NZ779757A - Pcna inhibitors - Google Patents
Pcna inhibitorsInfo
- Publication number
- NZ779757A NZ779757A NZ779757A NZ77975716A NZ779757A NZ 779757 A NZ779757 A NZ 779757A NZ 779757 A NZ779757 A NZ 779757A NZ 77975716 A NZ77975716 A NZ 77975716A NZ 779757 A NZ779757 A NZ 779757A
- Authority
- NZ
- New Zealand
- Prior art keywords
- unsubstituted
- cancer
- substituted
- nhc
- nhnh2
- Prior art date
Links
- 101150008755 PCNA gene Proteins 0.000 title 1
- 239000003112 inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 22
- 206010028980 Neoplasm Diseases 0.000 claims abstract 17
- 201000011510 cancer Diseases 0.000 claims abstract 17
- 108050006400 Cyclin Proteins 0.000 claims abstract 5
- 102000009339 Proliferating Cell Nuclear Antigen Human genes 0.000 claims abstract 5
- 230000000694 effects Effects 0.000 claims abstract 4
- 201000010099 disease Diseases 0.000 claims abstract 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract 2
- 229910052736 halogen Inorganic materials 0.000 claims 15
- 150000002367 halogens Chemical class 0.000 claims 15
- 125000004404 heteroalkyl group Chemical group 0.000 claims 13
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 12
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 11
- 229910006074 SO2NH2 Inorganic materials 0.000 claims 11
- 229910006069 SO3H Inorganic materials 0.000 claims 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 11
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims 11
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 10
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 10
- -1 -CONH2 Chemical group 0.000 claims 8
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims 8
- 229910052739 hydrogen Inorganic materials 0.000 claims 8
- 239000001257 hydrogen Substances 0.000 claims 8
- 239000008194 pharmaceutical composition Substances 0.000 claims 7
- 201000009030 Carcinoma Diseases 0.000 claims 6
- 239000002246 antineoplastic agent Substances 0.000 claims 6
- 150000002431 hydrogen Chemical class 0.000 claims 6
- 208000032839 leukemia Diseases 0.000 claims 6
- 150000003839 salts Chemical class 0.000 claims 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 6
- 208000017604 Hodgkin disease Diseases 0.000 claims 5
- 208000021519 Hodgkin lymphoma Diseases 0.000 claims 5
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims 5
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims 5
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims 5
- 208000009956 adenocarcinoma Diseases 0.000 claims 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims 4
- 206010009944 Colon cancer Diseases 0.000 claims 4
- 206010025323 Lymphomas Diseases 0.000 claims 4
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 4
- 206010017758 gastric cancer Diseases 0.000 claims 4
- 201000001441 melanoma Diseases 0.000 claims 4
- 201000011549 stomach cancer Diseases 0.000 claims 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 3
- 239000003814 drug Substances 0.000 claims 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 3
- 201000011649 lymphoblastic lymphoma Diseases 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 2
- 206010000830 Acute leukaemia Diseases 0.000 claims 2
- 206010003571 Astrocytoma Diseases 0.000 claims 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims 2
- 206010004146 Basal cell carcinoma Diseases 0.000 claims 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims 2
- 206010006187 Breast cancer Diseases 0.000 claims 2
- 208000026310 Breast neoplasm Diseases 0.000 claims 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 2
- 206010014733 Endometrial cancer Diseases 0.000 claims 2
- 206010014759 Endometrial neoplasm Diseases 0.000 claims 2
- 206010014958 Eosinophilic leukaemia Diseases 0.000 claims 2
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 claims 2
- 206010024218 Lentigo maligna Diseases 0.000 claims 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims 2
- 206010027406 Mesothelioma Diseases 0.000 claims 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims 2
- 206010029260 Neuroblastoma Diseases 0.000 claims 2
- 206010033128 Ovarian cancer Diseases 0.000 claims 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 2
- 206010039491 Sarcoma Diseases 0.000 claims 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims 2
- 206010042553 Superficial spreading melanoma stage unspecified Diseases 0.000 claims 2
- 208000024313 Testicular Neoplasms Diseases 0.000 claims 2
- 206010057644 Testis cancer Diseases 0.000 claims 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims 2
- 230000001919 adrenal effect Effects 0.000 claims 2
