WO2024086804A1 - Indolizine derivatives for treating cancer - Google Patents
Indolizine derivatives for treating cancer Download PDFInfo
- Publication number
- WO2024086804A1 WO2024086804A1 PCT/US2023/077433 US2023077433W WO2024086804A1 WO 2024086804 A1 WO2024086804 A1 WO 2024086804A1 US 2023077433 W US2023077433 W US 2023077433W WO 2024086804 A1 WO2024086804 A1 WO 2024086804A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- optionally substituted
- carcinoma
- adenocarcinoma
- squamous cell
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 209
- 201000011510 cancer Diseases 0.000 title claims abstract description 156
- 125000003406 indolizinyl group Chemical class C=1(C=CN2C=CC=CC12)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 277
- 150000003839 salts Chemical class 0.000 claims abstract description 112
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 claims description 173
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 claims description 168
- 125000000623 heterocyclic group Chemical group 0.000 claims description 166
- 229910052739 hydrogen Inorganic materials 0.000 claims description 152
- 239000001257 hydrogen Substances 0.000 claims description 152
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 117
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 108
- 150000002431 hydrogen Chemical group 0.000 claims description 99
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 97
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 75
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 75
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 72
- 238000000034 method Methods 0.000 claims description 67
- -1 cyano, hydroxyl Chemical group 0.000 claims description 65
- 230000035772 mutation Effects 0.000 claims description 63
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 52
- 229910052757 nitrogen Inorganic materials 0.000 claims description 46
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 41
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 38
- 229910052736 halogen Inorganic materials 0.000 claims description 35
- 150000002367 halogens Chemical group 0.000 claims description 35
- 125000001072 heteroaryl group Chemical group 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 12
- 125000005549 heteroarylene group Chemical group 0.000 claims description 9
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 8
- 125000004450 alkenylene group Chemical group 0.000 claims description 8
- 125000004419 alkynylene group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 6
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 18
- 201000010099 disease Diseases 0.000 abstract description 16
- 208000024891 symptom Diseases 0.000 abstract description 8
- 230000003247 decreasing effect Effects 0.000 abstract description 3
- 230000007170 pathology Effects 0.000 abstract description 3
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 156
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 156
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 151
- 201000005243 lung squamous cell carcinoma Diseases 0.000 description 146
- 206010033128 Ovarian cancer Diseases 0.000 description 143
- 206010061535 Ovarian neoplasm Diseases 0.000 description 143
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 142
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 129
- 201000005249 lung adenocarcinoma Diseases 0.000 description 129
- 208000037162 Ductal Breast Carcinoma Diseases 0.000 description 122
- 206010005084 bladder transitional cell carcinoma Diseases 0.000 description 102
- 201000001528 bladder urothelial carcinoma Diseases 0.000 description 102
- 201000010897 colon adenocarcinoma Diseases 0.000 description 88
- 208000029742 colonic neoplasm Diseases 0.000 description 88
- 201000003914 endometrial carcinoma Diseases 0.000 description 85
- 208000018463 endometrial serous adenocarcinoma Diseases 0.000 description 78
- 206010003571 Astrocytoma Diseases 0.000 description 76
- 208000005017 glioblastoma Diseases 0.000 description 73
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 71
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 description 69
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 69
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 69
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 69
- 206010061534 Oesophageal squamous cell carcinoma Diseases 0.000 description 64
- 208000036765 Squamous cell carcinoma of the esophagus Diseases 0.000 description 64
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 description 64
- 208000005431 Endometrioid Carcinoma Diseases 0.000 description 63
- 208000028730 endometrioid adenocarcinoma Diseases 0.000 description 63
- 206010073131 oligoastrocytoma Diseases 0.000 description 63
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 60
- 125000003342 alkenyl group Chemical group 0.000 description 59
- 125000000304 alkynyl group Chemical group 0.000 description 59
- 235000001014 amino acid Nutrition 0.000 description 52
- 150000001413 amino acids Chemical class 0.000 description 52
- 206010038019 Rectal adenocarcinoma Diseases 0.000 description 50
- 201000001281 rectum adenocarcinoma Diseases 0.000 description 50
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 47
- 208000030381 cutaneous melanoma Diseases 0.000 description 46
- 230000003211 malignant effect Effects 0.000 description 46
- 201000003708 skin melanoma Diseases 0.000 description 46
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 45
- 208000036764 Adenocarcinoma of the esophagus Diseases 0.000 description 43
- 206010030137 Oesophageal adenocarcinoma Diseases 0.000 description 43
- 208000028653 esophageal adenocarcinoma Diseases 0.000 description 43
- 201000005825 prostate adenocarcinoma Diseases 0.000 description 42
- 208000018142 Leiomyosarcoma Diseases 0.000 description 41
- 125000000217 alkyl group Chemical group 0.000 description 39
- 125000004433 nitrogen atom Chemical group N* 0.000 description 39
- 208000011892 carcinosarcoma of the corpus uteri Diseases 0.000 description 37
- 230000000968 intestinal effect Effects 0.000 description 37
- 201000005290 uterine carcinosarcoma Diseases 0.000 description 37
- 201000010133 Oligodendroglioma Diseases 0.000 description 32
- 208000006265 Renal cell carcinoma Diseases 0.000 description 32
- 125000003118 aryl group Chemical group 0.000 description 30
- 230000000694 effects Effects 0.000 description 27
- 101150080074 TP53 gene Proteins 0.000 description 26
- 210000000481 breast Anatomy 0.000 description 26
- 201000010240 chromophobe renal cell carcinoma Diseases 0.000 description 26
- 108700025694 p53 Genes Proteins 0.000 description 26
- 125000003545 alkoxy group Chemical group 0.000 description 25
- 206010014733 Endometrial cancer Diseases 0.000 description 24
- 206010014759 Endometrial neoplasm Diseases 0.000 description 24
- 230000008482 dysregulation Effects 0.000 description 24
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 22
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 21
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 21
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 21
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 20
- 125000000392 cycloalkenyl group Chemical group 0.000 description 19
- 208000024312 invasive carcinoma Diseases 0.000 description 19
- 206010039491 Sarcoma Diseases 0.000 description 18
- 208000034254 Squamous cell carcinoma of the cervix uteri Diseases 0.000 description 18
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 18
- 208000007128 adrenocortical carcinoma Diseases 0.000 description 18
- 201000006612 cervical squamous cell carcinoma Diseases 0.000 description 18
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 18
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 18
- 208000004548 serous cystadenocarcinoma Diseases 0.000 description 18
- 201000000270 spindle cell sarcoma Diseases 0.000 description 18
- 125000004103 aminoalkyl group Chemical group 0.000 description 17
- 125000001424 substituent group Chemical group 0.000 description 17
- 201000011047 colon mucinous adenocarcinoma Diseases 0.000 description 16
- 230000006870 function Effects 0.000 description 16
- 210000000664 rectum Anatomy 0.000 description 16
- 201000006580 rectum mucinous adenocarcinoma Diseases 0.000 description 16
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 15
- 206010053717 Fibrous histiocytoma Diseases 0.000 description 15
- 201000000284 histiocytoma Diseases 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 14
- 125000001188 haloalkyl group Chemical group 0.000 description 14
- 238000011282 treatment Methods 0.000 description 14
- 206010035603 Pleural mesothelioma Diseases 0.000 description 13
- 208000016080 mucinous gastric adenocarcinoma Diseases 0.000 description 12
- 201000006584 mucinous stomach adenocarcinoma Diseases 0.000 description 12
- 238000003556 assay Methods 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 208000030808 Clear cell renal carcinoma Diseases 0.000 description 10
- 206010073251 clear cell renal cell carcinoma Diseases 0.000 description 10
- 238000012217 deletion Methods 0.000 description 10
- 230000037430 deletion Effects 0.000 description 10
- 238000003780 insertion Methods 0.000 description 10
- 230000037431 insertion Effects 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 206010006187 Breast cancer Diseases 0.000 description 9
- 208000026310 Breast neoplasm Diseases 0.000 description 9
- 125000004122 cyclic group Chemical group 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 125000006413 ring segment Chemical group 0.000 description 9
- 238000006467 substitution reaction Methods 0.000 description 9
- 229940124597 therapeutic agent Drugs 0.000 description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 9
- 201000011062 Li-Fraumeni syndrome Diseases 0.000 description 8
- 208000003252 Signet Ring Cell Carcinoma Diseases 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- HAYYBYPASCDWEQ-UHFFFAOYSA-N n-[5-[(3,5-difluorophenyl)methyl]-1h-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)benzamide Chemical compound C1CN(C)CCN1C(C=C1NC2CCOCC2)=CC=C1C(=O)NC(C1=C2)=NNC1=CC=C2CC1=CC(F)=CC(F)=C1 HAYYBYPASCDWEQ-UHFFFAOYSA-N 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 201000008123 signet ring cell adenocarcinoma Diseases 0.000 description 8
- 210000002784 stomach Anatomy 0.000 description 8
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 8
- 206010066948 Myxofibrosarcoma Diseases 0.000 description 7
- 230000002489 hematologic effect Effects 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 7
- 206010073096 invasive lobular breast carcinoma Diseases 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 125000004076 pyridyl group Chemical group 0.000 description 7
- 150000003254 radicals Chemical class 0.000 description 7
- AILRADAXUVEEIR-UHFFFAOYSA-N 5-chloro-4-n-(2-dimethylphosphorylphenyl)-2-n-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine Chemical compound COC1=CC(N2CCC(CC2)N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1P(C)(C)=O AILRADAXUVEEIR-UHFFFAOYSA-N 0.000 description 6
- 201000000274 Carcinosarcoma Diseases 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- 229950004272 brigatinib Drugs 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- LVXJQMNHJWSHET-AATRIKPKSA-N dacomitinib Chemical compound C=12C=C(NC(=O)\C=C\CN3CCCCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 LVXJQMNHJWSHET-AATRIKPKSA-N 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 201000005202 lung cancer Diseases 0.000 description 6
- 208000020816 lung neoplasm Diseases 0.000 description 6
- 229950008835 neratinib Drugs 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- XYDNMOZJKOGZLS-NSHDSACASA-N 3-[(1s)-1-imidazo[1,2-a]pyridin-6-ylethyl]-5-(1-methylpyrazol-4-yl)triazolo[4,5-b]pyrazine Chemical compound N1=C2N([C@H](C3=CN4C=CN=C4C=C3)C)N=NC2=NC=C1C=1C=NN(C)C=1 XYDNMOZJKOGZLS-NSHDSACASA-N 0.000 description 5
- 206010009944 Colon cancer Diseases 0.000 description 5
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 5
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 5
- CXQHYVUVSFXTMY-UHFFFAOYSA-N N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 CXQHYVUVSFXTMY-UHFFFAOYSA-N 0.000 description 5
- 125000005631 S-sulfonamido group Chemical group 0.000 description 5
- 206010041067 Small cell lung cancer Diseases 0.000 description 5
- 208000009956 adenocarcinoma Diseases 0.000 description 5
- KDGFLJKFZUIJMX-UHFFFAOYSA-N alectinib Chemical compound CCC1=CC=2C(=O)C(C3=CC=C(C=C3N3)C#N)=C3C(C)(C)C=2C=C1N(CC1)CCC1N1CCOCC1 KDGFLJKFZUIJMX-UHFFFAOYSA-N 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 5
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 5
- 201000010879 mucinous adenocarcinoma Diseases 0.000 description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 5
- 201000010279 papillary renal cell carcinoma Diseases 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 description 5
- 238000001959 radiotherapy Methods 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 208000000587 small cell lung carcinoma Diseases 0.000 description 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 5
- LPFWVDIFUFFKJU-UHFFFAOYSA-N 1-[4-[4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]prop-2-en-1-one Chemical compound C=12C=C(OC3CCN(CC3)C(=O)C=C)C(OC)=CC2=NC=NC=1NC1=CC=C(Cl)C(Cl)=C1F LPFWVDIFUFFKJU-UHFFFAOYSA-N 0.000 description 4
- LIOLIMKSCNQPLV-UHFFFAOYSA-N 2-fluoro-n-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide Chemical group C1=C(F)C(C(=O)NC)=CC=C1C1=NN2C(CC=3C=C4C=CC=NC4=CC=3)=CN=C2N=C1 LIOLIMKSCNQPLV-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- QADPYRIHXKWUSV-UHFFFAOYSA-N BGJ-398 Chemical compound C1CN(CC)CCN1C(C=C1)=CC=C1NC1=CC(N(C)C(=O)NC=2C(=C(OC)C=C(OC)C=2Cl)Cl)=NC=N1 QADPYRIHXKWUSV-UHFFFAOYSA-N 0.000 description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 4
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 230000002051 biphasic effect Effects 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 208000006990 cholangiocarcinoma Diseases 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- 229940043355 kinase inhibitor Drugs 0.000 description 4
- IIXWYSCJSQVBQM-LLVKDONJSA-N lorlatinib Chemical compound N=1N(C)C(C#N)=C2C=1CN(C)C(=O)C1=CC=C(F)C=C1[C@@H](C)OC1=CC2=CN=C1N IIXWYSCJSQVBQM-LLVKDONJSA-N 0.000 description 4
- IKQFRXPMBGQJGE-UHFFFAOYSA-N n-(1,3-benzodioxol-5-ylmethyl)-4-([1]benzofuro[3,2-d]pyrimidin-4-yl)piperazine-1-carbothioamide;hydrochloride Chemical compound Cl.C12=CC=CC=C2OC2=C1N=CN=C2N(CC1)CCN1C(=S)NCC1=CC=C(OCO2)C2=C1 IKQFRXPMBGQJGE-UHFFFAOYSA-N 0.000 description 4
- JWNPDZNEKVCWMY-VQHVLOKHSA-N neratinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 JWNPDZNEKVCWMY-VQHVLOKHSA-N 0.000 description 4
- 229960003278 osimertinib Drugs 0.000 description 4
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical group COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 4
- 125000004043 oxo group Chemical group O=* 0.000 description 4
- 201000005163 papillary serous adenocarcinoma Diseases 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- 229950009876 poziotinib Drugs 0.000 description 4
- 102200106572 rs121912666 Human genes 0.000 description 4
- 102200106583 rs121912666 Human genes 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 125000005555 sulfoximide group Chemical group 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 description 4
- 208000008732 thymoma Diseases 0.000 description 4
- 229960001612 trastuzumab emtansine Drugs 0.000 description 4
- KEIPNCCJPRMIAX-HNNXBMFYSA-N 1-[(3s)-3-[4-amino-3-[2-(3,5-dimethoxyphenyl)ethynyl]pyrazolo[3,4-d]pyrimidin-1-yl]pyrrolidin-1-yl]prop-2-en-1-one Chemical compound COC1=CC(OC)=CC(C#CC=2C3=C(N)N=CN=C3N([C@@H]3CN(CC3)C(=O)C=C)N=2)=C1 KEIPNCCJPRMIAX-HNNXBMFYSA-N 0.000 description 3
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical group C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 3
- 101150111660 53 gene Proteins 0.000 description 3
- RHXHGRAEPCAFML-UHFFFAOYSA-N 7-cyclopentyl-n,n-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=C2N(C3CCCC3)C(C(=O)N(C)C)=CC2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 RHXHGRAEPCAFML-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ULXXDDBFHOBEHA-ONEGZZNKSA-N Afatinib Chemical compound N1=CN=C2C=C(OC3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-ONEGZZNKSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010005003 Bladder cancer Diseases 0.000 description 3
