoyl)-3-methylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid hydrochloride [ka]

[0160] To tert-butyl 3-(6-(7-(4-(dimethylcarbamoyl)-3-methylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (700 mg, 1.4 mmol) was added HCl in dioxane (4.0 M, 10 mL). The mixture was stirred at room temperature overnight. The precipitate was collected by filtration and washed with MTBE (2×10 mL) to give the title compound (650 mg, 87%). LC-MS (M+H) + = 498.6.

[0161] Step 3: 4-(2-(2-(3-(((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)amino)-3-oxopropyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N,2-trimethylbenzamide [ka]

[0162] Example 2 (4 mg, 3%) was prepared in a similar manner to step 18 of Example 1 from 3-(4-(4-(aminomethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione and 3-(6-(7-(4-(dimethylcarbamoyl)-3-methylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid hydrochloride (4 mg, 3%). 1H NMR (400 MHz, DMSO) δ 12.40 (s, 1H), 10.79 (s, 1H), 8.97 (s, 1H), 8.53 (s, 1H), 8.34 (s, 1H), 8.26 (d, J = 7.8 Hz, 1H), 8.10 (s, 1H), 7.96 (s, 1H), 7.91 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 3.66 - 3.57 (m, 3H), 3.50-3.47 (m, 2H), 3.38 (s, 3H), 3.08 (s, 3H), 3.05-3.00 (m, 4H), 2.90 - 2.84 (m, 5H), 2.78 (s, 2H), 2.49-2.42 (m, 4H), 2.36-2.34 (m, 6H), 1.97-1.89 (m, 2H), 1.75-1.72 (m, 2H), 1.24 - 1.10 (m, 2H). LC-MS (M+H) + = 781.9.

[0163] Example 3: 4-(2-(2-(3-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N,2-trimethylbenzamide [ka]

[0164] Step 1: tert-Butyl 4-(4-((3-ethoxy-3-oxopropyl)amino)phenyl)piperazine-1-carboxylate [ka]

[0165] A mixture of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (8.0 g, 28.2 mmol), DBU monolactate (5.59 g, 23.1 mmol) and ethyl acrylate (4.33 g, 43.7 mmol) was stirred at 90° C. for 3 h. The mixture was cooled to room temperature and partitioned between EtOAc (40 mL) and water (40 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (8.5 g, 78%). LC-MS (M+H) + = 378.2.

[0166] Step 2: tert-Butyl 4-(4-(N-(3-ethoxy-3-oxopropyl)cyanamid)phenyl)piperazine-1-carboxylate [ka]

[0167] To a mixture of tert-butyl 4-(4-((3-ethoxy-3-oxopropyl)amino)phenyl)piperazine-1-carboxylate (8.5 g, 22.5 mmol) in toluene (5 mL) was added cyanogen bromide (2.8 g, 27.0 mmol) and NaHCO3 (2.84 g, 33.8 mmol). The mixture was stirred at room temperature for 3 h and then diluted with EtOAc (20 mL). The organic layer was washed with water (20 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography eluting with PE / EtOAc=10:1 to give the title compound (9.0 g, 95%). LC-MS (M+H) + = 403.2.

[0168] Step 3: tert-Butyl 4-(4-(1-(3-ethoxy-3-oxopropyl)ureido)phenyl)piperazine-1-carboxylate [ka]

[0169] A mixture of tert-butyl 4-(4-(N-(3-ethoxy-3-oxopropyl)cyanamid)phenyl)piperazine-1-carboxylate (1.0 g, 2.5 mmol), acetaldehyde oxime (0.93 g, 7.5 mmol) and InCl3 (165 mg, 0.75 mmol) in toluene (10 mL) was heated to reflux for 1 h. The mixture was cooled to room temperature and partitioned between water (20 mL) and EtOAc (20 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (830 mg, 83%). LC-MS (M+H) + = 421.2.

[0170] Step 4: tert-Butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazine-1-carboxylate [ka]

[0171] A mixture of tert-butyl 4-(4-(1-(3-ethoxy-3-oxopropyl)ureido)phenyl)piperazine-1-carboxylate (7.5 g, 17.9 mmol) and Titron B 40% (11.2 g, 26.8 mmol) in CH3CN (30 mL) was heated at 60°C for 10 min. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with DCM / MeOH=50:1 to give the title compound (4.0 g, 58%). LC-MS (M+H) + = 375.2.

[0172] Step 5: 1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride [ka]

[0173] To a suspension of tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazine-1-carboxylate (930 mg, 2.4 mmol) in dioxane (10 mL) was added HCl in dioxane (4.0 M, 20 mL). After 4 h, the solid was filtered, washed with MTBE, and dried under vacuum to give the title compound (770 mg, 100%). LC-MS (M+H) + = 275.2.