- 201000005188 adrenal gland cancer Diseases 0.000 claims 2
- 208000024447 adrenal gland neoplasm Diseases 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 201000007455 central nervous system cancer Diseases 0.000 claims 2
- 208000006990 cholangiocarcinoma Diseases 0.000 claims 2
- 208000021668 chronic eosinophilic leukemia Diseases 0.000 claims 2
- 208000024207 chronic leukemia Diseases 0.000 claims 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims 2
- 208000029742 colonic neoplasm Diseases 0.000 claims 2
- 230000001054 cortical effect Effects 0.000 claims 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims 2
- 230000000762 glandular Effects 0.000 claims 2
- 208000005017 glioblastoma Diseases 0.000 claims 2
- 125000001072 heteroaryl group Chemical group 0.000 claims 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 201000007270 liver cancer Diseases 0.000 claims 2
- 208000014018 liver neoplasm Diseases 0.000 claims 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 2
- 201000000050 myeloid neoplasm Diseases 0.000 claims 2
- 201000002528 pancreatic cancer Diseases 0.000 claims 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical group [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims 2
- 230000005855 radiation Effects 0.000 claims 2
- 201000000849 skin cancer Diseases 0.000 claims 2
- 206010041823 squamous cell carcinoma Diseases 0.000 claims 2
- 208000030457 superficial spreading melanoma Diseases 0.000 claims 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- 201000003120 testicular cancer Diseases 0.000 claims 2
- 201000002510 thyroid cancer Diseases 0.000 claims 2
- 206010044412 transitional cell carcinoma Diseases 0.000 claims 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims 1
- 208000011691 Burkitt lymphomas Diseases 0.000 claims 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims 1
- 206010008342 Cervix carcinoma Diseases 0.000 claims 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims 1
- 208000029966 Hutchinson Melanotic Freckle Diseases 0.000 claims 1
- 208000008839 Kidney Neoplasms Diseases 0.000 claims 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 208000009018 Medullary thyroid cancer Diseases 0.000 claims 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims 1
- 206010033701 Papillary thyroid cancer Diseases 0.000 claims 1
- 206010060862 Prostate cancer Diseases 0.000 claims 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 1
- 206010038389 Renal cancer Diseases 0.000 claims 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims 1
- 206010000583 acral lentiginous melanoma Diseases 0.000 claims 1
- 230000001154 acute effect Effects 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 229940127093 camptothecin Drugs 0.000 claims 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims 1
- 230000001413 cellular effect Effects 0.000 claims 1
- 201000010881 cervical cancer Diseases 0.000 claims 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims 1
- 229960004316 cisplatin Drugs 0.000 claims 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 claims 1
- 229940121647 egfr inhibitor Drugs 0.000 claims 1
- 201000004101 esophageal cancer Diseases 0.000 claims 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims 1
- 229960005277 gemcitabine Drugs 0.000 claims 1
- 201000010536 head and neck cancer Diseases 0.000 claims 1
- 208000014829 head and neck neoplasm Diseases 0.000 claims 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- RGXCTRIQQODGIZ-UHFFFAOYSA-O isodesmosine Chemical group OC(=O)C(N)CCCC[N+]1=CC(CCC(N)C(O)=O)=CC(CCC(N)C(O)=O)=C1CCCC(N)C(O)=O RGXCTRIQQODGIZ-UHFFFAOYSA-O 0.000 claims 1
- 201000010982 kidney cancer Diseases 0.000 claims 1
- 208000011080 lentigo maligna melanoma Diseases 0.000 claims 1
- 210000004072 lung Anatomy 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- 208000020816 lung neoplasm Diseases 0.000 claims 1
- 208000003747 lymphoid leukemia Diseases 0.000 claims 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 claims 1
- 201000010879 mucinous adenocarcinoma Diseases 0.000 claims 1
- 201000008968 osteosarcoma Diseases 0.000 claims 1
- 201000010198 papillary carcinoma Diseases 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229910052697 platinum Inorganic materials 0.000 claims 1
- 210000001685 thyroid gland Anatomy 0.000 claims 1
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 claims 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 claims 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Described herein, inter alia, are compounds of Formula (VII) or (X) as PCNA modulators and methods for treating or preventing cancer or diseases associated with PCNA activity.