- GBLBJPZSROAGMF-RWYJCYHVSA-N CO[C@@]1(CC[C@@H](CC1)C1=NC(NC2=NNC(C)=C2)=CC(C)=N1)C(=O)N[C@@H](C)C1=CC=C(N=C1)N1C=C(F)C=N1 Chemical compound CO[C@@]1(CC[C@@H](CC1)C1=NC(NC2=NNC(C)=C2)=CC(C)=N1)C(=O)N[C@@H](C)C1=CC=C(N=C1)N1C=C(F)C=N1 GBLBJPZSROAGMF-RWYJCYHVSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 206010073135 Dedifferentiated liposarcoma Diseases 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 108010021466 Mutant Proteins Proteins 0.000 description 3
- 102000008300 Mutant Proteins Human genes 0.000 description 3
- 108700020796 Oncogene Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 3
- MUJMYVFVAWFUJL-SNAWJCMRSA-O [(e)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium Chemical compound CN1C=NC([N+]([O-])=O)=C1C[N+](C)(C)C\C=C\C(=O)NC(N=CC1=NC=N2)=CC1=C2NC1=CC=C(Cl)C(Br)=C1 MUJMYVFVAWFUJL-SNAWJCMRSA-O 0.000 description 3
- BEMNJULZEQTDJY-UHFFFAOYSA-N [5-amino-1-(2-methyl-3h-benzimidazol-5-yl)pyrazol-4-yl]-(1h-indol-2-yl)methanone Chemical compound C1=CC=C2NC(C(=O)C=3C=NN(C=3N)C=3C=C4N=C(NC4=CC=3)C)=CC2=C1 BEMNJULZEQTDJY-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 238000011374 additional therapy Methods 0.000 description 3
- 229960001686 afatinib Drugs 0.000 description 3
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 3
- 229960001611 alectinib Drugs 0.000 description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000001574 biopsy Methods 0.000 description 3
- 229910052796 boron Inorganic materials 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- VERWOWGGCGHDQE-UHFFFAOYSA-N ceritinib Chemical compound CC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)S(=O)(=O)C(C)C)C(Cl)=CN=2)C(OC(C)C)=CC=1C1CCNCC1 VERWOWGGCGHDQE-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229960001433 erlotinib Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 3
- 201000007450 intrahepatic cholangiocarcinoma Diseases 0.000 description 3
- 229960004891 lapatinib Drugs 0.000 description 3
- 206010024627 liposarcoma Diseases 0.000 description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 206010061289 metastatic neoplasm Diseases 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 229940124303 multikinase inhibitor Drugs 0.000 description 3
- OLAHOMJCDNXHFI-UHFFFAOYSA-N n'-(3,5-dimethoxyphenyl)-n'-[3-(1-methylpyrazol-4-yl)quinoxalin-6-yl]-n-propan-2-ylethane-1,2-diamine Chemical compound COC1=CC(OC)=CC(N(CCNC(C)C)C=2C=C3N=C(C=NC3=CC=2)C2=CN(C)N=C2)=C1 OLAHOMJCDNXHFI-UHFFFAOYSA-N 0.000 description 3
- UZWDCWONPYILKI-UHFFFAOYSA-N n-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine Chemical compound C1CN(CC)CCN1CC(C=N1)=CC=C1NC1=NC=C(F)C(C=2C=C3N(C(C)C)C(C)=NC3=C(F)C=2)=N1 UZWDCWONPYILKI-UHFFFAOYSA-N 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 229950010203 nimotuzumab Drugs 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical group N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 description 3
- 229960001972 panitumumab Drugs 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 102000016914 ras Proteins Human genes 0.000 description 3
- 238000002271 resection Methods 0.000 description 3
- 229950003687 ribociclib Drugs 0.000 description 3
- 102220116009 rs886040773 Human genes 0.000 description 3
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical group OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- VMWOETMUNAQFAX-UHFFFAOYSA-N spiro[3.5]nonane Chemical compound C1CCC21CCCCC2 VMWOETMUNAQFAX-UHFFFAOYSA-N 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- MDDUHVRJJAFRAU-YZNNVMRBSA-N tert-butyl-[(1r,3s,5z)-3-[tert-butyl(dimethyl)silyl]oxy-5-(2-diphenylphosphorylethylidene)-4-methylidenecyclohexyl]oxy-dimethylsilane Chemical compound C1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C(=C)\C1=C/CP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 MDDUHVRJJAFRAU-YZNNVMRBSA-N 0.000 description 3
- 229950003046 tesevatinib Drugs 0.000 description 3
- HVXKQKFEHMGHSL-QKDCVEJESA-N tesevatinib Chemical compound N1=CN=C2C=C(OC[C@@H]3C[C@@H]4CN(C)C[C@@H]4C3)C(OC)=CC2=C1NC1=CC=C(Cl)C(Cl)=C1F HVXKQKFEHMGHSL-QKDCVEJESA-N 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 201000005112 urinary bladder cancer Diseases 0.000 description 3
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 3
- BXTJCSYMGFJEID-XMTADJHZSA-N (2s)-2-[[(2r,3r)-3-[(2s)-1-[(3r,4s,5s)-4-[[(2s)-2-[[(2s)-2-[6-[3-[(2r)-2-amino-2-carboxyethyl]sulfanyl-2,5-dioxopyrrolidin-1-yl]hexanoyl-methylamino]-3-methylbutanoyl]amino]-3-methylbutanoyl]-methylamino]-3-methoxy-5-methylheptanoyl]pyrrolidin-2-yl]-3-met Chemical compound C([C@H](NC(=O)[C@H](C)[C@@H](OC)[C@@H]1CCCN1C(=O)C[C@H]([C@H]([C@@H](C)CC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)CCCCCN1C(C(SC[C@H](N)C(O)=O)CC1=O)=O)C(C)C)OC)C(O)=O)C1=CC=CC=C1 BXTJCSYMGFJEID-XMTADJHZSA-N 0.000 description 2
- SADXACCFNXBCFY-IYNHSRRRSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]-3-[(2r)-1-methylpyrrolidin-2-yl]prop-2-enamide Chemical compound C=12C=C(NC(=O)\C=C\[C@@H]3N(CCC3)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 SADXACCFNXBCFY-IYNHSRRRSA-N 0.000 description 2
- VXZCUHNJXSIJIM-MEBGWEOYSA-N (z)-but-2-enedioic acid;(e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound OC(=O)\C=C/C(O)=O.C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 VXZCUHNJXSIJIM-MEBGWEOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 2
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- PDGKHKMBHVFCMG-UHFFFAOYSA-N 2-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]spiro[7,8-dihydropyrazino[5,6]pyrrolo[1,2-d]pyrimidine-9,1'-cyclohexane]-6-one Chemical compound C1CN(C)CCN1C(C=N1)=CC=C1NC1=NC=C(C=C2N3C4(CCCCC4)CNC2=O)C3=N1 PDGKHKMBHVFCMG-UHFFFAOYSA-N 0.000 description 2
- HEVHTYMYEMEBPX-HZPDHXFCSA-N 3-[4-[(2r)-2-aminopropoxy]phenyl]-n-[(1r)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine Chemical compound C1=CC(OC[C@H](N)C)=CC=C1C1=CN=C2N1N=C(N[C@H](C)C=1C=C(F)C=CC=1)C=C2 HEVHTYMYEMEBPX-HZPDHXFCSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- ORRNXRYWGDUDOG-UHFFFAOYSA-N 4-[2-fluoro-4-[(2-phenylacetyl)carbamothioylamino]phenoxy]-7-methoxy-n-methylquinoline-6-carboxamide Chemical compound C1=CN=C2C=C(OC)C(C(=O)NC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=S)NC(=O)CC1=CC=CC=C1 ORRNXRYWGDUDOG-UHFFFAOYSA-N 0.000 description 2
- DQAZPZIYEOGZAF-UHFFFAOYSA-N 4-ethyl-n-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]piperazine-1-carboxamide Chemical compound C1CN(CC)CCN1C(=O)NC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(C#C)=C1 DQAZPZIYEOGZAF-UHFFFAOYSA-N 0.000 description 2
- MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 description 2
- UWXSAYUXVSFDBQ-CYBMUJFWSA-N 4-n-[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]-6-n-[(4r)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]quinazoline-4,6-diamine Chemical compound C[C@@H]1COC(NC=2C=C3C(NC=4C=C(Cl)C(OCC=5SC=CN=5)=CC=4)=NC=NC3=CC=2)=N1 UWXSAYUXVSFDBQ-CYBMUJFWSA-N 0.000 description 2
- SGJLSPUSUBJWHO-UHFFFAOYSA-N 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperidin-4-ylpyridin-2-yl)amino]pyrido[2,3-d]pyrimidin-7-one Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1C1CCNCC1 SGJLSPUSUBJWHO-UHFFFAOYSA-N 0.000 description 2
- QKDCLUARMDUUKN-XMMPIXPASA-N 6-ethyl-3-[4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-5-[(3r)-1-prop-2-enoylpyrrolidin-3-yl]oxypyrazine-2-carboxamide Chemical compound N1=C(O[C@H]2CN(CC2)C(=O)C=C)C(CC)=NC(C(N)=O)=C1NC(C=C1)=CC=C1N(CC1)CCC1N1CCN(C)CC1 QKDCLUARMDUUKN-XMMPIXPASA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- OONFNUWBHFSNBT-HXUWFJFHSA-N AEE788 Chemical compound C1CN(CC)CCN1CC1=CC=C(C=2NC3=NC=NC(N[C@H](C)C=4C=CC=CC=4)=C3C=2)C=C1 OONFNUWBHFSNBT-HXUWFJFHSA-N 0.000 description 2
- VRQMAABPASPXMW-HDICACEKSA-N AZD4547 Chemical compound COC1=CC(OC)=CC(CCC=2NN=C(NC(=O)C=3C=CC(=CC=3)N3C[C@@H](C)N[C@@H](C)C3)C=2)=C1 VRQMAABPASPXMW-HDICACEKSA-N 0.000 description 2
- NEZONWMXZKDMKF-JTQLQIEISA-N Alkannin Chemical compound C1=CC(O)=C2C(=O)C([C@@H](O)CC=C(C)C)=CC(=O)C2=C1O NEZONWMXZKDMKF-JTQLQIEISA-N 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 229940124297 CDK 4/6 inhibitor Drugs 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 230000004568 DNA-binding Effects 0.000 description 2
- VOMDIEGPEURZJO-UHFFFAOYSA-N Deoxyshikonin Chemical compound C1=CC(O)=C2C(=O)C(CCC=C(C)C)=CC(=O)C2=C1O VOMDIEGPEURZJO-UHFFFAOYSA-N 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229940125497 HER2 kinase inhibitor Drugs 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- FOFDIMHVKGYHRU-UHFFFAOYSA-N N-(1,3-benzodioxol-5-ylmethyl)-4-(4-benzofuro[3,2-d]pyrimidinyl)-1-piperazinecarbothioamide Chemical compound C12=CC=CC=C2OC2=C1N=CN=C2N(CC1)CCN1C(=S)NCC1=CC=C(OCO2)C2=C1 FOFDIMHVKGYHRU-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- BTYYWOYVBXILOJ-UHFFFAOYSA-N N-{4-[(3-bromophenyl)amino]quinazolin-6-yl}but-2-ynamide Chemical compound C12=CC(NC(=O)C#CC)=CC=C2N=CN=C1NC1=CC=CC(Br)=C1 BTYYWOYVBXILOJ-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 102100023347 Proto-oncogene tyrosine-protein kinase ROS Human genes 0.000 description 2
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- ITTRLTNMFYIYPA-UHFFFAOYSA-N WZ4002 Chemical compound COC1=CC(N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1OC1=CC=CC(NC(=O)C=C)=C1 ITTRLTNMFYIYPA-UHFFFAOYSA-N 0.000 description 2
- WNFXUXZJJKTDOZ-HNNXBMFYSA-N [(1s)-1-(5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl] acetate Chemical compound C1=CC(O)=C2C(=O)C([C@@H](OC(C)=O)CC=C(C)C)=CC(=O)C2=C1O WNFXUXZJJKTDOZ-HNNXBMFYSA-N 0.000 description 2
- 229950001573 abemaciclib Drugs 0.000 description 2
- UOFYSRZSLXWIQB-UHFFFAOYSA-N abivertinib Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(C=CN2)C2=N1 UOFYSRZSLXWIQB-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000005083 alkoxyalkoxy group Chemical group 0.000 description 2
- 125000000033 alkoxyamino group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 102220307537 c.99_100insT Human genes 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 2
- 150000003857 carboxamides Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229960005061 crizotinib Drugs 0.000 description 2
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical group O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 description 2
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- 229950002205 dacomitinib Drugs 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 229950008925 depatuxizumab mafodotin Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 229940121647 egfr inhibitor Drugs 0.000 description 2
- 229950000521 entrectinib Drugs 0.000 description 2
- 229950004444 erdafitinib Drugs 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 229950002140 futuximab Drugs 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- 229940087158 gilotrif Drugs 0.000 description 2
- 201000009277 hairy cell leukemia Diseases 0.000 description 2
- 125000000262 haloalkenyl group Chemical group 0.000 description 2
- 125000004438 haloalkoxy group Chemical group 0.000 description 2
- 125000000232 haloalkynyl group Chemical group 0.000 description 2
- 125000005347 halocycloalkyl group Chemical group 0.000 description 2
- 125000004475 heteroaralkyl group Chemical group 0.000 description 2
- 125000005553 heteroaryloxy group Chemical group 0.000 description 2
- 125000005113 hydroxyalkoxy group Chemical group 0.000 description 2
- QQLKULDARVNMAL-UHFFFAOYSA-N icotinib Chemical compound C#CC1=CC=CC(NC=2C3=CC=4OCCOCCOCCOC=4C=C3N=CN=2)=C1 QQLKULDARVNMAL-UHFFFAOYSA-N 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- YPJRHEKCFKOVRT-UHFFFAOYSA-N lerociclib Chemical compound C1CN(C(C)C)CCN1C(C=N1)=CC=C1NC1=NC=C(C=C2N3C4(CCCCC4)CNC2=O)C3=N1 YPJRHEKCFKOVRT-UHFFFAOYSA-N 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- JYIUNVOCEFIUIU-GHMZBOCLSA-N n-[(3r,4r)-4-fluoro-1-[6-[(3-methoxy-1-methylpyrazol-4-yl)amino]-9-methylpurin-2-yl]pyrrolidin-3-yl]prop-2-enamide Chemical compound COC1=NN(C)C=C1NC1=NC(N2C[C@H]([C@H](F)C2)NC(=O)C=C)=NC2=C1N=CN2C JYIUNVOCEFIUIU-GHMZBOCLSA-N 0.000 description 2
- FDMQDKQUTRLUBU-UHFFFAOYSA-N n-[3-[2-[4-(4-methylpiperazin-1-yl)anilino]thieno[3,2-d]pyrimidin-4-yl]oxyphenyl]prop-2-enamide Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(SC=C2)C2=N1 FDMQDKQUTRLUBU-UHFFFAOYSA-N 0.000 description 2
- HUFOZJXAKZVRNJ-UHFFFAOYSA-N n-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxyanilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide Chemical compound COC1=CC(N2CCN(CC2)C(C)=O)=CC=C1NC(N=1)=NC=C(C(F)(F)F)C=1NC1=CC=CC(NC(=O)C=C)=C1 HUFOZJXAKZVRNJ-UHFFFAOYSA-N 0.000 description 2
- 229950009708 naquotinib Drugs 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 2
- WPHGSKGZRAQSGP-UHFFFAOYSA-N norcarane Chemical compound C1CCCC2CC21 WPHGSKGZRAQSGP-UHFFFAOYSA-N 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 229960004390 palbociclib Drugs 0.000 description 2
- WVUNYSQLFKLYNI-AATRIKPKSA-N pelitinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC1=CC=C(F)C(Cl)=C1 WVUNYSQLFKLYNI-AATRIKPKSA-N 0.000 description 2
- 229960002087 pertuzumab Drugs 0.000 description 2
- 239000001472 potassium tartrate Substances 0.000 description 2
- 230000004853 protein function Effects 0.000 description 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 230000007420 reactivation Effects 0.000 description 2
- FIKPXCOQUIZNHB-WDEREUQCSA-N repotrectinib Chemical compound C[C@H]1CNC(=O)C2=C3N=C(N[C@H](C)C4=C(O1)C=CC(F)=C4)C=CN3N=C2 FIKPXCOQUIZNHB-WDEREUQCSA-N 0.000 description 2
- 102220032332 rs104895374 Human genes 0.000 description 2
- 102220234804 rs1131691022 Human genes 0.000 description 2
- 102200059506 rs281875236 Human genes 0.000 description 2
- 102200106582 rs530941076 Human genes 0.000 description 2
- 102220047514 rs587783062 Human genes 0.000 description 2
- 102220118104 rs886041787 Human genes 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
- 229940121610 selpercatinib Drugs 0.000 description 2
- WNFXUXZJJKTDOZ-UHFFFAOYSA-N shikonin acetate Natural products C1=CC(O)=C2C(=O)C(C(OC(C)=O)CC=C(C)C)=CC(=O)C2=C1O WNFXUXZJJKTDOZ-UHFFFAOYSA-N 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000011301 standard therapy Methods 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 229940120982 tarceva Drugs 0.000 description 2
- AHYMHWXQRWRBKT-UHFFFAOYSA-N tepotinib Chemical compound C1CN(C)CCC1COC1=CN=C(C=2C=C(CN3C(C=CC(=N3)C=3C=C(C=CC=3)C#N)=O)C=CC=2)N=C1 AHYMHWXQRWRBKT-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 2
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000006168 tricyclic group Chemical group 0.000 description 2
- 125000005423 trihalomethanesulfonamido group Chemical group 0.000 description 2
- 125000005152 trihalomethanesulfonyl group Chemical group 0.000 description 2
- 206010046766 uterine cancer Diseases 0.000 description 2
- 229960000241 vandetanib Drugs 0.000 description 2
- KGWWHPZQLVVAPT-STTJLUEPSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;6-(4-methylpiperazin-1-yl)-n-(5-methyl-1h-pyrazol-3-yl)-2-[(e)-2-phenylethenyl]pyrimidin-4-amine Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1CN(C)CCN1C1=CC(NC2=NNC(C)=C2)=NC(\C=C\C=2C=CC=CC=2)=N1 KGWWHPZQLVVAPT-STTJLUEPSA-N 0.000 description 1
- KPJDVVCDVBFRMU-AREMUKBSSA-N (6r)-6-(2-fluorophenyl)-n-[3-[2-(2-methoxyethylamino)ethyl]phenyl]-5,6-dihydrobenzo[h]quinazolin-2-amine Chemical compound COCCNCCC1=CC=CC(NC=2N=C3C4=CC=CC=C4[C@H](C=4C(=CC=CC=4)F)CC3=CN=2)=C1 KPJDVVCDVBFRMU-AREMUKBSSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- BSPLGGCPNTZPIH-IPZCTEOASA-N (e)-n-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]-4-piperidin-1-ylbut-2-enamide;hydrate Chemical compound O.C=12C=C(NC(=O)\C=C\CN3CCCCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 BSPLGGCPNTZPIH-IPZCTEOASA-N 0.000 description 1
- UZHVXJZEHGSWQV-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole Chemical compound C1NCC2CCCC21 UZHVXJZEHGSWQV-UHFFFAOYSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- ODMXWZROLKITMS-RISCZKNCSA-N 1-[(3r,4r)-3-[[5-chloro-2-[(1-methylpyrazol-4-yl)amino]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]oxymethyl]-4-methoxypyrrolidin-1-yl]prop-2-en-1-one Chemical compound CO[C@H]1CN(C(=O)C=C)C[C@@H]1COC1=NC(NC2=CN(C)N=C2)=NC2=C1C(Cl)=CN2 ODMXWZROLKITMS-RISCZKNCSA-N 0.000 description 1
- QQUFDFQHIUKUFP-UHFFFAOYSA-N 1-azaspiro[2.2]pentane Chemical group C1CC11NC1 QQUFDFQHIUKUFP-UHFFFAOYSA-N 0.000 description 1
- KSOGAEPLTWOWJN-UHFFFAOYSA-N 1-oxaspiro[2.2]pentane Chemical compound C1CC11OC1 KSOGAEPLTWOWJN-UHFFFAOYSA-N 0.000 description 1