[0174] Step 6: 4-(2-(2-(3-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N,2-trimethylbenzamide

[0175] A solution of 1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (57 mg, 0.18 mmol), 3-(6-(7-(4-(dimethylcarbamoyl)-3-methylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid hydrochloride (90 mg, 0.17 mmol), HATU (70 mg, 0.18 mmol) and triethylamine (0.12 mL, 0.84 mmol) in DMF (3 mL) was stirred at room temperature overnight. Water (15 mL) was added and the mixture was extracted with EtOAc (30 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative TLC, developed with DCM / MeOH=8:1 to give Example 3 (4 mg, 3%). 1H NMR (400 MHz, DMSO) δ 12.35 (s, 1H), 10.28 (s, 1H), 8.89 (s, 1H), 8.47 (d, J = 2.7 Hz, 1H), 8.26 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.89-7.75 (m, 2H), 7.24 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 3.77-3.52 (m, 5H), 3.32 (s, 6H), 3.20-3.13 (m, 2H), 3.13-3.07 (m, 2H), 3.03 (s, 3H), 2.97-2.90 (m, 2H), 2.83 (s, 3H), 2.77-2.70 (m, 2H), 2.69-2.63 (m, 2H), 2.33-2.20 (dm, 6H). LC-MS (M+H) + = 754.4.

[0176] Example 4: 4-(2-(2-(3-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)amino)-3-oxopropyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N,2-trimethylbenzamide [ka]

[0177] Example 4 was prepared in a similar manner to step 6 of example 3 from 3-(6-(7-(4-(dimethylcarbamoyl)-3-methylphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid hydrochloride and 1-(4-(4-aminopiperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (5 mg, 3%). 1 H NMR (400 MHz, DMSO) δ 12.30 (s, 1H), 10.19 (s, 1H), 8.83 (s, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.96 (s, 1H), 7.78 (s, 2H), 7.17 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 7.8 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H), 3.65-3.58 (m, 2H), 3.55-3.45 (m, 3H), 3.25 (s, 3H), 2.96 (s, 3H), 2.91 - 2.82 (m, 2H), 2.80-2.73 (m, 5H), 2.65-2.55 (m, 3H), 2.25-2.15 (m, 8H), 1.80-1.72 (m, 3H), 1.48-1.35 (m, 3H). LC-MS (M+H) + = 768.3.

[0178] Example 5: 4-(2-(2-(3-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N-dimethylbenzamide [ka]

[0179] Step 1: 4-(2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N-dimethylbenzamide [ka]

[0180] To a solution of 2-bromo-7-iodo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (4.77 g, 10 mmol) in dioxane (50 mL) and water (5 mL) was added (4-(dimethylcarbamoyl)phenyl)boronic acid (1.93 g, 10 mmol), K2CO3 (2.76 g, 20 mmol) and Pd(dppf)Cl 2. CH2Cl2 (818 mg, 1.0 mmol) was added and then stirred at 90 °C under N2 atmosphere for 16 h. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), and then washed successively with H2O (60 mL), brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using PE:EtOAc = 1:3 to give the title compound (2.20 g, 44%). LC-MS (M+H) + =499.1, 501.1.

[0181] Step 2: tert-Butyl 6-(7-(4-(dimethylcarbamoyl)phenyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka]

[0182] A solution of 4-(2-bromo-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N-dimethylbenzamide (996 mg, 2 mmol) in dioxane (10 mL) and water (1 mL) was treated with tert-butyl 8-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (746 mg, 2 mmol), K2CO3 (828 mg, 6 mmol) and Pd(dppf)Cl2 . CH2Cl2 (164 mg, 0.2 mmol) was added, and then the mixture was stirred at 100 °C under N2 for 3 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), washed successively with H2O (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography with EtOAc to give the title compound (1.1 g, 83%). LC-MS (M+H) + =666.4.

[0183] Step 3: N,N-Dimethyl-4-(2-(8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)benzamide hydrochloride [ka]

[0184] To a solution of tert-butyl 6-(7-(4-(dimethylcarbamoyl)phenyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.1 g, 1.9 mmol) in dioxane (2 mL) was added HCl / dioxane (4 M, 10 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo to give the title compound (0.99 g, 99%). LC-MS (M+H) + =566.3.

[0185] Step 4: tert-Butyl 3-(6-(7-(4-(dimethylcarbamoyl)phenyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoate [ka]

[0186] To a solution of N,N-dimethyl-4-(2-(8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)benzamide hydrochloride (678 mg, 1.13 mmol) in DMF (5 mL) was added tert-butyl 3-bromopropanoate (1.25 g, 6.0 mmol). The reaction mixture was stirred at 40° C. overnight, diluted with EtOAc (30 mL), washed successively with brine (2×15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC with MeOH:DCM=1:25 to give the title compound (300 mg, 38%). LC-MS (M+H) + =694.4.

[0187] Step 5: tert-Butyl 3-(6-(7-(4-(dimethylcarbamoyl)phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoate [ka]

[0188] To a solution of tert-butyl 3-(6-(7-(4-(dimethylcarbamoyl)phenyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (180 mg, 0.26 mmol) in dioxane (4 mL) and water (2 mL) was added K2CO3 (215 mg, 1.56 mmol). The reaction mixture was stirred at 100 °C for 16 h and then cooled to room temperature. The mixture was diluted with EtOAc (20 mL), washed with H2O (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC using MeOH:DCM=1:25 to give the title compound (110 mg, 79%). LC-MS (M+H) + =540.4.