Claims (31)
1. A compound having the formula: R2 O R1.1 N W2 N W3 O R3 R1.2 O R1.3 (R5)z3 R4.1 W1 R4.3 (VII) or R4.1 R2 O R1.1 N W2 W1 N W3 O R3 R4.3 O (R5)z3 5 wherein, W1 is N or ); W2 is N or C(R5.1); W3 is N or C(R5.2); R4.1, R4.2, and R4.3 are ndently a hydrogen, halogen, -CX43, -CHX42, 10 -CH2X4, -OCH2X4, -CN, -OH, -NH2, -COOH, , -NO2, -SH, -SO3H, -SO4H, -SO2NH2, , -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX43, 2, R39-substituted or unsubstituted C1-C8 alkyl, R39- tuted or unsubstituted 2 to 10 membered heteroalkyl, R39-substituted or unsubstituted C3-C8 cycloalkyl, R39-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R39- 15 substituted or unsubstituted C6-C10 aryl, or R39-substituted or unsubstituted 5 to 10 membered heteroaryl; R39 is independently oxo, halogen, -CX393, -CHX392, -CH2X39, -OCH2X39, -OCHX392, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, 20 -NHC(O)-OH, -NHOH, -OCX393, -OCHX392, bstituted or unsubstituted C1-C8 alkyl, R40-substituted or unsubstituted 2 to 10 membered heteroalkyl, R40-substituted or unsubstituted C3-C8 cycloalkyl, R40-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R40-substituted or unsubstituted C6-C10 aryl, or R40-substituted or unsubstituted 5 to 10 membered heteroaryl; R40 is independently oxo, halogen, -CX403, -CHX402, -CH2X40, -OCH2X40, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, 5 -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX403, -OCHX402, R41-substituted or unsubstituted C1-C8 alkyl, R41-substituted or unsubstituted 2 to 10 membered heteroalkyl, R41-substituted or unsubstituted C3-C8 cycloalkyl, R41-substituted or tituted 3 to 8 membered heterocycloalkyl, R41- substituted or unsubstituted C6-C10 aryl, or R41-substituted or unsubstituted 5 to 10 membered 10 heteroaryl; R5.1 and R5.2 are independently a hydrogen, halogen, -CX53, -CHX52, -CH2X5, -OCH2X5, -CN, -OH, -NH2, -COOH, , -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, O)NHNH2, -NHC=(O)NH2, -NHSO2H, O)H, )-OH, -NHOH, -OCX53, -OCHX52, R42-substituted or unsubstituted C1-C8 alkyl, R42- 15 substituted or tituted 2 to 10 membered alkyl, bstituted or tituted C3-C8 cycloalkyl, R42-substituted or unsubstituted 3 to 8 membered cycloalkyl, R42- substituted or unsubstituted C6-C10 aryl, or R42-substituted or unsubstituted 5 to 10 membered heteroaryl; R5 is independently halogen, -CX53, -CHX52, -CH2X5, -OCH2X5, -CN, -OH, 20 -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX53, -OCHX52, R42-substituted or unsubstituted C1-C8 alkyl, R42-substituted or unsubstituted 2 to 10 membered heteroalkyl, R42-substituted or unsubstituted C3-C8 cycloalkyl, R42-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R42- 25 substituted or unsubstituted C6-C10 aryl, or R42-substituted or unsubstituted 5 to 10 membered heteroaryl; R42 is independently oxo, halogen, -CX423, -CHX422, -CH2X42, -OCH2X42, 22, -CN, -OH, -NH2, -COOH, , -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, 30 -NHC(O)-OH, -NHOH, -OCX423, -OCHX422, R43-substituted or unsubstituted C1-C8 alkyl, R43-substituted or unsubstituted 2 to 10 membered heteroalkyl, R43-substituted or unsubstituted C3-C8 lkyl, R43-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R43-substituted or unsubstituted C6-C10 aryl, or R43-substituted or unsubstituted 5 to 10 membered heteroaryl; R43 is independently oxo, halogen, -CX433, -CHX432, -CH2X43, 43, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, 5 -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, O)H, -NHC(O)-OH, -NHOH, -OCX433, -OCHX432, R44-substituted or unsubstituted C1-C8 alkyl, R44-substituted or unsubstituted 2 to 10 membered heteroalkyl, R44-substituted or unsubstituted C3-C8 cycloalkyl, R44-substituted or unsubstituted 3 to 8 ed heterocycloalkyl, R44- substituted or unsubstituted C6-C10 aryl, or R44-substituted or tituted 5 to 10 ed 10 heteroaryl; R1.1, R1.2, and R1.3 are independently a hydrogen, halogen, -CX13, -CHX12, -CH2X1, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX13, -OCHX12, -OCH2X1, R30-substituted or unsubstituted C1-C8 15 alkyl, R30-substituted or unsubstituted 2 to 10 ed heteroalkyl, R30-substituted or unsubstituted C3-C8 cycloalkyl, bstituted or unsubstituted 3 to 8 membered cycloalkyl, R30-substituted or unsubstituted C6-C10 