- PVPJIEQYINHNPP-UHFFFAOYSA-N 1-sulfanylpyrrole Chemical compound SN1C=CC=C1 PVPJIEQYINHNPP-UHFFFAOYSA-N 0.000 description 1
- FPYJSJDOHRDAMT-KQWNVCNZSA-N 1h-indole-5-sulfonamide, n-(3-chlorophenyl)-3-[[3,5-dimethyl-4-[(4-methyl-1-piperazinyl)carbonyl]-1h-pyrrol-2-yl]methylene]-2,3-dihydro-n-methyl-2-oxo-, (3z)- Chemical compound C=1C=C2NC(=O)\C(=C/C3=C(C(C(=O)N4CCN(C)CC4)=C(C)N3)C)C2=CC=1S(=O)(=O)N(C)C1=CC=CC(Cl)=C1 FPYJSJDOHRDAMT-KQWNVCNZSA-N 0.000 description 1
- WCXFPLXZZSWROM-UHFFFAOYSA-N 1h-pyrazolo[4,3-c]pyridine Chemical compound C1=NC=C2C=NNC2=C1 WCXFPLXZZSWROM-UHFFFAOYSA-N 0.000 description 1
- HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 description 1
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- YFTAYXNRRVEWAU-UHFFFAOYSA-N 2,5-dioxaspiro[3.6]decane Chemical compound C1OCC11OCCCCC1 YFTAYXNRRVEWAU-UHFFFAOYSA-N 0.000 description 1
- YTUFHOKUFOQRDF-UHFFFAOYSA-N 2-(5-fluoro-2-hydroxyphenyl)-2-(3-oxo-1H-isoindol-2-yl)-N-(1,3-thiazol-2-yl)acetamide Chemical compound FC=1C=CC(=C(C=1)C(C(=O)NC=1SC=CN=1)N1C(C2=CC=CC=C2C1)=O)O YTUFHOKUFOQRDF-UHFFFAOYSA-N 0.000 description 1
- IQVHMRPINAMBJU-UHFFFAOYSA-N 2-(6-chloropyridazin-3-yl)oxy-N-[1-[(2,2-difluorocyclopropyl)methyl]piperidin-4-yl]-N-methylacetamide Chemical compound ClC1=CC=C(N=N1)OCC(=O)N(C)C1CCN(CC1)CC1C(C1)(F)F IQVHMRPINAMBJU-UHFFFAOYSA-N 0.000 description 1
- MAXZESONWXTISA-UHFFFAOYSA-N 2-[4-(2-aminoethoxy)anilino]-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7-one Chemical compound N=1C=C2C=C(C=3C(=CC=CC=3Cl)Cl)C(=O)N(C)C2=NC=1NC1=CC=C(OCCN)C=C1 MAXZESONWXTISA-UHFFFAOYSA-N 0.000 description 1
- IDXKJSSOUXWLDB-UHFFFAOYSA-N 2-[4-(4-ethoxy-6-oxo-1h-pyridin-3-yl)-2-fluorophenyl]-n-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]acetamide Chemical compound CCOC1=CC(=O)NC=C1C(C=C1F)=CC=C1CC(=O)NC1=NOC(C(C)(C)C(F)(F)F)=C1 IDXKJSSOUXWLDB-UHFFFAOYSA-N 0.000 description 1
- VLBZFDFQVGAJSP-UHFFFAOYSA-N 2-[4-[3-[1-[7-fluoro-3-(1-methylpyrazol-4-yl)quinolin-6-yl]ethyl]triazolo[4,5-b]pyrazin-5-yl]pyrazol-1-yl]ethanol Chemical compound CC(c1cc2cc(cnc2cc1F)-c1cnn(C)c1)n1nnc2ncc(nc12)-c1cnn(CCO)c1 VLBZFDFQVGAJSP-UHFFFAOYSA-N 0.000 description 1
- KOLQINCWMXQEOF-UHFFFAOYSA-N 2-[6-(6,7-dimethoxyquinolin-3-yl)pyridin-3-yl]-N-[3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-5-yl]acetamide Chemical compound COC=1C=C2C=C(C=NC2=CC=1OC)C1=CC=C(C=N1)CC(=O)NC1=CC(=NO1)C(C(F)(F)F)(C)C KOLQINCWMXQEOF-UHFFFAOYSA-N 0.000 description 1
- BCSHRERPHLTPEE-NRFANRHFSA-N 2-[[5-chloro-2-[[(6s)-6-[4-(2-hydroxyethyl)piperazin-1-yl]-1-methoxy-6,7,8,9-tetrahydro-5h-benzo[7]annulen-2-yl]amino]pyrimidin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=NC(NC=2C(=C3CCC[C@@H](CC3=CC=2)N2CCN(CCO)CC2)OC)=NC=C1Cl BCSHRERPHLTPEE-NRFANRHFSA-N 0.000 description 1
- NHGFMBKRFYOHGI-UHFFFAOYSA-N 2-azabicyclo[1.1.0]butane Chemical compound N1C2CC21 NHGFMBKRFYOHGI-UHFFFAOYSA-N 0.000 description 1
- IBODJKKYTBNWTD-UHFFFAOYSA-N 2-azaspiro[3.5]nonane Chemical compound C1NCC11CCCCC1 IBODJKKYTBNWTD-UHFFFAOYSA-N 0.000 description 1
- NINJAJLCZUYDGV-UHFFFAOYSA-N 2-azaspiro[4.4]nonane Chemical compound C1CCCC21CNCC2 NINJAJLCZUYDGV-UHFFFAOYSA-N 0.000 description 1
- SQRHNJRUPNFNHY-UHFFFAOYSA-N 2-oxabicyclo[1.1.0]butane Chemical compound O1C2CC21 SQRHNJRUPNFNHY-UHFFFAOYSA-N 0.000 description 1
- PNLURCRXZLVRJR-UHFFFAOYSA-N 2-oxaspiro[3.5]nonane Chemical compound C1OCC11CCCCC1 PNLURCRXZLVRJR-UHFFFAOYSA-N 0.000 description 1
- PLAXIXCHKPZHJA-UHFFFAOYSA-N 2-oxaspiro[4.4]nonane Chemical compound C1CCCC21COCC2 PLAXIXCHKPZHJA-UHFFFAOYSA-N 0.000 description 1
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- CAAMSDWKXXPUJR-UHFFFAOYSA-N 3,5-dihydro-4H-imidazol-4-one Chemical compound O=C1CNC=N1 CAAMSDWKXXPUJR-UHFFFAOYSA-N 0.000 description 1
- DORJQZDOULKINH-QNBGGDODSA-N 3-[4-[(2r)-2-aminopropoxy]phenyl]-n-[(1r)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine;hexanedioic acid Chemical compound OC(=O)CCCCC(O)=O.C1=CC(OC[C@H](N)C)=CC=C1C1=CN=C2N1N=C(N[C@H](C)C=1C=C(F)C=CC=1)C=C2 DORJQZDOULKINH-QNBGGDODSA-N 0.000 description 1
- DAPJDNAXUNPBRZ-UHFFFAOYSA-N 3-azabicyclo[2.1.0]pentane Chemical compound C1NC2CC21 DAPJDNAXUNPBRZ-UHFFFAOYSA-N 0.000 description 1
- KPUSZZFAYGWAHZ-UHFFFAOYSA-N 3-azabicyclo[2.2.2]octane Chemical compound C1CC2CCC1NC2 KPUSZZFAYGWAHZ-UHFFFAOYSA-N 0.000 description 1
- HGWUUOXXAIISDB-UHFFFAOYSA-N 3-azabicyclo[3.1.0]hexane Chemical compound C1NCC2CC21 HGWUUOXXAIISDB-UHFFFAOYSA-N 0.000 description 1
- NEOIOGUWEUTYIH-UHFFFAOYSA-N 3-azabicyclo[3.2.0]heptane Chemical compound C1NCC2CCC21 NEOIOGUWEUTYIH-UHFFFAOYSA-N 0.000 description 1
- CJQNJRRDTPULTL-UHFFFAOYSA-N 3-azabicyclo[3.2.1]octane Chemical compound C1C2CCC1CNC2 CJQNJRRDTPULTL-UHFFFAOYSA-N 0.000 description 1
- LIZKZVQBLDHKCY-UHFFFAOYSA-N 3-azaspiro[5.5]undecane Chemical compound C1CCCCC21CCNCC2 LIZKZVQBLDHKCY-UHFFFAOYSA-N 0.000 description 1
- NJGVTIXCHOYDJW-UHFFFAOYSA-N 3-oxa-9-azaspiro[5.5]undecane Chemical compound C1CNCCC21CCOCC2 NJGVTIXCHOYDJW-UHFFFAOYSA-N 0.000 description 1
- LPFNEVOOAWEOBF-UHFFFAOYSA-N 3-oxabicyclo[2.1.0]pentane Chemical compound C1OC2CC21 LPFNEVOOAWEOBF-UHFFFAOYSA-N 0.000 description 1
- CONVAEXWACQJSA-UHFFFAOYSA-N 3-oxabicyclo[2.2.2]octane Chemical compound C1CC2CCC1OC2 CONVAEXWACQJSA-UHFFFAOYSA-N 0.000 description 1
- ZXKBVCUVSLFOSC-UHFFFAOYSA-N 3-oxabicyclo[3.1.0]hexane Chemical compound C1OCC2CC21 ZXKBVCUVSLFOSC-UHFFFAOYSA-N 0.000 description 1
- DILRGJHTNZOQNK-UHFFFAOYSA-N 3-oxabicyclo[3.2.0]heptane Chemical compound C1OCC2CCC21 DILRGJHTNZOQNK-UHFFFAOYSA-N 0.000 description 1
- FLGYHCOAXRKEIN-UHFFFAOYSA-N 3-oxabicyclo[3.2.1]octane Chemical compound C1C2CCC1COC2 FLGYHCOAXRKEIN-UHFFFAOYSA-N 0.000 description 1
- SPWYSCDHFSCQMA-UHFFFAOYSA-N 3-oxaspiro[5.5]undecane Chemical compound C1CCCCC21CCOCC2 SPWYSCDHFSCQMA-UHFFFAOYSA-N 0.000 description 1
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- MZFQJBMXUXJUHF-UHFFFAOYSA-N 4-azabicyclo[4.1.0]heptane Chemical compound C1CNCC2CC21 MZFQJBMXUXJUHF-UHFFFAOYSA-N 0.000 description 1
- HVFHYYCWZWCTMW-UHFFFAOYSA-N 4-azaspiro[2.5]octane Chemical group C1CC11NCCCC1 HVFHYYCWZWCTMW-UHFFFAOYSA-N 0.000 description 1
- ZVOMLHIUENREGH-UHFFFAOYSA-N 4-oxabicyclo[4.1.0]heptane Chemical compound C1COCC2CC21 ZVOMLHIUENREGH-UHFFFAOYSA-N 0.000 description 1
- YCBIWVHDKSQGFJ-UHFFFAOYSA-N 4-oxaspiro[2.5]octane Chemical compound C1CC11OCCCC1 YCBIWVHDKSQGFJ-UHFFFAOYSA-N 0.000 description 1
- UOVCGJXDGOGOCZ-UHFFFAOYSA-N 5-(2-chlorophenyl)-7-fluoro-8-methoxy-3-methyl-1,2-dihydropyrazolo[3,4-b][1,4]benzodiazepine Chemical compound C1=2C=C(F)C(OC)=CC=2N=C2NNC(C)=C2N=C1C1=CC=CC=C1Cl UOVCGJXDGOGOCZ-UHFFFAOYSA-N 0.000 description 1
- WYVFAIDIZFAWMI-UHFFFAOYSA-N 5-azabicyclo[2.1.1]hexane Chemical compound C1CC2CC1N2 WYVFAIDIZFAWMI-UHFFFAOYSA-N 0.000 description 1
- ZQCZKNJMUNAGGK-UHFFFAOYSA-N 5-oxabicyclo[2.1.1]hexane Chemical compound C1CC2CC1O2 ZQCZKNJMUNAGGK-UHFFFAOYSA-N 0.000 description 1
- DIJLFIHLUYAZCI-UHFFFAOYSA-N 6-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-amine Chemical compound C1=CC(OC)=CC=C1C1=CC2=C(N)N=CN=C2O1 DIJLFIHLUYAZCI-UHFFFAOYSA-N 0.000 description 1
- GLYMPHUVMRFTFV-QLFBSQMISA-N 6-amino-5-[(1r)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-n-[4-[(3r,5s)-3,5-dimethylpiperazine-1-carbonyl]phenyl]pyridazine-3-carboxamide Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NN=1)N)=CC=1C(=O)NC(C=C1)=CC=C1C(=O)N1C[C@H](C)N[C@H](C)C1 GLYMPHUVMRFTFV-QLFBSQMISA-N 0.000 description 1
- DENNCEQUAZKJGC-UHFFFAOYSA-N 6-azabicyclo[3.1.1]heptane Chemical compound C1CCC2CC1N2 DENNCEQUAZKJGC-UHFFFAOYSA-N 0.000 description 1
- SUKDJGHHYOXCIW-UHFFFAOYSA-N 6-azaspiro[2.6]nonane Chemical compound C1CC11CCNCCC1 SUKDJGHHYOXCIW-UHFFFAOYSA-N 0.000 description 1
- SDEAXTCZPQIFQM-UHFFFAOYSA-N 6-n-(4,4-dimethyl-5h-1,3-oxazol-2-yl)-4-n-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]quinazoline-4,6-diamine Chemical compound C=1C=C(OC2=CC3=NC=NN3C=C2)C(C)=CC=1NC(C1=C2)=NC=NC1=CC=C2NC1=NC(C)(C)CO1 SDEAXTCZPQIFQM-UHFFFAOYSA-N 0.000 description 1
- KFZRLMPLQBLWMG-UHFFFAOYSA-N 6-oxabicyclo[3.1.1]heptane Chemical compound C1CCC2CC1O2 KFZRLMPLQBLWMG-UHFFFAOYSA-N 0.000 description 1
- OSOGFIXZYBHTIX-UHFFFAOYSA-N 6-oxaspiro[2.6]nonane Chemical compound C1CC11CCOCCC1 OSOGFIXZYBHTIX-UHFFFAOYSA-N 0.000 description 1
- PLIVFNIUGLLCEK-UHFFFAOYSA-N 7-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]oxy-n-hydroxyheptanamide Chemical compound C=12C=C(OCCCCCCC(=O)NO)C(OC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 PLIVFNIUGLLCEK-UHFFFAOYSA-N 0.000 description 1
- SNZSSCZJMVIOCR-UHFFFAOYSA-N 7-azabicyclo[2.2.1]heptane Chemical compound C1CC2CCC1N2 SNZSSCZJMVIOCR-UHFFFAOYSA-N 0.000 description 1
- OQDPEXFDRKDVPE-UHFFFAOYSA-N 7-azabicyclo[4.2.0]octane Chemical compound C1CCCC2CNC21 OQDPEXFDRKDVPE-UHFFFAOYSA-N 0.000 description 1
- BSQKGAVROUDOTE-UHFFFAOYSA-N 7-azaspiro[3.5]nonane Chemical compound C1CCC21CCNCC2 BSQKGAVROUDOTE-UHFFFAOYSA-N 0.000 description 1
- DLONSBIGPVMEHH-UHFFFAOYSA-N 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane Chemical compound C1NCC12NCCCCC2.C2CCCC21CNCCC1 DLONSBIGPVMEHH-UHFFFAOYSA-N 0.000 description 1
- KDBXRAQKSXYXFU-UHFFFAOYSA-N 7-oxabicyclo[4.2.0]octane Chemical compound C1CCCC2COC21 KDBXRAQKSXYXFU-UHFFFAOYSA-N 0.000 description 1
- ICUNWSURIXTWCL-UHFFFAOYSA-N 7-oxaspiro[3.5]nonane Chemical compound C1CCC11CCOCC1 ICUNWSURIXTWCL-UHFFFAOYSA-N 0.000 description 1
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 1
- MGGBYMDAPCCKCT-UHFFFAOYSA-N ASP-3026 Chemical compound COC1=CC(N2CCC(CC2)N2CCN(C)CC2)=CC=C1NC(N=1)=NC=NC=1NC1=CC=CC=C1S(=O)(=O)C(C)C MGGBYMDAPCCKCT-UHFFFAOYSA-N 0.000 description 1
- ZFXQNADNEBRERM-BJDJZHNGSA-N Ala-Ala-Pro-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 ZFXQNADNEBRERM-BJDJZHNGSA-N 0.000 description 1
- 229940122531 Anaplastic lymphoma kinase inhibitor Drugs 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 229940126029 BDTX-189 Drugs 0.000 description 1
- 229940124649 Balversa Drugs 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- KSEBMYQBYZTDHS-SQDGEFSZSA-N COc1cc(ccc1O)\[13CH]=[13CH]\[13C](O)=O Chemical compound COc1cc(ccc1O)\[13CH]=[13CH]\[13C](O)=O KSEBMYQBYZTDHS-SQDGEFSZSA-N 0.000 description 1
- LLVZBTWPGQVVLW-SNAWJCMRSA-N CP-724714 Chemical compound C12=CC(/C=C/CNC(=O)COC)=CC=C2N=CN=C1NC(C=C1C)=CC=C1OC1=CC=C(C)N=C1 LLVZBTWPGQVVLW-SNAWJCMRSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 1
- 101710150820 Cellular tumor antigen p53 Proteins 0.000 description 1
- 102220572812 Cellular tumor antigen p53_A138T_mutation Human genes 0.000 description 1
- 102220571876 Cellular tumor antigen p53_A161P_mutation Human genes 0.000 description 1
- 102220571873 Cellular tumor antigen p53_A161S_mutation Human genes 0.000 description 1
- 102220571874 Cellular tumor antigen p53_A161T_mutation Human genes 0.000 description 1
- 102220571883 Cellular tumor antigen p53_A161V_mutation Human genes 0.000 description 1
- 102220584271 Cellular tumor antigen p53_A74T_mutation Human genes 0.000 description 1
- 102220584245 Cellular tumor antigen p53_A79V_mutation Human genes 0.000 description 1
- 102220572779 Cellular tumor antigen p53_C135R_mutation Human genes 0.000 description 1
- 102220573675 Cellular tumor antigen p53_C141G_mutation Human genes 0.000 description 1
- 102220565313 Cellular tumor antigen p53_C238W_mutation Human genes 0.000 description 1
- 102220594185 Cellular tumor antigen p53_C275G_mutation Human genes 0.000 description 1
- 102220594231 Cellular tumor antigen p53_C277G_mutation Human genes 0.000 description 1
- 102220594227 Cellular tumor antigen p53_C277W_mutation Human genes 0.000 description 1
- 102220551426 Cellular tumor antigen p53_D208N_mutation Human genes 0.000 description 1
- 102220551427 Cellular tumor antigen p53_D208V_mutation Human genes 0.000 description 1
- 102220552844 Cellular tumor antigen p53_D228E_mutation Human genes 0.000 description 1
- 102220552852 Cellular tumor antigen p53_D228N_mutation Human genes 0.000 description 1
- 102220566733 Cellular tumor antigen p53_D259N_mutation Human genes 0.000 description 1
- 102220594201 Cellular tumor antigen p53_D281A_mutation Human genes 0.000 description 1
- 102220593403 Cellular tumor antigen p53_D281H_mutation Human genes 0.000 description 1
- 102220594166 Cellular tumor antigen p53_D281Y_mutation Human genes 0.000 description 1
- 102220583784 Cellular tumor antigen p53_D61G_mutation Human genes 0.000 description 1
- 102220551340 Cellular tumor antigen p53_E204D_mutation Human genes 0.000 description 1
- 102220551343 Cellular tumor antigen p53_E204Q_mutation Human genes 0.000 description 1
- 102220566654 Cellular tumor antigen p53_E258D_mutation Human genes 0.000 description 1
- 102220566729 Cellular tumor antigen p53_E258Q_mutation Human genes 0.000 description 1
- 102220592775 Cellular tumor antigen p53_E271Q_mutation Human genes 0.000 description 1
- 102220592780 Cellular tumor antigen p53_E271V_mutation Human genes 0.000 description 1
- 102220597445 Cellular tumor antigen p53_E285Q_mutation Human genes 0.000 description 1
- 102220597399 Cellular tumor antigen p53_E286Q_mutation Human genes 0.000 description 1
- 102220597393 Cellular tumor antigen p53_E286V_mutation Human genes 0.000 description 1
- 102220574548 Cellular tumor antigen p53_F113L_mutation Human genes 0.000 description 1
- 102220573038 Cellular tumor antigen p53_F134V_mutation Human genes 0.000 description 1
- 102220592766 Cellular tumor antigen p53_F270V_mutation Human genes 0.000 description 1
- 102220568599 Cellular tumor antigen p53_G154V_mutation Human genes 0.000 description 1
- 102220522503 Cellular tumor antigen p53_G187S_mutation Human genes 0.000 description 1
- 102220566988 Cellular tumor antigen p53_G266E_mutation Human genes 0.000 description 1
- 102220592710 Cellular tumor antigen p53_G334V_mutation Human genes 0.000 description 1
- 102220575994 Cellular tumor antigen p53_H168L_mutation Human genes 0.000 description 1
- 102220575992 Cellular tumor antigen p53_H168P_mutation Human genes 0.000 description 1
- 102220574475 Cellular tumor antigen p53_H179D_mutation Human genes 0.000 description 1
- 102220574491 Cellular tumor antigen p53_H179P_mutation Human genes 0.000 description 1
- 102220523396 Cellular tumor antigen p53_H193P_mutation Human genes 0.000 description 1
- 102220571881 Cellular tumor antigen p53_I162F_mutation Human genes 0.000 description 1
- 102220571925 Cellular tumor antigen p53_I162N_mutation Human genes 0.000 description 1
- 102220523375 Cellular tumor antigen p53_I195F_mutation Human genes 0.000 description 1
- 102220523372 Cellular tumor antigen p53_I195S_mutation Human genes 0.000 description 1
- 102220552334 Cellular tumor antigen p53_I232F_mutation Human genes 0.000 description 1
- 102220552336 Cellular tumor antigen p53_I232N_mutation Human genes 0.000 description 1
- 102220566713 Cellular tumor antigen p53_I254S_mutation Human genes 0.000 description 1
- 102220566719 Cellular tumor antigen p53_I255S_mutation Human genes 0.000 description 1
- 102220592726 Cellular tumor antigen p53_K319N_mutation Human genes 0.000 description 1
- 102220575227 Cellular tumor antigen p53_L130R_mutation Human genes 0.000 description 1
- 102220572800 Cellular tumor antigen p53_L137Q_mutation Human genes 0.000 description 1
- 102220573320 Cellular tumor antigen p53_L145R_mutation Human genes 0.000 description 1
- 102220566990 Cellular tumor antigen p53_L265R_mutation Human genes 0.000 description 1
- 102220593825 Cellular tumor antigen p53_L289F_mutation Human genes 0.000 description 1
- 102220592255 Cellular tumor antigen p53_L330R_mutation Human genes 0.000 description 1
- 102220590417 Cellular tumor antigen p53_L348F_mutation Human genes 0.000 description 1
- 102220590418 Cellular tumor antigen p53_L348S_mutation Human genes 0.000 description 1
- 102220573019 Cellular tumor antigen p53_M133K_mutation Human genes 0.000 description 1
- 102220573025 Cellular tumor antigen p53_M133R_mutation Human genes 0.000 description 1
- 102220574259 Cellular tumor antigen p53_M169I_mutation Human genes 0.000 description 1
- 102220574255 Cellular tumor antigen p53_M169T_mutation Human genes 0.000 description 1
- 102220552317 Cellular tumor antigen p53_M237L_mutation Human genes 0.000 description 1
- 102220565308 Cellular tumor antigen p53_M243I_mutation Human genes 0.000 description 1
- 102220575239 Cellular tumor antigen p53_N131S_mutation Human genes 0.000 description 1
- 102220573384 Cellular tumor antigen p53_P142L_mutation Human genes 0.000 description 1