[0189] Step 6: 3-(6-(7-(4-(dimethylcarbamoyl)phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid trifluoroacetic acid [ka]

[0190] To a solution of tert-butyl 3-(6-(7-(4-(dimethylcarbamoyl)phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (110 mg, 0.2 mmol) in DCM (4 mL) was added TFA (2 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo to give the title compound (120 mg, 99%). LC-MS (M+H) + =484.3.

[0191] Step 7: 4-(2-(2-(3-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N-dimethylbenzamide

[0192] To a solution of 3-(6-(7-(4-(dimethylcarbamoyl)phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid trifluoroacetate (100 mg, 0.17 mmol) in DMF (4 mL) was added EtN (121 mg, 1.2 mmol), EDCI (77 mg, 0.4 mmol), HOBT (54 mg, 0.40 mmol) and 1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (57 mg, 0.20 mmol). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc (20 mL), washed with brine (2×10 mL), dried over NaSO, filtered and concentrated in vacuo. The residue was purified by TLC using MeOH:DCM=1:8, and the resulting crude product was purified by preparative HPLC to give the title compound (17 mg, 11%) as a white solid. LC-MS (M+H) + =740.4.

[0193] 1H NMR (400 MHz, DMSO) δ 12.40 (s, 1H), 10.28 (s, 1H), 8.88 (s, 1H), 8.53 - 8.50 (m, 1H), 8.40 - 8.36 (m, 2H), 7.84 (s, 1H), 7.79 (s, 1H), 7.54 - 7.49 (m, 2H), 7.18 - 7.14 (m, 2H), 6.98 - 6.94 (m, 2H), 3.71 - 3.65 (m, 4H), 3.64 - 3.61 (m, 2H), 3.60 - 3.57 (m, 2H), 3.19 - 3.14 (m, 2H), 3.12 - 3.08 (m, 2H), 3.01 (s, 6H), 2.97 - 2.91 (m, 2H), 2.87 - 2.81 (m, 2H), 2.77 - 2.70 (m, 4H), 2.69 - 2.64 (m, 2H), 2.31 (s, 3H).

[0194] Example 6: 4-(5-(2-(3-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide [ka]

[0195] Step 1: 4-(5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide [ka] To a solution of 5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (2.38 g, 5 mmol) in dioxane (30 mL) and water (3 mL) was added (4-(dimethylcarbamoyl)phenyl)boronic acid (965 mg, 5 mmol), KCO (1.38 g, 10 mmol) and Pd(dppf)Cl. 2.CH2Cl2 (409 mg, 0.5 mmol) was added and the mixture was stirred at 90 °C under N2 for 16 h. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with H2O (30 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using PE:EtOAc = 1:5 to give the title compound (1.50 g, 60%). LC-MS (M+H) + =498.1, 500.1.

[0196] Step 2: tert-Butyl 6-(3-(4-(dimethylcarbamoyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka]

[0197] To a solution of 4-(5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide (994 mg, 2 mmol) in dioxane (10 mL) and water (1 mL) was added tert-butyl 8-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (746 mg, 2 mmol), K2CO3 (828 mg, 6 mmol) and Pd(dppf)Cl 2. CH2Cl2 (164 mg, 0.2 mmol) was added and then stirred at 100 °C under N2 for 3 h. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), washed with H2O (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with EtOAc to give the title compound (1.0 g, 75%). LC-MS (M+H) + =665.4.

[0198] Step 3: N,N-Dimethyl-4-(5-(8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide hydrochloride [ka]

[0199] To a solution of tert-butyl 6-(3-(4-(dimethylcarbamoyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.0 g, 1.5 mmol) in dioxane (2 mL) was added HCl / dioxane (4 M, 10 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo to give the title compound (0.90 g, 99%). LC-MS (M+H) + =565.3.

[0200] Step 4: tert-Butyl 3-(6-(3-(4-(dimethylcarbamoyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoate [ka]

[0201] To a solution of N,N-dimethyl-4-(5-(8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide hydrochloride (400 mg, 0.67 mmol) in DMF (5 mL) was added tert-butyl 3-bromopropanoate (890 mg, 4.26 mmol). The reaction mixture was stirred at 40° C. overnight, diluted with EtOAc (30 mL), washed with brine (2×15 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC with MeOH:DCM=1:25 to give the title compound (200 mg, 43%). LC-MS (M+H) +=693.4.

[0202] Step 5: tert-Butyl 3-(6-(3-(4-(dimethylcarbamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoate [ka]

[0203] To a solution of tert-butyl 3-(6-(3-(4-(dimethylcarbamoyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (200 mg, 0.29 mmol) in dioxane (4 mL) and water (2 mL) was added K2CO3 (239 mg, 1.73 mmol). The reaction mixture was stirred at 100° C. for 16 h, diluted with EtOAc (20 mL), washed with H2O (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC with MeOH:DCM=1:25 to give the title compound (120 mg, 77%). LC-MS (M+H) + =539.4.

[0204] Step 6: 3-(6-(3-(4-(dimethylcarbamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid trifluoroacetic acid [ka]

[0205] To a solution of tert-butyl 3-(6-(3-(4-(dimethylcarbamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (120 mg, 0.22 mmol) in DCM (4 mL) was added TFA (2 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo to give the title compound (132 mg, 100%). LC-MS (M+H) + =483.3.