aryl, or R30-substituted or unsubstituted 5 to 10 membered aryl; R30 is independently oxo, halogen, -CX303, -CHX302, -CH2X30, -OCH2X30, 20 -OCHX302, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX303, bstituted or unsubstituted C1-C8 alkyl, R31- substituted or unsubstituted 2 to 10 membered heteroalkyl, R31-substituted or unsubstituted C3-C8 cycloalkyl, R31-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R31- 25 tuted or tituted C6-C10 aryl, or R31-substituted or unsubstituted 5 to 10 membered heteroaryl; R31 is independently oxo, halogen, -CX313, -CHX312, -CH2X31, -OCH2X31, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, 30 -NHOH, -OCX313, -OCHX312, R32-substituted or unsubstituted C1-C8 alkyl, R32-substituted or unsubstituted 2 to 10 membered heteroalkyl, R32-substituted or unsubstituted C3-C8 cycloalkyl, R32-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R32- tuted or unsubstituted C6-C10 aryl, or R32-substituted or unsubstituted 5 to 10 membered heteroaryl; R32, R41 and R44 are independently oxo, halogen, -CF3, -CHF2, -CH2F, -OCH2F, -OCF3, -OCHF2, -CCl3, -CHCl2, -CH2Cl, -OCH2Cl, -OCCl3, 2, -CBr3, 5 , -CH2Br, -OCH2Br, -OCBr3, -OCHBr2, -CI3, -CHI2, -CH2I, -OCH2I, -OCI3, -OCHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted C1-C8 alkyl, unsubstituted 2 to 10 membered heteroalkyl, unsubstituted C3-C8 cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl, 10 unsubstituted C6-C10 aryl, or unsubstituted 5 to 10 membered heteroaryl; R2 is hydrogen, unsubstituted methyl, unsubstituted ethyl, tituted isopropyl, or unsubstituted tert-butyl; R3 is en, unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, or unsubstituted tert-butyl; 15 z3 is an integer from 0 to 5; and X1, X4, X5, X30, X31, X39, X40, X42, and X43 are independently –Cl, -Br, -I, or -F.
2. The compound of claim 1, wherein R1.1, R1.2, and R1.3 are ndently halogen, -CF3, -OH, -NH2, -SH, unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 20 membered heteroalkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or tituted 5 to 6 membered heteroaryl.
3. The compound of claim 1, wherein R1.1, R1.2, and R1.3 are independently n, -OH, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, -OCH2F, unsubstituted , or unsubstituted methoxy. 25 4. The compound of any one of claims 1 to 3, wherein R4.1, R4.2, and R4.3 are independently unsubstituted 2 to 4 membered heteroalkyl, halogen, -CF3, -OH, -NH2,
4.-SH, unsubstituted C1-C4 alkyl, unsubstituted C3-C6 lkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl.
5. The compound of any one of claims 1 to 3, wherein R4.1, R4.2, and R4.3 are independently unsubstituted methoxy, halogen, -CF3, –CHF2, –CH2F, -OCF3, -OCHF2, , -OH, or unsubstituted methyl.
6. The nd of any one of claims 1 to 3, wherein R4.1, R4.2, and R4.3 5 are independently tituted methoxy or -OH.
7. The compound of any one of claims 1 to 6, n R5 is independently halogen, -CF3, -OH, -NH2, -SH, unsubstituted C1-C4 alkyl, tituted 2 to 4 membered heteroalkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. 10
8. The compound of any one of claims 1 to 7, wherein R2 is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.
9. The compound of any one of claims 1 to 7, wherein R2 is hydrogen.
10. The compound of any one of claims 1 to 9, wherein R3 is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted pyl. 15
11. The compound of any one of claims 1 to 9, wherein R3 is hydrogen.
12. A pharmaceutical composition comprising a compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
13. The pharmaceutical composition of claim 12, further comprising an 20 anti-cancer agent.
14. The pharmaceutical composition of claim 13, wherein the anti-cancer agent is a platinum-based compound.
15. The pharmaceutical composition of claim 13, wherein the anti-cancer agent is a cisplatin. 25
16. The pharmaceutical composition of claim 13, wherein the anti-cancer agent is a topoisomerase inhibitor.
17. The pharmaceutical composition of claim 13, wherein the anti-cancer agent is ide, camptothecin, or gemcitabine.
18. The pharmaceutical composition of claim 13, wherein the anti-cancer agent is an EGFR inhibitor. 5
19. Use of a compound of any one of claims 1 to 11, or a ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with PCNA activity.