- 102220573659 Cellular tumor antigen p53_P151L_mutation Human genes 0.000 description 1
- 102220571850 Cellular tumor antigen p53_P152Q_mutation Human genes 0.000 description 1
- 102220575772 Cellular tumor antigen p53_P177H_mutation Human genes 0.000 description 1
- 102220575797 Cellular tumor antigen p53_P177S_mutation Human genes 0.000 description 1
- 102220522406 Cellular tumor antigen p53_P191L_mutation Human genes 0.000 description 1
- 102220551322 Cellular tumor antigen p53_P219T_mutation Human genes 0.000 description 1
- 102220597107 Cellular tumor antigen p53_P301T_mutation Human genes 0.000 description 1
- 102220583823 Cellular tumor antigen p53_P67S_mutation Human genes 0.000 description 1
- 102220587348 Cellular tumor antigen p53_P92S_mutation Human genes 0.000 description 1
- 102220587405 Cellular tumor antigen p53_Q104H_mutation Human genes 0.000 description 1
- 102220573300 Cellular tumor antigen p53_Q144H_mutation Human genes 0.000 description 1
- 102220592256 Cellular tumor antigen p53_Q331H_mutation Human genes 0.000 description 1
- 102220568566 Cellular tumor antigen p53_R156G_mutation Human genes 0.000 description 1
- 102220568617 Cellular tumor antigen p53_R158G_mutation Human genes 0.000 description 1
- 102220572078 Cellular tumor antigen p53_R158S_mutation Human genes 0.000 description 1
- 102220575713 Cellular tumor antigen p53_R174W_mutation Human genes 0.000 description 1
- 102220573715 Cellular tumor antigen p53_R181P_mutation Human genes 0.000 description 1
- 102220551419 Cellular tumor antigen p53_R209I_mutation Human genes 0.000 description 1
- 102220551430 Cellular tumor antigen p53_R209K_mutation Human genes 0.000 description 1
- 102220565590 Cellular tumor antigen p53_R248G_mutation Human genes 0.000 description 1
- 102220566932 Cellular tumor antigen p53_R267G_mutation Human genes 0.000 description 1
- 102220594193 Cellular tumor antigen p53_R280I_mutation Human genes 0.000 description 1
- 102220575168 Cellular tumor antigen p53_S127P_mutation Human genes 0.000 description 1
- 102220575175 Cellular tumor antigen p53_S127T_mutation Human genes 0.000 description 1
- 102220575176 Cellular tumor antigen p53_S127Y_mutation Human genes 0.000 description 1
- 102220590718 Cellular tumor antigen p53_S315C_mutation Human genes 0.000 description 1
- 102220568608 Cellular tumor antigen p53_T155I_mutation Human genes 0.000 description 1
- 102220568567 Cellular tumor antigen p53_T155P_mutation Human genes 0.000 description 1
- 102220549433 Cellular tumor antigen p53_T211I_mutation Human genes 0.000 description 1
- 102220552799 Cellular tumor antigen p53_T230P_mutation Human genes 0.000 description 1
- 102220563809 Cellular tumor antigen p53_T253A_mutation Human genes 0.000 description 1
- 102220563808 Cellular tumor antigen p53_T253I_mutation Human genes 0.000 description 1
- 102220566653 Cellular tumor antigen p53_T256I_mutation Human genes 0.000 description 1
- 102220573351 Cellular tumor antigen p53_V143A_mutation Human genes 0.000 description 1
- 102220573349 Cellular tumor antigen p53_V143E_mutation Human genes 0.000 description 1
- 102220573647 Cellular tumor antigen p53_V147G_mutation Human genes 0.000 description 1
- 102220572065 Cellular tumor antigen p53_V157G_mutation Human genes 0.000 description 1
- 102220572063 Cellular tumor antigen p53_V157L_mutation Human genes 0.000 description 1
- 102220574273 Cellular tumor antigen p53_V172D_mutation Human genes 0.000 description 1
- 102220522484 Cellular tumor antigen p53_V197G_mutation Human genes 0.000 description 1
- 102220549598 Cellular tumor antigen p53_V216E_mutation Human genes 0.000 description 1
- 102220549599 Cellular tumor antigen p53_V216G_mutation Human genes 0.000 description 1
- 102220549704 Cellular tumor antigen p53_V218E_mutation Human genes 0.000 description 1
- 102220592999 Cellular tumor antigen p53_V274D_mutation Human genes 0.000 description 1
- 102220593001 Cellular tumor antigen p53_V274F_mutation Human genes 0.000 description 1
- 102220573642 Cellular tumor antigen p53_W146S_mutation Human genes 0.000 description 1
- 102220574916 Cellular tumor antigen p53_Y107D_mutation Human genes 0.000 description 1
- 102220575164 Cellular tumor antigen p53_Y126H_mutation Human genes 0.000 description 1
- 102220575169 Cellular tumor antigen p53_Y126S_mutation Human genes 0.000 description 1
- 102220551347 Cellular tumor antigen p53_Y205F_mutation Human genes 0.000 description 1
- 102220551532 Cellular tumor antigen p53_Y205S_mutation Human genes 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- CUDVHEFYRIWYQD-UHFFFAOYSA-N E-3810 free base Chemical compound C=1C=C2C(C(=O)NC)=CC=CC2=CC=1OC(C1=CC=2OC)=CC=NC1=CC=2OCC1(N)CC1 CUDVHEFYRIWYQD-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 1
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010081348 HRT1 protein Hairy Proteins 0.000 description 1
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 description 1
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 1
- BVRYLTBIGIAADD-MRXNPFEDSA-N Isobutylshikonin Chemical compound C1=CC(O)=C2C(=O)C([C@@H](CC=C(C)C)OC(=O)C(C)C)=CC(=O)C2=C1O BVRYLTBIGIAADD-MRXNPFEDSA-N 0.000 description 1
- 208000007666 Klatskin Tumor Diseases 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- UCEQXRCJXIVODC-PMACEKPBSA-N LSM-1131 Chemical compound C1CCC2=CC=CC3=C2N1C=C3[C@@H]1C(=O)NC(=O)[C@H]1C1=CNC2=CC=CC=C12 UCEQXRCJXIVODC-PMACEKPBSA-N 0.000 description 1
- 241001071917 Lithospermum Species 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- PVZAGAKBJFLDBW-RBUKOAKNSA-N N-[(3R,4S)-4-[[6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-(4-methoxypiperidin-1-yl)pyrido[3,4-d]pyrimidin-2-yl]amino]oxolan-3-yl]prop-2-enamide Chemical compound COC1CCN(CC1)c1nc(cc2cnc(N[C@@H]3COC[C@@H]3NC(=O)C=C)nc12)-c1c(Cl)c(OC)cc(OC)c1Cl PVZAGAKBJFLDBW-RBUKOAKNSA-N 0.000 description 1
- USOCZVZOXKTJTI-UHFFFAOYSA-N N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-[1-(2,2,2-trifluoroethyl)indol-3-yl]pyrimidin-2-yl]amino]phenyl]prop-2-enamide Chemical compound C(N1C2=C(C(=C1)C1=NC(=NC=C1)NC1=C(C=C(N(CCN(C)C)C)C(NC(=O)C=C)=C1)OC)C=CC=C2)C(F)(F)F USOCZVZOXKTJTI-UHFFFAOYSA-N 0.000 description 1
- UYMSIPINLJNNOU-UHFFFAOYSA-N N-[3-fluoro-4-[(7-methoxy-4-quinolinyl)oxy]phenyl]-1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-4-pyrazolecarboxamide Chemical compound C=1C=NC2=CC(OC)=CC=C2C=1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=C(C)N(CC(C)(C)O)N1C1=CC=CC=C1 UYMSIPINLJNNOU-UHFFFAOYSA-N 0.000 description 1
- UQNRMYUOJMQZHQ-UHFFFAOYSA-N N-[4-[2-(ethylsulfamoyl)anilino]-2-[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]pyrimidin-5-yl]-3,5-dimethoxybenzamide Chemical compound C(C)NS(=O)(=O)C1=C(NC2=NC(=NC=C2NC(C2=CC(=CC(=C2)OC)OC)=O)NC2=CC(=C(C=C2)N2CCC(CC2)N2CCN(CC2)C)OC)C=CC=C1 UQNRMYUOJMQZHQ-UHFFFAOYSA-N 0.000 description 1
- HIBPKFXWOPYJPZ-UHFFFAOYSA-N N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-7-(2-morpholin-4-ylethoxy)quinazolin-6-yl]prop-2-enamide Chemical compound ClC1=C(OCC2=NC=CC=C2)C=CC(NC2=NC=NC3=CC(OCCN4CCOCC4)=C(NC(=O)C=C)C=C23)=C1 HIBPKFXWOPYJPZ-UHFFFAOYSA-N 0.000 description 1
- DOEOECWDNSEFDN-UHFFFAOYSA-N N-[5-[[4-(1-cyclopropylindol-3-yl)pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methylamino]-4-methoxyphenyl]prop-2-enamide Chemical compound C1(CC1)N1C=C(C2=CC=CC=C12)C1=NC(=NC=C1)NC=1C(=CC(=C(C=1)NC(C=C)=O)N(C)CCN(C)C)OC DOEOECWDNSEFDN-UHFFFAOYSA-N 0.000 description 1
- BHKDKKZMPODMIQ-UHFFFAOYSA-N N-[5-cyano-4-(2-methoxyethylamino)pyridin-2-yl]-7-formyl-6-[(4-methyl-2-oxopiperazin-1-yl)methyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide Chemical compound COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)CC4=O)c(C=O)nc23)ncc1C#N BHKDKKZMPODMIQ-UHFFFAOYSA-N 0.000 description 1
- YJUANBRSJHPDHJ-UHFFFAOYSA-N N-ethyl-2-[[4-[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-1,3,5-triazin-2-yl]amino]benzenesulfonamide Chemical compound CCNS(=O)(=O)C1=CC=CC=C1NC2=NC=NC(=N2)NC3=CC(=C(C=C3)N4CCC(CC4)N5CCN(CC5)C)OC YJUANBRSJHPDHJ-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 108020004485 Nonsense Codon Proteins 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- QITOONQVTOGMOJ-IUJXYRIYSA-N O.O.OC(=O)\C=C/C(O)=O.CN1CCN(CC1)c1ccc(Nc2nc(Oc3cccc(NC(=O)C=C)c3)c3cc[nH]c3n2)cc1F Chemical compound O.O.OC(=O)\C=C/C(O)=O.CN1CCN(CC1)c1ccc(Nc2nc(Oc3cccc(NC(=O)C=C)c3)c3cc[nH]c3n2)cc1F QITOONQVTOGMOJ-IUJXYRIYSA-N 0.000 description 1
- BYYQDEOVMILBQT-XZJROXQQSA-N O1C=2C=3N([C@@H]4CCC[C@H]14)CC1=CC(F)=CN=C1O[C@@H](C)CNC(=O)C1=C(N=3)N(C=2)N=C1 Chemical compound O1C=2C=3N([C@@H]4CCC[C@H]14)CC1=CC(F)=CN=C1O[C@@H](C)CNC(=O)C1=C(N=3)N(C=2)N=C1 BYYQDEOVMILBQT-XZJROXQQSA-N 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 239000012661 PARP inhibitor Substances 0.000 description 1
- OYONTEXKYJZFHA-SSHUPFPWSA-N PHA-665752 Chemical compound CC=1C(C(=O)N2[C@H](CCC2)CN2CCCC2)=C(C)NC=1\C=C(C1=C2)/C(=O)NC1=CC=C2S(=O)(=O)CC1=C(Cl)C=CC=C1Cl OYONTEXKYJZFHA-SSHUPFPWSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229940126233 Pemazyre Drugs 0.000 description 1
- 208000031839 Peripheral nerve sheath tumour malignant Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 229940126232 Tabrecta Drugs 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- MXDSJQHFFDGFDK-CYBMUJFWSA-N [4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl] (2r)-2,4-dimethylpiperazine-1-carboxylate Chemical compound C=12C=C(OC(=O)N3[C@@H](CN(C)CC3)C)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F MXDSJQHFFDGFDK-CYBMUJFWSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000037844 advanced solid tumor Diseases 0.000 description 1
- 229940083773 alecensa Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- UNNKKUDWEASWDN-UHFFFAOYSA-N alkannin Natural products CC(=CCC(O)c1cc(O)c2C(=O)C=CC(=O)c2c1O)C UNNKKUDWEASWDN-UHFFFAOYSA-N 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000008850 allosteric inhibition Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940008421 amivantamab Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 239000000611 antibody drug conjugate Substances 0.000 description 1
- 229940049595 antibody-drug conjugate Drugs 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- LASLVGACQUUOEB-UHFFFAOYSA-N bicyclo[1.1.0]butane Chemical compound C1C2CC21 LASLVGACQUUOEB-UHFFFAOYSA-N 0.000 description 1
- JSMRMEYFZHIPJV-UHFFFAOYSA-N bicyclo[2.1.1]hexane Chemical compound C1C2CC1CC2 JSMRMEYFZHIPJV-UHFFFAOYSA-N 0.000 description 1
- GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 description 1
- JAPMJSVZDUYFKL-UHFFFAOYSA-N bicyclo[3.1.0]hexane Chemical compound C1CCC2CC21 JAPMJSVZDUYFKL-UHFFFAOYSA-N 0.000 description 1
- SHOMMGQAMRXRRK-UHFFFAOYSA-N bicyclo[3.1.1]heptane Chemical compound C1C2CC1CCC2 SHOMMGQAMRXRRK-UHFFFAOYSA-N 0.000 description 1
- AWYMFBJJKFTCFO-UHFFFAOYSA-N bicyclo[3.2.0]heptane Chemical compound C1CCC2CCC21 AWYMFBJJKFTCFO-UHFFFAOYSA-N 0.000 description 1
- RPZUBXWEQBPUJR-UHFFFAOYSA-N bicyclo[4.2.0]octane Chemical compound C1CCCC2CCC21 RPZUBXWEQBPUJR-UHFFFAOYSA-N 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 102220003872 c.102del Human genes 0.000 description 1
- 102220360961 c.140delC Human genes 0.000 description 1
- 102200107885 c.314G>T Human genes 0.000 description 1
- 102200107845 c.326T>G Human genes 0.000 description 1
- 102200107823 c.338T>G Human genes 0.000 description 1
- 102220353798 c.362_363delCT Human genes 0.000 description 1
- 102220391117 c.371dup Human genes 0.000 description 1
- 102200109030 c.400T>C Human genes 0.000 description 1
- 102200108873 c.407A>C Human genes 0.000 description 1
- 102200108844 c.417G>T Human genes 0.000 description 1
- 102200108567 c.442G>A Human genes 0.000 description 1
- 102220391122 c.444dup Human genes 0.000 description 1
- 102200108625 c.467G>C Human genes 0.000 description 1
- 102220360284 c.501delG Human genes 0.000 description 1
- 102200106089 c.534C>A Human genes 0.000 description 1
- 102220397853 c.565del Human genes 0.000 description 1
- 102200105416 c.623A>G Human genes 0.000 description 1
- 102220391141 c.643dup Human genes 0.000 description 1
- 102200106707 c.672G>T Human genes 0.000 description 1
- 102200106407 c.695T>G Human genes 0.000 description 1
- 102200106201 c.718A>G Human genes 0.000 description 1
- 102220344661 c.720_723del Human genes 0.000 description 1
- 102200104322 c.775G>T Human genes 0.000 description 1
- 102200103785 c.808T>C Human genes 0.000 description 1
- 102200103768 c.815T>C Human genes 0.000 description 1
- 102200104043 c.817C>G Human genes 0.000 description 1
- 102200104863 c.840A>C Human genes 0.000 description 1
- 102220002159 c.885delG Human genes 0.000 description 1
- 102220420252 c.946_947insTACT Human genes 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 1
- 229950005852 capmatinib Drugs 0.000 description 1
- 229940056434 caprelsa Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000004637 cellular stress Effects 0.000 description 1
- 229960001602 ceritinib Drugs 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- ZXIJMRYMVAMXQP-UHFFFAOYSA-N cycloheptene Chemical compound C1CCC=CCC1 ZXIJMRYMVAMXQP-UHFFFAOYSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229940074165 dalpiciclib Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000001064 degrader Substances 0.000 description 1
- 229950002756 depatuxizumab Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000005051 dihydropyrazinyl group Chemical group N1(CC=NC=C1)* 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 201000003683 endocervical adenocarcinoma Diseases 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 1
- 229940125829 fibroblast growth factor receptor inhibitor Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 229950008692 foretinib Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000037433 frameshift Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229940121446 futibatinib Drugs 0.000 description 1
- 229940124667 gavreto Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- MHLPKAGDPWUOOT-UHFFFAOYSA-N housane Chemical compound C1CC2CC21 MHLPKAGDPWUOOT-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 description 1
- 229940061301 ibrance Drugs 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- 229950007440 icotinib Drugs 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 125000005298 iminyl group Chemical group 0.000 description 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical class C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 229950005712 infigratinib Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 208000030776 invasive breast carcinoma Diseases 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- BVRYLTBIGIAADD-UHFFFAOYSA-N isobutyryl shikonin Natural products C1=CC(O)=C2C(=O)C(C(CC=C(C)C)OC(=O)C(C)C)=CC(=O)C2=C1O BVRYLTBIGIAADD-UHFFFAOYSA-N 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940121577 lerociclib Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000004335 litholrubine BK Substances 0.000 description 1
- 229950001290 lorlatinib Drugs 0.000 description 1
- 208000030173 low grade glioma Diseases 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000004137 magnesium phosphate Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 201000009020 malignant peripheral nerve sheath tumor Diseases 0.000 description 1
- WJEOLQLKVOPQFV-UHFFFAOYSA-N masitinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3SC=C(N=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 WJEOLQLKVOPQFV-UHFFFAOYSA-N 0.000 description 1
- 229950008001 matuzumab Drugs 0.000 description 1
- 229940121300 mavelertinib Drugs 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 208000037843 metastatic solid tumor Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000006393 methylpyrimidinyl group Chemical group 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002324 minimally invasive surgery Methods 0.000 description 1
- 229940015637 mobocertinib Drugs 0.000 description 1
- 229950005674 modotuximab Drugs 0.000 description 1
- 230000009149 molecular binding Effects 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- TXEBNKKOLVBTFK-UHFFFAOYSA-N n-[2-[[6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl]amino]-3-methylphenyl]prop-2-enamide Chemical compound COC1=CC(OC)=C(Cl)C(C=2C=C3C=NC(NC=4C(=CC=CC=4C)NC(=O)C=C)=NC3=CC=2)=C1Cl TXEBNKKOLVBTFK-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- ZAJXXUDARPGGOC-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[3-methyl-3-(4-methylpiperazin-1-yl)but-1-ynyl]quinazolin-6-yl]prop-2-enamide Chemical compound C1CN(C)CCN1C(C)(C)C#CC1=CC2=NC=NC(NC=3C=C(Cl)C(F)=CC=3)=C2C=C1NC(=O)C=C ZAJXXUDARPGGOC-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 229960000513 necitumumab Drugs 0.000 description 1