[0206] Step 7: 4-(5-(2-(3-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylbenzamide

[0207] To a solution of 3-(6-(3-(4-(dimethylcarbamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid trifluoroacetate (90 mg, 0.15 mmol) in DMF (4 mL) was added EtN (121 mg, 1.2 mmol), EDCI (73 mg, 0.38 mmol), HOBT (51 mg, 0.38 mmol) and 1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (51 mg, 019 mmol). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc (20 mL), washed with brine (2×10 mL), dried over NaSO, filtered and concentrated in vacuo. The residue was purified by preparative TLC with MeOH:DCM=1:8, then by preparative HPLC to give the title compound (20 mg, 15%). 1H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 10.28 (s, 1H), 8.54 (s, 1H), 8.42 (s, 1H), 8.02 - 7.98 (m, 1H), 7.87 - 7.82 (m, 2H), 7.52 - 7.47 (m, 2H), 7.39 (s, 1H), 7.34 (s, 1H), 7.19 - 7.14 (m, 2H), 6.99 - 6.93 (m, 2H), 3.71 - 3.65 (m, 4H), 3.64 - 3.61 (m, 2H), 3.58 - 3.53 (m, 2H), 3.19 - 3.14 (m, 2H), 3.12 - 3.08 (m, 2H), 3.01 (s, 6H), 2.97 - 2.91 (m, 2H), 2.87 - 2.81 (m, 2H), 2.74 - 2.66 (m, 6H), 2.27 (s, 3H). LC-MS (M+H) + =739.4.

[0208] Example 7: (S)-4-(2-(2-(3-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N-(2-hydroxypropyl)-N-methylbenzamide [ka]

[0209] Step 1: (S)-4-Bromo-N-(2-hydroxypropyl)benzamide [ka]

[0210] To a solution of 4-bromobenzoic acid (11.80 g, 55.8 mmol) in DMF (120 mL) was added DIPEA (10.50 g, 104 mmol), HATU (22.40 g, 58.9 mmol) and (2S)-1-aminopropan-2-ol (4.00 g, 53.3 mmol). The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched by adding water. The resulting mixture was extracted with EtOAc (600 mL x 3). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (30:70) to give the title compound (12.0 g, 88%). LC-MS (M+H) + = 258.1

[0211] Step 2: (S)-4-Bromo-N-(2-((tert-butyldimethylsilyl)oxy)propyl)benzamide [ka]

[0212] (S)-4-Bromo-N-(2-hydroxypropyl)benzamide (2.45 g, 9.5 mmol), TBSCl (1.56 g, 10.4 mmol) and Et3N (2.6 mL, 19.0 mmol) were added to DCM (40 mL) at room temperature. The mixture was stirred overnight. Water (40 mL) was added and the organic layer was separated. The aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated to give the title compound (2.9 g, 83%). LC-MS (M+H) + = 372.2.

[0213] Step 3: (S)-4-Bromo-N-(2-((tert-butyldimethylsilyl)oxy)propyl)-N-methylbenzamide [ka]

[0214] To a solution of (S)-4-bromo-N-(2-((tert-butyldimethylsilyl)oxy)propyl)benzamide (2.9 g, 7.8 mmol) in DMF (20 mL) was added NaH (470 mg, 11.7 mmol) at 0° C. and stirred for 1 h, then CHI (1.3 g, 9.4 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. Water (80 mL) was added and the mixture was extracted with EtOAc (50 mL). The organic layer was dried over NaSO, filtered and concentrated in vacuo to give the title compound (3.0 g, 100%). LC-MS (M+H) + = 386.1.

[0215] Step 4: (S)-N-(2-((tert-butyldimethylsilyl)oxy)propyl)-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka]

[0216] A mixture of (S)-4-bromo-N-(2-((tert-butyldimethylsilyl)oxy)propyl)-N-methylbenzamide (3.0 g, 7.8 mmol), BPD (2.4 g, 9.3 mmol), Pd(dppf)Cl2 (400 mg, 0.54 mmol) and AcOK (1.5 g, 15.5 mmol) in dioxane (40 mL) was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, concentrated and the residue was purified by preparative TLC (PE / EtOAc=4:1) to give the title compound (3.6 g, quantitative).

[0217] Step 5: (S)-4-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N-(2-((tert-butyldimethylsilyl)oxy)propyl)-N-methylbenzamide [ka]

[0218] A mixture of 2-bromo-7-iodo-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (1.1 g, 2.3 mmol), (S)-N-(2-((tert-butyldimethylsilyl)oxy)propyl)-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.0 g, 2.3 mmol), Pd(PPh3)4 (133 mg, 0.12 mmol) and Na2CO3 (294 mg, 2.8 mmol) in dioxane (40 mL) and water (10 mL) was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, concentrated in vacuo and the residue was purified by silica gel chromatography eluting with PE / EtOAc=2:1 to give the title compound (690 mg, 60%). LC-MS (M+H) + = 503.1.

[0219] Step 6: tert-Butyl (S)-6-(7-(4-((2-((tert-butyldimethylsilyl)oxy)propyl)(methyl)carbamoyl)phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka]

[0220] The title compound (560 mg, 61%) was prepared in a similar manner to step 12 of Example 1 from tert-butyl 8-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate and (S)-4-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N-(2-((tert-butyldimethylsilyl)oxy)propyl)-N-methylbenzamide. LC-MS (M+H) + = 670.3.