20. Use of a compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. 10
21. The use of claim 20, wherein said cancer is a sarcoma, adenocarcinoma, leukemia, or lymphoma.
22. The use of claim 20, wherein said cancer is a lung cancer, colon cancer, a central nervous system cancer, brain cancer, neuroblastoma, skin cancer, head and neck , melanoma, ovarian cancer, renal cancer, te cancer, breast cancer, 15 mesothelioma, liver cancer, stomach cancer, esophageal , r cancer, al cancer, osteosarcoma, pancreatic cancer, adrenal cortical cancer, adrenal gland cancer, colorectal cancer, testicular cancer, myeloma, B-acute blastic lymphoma, non-
23.Hodgkin’s lymphoma, n’s lymphoma, chronic leukemia, acute leukemia, glandular carcinoma, hematoid carcinoma, or thyroid . 20 23. The use of claim 20, wherein said cancer is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myelomonocytic leukemia, eosinophilic leukemia, lymphoblastic leukemia, acute myeloid leukemia, squamous cell carcinoma, adenocarcinoma, glioblastoma, astrocytoma, superficial spreading melanoma, r melanoma, lentigo maligna melanoma, acral- 25 lentiginous melanoma, endometrial cancer, mucinous carcinoma, papillary carcinoma, papillary thyroid cancer, ary d , basal cell carcinoma, hepatocellular carcinoma, cholangiocellular carcinoma, gastric cancer, transitional cell carcinoma, B-acute lymphoblastic lymphoma, non-Hodgkin’s lymphoma, Burkitt’s ma, or Hodgkin’s lymphoma.
24. The use of claim 20, wherein the treatment of cancer further comprises radiation.
25. A compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use in the treatment of a e associated with PCNA activity. 5
26. A compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt f, for use in the treatment of cancer.
27. The compound for use of claim 26, wherein said cancer is a sarcoma, adenocarcinoma, leukemia, or lymphoma.
28. The compound for use of claim 26, wherein said cancer is a lung 10 cancer, colon cancer, a central nervous system cancer, brain cancer, neuroblastoma, skin cancer, head and neck cancer, melanoma, ovarian cancer, renal , prostate cancer, breast cancer, mesothelioma, liver cancer, stomach cancer, esophageal cancer, bladder , cervical cancer, arcoma, pancreatic cancer, adrenal cortical cancer, adrenal gland cancer, colorectal cancer, testicular cancer, myeloma, B-acute lymphoblastic lymphoma, non- 15 Hodgkin’s lymphoma, Hodgkin’s lymphoma, chronic leukemia, acute leukemia, glandular carcinoma, hematoid carcinoma, or thyroid cancer.
29. The compound for use of claim 26, n said cancer is acute myelogenous leukemia, chronic myelogenous leukemia, acute cytic leukemia, chronic lymphocytic leukemia, myelomonocytic leukemia, eosinophilic leukemia, lymphoblastic 20 leukemia, acute myeloid leukemia, squamous cell carcinoma, adenocarcinoma, glioblastoma, astrocytoma, superficial spreading melanoma, nodular ma, lentigo maligna ma, acral-lentiginous melanoma, endometrial cancer, us carcinoma, papillary oma, ary thyroid cancer, medullary thyroid cancer, basal cell carcinoma, cellular carcinoma, cholangiocellular carcinoma, gastric cancer, transitional cell carcinoma, B-acute 25 lymphoblastic lymphoma, non-Hodgkin’s lymphoma, Burkitt’s lymphoma, or Hodgkin’s lymphoma.
30. The compound for use of claim 26, wherein the ent of cancer further ses radiation.
31. Use of a compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt f, in the manufacture of a medicament for inhibiting PCNA activity. O cmN 0 Moiecuiar : 396.44 30900 g S .. a: (9 :3“ 20009 a... 0 E g g 3 .3 § 10000 £15 E .3 .2 .1 o 1 2 LDQWM 0f ADHWSG) Logucnmpound] in pM) W0 49206
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562220014P | 2015-09-17 | 2015-09-17 | |
| US201662313592P | 2016-03-25 | 2016-03-25 | |
| US201662340964P | 2016-05-24 | 2016-05-24 | |
| NZ740817A NZ740817B2 (en) | 2016-09-16 | Pcna inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ779757A true NZ779757A (en) | 2024-03-22 |
| NZ779757B2 NZ779757B2 (en) | 2024-06-25 |
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| NZ779760A (en) | 2024-03-22 |
| NZ779756A (en) | 2024-03-22 |
| NZ779762A (en) | 2024-03-22 |
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