- 208000029974 neurofibrosarcoma Diseases 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- 230000037434 nonsense mutation Effects 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 229950000778 olmutinib Drugs 0.000 description 1
- 230000006508 oncogene activation Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- YBKGERLDRMINOV-UHFFFAOYSA-N oxathiine Chemical compound O1SC=CC=C1 YBKGERLDRMINOV-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000000369 oxido group Chemical group [*]=O 0.000 description 1
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229940016624 pamufetinib Drugs 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229950006299 pelitinib Drugs 0.000 description 1
- 229940121317 pemigatinib Drugs 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000005004 perfluoroethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 208000037993 perihilar cancer Diseases 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000004297 potassium metabisulphite Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940121597 pralsetinib Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- AZSRSNUQCUDCGG-UHFFFAOYSA-N propan-2-yl 2-[4-[2-(dimethylamino)ethyl-methylamino]-2-methoxy-5-(prop-2-enoylamino)anilino]-4-(1-methylindol-3-yl)pyrimidine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C(=CC(=C(C=1)NC1=NC=C(C(=N1)C1=CN(C2=CC=CC=C12)C)C(=O)OC(C)C)OC)N(C)CCN(C)C AZSRSNUQCUDCGG-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 201000002709 prostate leiomyosarcoma Diseases 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 229940075576 pyrotinib Drugs 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 229940121602 repotrectinib Drugs 0.000 description 1
- OAKGNIRUXAZDQF-TXHRRWQRSA-N retaspimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(O)C1=CC(O)=C2NCC=C OAKGNIRUXAZDQF-TXHRRWQRSA-N 0.000 description 1
- 229940124668 retevmo Drugs 0.000 description 1
- 229940121323 roblitinib Drugs 0.000 description 1
- 229950009855 rociletinib Drugs 0.000 description 1
- 102200106263 rs1019340046 Human genes 0.000 description 1
- 102220193326 rs1057516395 Human genes 0.000 description 1
- 102220194246 rs1057516783 Human genes 0.000 description 1
- 102220194510 rs1057517215 Human genes 0.000 description 1
- 102220196216 rs1057517840 Human genes 0.000 description 1
- 102200102897 rs1057519747 Human genes 0.000 description 1
- 102200102909 rs1057519747 Human genes 0.000 description 1
- 102200108887 rs1057519976 Human genes 0.000 description 1
- 102200108787 rs1057519977 Human genes 0.000 description 1
- 102200108789 rs1057519978 Human genes 0.000 description 1
- 102200108810 rs1057519978 Human genes 0.000 description 1
- 102200102872 rs1057519980 Human genes 0.000 description 1
- 102200106221 rs1057519981 Human genes 0.000 description 1
- 102200106223 rs1057519981 Human genes 0.000 description 1
- 102200106293 rs1057519982 Human genes 0.000 description 1
- 102200106299 rs1057519982 Human genes 0.000 description 1
- 102200106302 rs1057519982 Human genes 0.000 description 1
- 102200103996 rs1057519983 Human genes 0.000 description 1
- 102200104855 rs1057519984 Human genes 0.000 description 1
- 102200104949 rs1057519985 Human genes 0.000 description 1
- 102200104954 rs1057519985 Human genes 0.000 description 1
- 102200103784 rs1057519986 Human genes 0.000 description 1
- 102200103789 rs1057519986 Human genes 0.000 description 1
- 102200103788 rs1057519988 Human genes 0.000 description 1
- 102200106284 rs1057519989 Human genes 0.000 description 1
- 102200106288 rs1057519989 Human genes 0.000 description 1
- 102200103808 rs1057519990 Human genes 0.000 description 1
- 102200106084 rs1057519991 Human genes 0.000 description 1
- 102200106085 rs1057519991 Human genes 0.000 description 1
- 102200105316 rs1057519992 Human genes 0.000 description 1
- 102220198383 rs1057519992 Human genes 0.000 description 1
- 102220198388 rs1057519994 Human genes 0.000 description 1
- 102200104254 rs1057519995 Human genes 0.000 description 1
- 102200109040 rs1057519996 Human genes 0.000 description 1
- 102200109041 rs1057519996 Human genes 0.000 description 1
- 102200109044 rs1057519996 Human genes 0.000 description 1
- 102200107825 rs1057519997 Human genes 0.000 description 1
- 102200107827 rs1057519997 Human genes 0.000 description 1
- 102200107830 rs1057519997 Human genes 0.000 description 1
- 102200105979 rs1057519998 Human genes 0.000 description 1
- 102200106019 rs1057519998 Human genes 0.000 description 1
- 102200106022 rs1057519998 Human genes 0.000 description 1
- 102200106204 rs1057519999 Human genes 0.000 description 1
- 102200108678 rs1057520000 Human genes 0.000 description 1
- 102200108679 rs1057520000 Human genes 0.000 description 1
- 102200106655 rs1057520001 Human genes 0.000 description 1
- 102200106178 rs1057520002 Human genes 0.000 description 1
- 102200106185 rs1057520002 Human genes 0.000 description 1
- 102200107928 rs1057520003 Human genes 0.000 description 1
- 102200104002 rs1057520005 Human genes 0.000 description 1
- 102200104000 rs1057520006 Human genes 0.000 description 1
- 102200105621 rs1057520007 Human genes 0.000 description 1
- 102200105618 rs1057520008 Human genes 0.000 description 1
- 102200105620 rs1057520008 Human genes 0.000 description 1
- 102200105622 rs1057520008 Human genes 0.000 description 1
- 102220209972 rs1057523496 Human genes 0.000 description 1
- 102200103771 rs1060501191 Human genes 0.000 description 1
- 102220223798 rs1060501194 Human genes 0.000 description 1
- 102200107871 rs1060501195 Human genes 0.000 description 1
- 102200107872 rs1060501195 Human genes 0.000 description 1
- 102200105394 rs1060501198 Human genes 0.000 description 1
- 102200104212 rs1060501201 Human genes 0.000 description 1
- 102200104225 rs1060501201 Human genes 0.000 description 1
- 102220216918 rs1060502667 Human genes 0.000 description 1
- 102220230258 rs1064793279 Human genes 0.000 description 1
- 102220230560 rs1064793436 Human genes 0.000 description 1
- 102200103913 rs1064793881 Human genes 0.000 description 1
- 102220230255 rs1064793929 Human genes 0.000 description 1
- 102200104147 rs1064794311 Human genes 0.000 description 1
- 102200102856 rs1064795203 Human genes 0.000 description 1
- 102220230256 rs1064795434 Human genes 0.000 description 1
- 102200108402 rs1064795691 Human genes 0.000 description 1
- 102200107849 rs1064796722 Human genes 0.000 description 1
- 102220012835 rs111033238 Human genes 0.000 description 1
- 102220232097 rs1114167407 Human genes 0.000 description 1
- 102220234555 rs1114167506 Human genes 0.000 description 1
- 102200104953 rs112431538 Human genes 0.000 description 1
- 102220234825 rs1131691010 Human genes 0.000 description 1
- 102200109052 rs1131691013 Human genes 0.000 description 1
- 102220234827 rs1131691014 Human genes 0.000 description 1
- 102220234832 rs1131691018 Human genes 0.000 description 1
- 102200102895 rs1131691021 Human genes 0.000 description 1
- 102200108475 rs1131691023 Human genes 0.000 description 1
- 102200103756 rs1131691025 Human genes 0.000 description 1
- 102220234811 rs1131691027 Human genes 0.000 description 1
- 102200103958 rs1131691029 Human genes 0.000 description 1
- 102200109051 rs1131691037 Human genes 0.000 description 1
- 102220234828 rs1131691041 Human genes 0.000 description 1
- 102200102900 rs1131691043 Human genes 0.000 description 1
- 102200104164 rs11540652 Human genes 0.000 description 1
- 102200104166 rs11540652 Human genes 0.000 description 1
- 102200104167 rs11540652 Human genes 0.000 description 1
- 102200107832 rs11540654 Human genes 0.000 description 1
- 102200107834 rs11540654 Human genes 0.000 description 1
- 102220259776 rs1187336837 Human genes 0.000 description 1
- 102200104161 rs121912651 Human genes 0.000 description 1
- 102200104218 rs121912652 Human genes 0.000 description 1
- 102200104281 rs121912653 Human genes 0.000 description 1
- 102200108481 rs121912654 Human genes 0.000 description 1
- 102200106301 rs121912655 Human genes 0.000 description 1
- 102200106303 rs121912655 Human genes 0.000 description 1
- 102200106274 rs121912656 Human genes 0.000 description 1
- 102200106277 rs121912656 Human genes 0.000 description 1
- 102200103763 rs121912657 Human genes 0.000 description 1
- 102200103766 rs121912657 Human genes 0.000 description 1
- 102200107958 rs121912658 Human genes 0.000 description 1
- 102200104853 rs121912660 Human genes 0.000 description 1
- 102200104859 rs121912660 Human genes 0.000 description 1
- 102200108135 rs121912661 Human genes 0.000 description 1
- 102200140664 rs121912664 Human genes 0.000 description 1
- 102200140666 rs121912664 Human genes 0.000 description 1
- 102200140684 rs121912664 Human genes 0.000 description 1
- 102200104955 rs121912667 Human genes 0.000 description 1
- 102200103765 rs121913343 Human genes 0.000 description 1
- 102200104037 rs121913343 Human genes 0.000 description 1
- 102220045790 rs137852790 Human genes 0.000 description 1
- 102220039648 rs137852794 Human genes 0.000 description 1
- 102200102876 rs138729528 Human genes 0.000 description 1
- 102200102889 rs138729528 Human genes 0.000 description 1
- 102220025474 rs141402957 Human genes 0.000 description 1
- 102220372282 rs144900708 Human genes 0.000 description 1
- 102200102846 rs147002414 Human genes 0.000 description 1
- 102220331974 rs1553159575 Human genes 0.000 description 1
- 102220244844 rs1553958127 Human genes 0.000 description 1
- 102220331645 rs1554578304 Human genes 0.000 description 1
- 102220341881 rs1555418701 Human genes 0.000 description 1
- 102220284588 rs1555515284 Human genes 0.000 description 1
- 102200140465 rs1555524094 Human genes 0.000 description 1
- 102220272145 rs1555524949 Human genes 0.000 description 1
- 102220282999 rs1555525156 Human genes 0.000 description 1
- 102220283635 rs1555525226 Human genes 0.000 description 1
- 102200103905 rs1555525248 Human genes 0.000 description 1
- 102200103986 rs1555525279 Human genes 0.000 description 1
- 102200104275 rs1555525465 Human genes 0.000 description 1
- 102220283028 rs1555525470 Human genes 0.000 description 1
- 102200106609 rs1555525743 Human genes 0.000 description 1
- 102200105649 rs1555525857 Human genes 0.000 description 1
- 102220272194 rs1555525902 Human genes 0.000 description 1
- 102200108436 rs1555526131 Human genes 0.000 description 1
- 102220288176 rs1555526137 Human genes 0.000 description 1
- 102220328629 rs1555526166 Human genes 0.000 description 1
- 102200108969 rs1555526241 Human genes 0.000 description 1
- 102200108877 rs1555526268 Human genes 0.000 description 1
- 102200107911 rs1555526335 Human genes 0.000 description 1
- 102200107865 rs1555526581 Human genes 0.000 description 1
- 102220272216 rs1555526795 Human genes 0.000 description 1
- 102220283721 rs1555526933 Human genes 0.000 description 1
- 102220296475 rs1555898000 Human genes 0.000 description 1
- 102220253039 rs1556121448 Human genes 0.000 description 1
- 102220276245 rs1556297749 Human genes 0.000 description 1
- 102220289957 rs1557007035 Human genes 0.000 description 1
- 102200103911 rs17849781 Human genes 0.000 description 1
- 102200103914 rs17849781 Human genes 0.000 description 1
- 102200103947 rs17849781 Human genes 0.000 description 1
- 102220336819 rs180177171 Human genes 0.000 description 1
- 102200103811 rs193920774 Human genes 0.000 description 1
- 102220010393 rs199422315 Human genes 0.000 description 1
- 102200114509 rs201382018 Human genes 0.000 description 1
- 102220286925 rs267602038 Human genes 0.000 description 1
- 102220026502 rs267608037 Human genes 0.000 description 1
- 102200104154 rs28934571 Human genes 0.000 description 1
- 102200106179 rs28934573 Human genes 0.000 description 1
- 102200106180 rs28934573 Human genes 0.000 description 1
- 102200106184 rs28934573 Human genes 0.000 description 1
- 102200104845 rs28934574 Human genes 0.000 description 1
- 102200104847 rs28934574 Human genes 0.000 description 1
- 102200106272 rs28934575 Human genes 0.000 description 1
- 102200106275 rs28934575 Human genes 0.000 description 1
- 102200106276 rs28934575 Human genes 0.000 description 1
- 102200104035 rs28934576 Human genes 0.000 description 1
- 102200104041 rs28934576 Human genes 0.000 description 1
- 102200104046 rs28934576 Human genes 0.000 description 1
- 102200104233 rs28934577 Human genes 0.000 description 1
- 102200104234 rs28934577 Human genes 0.000 description 1
- 102200104236 rs28934577 Human genes 0.000 description 1
- 102200102887 rs28934578 Human genes 0.000 description 1
- 102200102892 rs28934578 Human genes 0.000 description 1
- 102200108664 rs28934874 Human genes 0.000 description 1
- 102200108665 rs28934874 Human genes 0.000 description 1
- 102200108672 rs28934874 Human genes 0.000 description 1
- 102220004762 rs33932070 Human genes 0.000 description 1
- 102200104834 rs371409680 Human genes 0.000 description 1
- 102200104836 rs371409680 Human genes 0.000 description 1
- 102200108629 rs371524413 Human genes 0.000 description 1
- 102200140669 rs375338359 Human genes 0.000 description 1
- 102200106071 rs397514495 Human genes 0.000 description 1
- 102220230246 rs397516434 Human genes 0.000 description 1
- 102200105357 rs397516436 Human genes 0.000 description 1
- 102200106268 rs483352695 Human genes 0.000 description 1
- 102200105582 rs483352697 Human genes 0.000 description 1
- 102200106578 rs530941076 Human genes 0.000 description 1
- 102200106579 rs530941076 Human genes 0.000 description 1
- 102200108161 rs534447939 Human genes 0.000 description 1
- 102200103802 rs55832599 Human genes 0.000 description 1
- 102220054759 rs55863639 Human genes 0.000 description 1
- 102200108627 rs563378859 Human genes 0.000 description 1
- 102220008038 rs587776897 Human genes 0.000 description 1
- 102200105308 rs587778720 Human genes 0.000 description 1
- 102200105309 rs587778720 Human genes 0.000 description 1
- 102200105349 rs587778720 Human genes 0.000 description 1
- 102220036826 rs587780066 Human genes 0.000 description 1
- 102220036827 rs587780067 Human genes 0.000 description 1
- 102200108474 rs587780068 Human genes 0.000 description 1
- 102200106083 rs587780070 Human genes 0.000 description 1
- 102200106088 rs587780070 Human genes 0.000 description 1
- 102200106021 rs587780071 Human genes 0.000 description 1
- 102200106095 rs587780073 Human genes 0.000 description 1
- 102200106102 rs587780073 Human genes 0.000 description 1
- 102200106264 rs587780074 Human genes 0.000 description 1
- 102200106269 rs587780074 Human genes 0.000 description 1
- 102200103806 rs587780075 Human genes 0.000 description 1
- 102200103807 rs587780075 Human genes 0.000 description 1
- 102200108793 rs587781288 Human genes 0.000 description 1
- 102200108808 rs587781288 Human genes 0.000 description 1
- 102200107842 rs587781371 Human genes 0.000 description 1
- 102200107867 rs587781504 Human genes 0.000 description 1
- 102200104843 rs587781525 Human genes 0.000 description 1
- 102200106406 rs587781589 Human genes 0.000 description 1
- 102200107804 rs587781642 Human genes 0.000 description 1
- 102200102699 rs587781845 Human genes 0.000 description 1
- 102200108879 rs587781991 Human genes 0.000 description 1
- 102200109026 rs587781991 Human genes 0.000 description 1
- 102200104151 rs587782082 Human genes 0.000 description 1
- 102200104158 rs587782082 Human genes 0.000 description 1
- 102200108445 rs587782144 Human genes 0.000 description 1
- 102200108469 rs587782144 Human genes 0.000 description 1
- 102200108470 rs587782144 Human genes 0.000 description 1
- 102200106653 rs587782177 Human genes 0.000 description 1
- 102200106657 rs587782177 Human genes 0.000 description 1
- 102200108940 rs587782197 Human genes 0.000 description 1
- 102200108958 rs587782197 Human genes 0.000 description 1
- 102220045646 rs587782270 Human genes 0.000 description 1
- 102200106241 rs587782289 Human genes 0.000 description 1
- 102200106245 rs587782289 Human genes 0.000 description 1
- 102200104156 rs587782329 Human genes 0.000 description 1
- 102200104159 rs587782329 Human genes 0.000 description 1
- 102200107847 rs587782461 Human genes 0.000 description 1
- 102200140682 rs587782529 Human genes 0.000 description 1
- 102200106077 rs587782596 Human genes 0.000 description 1
- 102200108973 rs587782620 Human genes 0.000 description 1