[0221] Step 7: (S)-N-(2-hydroxypropyl)-N-methyl-4-(2-(8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)benzamide hydrochloride [ka]

[0222] The title compound (460 mg, quantitative) was prepared from tert-butyl (S)-6-(7-(4-((2-((tert-butyldimethylsilyl)oxy)propyl)(methyl)carbamoyl)phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate in a similar manner to step 14 of example 1. LC-MS (M+H) + = 456.2.

[0223] Step 8: tert-Butyl (S)-3-(6-(7-(4-((2-hydroxypropyl)(methyl)carbamoyl)phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoate [ka]

[0224] A mixture of (S)-N-(2-hydroxypropyl)-N-methyl-4-(2-(8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)benzamide hydrochloride (460 mg, 0.93 mmol), tert-butyl 3-bromopropanoate (176 mg, 0.84 mmol) and K2CO3 (322 mg, 23.4 mmol) in DMF (5 mL) was stirred at room temperature overnight. Water (40 mL) was added and the mixture was extracted with EtOAc (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=8:1) to give the title compound (200 mg, 37%). LC-MS (M+H) + = 584.3.

[0225] Step 9: (S)-3-(6-(7-(4-((2-hydroxypropyl)(methyl)carbamoyl)phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid hydrochloride [ka]

[0226] The title compound (460 mg, quantitative) was prepared from tert-butyl (S)-3-(6-(7-(4-((2-hydroxypropyl)(methyl)carbamoyl)phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoate in a similar manner to step 2 of example 2. LC-MS (M+H) + = 528.2.

[0227] Step 10: (S)-4-(2-(2-(3-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N-(2-hydroxypropyl)-N-methylbenzamide

[0228] Example 7 (20 mg, 21%) was prepared in a similar manner to step 18 of example 1 from 3-methyl-1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride and (S)-3-(6-(7-(4-((2-hydroxypropyl)(methyl)carbamoyl)phenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid hydrochloride. 1 H NMR (400 MHz, DMSO) δ 12.38 (s, 1H), 10.24 (s, 1H), 8.87 (s, 1H), 8.48 (s, 1H), 8.33 (s, 2H), 7.85 (s, 2H), 7.47 (d, J = 7.7 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 4.83-4.79 (m, 1H), 4.00-3.90 (m, 1H), 3.85-3.79 (m, 1H), 3.69 - 3.57 (m, 7H), 3.47 (s, 1H), 3.27 (s, 3H), 3.20-3.12 (m, 3H), 3.12-3.05 (m, 4H), 3.05-2.97 (m, 4H), 2.63 (t, J = 6.6 Hz, 3H), 2.30 (s, 3H), 1.14-1.08 (m, 2H), 0.90-0.85 (m, 2H). LC-MS (M+H) + = 784.3.

[0229] Example 8: 4-(2-(2-(2-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetamido)ethyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N,2-trimethylbenzamide [ka]

[0230] Example 8 (25 mg, 17%) was prepared in a similar manner to step 18 of example 1 from 2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetic acid and 4-(2-(2-(2-aminoethyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N,2-trimethylbenzamide dihydrochloride. 1 H NMR (400 MHz, DMSO) δ 12.31 (s, 1H), 10.68 (s, 1H), 8.86 (s, 1H), 8.42 (s, 1H), 8.20 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.83 (s, 3H), 7.17 (d, J = 7.9 Hz, 1H), 6.70 (s, 4H), 3.57-3.48 (m, 3H), 3.26 (s, 3H), 2.96 (s, 3H), 2.95 - 2.83 (m, 2H), 2.76 (s, 3H), 2.74 - 2.65 (m, 1H), 2.65-2.55 (m, 1H), 2.55-2.48 (m, 2H), 2.40 - 2.31 (m, 3H), 2.25 (s, 3H), 2.25-2.20 (m, 5H), 2.03-1.90 (m, 4H), 1.72-1.60 (m, 2H), 1.70-1.62 (m,3H), 1.20-1.16 (m, 3H). LC-MS (M+H) + = 781.9.

[0231] Example 9: (S)-4-(5-(2-(3-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(2-hydroxypropyl)-N-methylbenzamide [ka]

[0232] Step 1: 5-Bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine [ka]

[0233] To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (5.0 g, 25.4 mmol) in THF (80 mL) was added NIS (6.85 g, 30.4 mmol, 1.2 equiv.) at room temperature. After 2 h, the reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography using PE / EtOAc (15 / 1) to give the title compound (8.0 g, 97%). LCMS (M+H) + = 322.6.

[0234] Step 2: tert-Butyl 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate [ka]

[0235] A solution of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (8.0 g, 24.7 mmol), Boc2O (7.5 g, 34.6 mmol) and Et3N (7.4 g, 74 mmol) in THF (80 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography using PE / EtOAc (20 / 1) to give the title compound (10 g, 95%). LCMS (M+H) + = 422.6.