- 102200106230 rs587782664 Human genes 0.000 description 1
- 102200108666 rs587782705 Human genes 0.000 description 1
- 102220283048 rs587782769 Human genes 0.000 description 1
- 102220033544 rs61753258 Human genes 0.000 description 1
- 102220034887 rs62508587 Human genes 0.000 description 1
- 102220027794 rs63750786 Human genes 0.000 description 1
- 102220054261 rs727504416 Human genes 0.000 description 1
- 102220057317 rs730880454 Human genes 0.000 description 1
- 102220058321 rs730881995 Human genes 0.000 description 1
- 102200107932 rs730881997 Human genes 0.000 description 1
- 102200107902 rs730881999 Human genes 0.000 description 1
- 102200107903 rs730881999 Human genes 0.000 description 1
- 102200108435 rs730882000 Human genes 0.000 description 1
- 102200105803 rs730882002 Human genes 0.000 description 1
- 102200105633 rs730882003 Human genes 0.000 description 1
- 102200106225 rs730882004 Human genes 0.000 description 1
- 102200106208 rs730882005 Human genes 0.000 description 1
- 102200106222 rs730882005 Human genes 0.000 description 1
- 102200106224 rs730882005 Human genes 0.000 description 1
- 102200104841 rs730882008 Human genes 0.000 description 1
- 102220058320 rs730882015 Human genes 0.000 description 1
- 102220058323 rs730882018 Human genes 0.000 description 1
- 102220058316 rs730882019 Human genes 0.000 description 1
- 102200106630 rs730882025 Human genes 0.000 description 1
- 102200106632 rs730882025 Human genes 0.000 description 1
- 102200106246 rs730882026 Human genes 0.000 description 1
- 102200140670 rs730882028 Human genes 0.000 description 1
- 102200060141 rs74315507 Human genes 0.000 description 1
- 102200104323 rs745425759 Human genes 0.000 description 1
- 102200109038 rs747342068 Human genes 0.000 description 1
- 102200109042 rs747342068 Human genes 0.000 description 1
- 102200104938 rs748891343 Human genes 0.000 description 1
- 102220062187 rs749061599 Human genes 0.000 description 1
- 102200108842 rs750600586 Human genes 0.000 description 1
- 102200102843 rs751477326 Human genes 0.000 description 1
- 102200102850 rs751477326 Human genes 0.000 description 1
- 102200103907 rs753660142 Human genes 0.000 description 1
- 102200108882 rs758781593 Human genes 0.000 description 1
- 102200105975 rs760043106 Human genes 0.000 description 1
- 102200105977 rs760043106 Human genes 0.000 description 1
- 102200103949 rs763098116 Human genes 0.000 description 1
- 102200103951 rs763098116 Human genes 0.000 description 1
- 102200104848 rs764146326 Human genes 0.000 description 1
- 102200106183 rs764342812 Human genes 0.000 description 1
- 102200106228 rs765848205 Human genes 0.000 description 1
- 102200108663 rs767328513 Human genes 0.000 description 1
- 102220062191 rs769934890 Human genes 0.000 description 1
- 102200104916 rs770374782 Human genes 0.000 description 1
- 102200108415 rs772354334 Human genes 0.000 description 1
- 102200107925 rs786201057 Human genes 0.000 description 1
- 102200104951 rs786201059 Human genes 0.000 description 1
- 102200104173 rs786201762 Human genes 0.000 description 1
- 102200106009 rs786201838 Human genes 0.000 description 1
- 102200106013 rs786201838 Human genes 0.000 description 1
- 102220062161 rs786202055 Human genes 0.000 description 1
- 102200103988 rs786202082 Human genes 0.000 description 1
- 102200103990 rs786202082 Human genes 0.000 description 1
- 102220004381 rs786202525 Human genes 0.000 description 1
- 102200108634 rs786202752 Human genes 0.000 description 1
- 102200102859 rs786202962 Human genes 0.000 description 1
- 102200102871 rs786202962 Human genes 0.000 description 1
- 102200108957 rs786203071 Human genes 0.000 description 1
- 102200108963 rs786203071 Human genes 0.000 description 1
- 102200102922 rs786203436 Human genes 0.000 description 1
- 102200102924 rs786203436 Human genes 0.000 description 1
- 102200102927 rs786203436 Human genes 0.000 description 1
- 102200105569 rs786204041 Human genes 0.000 description 1
- 102200105572 rs786204041 Human genes 0.000 description 1
- 102220073975 rs796052021 Human genes 0.000 description 1
- 102220076542 rs796053424 Human genes 0.000 description 1
- 102220004382 rs863223301 Human genes 0.000 description 1
- 102200103984 rs863224451 Human genes 0.000 description 1
- 102200103993 rs863224451 Human genes 0.000 description 1
- 102200103994 rs863224451 Human genes 0.000 description 1
- 102220083770 rs863224516 Human genes 0.000 description 1
- 102200109053 rs863224683 Human genes 0.000 description 1
- 102200109064 rs863224683 Human genes 0.000 description 1
- 102220085288 rs864309495 Human genes 0.000 description 1
- 102220234815 rs864309495 Human genes 0.000 description 1
- 102200106100 rs864622237 Human genes 0.000 description 1
- 102200106101 rs864622237 Human genes 0.000 description 1
- 102200109039 rs866775781 Human genes 0.000 description 1
- 102200102774 rs867114783 Human genes 0.000 description 1
- 102220091820 rs876657674 Human genes 0.000 description 1
- 102200105795 rs876658468 Human genes 0.000 description 1
- 102200106008 rs876658468 Human genes 0.000 description 1
- 102200106012 rs876658468 Human genes 0.000 description 1
- 102220097771 rs876659215 Human genes 0.000 description 1
- 102200104242 rs876659675 Human genes 0.000 description 1
- 102200104256 rs876659675 Human genes 0.000 description 1
- 102200103895 rs876659802 Human genes 0.000 description 1
- 102200103896 rs876659802 Human genes 0.000 description 1
- 102200103912 rs876659802 Human genes 0.000 description 1
- 102200103764 rs876660333 Human genes 0.000 description 1
- 102220097402 rs876660726 Human genes 0.000 description 1
- 102200102908 rs876660754 Human genes 0.000 description 1
- 102200102912 rs876660754 Human genes 0.000 description 1
- 102200106214 rs876660807 Human genes 0.000 description 1
- 102200106082 rs876660821 Human genes 0.000 description 1
- 102200105828 rs876660825 Human genes 0.000 description 1
- 102200105844 rs876660825 Human genes 0.000 description 1
- 102220105063 rs879253905 Human genes 0.000 description 1
- 102200106080 rs879253911 Human genes 0.000 description 1
- 102200103813 rs879253942 Human genes 0.000 description 1
- 102220105064 rs879254214 Human genes 0.000 description 1
- 102200102918 rs879254249 Human genes 0.000 description 1
- 102220105396 rs879254491 Human genes 0.000 description 1
- 102220003083 rs886037613 Human genes 0.000 description 1
- 102200107909 rs886039483 Human genes 0.000 description 1
- 102200107910 rs886039483 Human genes 0.000 description 1
- 102200105318 rs886039484 Human genes 0.000 description 1
- 102220115964 rs886040340 Human genes 0.000 description 1
- 102220118387 rs886041254 Human genes 0.000 description 1
- 102220118096 rs886041285 Human genes 0.000 description 1
- 102220118030 rs886041861 Human genes 0.000 description 1
- 102220127267 rs886044525 Human genes 0.000 description 1
- 102220328897 rs922736614 Human genes 0.000 description 1
- 102200102857 rs967461896 Human genes 0.000 description 1
- 102200102861 rs967461896 Human genes 0.000 description 1
- 102200102862 rs967461896 Human genes 0.000 description 1
- 102200106287 rs985033810 Human genes 0.000 description 1
- 102200106291 rs985033810 Human genes 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- DFJSJLGUIXFDJP-UHFFFAOYSA-N sapitinib Chemical compound C1CN(CC(=O)NC)CCC1OC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(Cl)=C1F DFJSJLGUIXFDJP-UHFFFAOYSA-N 0.000 description 1
- 229950003500 savolitinib Drugs 0.000 description 1
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulphite Substances [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- OGNAOIGAPPSUMG-UHFFFAOYSA-N spiro[2.2]pentane Chemical compound C1CC11CC1 OGNAOIGAPPSUMG-UHFFFAOYSA-N 0.000 description 1
- FOEYMRPOKBCNCR-UHFFFAOYSA-N spiro[2.5]octane Chemical compound C1CC11CCCCC1 FOEYMRPOKBCNCR-UHFFFAOYSA-N 0.000 description 1
- DVDJICIUXXAIKJ-UHFFFAOYSA-N spiro[2.6]nonane Chemical compound C1CC11CCCCCC1 DVDJICIUXXAIKJ-UHFFFAOYSA-N 0.000 description 1
- PLDXRPSSERMPSV-UHFFFAOYSA-N spiro[3.6]decane Chemical compound C1CCC21CCCCCC2 PLDXRPSSERMPSV-UHFFFAOYSA-N 0.000 description 1
- PHICBFWUYUCFKS-UHFFFAOYSA-N spiro[4.4]nonane Chemical compound C1CCCC21CCCC2 PHICBFWUYUCFKS-UHFFFAOYSA-N 0.000 description 1
- NECLQTPQJZSWOE-UHFFFAOYSA-N spiro[5.5]undecane Chemical compound C1CCCCC21CCCCC2 NECLQTPQJZSWOE-UHFFFAOYSA-N 0.000 description 1
- CTDQAGUNKPRERK-UHFFFAOYSA-N spirodecane Chemical compound C1CCCC21CCCCC2 CTDQAGUNKPRERK-UHFFFAOYSA-N 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 229940074352 taletrectinib Drugs 0.000 description 1
- AYUNIORJHRXIBJ-TXHRRWQRSA-N tanespimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCC=C)C(=O)C=C1C2=O AYUNIORJHRXIBJ-TXHRRWQRSA-N 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940125442 tepmetko Drugs 0.000 description 1
- 229950009455 tepotinib Drugs 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 229950007127 trilaciclib Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229940125460 truseltiq Drugs 0.000 description 1
- 229950003463 tucatinib Drugs 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- 230000002100 tumorsuppressive effect Effects 0.000 description 1
- 229940094060 tykerb Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229950008250 zalutumumab Drugs 0.000 description 1
- 229940125135 zeteletinib Drugs 0.000 description 1
- 229940073676 zoligratinib Drugs 0.000 description 1
- 229940052129 zykadia Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and/or symptoms and/or progression of the disease (e.g., cancer) in a subject (e g., a human).
- a disease in which decreased p53 function contributes to the pathology and/or symptoms and/or progression of the disease (e.g., cancer) in a subject (e g., a human).
- the tumor suppressor p53 encoded by the TP53 gene, is a transcription factor that regulates the expression of genes required for DNA repair, cell cycle arrest, senescence, and apoptosis, and p53 plays a critical role in mediating each of these processes (Alvarado-Ortiz et al., Frontiers in Cell and Developmental Biology (2021) 8, Article 607670; Vousden et al., Cell (2009) 137, 413-431; Bieging et al., Nat. Rev. Cancer (2014) 14, 359-370).
- TP53 is altered in over 50% of all human cancers, making it the most frequently mutated gene among oncogenes and tumor suppressor genes (Hainaut et al., Adv Cancer Res (2000) 77, 81-137; Joerger et al., Cold Spring Harb. Perspect. Biol. (2010) 2(6), Article a000919). Mutations in TP53 result in loss of its normal function, rendering cells incapable of responding to a variety of cellular stresses such as DNA damage or oncogene activation, making them susceptible to tumorigenesis (Joerger et al., Oncogene (2007) 26, 2226-2242).
- mutant p53 reactivation will restore its tumor suppressive functions, stimulating p53-dependent arrest or apoptosis and resulting in efficient elimination of tumor cells (Selivanova et al., Oncogene (2007) 26, 2243-2254).
- the p53 Y220C mutation occurs in -1% of human cancers; -100,000 new cancer cases per year worldwide (Joerger et al., Annu. Rev. Biochem.
- Stabilization of the mutant protein may restore and/or maintain the functional conformation of the protein (Baud et al., Eur J Med Chem. (2016) 25, 101-114; Rauf et al., Protein J (2013) 32, 68- 74).
- the Y200C mutation there is a small molecule binding pocket far away from the binding interface between p53 and DNA, such that small molecule engagement at this pocket will not disrupt DNA binding (Bauer et al., Future Med. Chem. (2019) 11, 2491-2504).
- Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
- X 1 is CR 1 or N
- L is an optionally substituted 4-6 membered heterocyclylene or an optionally substituted 5-6 membered heteroarylene; m is 0, 1, or 2; and each R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
- a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
- Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
- a method of treating a p53-associated cancer in a subject comprising administering to a subject identified or diagnosed as having a p53-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
- This disclosure also provides a method of treating a p53-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a p53 -associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
- a method of treating a p53-associated cancer in a subject comprising administering to a subject identified or diagnosed as having a p53-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
- This disclosure also provides a method of treating a p53-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a p53 -associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
- a method of treating a subject comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
- This disclosure also provides a method for restoring p53 function in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
- terapéuticaally effective amount means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a p53 protein-associated cancer, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular cancer or (iii) delay the onset of one or more symptoms of the particular cancer, described herein.
- pharmaceutically acceptable excipient means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material.
- each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
- pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
- pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
- a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
- Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt.
- the salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.
- mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
- organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tart
- the “subject” refers to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans.
- the subject is a human.
- the subject has experienced and/or exhibited at least one symptom of the cancer to be treated.
- treat or “treatment” refer to therapeutic or palliative measures.
- Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a cancer, diminishment of the extent of the cancer, stabilized (i.e., not worsening) state of disease, delay or slowing of cancer progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the cancer), and remission (whether partial or total), whether detectable or undetectable.
- Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
- Non-limiting examples of optional substituents are halogen, cyano, hydroxyl, nitro, nitroso, azido, sulfhydryl, acyl, alkyl, hydroxyalkyl, aminoalkyl, alkoxyamino, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, hydroxyalkoxy, alkoxyalkoxy, alkenoxy, alkynoxy, haloalkoxy, haloalkenoxy, haloalkynoxy, cycloalkyl, halocycloalkyl, cycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, aralkyl, cycloalkylalkyl, heteroaralkyl, alkoxyalkyl, heterocyclylalkyl, thiocarbonyl, O-carbamyl,
- halogen refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
- hydroxyl refers to an -OH radical.
- sulfhydryl refers to a –SH radical.
- cyano refers to a -CN radical.
- zido refers to a –N3 radical.
- nitro refers to a –NO2 radical.
- alkyl refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-C10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, /e/7-butyl, w-hexyl.
- saturated as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.
- alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
- An alkenyl group may be unsubstituted or substituted.
- alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
- An alkynyl group may be unsubstituted or substituted.
- aryl refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent.
- aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.
- cycloalkyl refers to cyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted.
- cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
- Cycloalkyl may include multiple fused and/or bridged rings.
- Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[l.l. l]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2. l]octane, bicyclo[2.2.2]octane, and the like.
- Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
- spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.
- saturated as used in this context means only single bonds present between constituent carbon atoms.
- heteroaryl means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, S, P, B, and Si and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e g., tetrahydroquinolinyl). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents.