[0236] Step 3: (S)-4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(2-((tert-butyldimethylsilyl)oxy)propyl)-N-methylbenzamide [ka]

[0237] A mixture of tert-butyl 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (2.0 g, 4.7 mmol), (S)-N-(2-((tert-butyldimethylsilyl)oxy)propyl)-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.4 g, 3.3 mmol), Pd(dppf)Cl2 (196 mg, 0.27 mmol) and K2CO3 (630 mg, 4.6 mmol) in dioxane (35 mL) and water (10 mL) was heated to reflux overnight. The mixture was cooled to room temperature and then partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative TLC (DCM / MeOH=10:1) to give the title compound (740 mg, 46%). LC-MS (M+H) + = 502.1.

[0238] Step 4: tert-Butyl (S)-6-(3-(4-((2-((tert-butyldimethylsilyl)oxy)propyl)(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate [ka]

[0239] The title compound was prepared in a similar manner to step 12 of Example 1 from (S)-4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(2-((tert-butyldimethylsilyl)oxy)propyl)-N-methylbenzamide and tert-butyl 8-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (220 mg, 61%). LC-MS (M+H) + = 669.3.

[0240] Step 5: (S)-N-(2-hydroxypropyl)-N-methyl-4-(5-(8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide hydrochloride [ka]

[0241] The title compound was prepared in a similar manner to step 3 of Example 6 from tert-butyl (S)-6-(3-(4-((2-((tert-butyldimethylsilyl)oxy)propyl)(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (150 mg, 86%). LC-MS (M+H) + = 455.2.

[0242] Step 6: tert-Butyl (S)-3-(6-(3-(4-((2-hydroxypropyl)(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoate [ka]

[0243] The title compound was prepared in a similar manner to step 8 of Example 7 from (S)-N-(2-hydroxypropyl)-N-methyl-4-(5-(8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide hydrochloride and tert-butyl 3-bromopropanoate (50 mg, 31%). LC-MS (M+H) + = 583.3.

[0244] Step 7: (S)-3-(6-(3-(4-((2-hydroxypropyl)(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid hydrochloride [ka]

[0245] The title compound was prepared in a similar manner to step 2 of Example 2 from tert-butyl (S)-3-(6-(3-(4-((2-hydroxypropyl)(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (45 mg, 94%). LC-MS (M+H) + = 527.2.

[0246] Step 8: (S)-4-(5-(2-(3-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)-3-oxopropyl)-8-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(2-hydroxypropyl)-N-methylbenzamide

[0247] Example 9 was prepared in a similar manner to step 6 of example 3 from (S)-3-(6-(3-(4-((2-hydroxypropyl)(methyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-methyl-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid hydrochloride and 1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (15 mg, 7%). 1 H NMR (400 MHz, DMSO) δ 12.06 (s, 1H), 10.27 (s, 1H), 8.54 (s, 1H), 8.42 (s, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.84 (d, J = 7.9 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.39 (s, 1H), 7.34 (s, 1H), 7.16 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 4.88-4.83 (m, 1H), 3.99-3.88 (m, 1H), 3.70-3.67 (m, 6H), 3.56 (s, 2H), 3.16 (s, 2H), 3.10 (s, 2H), 3.06-2.97 (m, 4H), 2.90 (s, 2H), 2.83 (t, J = 7.0 Hz, 2H), 2.72-2.67 (m, 6H), 2.26 (s, 3H), 1.11-0.92 (m, 3H). LC-MS (M+H) + = 783.3.

[0248] biological activity HPK kinase activity assay at 1mM ATP

[0249] Compounds disclosed herein were tested for inhibition of HPK1 kinase (aa1-346, Life Technologies) activity in an assay based on time-resolved fluorescence resonance energy transfer (TR-FRET). The assay was performed in 384-well low volume black plates in reaction mixtures containing HPK1 kinase (40 nM), 1 mM ATP, 0.5 μM STK1 substrate, and 0-10 μM of compound in a buffer containing 50 mM HEPES, 0.01% BSA, 0.1 mM orthovanadate, 10 mM MgCl2, 1 mM DTT, pH=7.0, 0.005% Tween-20. Kinases were incubated with compounds disclosed herein or DMSO for 60 min at room temperature, and the reaction was initiated by adding ATP and STK1 substrate. After 120 min at room temperature, an equal volume of stop / detection solution was added according to the manufacturer's instructions (CisBio). The stop / detection solution contained STK antibody-cryptate and XL665-conjugated streptavidin in detection buffer. The TR-FRET signal (ratio of fluorescence emission at 665 nm to emission at 620 nm with excitation at 337 nm wavelength) was recorded on a PHERAstar FS plate reader (BMG Labtech). Phosphorylation of the STK1 substrate was monitored by the fluorescence donor (Eu 3+ This results in binding of the STK antibody-cryptate to the biotinylated STK1 substrate, which places the STK antibody (cryptate) in close proximity to the acceptor (streptavidin-XL665), thus resulting in a high degree of fluorescence resonance energy transfer. Inhibition of HPK1 in the presence of increasing concentrations of compound was calculated based on the ratio of fluorescence at 665 nm to 620 nm. IC 50 Determination of was performed by curve fitting percent inhibition versus log inhibitor concentration using Dotmatics. Compounds disclosed herein exhibited enzyme activity values ​​as shown in Table 1.