- heteroaryl examples include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-J]pyrimidinyl, pyrrolo[2,3-/>]pyridinyl, quinazoliny
- the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
- heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more
- heterocyclyl refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, P, S, B, or Si (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, P, S, B, or Si if monocyclic, bicyclic, or tricyclic, respectively), wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g
- heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, di hydrofuranyl, dihydrothiophenyl, oxaphosphinanyl oxide, azaphosphinanyl oxide, and the like.
- Heterocyclyl may include multiple fused and bridged rings.
- Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2- azabicyclo[l.l.l]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3- azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7- azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2- azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2- oxabicyclo[2.1.0]pentane, 2-oxabicyclo
- Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
- spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4- azaspiro[2.5]octane, l-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2- azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4- oxaspiro[2.5]octane, l-oxaspiro[[
- aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.
- haloalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
- halocycloalkyl refers to a cycloalkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
- hydroxyalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with hydroxyl.
- haloalkenyl refers to an alkenyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
- haloalkynyl refers to an alkynyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
- alkoxy refers to an -O-alkyl radical (e.g., -OCH3).
- alkoxyalkyl refers to an alkyl, in which one or two hydrogen atoms is/are replaced with an independently selected alkoxy (e.g., methoxy ethyl).
- hydroxyalkoxy refers to an alkoxy group, in which one or two hydrogen atoms is/are replaced with hydroxy.
- alkoxyalkoxy refers to an alkoxy group, in which one or two hydrogen atoms is/are replaced with an independently selected alkoxy.
- alkoxyamino refers to an -O-amino radical (e.g., -OCH2CH2N(CH3)2).
- haloalkoxy refers to an -O-haloalkyl radical (e g., -OCF3).
- alkenoxy refers to an -O-alkenyl radical (e.g., -O-allyl).
- haloalkenoxy refers to an -O-haloalkenyl radical.
- alkynoxy refers to an -O-alkynyl radical (e.g., -O-propargyl).
- haloalkynoxy refers to an -O-haloalkynyl radical.
- cycloalkoxy refers to an -O-cycloalkyl radical (e.g., -O-cyclopropyl).
- aryloxy refers to an -O-aryl radical (e.g., phenoxy).
- heteroaryloxy refers to an -O-heteroaryl radical (e.g., pyridinoxy).
- heterocyclyloxy refers to an -O-heterocyclyl radical (e.g., -O-pyrrolidinyl or -O-oxetanyl).
- aralkyl refer to an aryl group connected, as a substituent, via an alkyl group (e.g., benzyl).
- cycloalkylalkyl refers to a cycloalkyl group connected, as a substituent, via an alkyl group (e.g., ethylcyclobutyl).
- heteroarylkyl refers to a heteroaryl group connected, as a substituent, via an alkyl group (e.g., methylpyrimidinyl).
- heterocyclylalkyl refers to a heterocyclyl group connected, as a substituent, via an alkyl group (e.g., methyloxetanyl).
- aralkoxy refers to an aryl group connected, as a substituent, via an alkoxy group (e.g., benzyl oxy).
- cycloalkylalkoxy refers to a cycloalkyl connected, as a substituent, via an alkoxy group (e.g., methoxycyclopropyl).
- aminoalkyl refers to an amino group connected, as a substituent, via an alkyl group (e.g., methyl(dimethylamino)).
- a “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
- halosulfenyl group refers to a sulfenyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen (e.g., -S(CFs) or -S(CHF2)).
- halogen e.g., -S(CFs) or -S(CHF2)
- a “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl.
- a “trihalomethanesulfonyl” group refers to an “X3CSO2-” group wherein each X is a halogen.
- a “trihalomethanesulfonamido” group refers to an “X3CS(O)2N(R’)-” group wherein each X is a halogen, and R’ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
- S-sulfonamido refers to a “-S02N(RR’)” group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
- N-sulfonamido refers to a “RS02N(R’)-” group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
- amino refers to a -NRR’ radical, where R and R’ are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
- an amino group is -NH2
- R is hydrogen and R’ is alkyl
- a dialkylamine R and R’ are independently selected alkyl.
- a ring when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic.
- additional degrees of unsaturation in addition to the degree of unsaturation attributed to the ring itself; e g., one or more double or triple bonds between constituent ring atoms
- examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.
- rings and cyclic groups e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein
- rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms
- ring systems e.g., [x.x.O] ring systems, in which 0 represents a zero atom bridge (e.g., )
- a single ring atom spiro-fused ring systems
- bridged ring systems having all bridge lengths > 0
- atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms.
- Isotopes include those atoms having the same atomic number but different mass numbers.
- isotopes of hydrogen include tritium and deuterium
- isotopes of carbon include 13 C and 14 C.
- a compound containing the moiety encompasses the tautomeric form containing the moiety: H 5
- a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
- the compounds provided herein may encompass various stereochemical forms.
- the compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds.
- enantiomers e.g., R and S isomers
- diastereomers e.g., R and S isomers
- mixtures of enantiomers e.g., R and S isomers
- a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and/or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound.
- This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and/or symptoms and/or progression of the disease (e.g., cancer) in a subject (e.g., a human).
- a disease in which decreased p53 function contributes to the pathology and/or symptoms and/or progression of the disease (e.g., cancer) in a subject (e.g., a human).
- Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
- X 1 is CR 1 or N
- R 2B each R is ;
- Z 2 is CR 2C , N, O, or a bond; wherein when Z 2 is O, R 2B is absent, and when Z 1 is a bond and Z 2 is a bond, R 2B is absent and R 2A is directly connected to Formula (I) via Z 1 ;
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of: pharmaceutically acceptable salt of any of the foregoing.
- one of X 2 , X 3 , X 4 , and X 5 is N.
- two of X 2 , X 3 , X 4 , and X 5 are N.
- X 1 is CR 1 .
- R 1 is hydrogen
- R 1 is halogen
- R 1 is cyano
- R 1 is -OR 4 .
- R 1 is -NR 4 R 5 .
- R 1 is -SR 4 .
- R 1 is -S(O2)R 4 .
- R 4 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 4 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
- R 4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 4 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
- R 4 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 4 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
- R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 5 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
- R’ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 5 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
- R 5 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 5 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R 4 and R 3 are attached to the same nitrogen atom, R 4 and R 5 are the same. In some embodiments, when R 4 and R 5 are attached to the same nitrogen atom, R 4 and R 5 are different. In some embodiments, when R 4 and R 3 are attached to the same nitrogen atom, R 4 and R 5 are each hydrogen. In some embodiments, when R 4 and R 3 are attached to the same nitrogen atom, R 4 and R 5 are each an independently selected C1-C6 alkyl.
- R 4 and R 5 when R 4 and R 5 are attached to the same nitrogen atom, one of R 4 and R 5 is hydrogen and the other of R 4 and R 5 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 4 and R 5 when R 4 and R 5 are attached to the same nitrogen atom, one of R 4 and R 3 is hydrogen and the other of R 4 and R 5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 1 is optionally substituted C1-C6 alkyl. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R x is methyl or ethyl.
- R 1 is optionally substituted C2-C6 alkenyl. In some embodiments, R 1 is C2-C6 alkenyl. In some embodiments, R x is optionally substituted C2-C3 alkenyl. In some embodiments, R x is C2-C3 alkenyl.
- R 1 is optionally substituted C2-C6 alkynyl. In some embodiments, R 1 is C2-C6 alkynyl. In some embodiments, R 4 is optionally substituted C2-C3 alkynyl. In some embodiments, R x is C2-C3 alkynyl.
- R 1 is optionally substituted C3-C6 cycloalkyl.
- R x is C3-C6 cycloalkyl.
- R 1 is optionally substituted phenyl. In some embodiments, R 1 is phenyl.
- R 1 is optionally substituted 4-6 membered heterocyclyl. In some embodiments, R 1 is 4-6 membered heterocyclyl.
- R 1 is optionally substituted 5-6 membered heteroaryl. In some embodiments, R 1 is 5-6 membered heteroaryl.
- X 1 is N.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of: a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
- ADa ADa
- I-AEa a pharmaceutically acceptable salt of any of the foregoing.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof is (I-X21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof is (I-Z21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is (I-AA21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is
- R 2 R 1 pharmaceutically acceptable salt thereof is (I-AD21).
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof is
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of
- R 2B is hydrogen or an optionally substituted C1-C6 alkyl.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of
- R 2B is hydrogen or an optionally substituted C1-C6 alkyl.
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
- the compound of Formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of
- R A is hydrogen
- R A is -OR 6 .
- R A is -SR 6 .
- R A is -S(O2)R 6 .
- R A is -S(O2)NR 6
- R A is -NR 6 S(O2)R 7 .
- R A is -SiR 6 R 7 R 8 .
- R 6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 6 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
- R 6 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 6 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
- R 6 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 6 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R 7 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 7 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
- R 7 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 7 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
- R 7 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 7 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
- R 6 and R 7 when R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are the same. In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are different. In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are each hydrogen. In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 are each an independently selected C1-C6 alkyl.
- R 6 and R 7 when R 6 and R 7 are attached to the same nitrogen atom, one of R 6 and R 7 is hydrogen and the other of R 6 and R 7 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 6 and R 7 when R 6 and R 7 are attached to the same nitrogen atom, one of R 6 and R 7 is hydrogen and the other of R 6 and R 7 is optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R 6 and R 7 are attached to the same nitrogen atom, one of R 6 and R 7 is hydrogen and the other of R 6 and R 7 is substituted phenyl or optionally 5-10 membered heteroaryl.
- R 6 and R 7 when R 6 and R 7 are attached to the same nitrogen atom, one of R 6 and R 7 is hydrogen and the other of R 6 and R 7 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 8 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
- R 8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 8 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
- R 8 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. In some embodiments, R 8 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
- R A is optionally substituted C1-C6 alkyl. In some embodiments, R A is C1-C6 alkyl. In some embodiments, R A is methyl, ethyl, or n-propyl.
- R A is C1-C6 haloalkyl. In some embodiments, R A is C1-C3 haloalkyl. In some embodiments, R A is trifluoromethyl.
- R A is optionally substituted C2-C6 alkenyl. In some embodiments, R A is C2-C6 alkenyl. In some embodiments, R A is optionally substituted C2-C3 alkenyl. In some embodiments, R A is C2-C3 alkenyl.
- R A is optionally substituted C2-C6 alkynyl. In some embodiments, R A is C2-C6 alkynyl. In some embodiments, R A is optionally substituted C2-C3 alkynyl. In some embodiments, R A is C2-C3 alkynyl.
- R A is optionally substituted C3-C10 cycloalkyl. In some embodiments, R A is optionally substituted C3-C6 cycloalkyl. In some embodiments, R A is C3- C10 cycloalkyl. In some embodiments, R A is C3-C6 cycloalkyl. In some embodiments, R A is optionally substituted phenyl. In some embodiments, R A is phenyl.
- R A is optionally substituted 3-12 membered heterocyclyl. In some embodiments, R A is optionally substituted 4-8 membered heterocyclyl. In some embodiments, R A is 3-12 membered heterocyclyl. In some embodiments, R A is 4-8 membered heterocyclyl.
- R A is optionally substituted 5-10 membered heteroaryl. In some embodiments, R A is optionally substituted 5-6 membered heteroaryl. In some embodiments, R A is 5-10 membered heteroaryl. In some embodiments, R A is 5-6 membered heteroaryl. In some embodiments, R A is an optionally substituted 9-10 membered heteroaryl. In some embodiments, R A is a 9-10 membered heteroaryl.
- R A is phenyl optionally substituted with 1-3 independently selected R Ai .
- R A is pyridinyl, pyrimidinyl, pyridizinyl, orpyrazinyl, each optionally substituted with 1-3 independently selected R A2 .
- R A is a 9 membered heteroaryl optionally substituted with 1-3 independently selected R A3 .
- each R A1 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkyl, (hydroxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3amino, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphoxide, and C-carboxy.
- each R A2 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkyl, (hydroxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkoxy, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphine oxide, and C-carboxy.
- each R A3 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkyl, (hydroxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkoxy, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphine oxide, and C-carboxy.
- R A is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
- R A is In some embodiments, R A is ° , ° , 0 , 0 o o o o o o o o o o o O O O O o or o n some embodiments, R B is halogen. In some embodiments, R B is fluoro or chloro.
- R B is cyano
- R B is hydroxyl. In some embodiments, R B is -NR 8 R 9 .
- R B is -OR 8 .
- R B is -SR 8 .
- R B is -S(O2)R 8 .
- R B is -S(O2)NR 8 .
- R B is -NR 8 S(Ch)R 9 .
- R B is -R 8 C( :::; O)R 9 .
- R 8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 8 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
- R 8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 8 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
- R 8 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. In some embodiments, R 8 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
- R 9 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 9 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
- R 9 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 9 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
- R 9 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 9 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
- R 8 and R 9 when R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are the same. In some embodiments, when R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are different. In some embodiments, when R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are each hydrogen. In some embodiments, when R 8 and R 9 are attached to the same nitrogen atom, R 8 and R 9 are each an independently selected C1-C6 alkyl.
- R 8 and R 9 when R 8 and R 9 are attached to the same nitrogen atom, one of R 8 and R 9 is hydrogen and the other of R 8 and R 9 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 8 and R 9 when R 8 and R 9 are attached to the same nitrogen atom, one of R 8 and R 9 is hydrogen and the other of R 8 and R 9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
- R B is optionally substituted C1-C6 alkyl. In some embodiments, R B is C1-C6 alkyl. In some embodiments, R B is methyl, ethyl, or n-propyl.
- R B is C1-C6 haloalkyl. In some embodiments, R B is C1-C3 haloalkyl. In some embodiments, R B is a C1-C3 fluoroalkyl. In some embodiments, R B is trifluoromethyl or 2,2,2-trifluoroethyl. In some embodiments, R B is 2,2,2-trifluoroethyl.
- R B is optionally substituted C2-C6 alkenyl. In some embodiments, R B is C2-C6 alkenyl. In some embodiments, R B is optionally substituted C2-C3 alkenyl. In some embodiments, R B is C2-C3 alkenyl. In some embodiments, R B is optionally substituted C2-C6 alkynyl. In some embodiments, R B is C2-C6 alkynyl. In some embodiments, R B is optionally substituted C2-C3 alkynyl. In some embodiments, R B is C2-C3 alkynyl.
- R B is optionally substituted C3-C10 cycloalkyl. In some embodiments, R B is optionally substituted C3-C6 cycloalkyl. In some embodiments, R B is C3- C10 cycloalkyl. In some embodiments, R B is C3-C6 cycloalkyl.
- R B is optionally substituted phenyl. In some embodiments, R B is phenyl.
- R B is optionally substituted 3-12 membered heterocyclyl. In some embodiments, R B is optionally substituted 4-8 membered heterocyclyl. In some embodiments, R B is 3-12 membered heterocyclyl. In some embodiments, R B is 4-8 membered heterocyclyl.
- R B is optionally substituted 5-10 membered heteroaryl. In some embodiments, R B is optionally substituted 5-6 membered heteroaryl. In some embodiments, R B is 5-10 membered heteroaryl. In some embodiments, R B is 5-6 membered heteroaryl.
- R B is methyl, ethyl, or n-propyl.
- R B is hydroxyl, F , or F .
- R B is or . In some embodiments, R B is ,
- R B is CF3 , . In some embodiments, R B is CFs , f o p
- R B is In some embodiments, R B is
- each R is X R 2B .
- one of X 2 , X 3 , X 4 , and X 5 is CR 2 and the remaining X 2 , X 3 , X 4 , and X 5 are CH, N, or CR 3 .
- Z 1 is a bond
- Z 1 is -S(O2)-.
- Z 1 is optionally substituted C1-C6 alkylene. In some embodiments, Z 1 is optionally substituted C1-C3 alkylene. In some embodiments, Z 1 is C1-C6 alkylene. In some embodiments, Z 1 is C1-C3 alkylene. In some embodiments, Z 1 is methylene or ethylene.
- Z 1 is optionally substituted C2-C6 alkenylene. In some embodiments, Z 1 is optionally substituted C2-C3 alkenylene. In some embodiments, Z 1 is C2-C6 alkenylene. In some embodiments, Z 1 is C2-C3 alkenylene.
- Z 1 is optionally substituted C2-C6 alkynylene. In some embodiments, Z 1 is optionally substituted C2-C3 alkynylene. In some embodiments, Z 1 is C2-C6 alkynylene. In some embodiments, Z 1 is C2-C3 alkynylene.
- Z 1 is an optionally substituted C3-C4 cycloalkylene. In some embodiments, Z 1 is C3-C4 cycloalkylene.
- Z 2 is N.
- Z 2 is O and R 2B is absent.
- Z 2 is a bond
- Z 2 is CR 2C .
- R 2C is hydrogen. In some embodiments, R 2C is halogen. In some embodiments, R 2C is fluoro or chloro.
- R 2C is C1-C6 alkyl. In some embodiments, R 2C is C1-C3 alkyl. In some embodiments, R 2C is methyl.
- R 2B when Z 1 is a bond and Z 2 is a bond, R 2B is absent and R 2A is directly connected to Formula (I) via Z 1 . In some embodiments, when Z 2 is a bond, R 2B is absent and R 2A is directly connected to Z 1 . In some embodiments, Z 2 is O and R 2B is absent.
- R 2 is -NR 2A R 2B , i.e., Z 1 is a bond and Z 2 is N.
- R 2 is R 2B , i.e., Z 1 and Z 2 are both a bond, R 2A is absent and R 2B is directly connected to Formula (I) via Z 1 .
- R 2B when Z 1 is a not a bond and Z 2 is a bond, R 2B is absent and R 2A is directly connected to Z 1 .
- R 2A is hydrogen
- R 2A is -S(O2)R 10 .
- R 10 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 10 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
- R 10 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 10 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 10 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R 10 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl.
- R 11 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 11 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
- R u is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 11 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
- R 11 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 11 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
- R 10 and R 11 when R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 are the same. In some embodiments, when R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 are different. In some embodiments, when R 10 and R 11 are attached to the same nitrogen atom, R 10 and R 11 are each hydrogen. In some embodiments, when R 10 and R 11 are attached to the same nitrogen atom, R 10 and R n are each an independently selected C1-C6 alkyl.
- R 10 and R 11 when R 10 and R 11 are attached to the same nitrogen atom, one of R 10 and R 11 is hydrogen and the other of R 10 and R 11 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 10 and R 11 when R 10 and R 11 are attached to the same nitrogen atom, one of R 10 and R 11 is hydrogen and the other of R 10 and R 11 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 2A is optionally substituted C1-C6 alkyl. In some embodiments, R 2A is C1-C6 alkyl. In some embodiments, R 2A is methyl or ethyl.