[0250] [Table 2]

[0251] Cellular pSLP76(S376) HTRF assay The Jurkat cell line was used in this study. Cells were maintained in RPMI 1640 supplemented with heat-inactivated 10% fetal bovine serum (Thermo Fisher), 50 units / mL penicillin and streptomycin (Thermo Fisher) and kept at 37 °C in a humidified atmosphere of 5% CO2 in air. Cells were restored from frozen stocks within 30 passages from the original cells purchased. After 18 h of cell starvation in assay buffer (RPMI 1640 supplemented with heat-inactivated 0.1% fetal bovine serum), cells were seeded at a per well density of 150,000 cells in round-bottom 96-well plates. Cells were treated with a 9-point dilution series of test compounds. Final compound concentrations ranged from 0 to 2 μM. After 2 h of compound treatment, cells were stimulated with 0.05 μg / mL of anti-human CD3 (OKT3, Bioxcell) for 30 min at 37 °C. The cells were then lysed and the pSLP76 (S376) levels in the cell lysates were detected by HTRF kit (Cisbio). A total of 16 μL of cell lysate from each well of the 96-well plate was transferred to a 384-well small volume white assay plate. The lysate from each well was diluted with 2 μL of Eu 3+ The cells were incubated overnight in the dark at room temperature with 2 μL of 10 ... 50 Determination of was performed by curve fitting percent inhibition versus log inhibitor concentration using Dotmatics. Compounds disclosed herein exhibited cellular activity values ​​as shown in Table 2.

[0252] [Table 3]

[0253] HPK1 proteolysis assay (Western blot) in human PBMCs

[0254] Human PBMCs (AllCells) were used in this study. Cells were thawed 1 day before and maintained in RPMI-1640 supplemented with 10% fetal bovine serum (Thermo Fisher), 50 units / mL penicillin and streptomycin (Thermo Fisher), and the mixture was maintained at 37 °C in a humidified atmosphere containing 5% CO2. 3 × 10 cells were cultured per well in 1 mL culture medium. 6 PBMCs were seeded in 12-well plates and cells were treated with appropriate dilution series of compounds to a final concentration of 10 mM. After 24 h of compound incubation, the medium was aspirated, cells were washed with PBS, and then 30 μL of 1X protein lysis buffer (Cell Signaling Technology) containing protease inhibitors (Merck) and phosphatase inhibitors (Sigma) was added. Cells were lysed. After centrifugation, the supernatant was quantified by BCA protein assay kit (Thermo Fisher). 4X loading buffer (Thermo Fisher) was added to equal amounts of total protein from each sample and heated at 95 °C for 5 min. 30–50 μg of cell lysate was loaded onto 4%–12% NuPAGE Bis-Tris Gel (Thermo Fisher) and electrotransferred to NC membrane (Thermo Fisher). The membrane was blocked with blocking agent (LI-COR) for at least 1 hour, then incubated overnight with anti-HPK1 (Cell Signaling Technology, 4472S) antibody, anti-β-actin (Cell Signaling Technology, 3700S) or anti-GAPDH (Cell Signaling Technology, 97166S) as loading control with gentle shaking at 4°C. The membrane was washed three times with TBST and incubated with anti-mouse or anti-rabbit secondary fluorescent antibody (Thermo Fisher, A32729; LI-COR, 926-32213) at room temperature for at least 1 hour. The membrane was then washed three times with TBST and once with water. Immunoreactive bands were visualized by Odyssey CLx and analyzed by GraphPad Prism 8. The compounds disclosed herein were used in the Dmax , D.C. 50 and D.C. 90 The values ​​were shown.

[0255] [Table 4]

[0256] HPK1 proteolysis assay in human PBMCs (FACS)

[0257] Human PBMCs (AllCells) were used in this study. Cells were thawed 1 day before and maintained in RPMI-1640 supplemented with 10% fetal bovine serum (Thermo Fisher), 50 units / mL penicillin and streptomycin (Thermo Fisher), and the mixture was maintained at 37 °C in a humidified atmosphere containing 5% CO2. 3 × 10 cells were cultured per well in 95 μL culture medium. 6 PBMCs were seeded in 96-well plates and cells were treated with appropriate dilution series of compounds. After 24 hours of compound treatment, 100 μL of 1× Lyse / Fix buffer (BD, diluted in water, warmed at 37°C) was added to the cells and the cells were incubated at 37°C for 10 minutes. After fixation, cells were transferred to V-bottom plates (Corning) and washed with FACS buffer (cold 2% FBS DPBS). Cells were permeabilized by adding 100 μL of pre-chilled BD Phosflow Perm Buffer III (BD) for 30 minutes on ice. After washing twice with FACS buffer, cells were incubated with 50 μL of antibody cocktail (HPK1 (CST) (1:50), anti-human CD4 BV421 (BD) (1:25), anti-human CD8 APC (BD) (1:25)) for 1 hour at room temperature. After washing twice with FACS buffer, the cells were further incubated with 50 μL of secondary antibody cocktail (Biolegend) (1:50) at room temperature for 1 h. After washing twice with FACS buffer, the signals were detected by BD FACS Celesta. Data were analyzed by Excel and GraphPad Prism 8. Compounds disclosed herein were used in the DMS analysis as shown in Table 4. max , D.C. 50and D.C. 90 The values ​​were shown.

[0258] [Table 5]

[0259] The foregoing examples and descriptions of specific embodiments should be construed as illustrative rather than limiting the invention defined by the claims. As will be readily appreciated, numerous variations and combinations of the features described above can be utilized without departing from the invention as set forth in the claims. All such variations are intended to be included within the scope of the present invention. All references are incorporated herein by reference in their entirety.

[0260] It will be understood that if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms part of the common general knowledge in the art in any country.

[0261] The disclosures of all publications, patents, patent applications, and published patent applications mentioned herein by an identifying citation are hereby incorporated by reference in their entireties.

[0262] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain minor changes and modifications may be practiced. Therefore, the descriptions and examples should not be construed as limiting the scope of the invention.

Claims

1. A compound of formula (I), 【Chemical Formula 1】 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Z is N or CR ｚａ Selected from: R ｚａ is hydrogen, -C １－８ alkyl, cycloalkyl; R １ and R ２ are each independently hydrogen, —CD 3 , methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2-hydroxypropyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, or 4-hydroxybutyl; n1 is 0, 1, 2, 3 or 4; n2 is 0, 1, 2, or 3; Each 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 ; each R 4 is from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —OR 4a or —NR 4a R 4b , wherein said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl is optionally substituted with at least one substituent —OH, —F, —Cl, —Br, —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: R 5 and R 6 are each independently hydrogen or —C 1-8 alkyl; X 1 and X 2 each independently represent a single bond, —CH 2 —, —CH 2 CH 2 —, or —CH 2 CH 2 CH 2 —; part 【Chemistry 7】 teeth, 【Chemistry 8】 where *LN is the moiety 【Chemistry 9】 and **LN refers to the position where 【Chemistry 10】 refers to the position at which the 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;The —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 , each of -C 1-8 alkylene-, -C 2-8 alkenylene, or -C 2-8 alkynylene- is optionally substituted with at least one R L1c ; u1 and v1 are each independently selected from 1, 2, 3, 4, 5, 6, 7, or 8; 【Chemistry 11】 and **L1 refers to the position where 【Chemistry 12】 refers to the position at which the L 2 is 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;The —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 each of —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- is 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; In the formula, *L2 is the site 【Chemistry 13】 and **L2 refers to the position where 【Chemistry 14】 refers to the position at which the L 3 is 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 selected from L3a R L3b ) u3 - **L3, *L3 -(CR L3a R L3b) u3 -CO- **L3, *L3 -(CR L3a R L3b) u3 - **L3;The —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)C 1-8 alkylene-**L3 , *L3 each of —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- is 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; In the formula, *L3 is the site 【Chemistry 15】 and **L3 refers to the position where 【Chemistry 16】 refers to the position at which the R L1a , R L1b , R L1c , R L2a , R L2b , R L2c , R L3a , R L3b and 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, each of said —C 1-8 alkyl, —C 2-8 alkenyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with at least one substituent R L3d ; R L3d is selected from halogen, hydroxy, —C 1-8 alkyl, -haloC 1-8 alkyl, —C 1-8 alkynyl, —C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; The degron site is 【Chemistry 2】 is selected from: 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 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 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 , wherein 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 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; A compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein 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.

2. The degron site 【Chemistry 3】 wherein R ８ and n5 are as defined above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

3. The degron site 【Chemistry 4】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from:

4. The degron site 【Chemistry 5】 wherein R ８ and n5 are as defined above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

5. The degron site 【Chemistry 6】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from:

6. R ８ is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

7. 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 [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​、 ＊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 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:

8. L １ teeth, ＊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 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:

9. 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 , <00,00317>-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 , <000035x>-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 H ８ -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 ６ 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 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:

10. L ２ represents 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 2. The compound of claim 1, wherein:

11. 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 , ＊Ｌ３ -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 [[ID=CO]] ＊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 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:

12. L ３ is a single bond, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

13. part 【Chemistry 17】 teeth, 【Chemistry 18】 where: ＊ＬＮ is the part 【Chemistry 19】 and ＊＊ＬＮ is the part 【Chemistry 20】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:

14. part ​ teeth, 【Chemical 22】 where: ＊ＬＮ is the part 【Chemical 23】 and ＊＊ＬＮ is the part 【Chemistry 24】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:

15. part 【Chemical 27】 teeth, 【Chemical 28】 2. The compound of claim 1, wherein:

16. R ５ and R ６ is each independently hydrogen or methyl, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

17. X １ Ga-CH ２ If -, X ２ is -CH ２ CH ２ -or X １ Ga-CH ２ CH ２ If -, X ２ is -CH ２ - or X １ When is a single bond, X ２ is -CH ２ CH ２ CH ２ - or X １ Ga-CH ２ CH ２ CH ２ If -, X ２ is a single bond, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

18. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound is selected from the following: 【Chemical Formula 29】

19. 19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.

20. 20. A composition for reducing HPK1 activity by inhibition and / or proteolysis, comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

21. A composition for treating a disease or disorder in a patient, comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as an HPK1 degradation inducer.

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