- R 2A is C1-C6 haloalkyl. In some embodiments, R 2A is C1-C3 haloalkyl. In some embodiments, R 2A is trifluoromethyl.
- R 2A is optionally substituted C2-C6 alkenyl. In some embodiments, R 2A is C2-C6 alkenyl. In some embodiments, R 2A is optionally substituted C2-C3 alkenyl. In some embodiments, R 2A is C2-C3 alkenyl.
- R 2A is optionally substituted C2-C6 alkynyl. In some embodiments, R 2A is C2-C6 alkynyl. In some embodiments, R 2A is optionally substituted C2-C3 alkynyl. In some embodiments, R 2A is C2-C3 alkynyl.
- R 2A is optionally substituted C3-C10 cycloalkyl. In some embodiments, R 2A is optionally substituted C3-C6 cycloalkyl. In some embodiments, R 2A is C3- C10 cycloalkyl. In some embodiments, R 2A is C3-C6 cycloalkyl.
- R 2A is optionally substituted phenyl. In some embodiments, R 2A is phenyl.
- R 2A is optionally substituted 3-12 membered heterocyclyl. In some embodiments, R 2A is optionally substituted 4-8 membered heterocyclyl. In some embodiments, R 2A is 3-12 membered heterocyclyl. In some embodiments, R 2A is 4-8 membered heterocyclyl.
- R 2A is optionally substituted 5-10 membered heteroaryl. In some embodiments, R 2A is optionally substituted 5-6 membered heteroaryl. In some embodiments, R 2A is 5-10 membered heteroaryl. In some embodiments, R 2A is 5-6 membered heteroaryl.
- R 2B is hydrogen
- R 2B is -S(O2)R 10 .
- R 2B is optionally substituted C1-C6 alkyl. In some embodiments, R 2B is C1-C6 alkyl. In some embodiments, R 2B is methyl or ethyl.
- R 2B is C1-C6 haloalkyl. In some embodiments, R 2B is C1-C3 haloalkyl. In some embodiments, R 2B is trifluoromethyl. In some embodiments, R 2B is optionally substituted C2-C6 alkenyl. In some embodiments, R 2B is C2-C6 alkenyl. In some embodiments, R 2B is optionally substituted C2-C3 alkenyl. In some embodiments, R 2B is C2-C3 alkenyl.
- R 2B is optionally substituted C2-C6 alkynyl. In some embodiments, R 2B is C2-C6 alkynyl. In some embodiments, R 2B is optionally substituted C2-C3 alkynyl. In some embodiments, R 2B is C2-C3 alkynyl.
- R 2B is optionally substituted C3-C10 cycloalkyl. In some embodiments, R 2B is optionally substituted C3-C6 cycloalkyl. In some embodiments, R 2B is C3- C10 cycloalkyl. In some embodiments, R 2B is C3-C6 cycloalkyl.
- R 2B is optionally substituted phenyl. In some embodiments, R 2B is phenyl.
- R 2B is optionally substituted 3-12 membered heterocyclyl. In some embodiments, R 2B is optionally substituted 4-8 membered heterocyclyl. In some embodiments, R 2B is 3-12 membered heterocyclyl. In some embodiments, R 2B is 4-8 membered heterocyclyl.
- R 2B is optionally substituted 5-10 membered heteroaryl. In some embodiments, R 2B is optionally substituted 5-6 membered heteroaryl. In some embodiments, R 2B is 5-10 membered heteroaryl. In some embodiments, R 2B is 5-6 membered heteroaryl.
- one of R 2A and R 2B is hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl
- one of R 2A and R 2B is hydrogen and the other of R 2A and R 2B is an optionally substituted 4-12 membered heterocyclyl or an optionally substituted 5-6 membered heteroaryl. In some embodiments, one of R 2A and R 2B is hydrogen and the other of R 2A and R 2B is an optionally substituted 4-12 membered heterocyclyl. In some embodiments, one of R 2A and R 2B is hydrogen and the other of R 2A and R 2B is a substituted 4-12 membered heterocyclyl.
- R 2A and R 2B together with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl.
- R 2 is or CF ’ , i.e., Z 1 is optionally
- R 2 is
- R 2 is NHz , or
- Z 1 is optionally substituted alkylene
- Z 2 is a bond
- R 2A is absent.
- R 2 is NHz , RH 2 , / NH , x R 2B , or R 2B O
- R 2A is hydrogen.
- R 2B is , or . In some embodiments,
- R 2B is , or ' F. F. F. F,
- R 2B is
- R 2 as defined herein comprises an a, P-unsaturated system or an electrophilic group.
- X 3 is CR 2 and R 2 as defined herein comprises an a, 0-unsaturated system or an electrophilic group, as described herein.
- one of X 2 , X 3 , X 4 , and X 5 is CR 2
- one of X 2 , X 3 , X 4 , and X 5 is CR 3
- the remaining X 2 , X 3 , X 4 , and X 5 are CH or N.
- one of X 2 , X 3 , X 4 , and X 5 is CR 2
- one of X 2 , X 3 , X 4 , and X 5 is CR 3
- the remaining X 2 , X 3 , X 4 , and X 3 are CH.
- R 3 is halogen.
- R 3 is fluoro.
- R 3 is chloro.
- R 3 is cyano
- R 3 is -NR 12 R 13 .
- R 3 is -OR 12 .
- R 3 is -SR 12 .
- R 3 is -S(O2)R 12 .
- R 3 is -S(O2)NR 12 R 13 .
- R 3 is -NR 12 S(O2)NR 13 R 14 .
- R 12 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 12 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
- R 12 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 12 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 12 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 12 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
- R 13 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R lj is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
- R 13 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 13 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
- R 13 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 13 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
- R 14 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 14 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
- R 14 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 14 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R 14 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R 14 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
- R 12 and R 13 when R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are the same. In some embodiments, when R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are different. In some embodiments, when R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are each hydrogen. In some embodiments, when R 12 and R 13 are attached to the same nitrogen atom, R 12 and R 13 are each an independently selected C1-C6 alkyl.
- R 12 and R 13 when R 12 and R 13 are attached to the same nitrogen atom, one of R 12 and R 13 is hydrogen and the other of R 12 and R 13 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 12 and R 13 when R 12 and R 13 are attached to the same nitrogen atom, one of R 12 and R 13 is hydrogen and the other of R 12 andR 13 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 13 and R 14 when R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are the same. In some embodiments, when R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are different. In some embodiments, when R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are each hydrogen. In some embodiments, when R 13 and R 14 are attached to the same nitrogen atom, R 13 and R 14 are each an independently selected C1-C6 alkyl.
- one of R 13 and R 14 is hydrogen and the other of R 13 and R 14 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
- R 13 and R 14 when R lj and R 14 are attached to the same nitrogen atom, one of R 13 and R 14 is hydrogen and the other of R 13 andR 14 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
- R 3 is optionally substituted C1-C6 alkyl. In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is methyl or ethyl. In some embodiments, R 3 is optionally substituted C2-C6 alkenyl. In some embodiments, R 3 is C2-C6 alkenyl. In some embodiments, R 3 is optionally substituted C2-C3 alkenyl. In some embodiments, R 3 is C2-C3 alkenyl.
- R 3 is optionally substituted C2-C6 alkynyl. In some embodiments, R 3 is C2-C6 alkynyl. In some embodiments, R 3 is optionally substituted C2-C3 alkynyl. In some embodiments, R 3 is C2-C3 alkynyl.
- R 3 is optionally substituted C3-C6 cycloalkyl. In some embodiments, R 3 is C3-C6 cycloalkyl.
- R 3 is optionally substituted phenyl. In some embodiments, R 3 is phenyl.
- R 3 is optionally substituted 4-6 membered heterocyclyl. In some embodiments, R 3 is 4-6 membered heterocyclyl.
- R 3 is optionally substituted 5-6 membered heteroaryl. In some embodiments, R 3 is 5-6 membered heteroaryl.
- n is 0. In some embodiments, m is 1. In some embodiments, m is 2.
- L is an optionally substituted 5-6 membered heteroarylene. In some embodiments, L is a 5-6 membered heteroarylene. In some embodiments, L is a substituted 6 membered heteroarylene. In some embodiments, L is a 5 membered heteroarylene. In some embodiments, L is a 2,5-(l,3,4-oxadiazolyl)ene, a 2,5-(l,3,4-thiadiazolyl)ene, or a 3,5-(l,2,4- oxadiazolyl)ene. In some embodiments, L is
- L is an optionally substituted 4-6 membered heterocyclylene. In some embodiments, L is a 4-6 membered heterocyclylene. In some embodiments, L is a 4 membered heterocyclylene.
- the compound is selected from the group consisting of the compounds delineated in Table 1, or a pharmaceutically acceptable salt thereof. w Table 1
- V "" ⁇ -' ⁇ 1 N —./ r f V -'- ⁇
- the compound is selected from the group consisting of the compounds delineated in List 1, or a pharmaceutically acceptable salt thereof.
- Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
- telomere encoding telomere sequence a telomere sequence that is useful for treating or preventing diseases associated with dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same (i.e., a p53 -associated disease), such as cancer (e.g., p53-associated cancer).
- a p53 -associated disease such as cancer (e.g., p53-associated cancer).
- restoration means to increase the activity and/or function of the specified target by a measurable amount.
- restoration of a mutant p53 with a compound of Formula (I) refers to increasing the function of the mutant p53 in the presence of the compound to a higher level than the function of the mutant p53 in the absence of the compound.
- test compounds to act as a p53 restorer may be demonstrated by assays known in the art.
- the activity of the compounds and compositions provided herein as p53 restorers can be assayed in vitro, in vivo, or in a cell line.
- In vitro assays include assays that determine activation of the protein and/or a change in its conformation.
- Potency of a p53 restorer as provided herein can be determined by EC50 value. A compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent p53 restorer relative to a compound with a higher EC50 value.
- p53-associated diseases e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors).
- p53-associated diseases or disorder is Li -Fraumeni syndrome.
- Some embodiments provide a method of treating cancer in a subject in need thereof, compirising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
- the cancer is a p53 -associated cancer.
- Some embodiments provide a method of treating cancer in a subj ect that has been identified or diagnosed as having a p53 -associated cancer, compirising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
- the p53 -associated cancer harbors a Y220C mutation.
- Some embodiments provide a method of treating a p53 -associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the compound of Examples 1 -1 10, or a pharmaceutically acceptable salt thereof.
- the p53-associated cancer harbors a Y220C mutation.
- Some embodiments provide a method of treating cancer in a subject in need thereof, comprising (a) determing that the subject has a p53 -associated cancer, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
- Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, compirising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
- Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject that has been identified or diagnosed as having Li-Fraumeni syndrome, compirising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
- Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising (a) determing that the subject has Li-Fraumeni syndrome, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
- a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered prophylactically to a subject with Li-Fraumeni syndrome.
- a therapeutically effective amount of Formula (I), or a pharmaceutically acceptable salt thereof is administered prophylactically to a subject with Li-Fraumeni syndrome.
- p53 -associated disease refers to diseases associated with or having a dysregulation of a TP53 gene, a p53 protein, or the activity of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a TP53 gene, or a p53 protein, or the activity of any of the same described herein).
- Non-limiting examples of a p53-associated disease include, for example, cancer (e.g., p53-associated cancer).
- p53 -associated cancer refers to cancers associated with or having a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. Non-limiting examples of p53-associated cancers are described herein.
- wild type or wild-type describes a nucleic acid (e.g., a TP53 gene or a p53 mRNA) or protein (e.g., a p53) sequence that is typically found in a subject that does not have a cancer related to the reference nucleic acid or protein.
- a method of treating cancer e.g., a p53-associated cancer
- the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
- methods for treating p53- associated cancer in a subject in need of such treatment comprising a) detecting a dysregulation of TP53 gene, a p53 protein, or the activity of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
- the dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same includes one or more a p53 protein substitutions/point mutations/insertions.
- p53 protein substitutions/insertions/deletions are described in Table 1.
- the p53 protein substitution / insertion / deletion is Y220X, where X is any amino acid other than Y.
- the p53 protein substitution/insertion/deletion is selected from the group consisting of Y220C, Y220S, Y220N, Y220D, and combinations thereof.
- the p53 protein substitution/insertion/deletion is selected from the group consisting of Y220C or Y220S, or a combination thereof.
- the p53 protein substitution/insertion/deletion is Y220C.
- the p53 protein substitution/insertion/deletion is Y220S.
- the dysregulation of a TP53 gene, a p53 protein, or activity of any of the same includes at least one point mutation in a TP53 gene that results in the production of a p53 protein that has one or more amino acid substitutions or insertions or deletions in a TP53 gene that results in the production of a p53 protein that has one or more amino acids inserted or removed, as compared to the wild type p53 protein.
- the resulting mutant p53 protein has reduced function, as compared to a wild type p53 protein or a p53 protein not including the same mutation.
- the compounds described herein restore the resulting mutant p53 protein function relative to the mutant p53 protein function in the absence of the compounds described herein, for example, by stabilizing the mutant protein into an active conformation.
- compounds of Formula (I), or pharmaceutically acceptable thereof are useful for treating a cancer that has been identified as having one or more p53 mutations. Accordingly, provided herein are methods for treating a subject diagnosed with (or identified as having) a cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
- Also provided herein are methods for treating a subject identified or diagnosed as having a p53 -associated cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
- the subject that has been identified or diagnosed as having a p53 -associated cancer through the use of a regulatory agency-approved, e.g., FDA- approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject or by performing any of the nonlimiting examples of assays described herein.
- the test or assay is provided as a kit.
- the cancer is an p53-associated cancer.
- Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., an immunotherapy).
- the subj ect was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy.
- the subject is determined to have a p53-associated cancer through the use of a regulatory agency- approved, e.g., FDA-approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein.
- a regulatory agency- approved e.g., FDA-approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same
- the test or assay is provided as a kit.
- the cancer is an p53-associated cancer.
- a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating a p53-associated cancer in a subject identified or diagnosed as having a p53 -associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, where the presence of a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, identifies that the subject has a p53-associated cancer.
- an assay e.g., an in vitro assay
- a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer in a subject in need thereof, or a subject identified or diagnosed as having a p53-associated cancer. Also provided is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having a p53 -associated cancer.
- a subject is identified or diagnosed as having a p53-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject.
- a regulatory agency-approved e.g., FDA-approved, kit for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject.
- the subject has been identified or diagnosed as having a cancer with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
- the subject has a tumor that is positive for a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
- the subject can be a subject with a tumor(s) that is positive for a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
- the subject can be a subject whose tumors have a dysregulation of a TP 53 gene, a p53 protein, or activity of any of the same.
- the subject is suspected of having a p53-associated cancer.
- methods for treating a p53 -associated cancer in a subject in need of such treatment comprising a) detecting a dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
- the dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same includes one or more p53 protein point mutations/insertions/deletions, as described herein.
- the cancer with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
- the tumor with a dysregulation of a TP 53 gene, a p53 protein, or activity of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
- the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a TP 53 gene, a p53 protein, or activity of any of the same.
- methods of treating a subject that include administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a clinical record that indicates that the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
- a method for restoring p53 function in a cell comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
- the contacting is in vitro.
- the contacting is in vivo.
- the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant p53 function.
- the cell is a cancer cell.
- the cancer cell is any cancer as described herein.
- the cancer cell is a p53-associated cancer cell.
- contacting refers to the bringing together of indicated moi eties in an in vitro system or an in vivo system.
- "contacting" a p53 protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a p53 protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the p53 protein.
- Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Further provided herein is a method of increase cell death, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject. The method comprises administering to the subject an effective compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.
- the cancer e.g., p53- associated cancer
- the cancer is selected from a hematological cancer and a solid tumor.
- the cancer is a hematological cancer.
- the hematological cancer is a leukemia.
- the hematological cancer is a lymphoma.
- the hematological cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or hairy cell leukemia (HCL).
- the hematological cancer is acute myeloid leukemia (AML).
- the cancer e.g., p53- associated cancer
- the cancer is selected from brain cancer, bladder cancer, breast cancer, colorectal cancer, skin cancer, esophageal cancer, lung cancer, gastric cancer, kidney cancer, uterine cancer, ovarian cancer, liver cancer, pancreatic cancer, prostate cancer, leiomyosarcoma, and head and neck squamous cell carcinoma.
- the cancer e.g., p53- associated cancer
- the cancer is selected from colorectal cancer, ovarian cancer, pancreatic cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, endometrial cancer, and bladder cancer.
- the brain cancer is astrocytoma, oligoastrocytoma, oligodendroglioma, or glioblastoma multiforme.
- the bladder cancer is bladder urothelial carcinoma.
- the esophageal cancer is esophageal adenocarcinoma or esophageal squamous cell carcinoma.
- the skin cancer is cutaneous melanoma.
- the lung cancer is small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is lung adenocarcinoma or lung squamous cell carcinoma.
- the gastric cancer is mucinous stomach adenocarcinoma or intestinal type stomach adenocarcinoma.
- the breast cancer is breast invasive ductal carcinoma.
- the uterine cancer is uterine mixed endometrial carcinoma, uterine endometrioid carcinoma, uterine serous carcinoma, or uterine papillary serous carcinoma.
- the ovarian cancer is serous ovarian cancer.
- the kidney cancer is chromophobe renal cell carcinoma.
- the colorectal cancer is colon adenocarcinoma.
- the liver cancer is hepatocellular carcinoma.
- the pancreatic cancer is pancreatic adenocarcinoma.
- the cancer is prostate cancer.
- the p53-associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the p53 -associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is lung cancer.
- the p53-associated cancer is selected from the cancers described in Table 1.
- T125 Acute Myeloid Leukemia (splice region) Adrenocortical Carcinoma
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and/or symptoms and/or progression of the disease (e.g., cancer) in a subject (e.g., a human).
Description
INDOLIZINE DERIVATIVES FOR TREATING CANCER
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application Serial No. 63/418,102, filed on October 21, 2022; which is incorporated herein by reference in its entirety.
SEQUENCE LISTING
This application contains a Sequence Listing that has been submitted electronically as an XML file named 50006-0109W01_ST26_SL.XML.” The XML file, created on October 19, 2023, is 2,257 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety.
TECHNICAL FIELD
This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and/or symptoms and/or progression of the disease (e.g., cancer) in a subject (e g., a human).
BACKGROUND
The tumor suppressor p53, encoded by the TP53 gene, is a transcription factor that regulates the expression of genes required for DNA repair, cell cycle arrest, senescence, and apoptosis, and p53 plays a critical role in mediating each of these processes (Alvarado-Ortiz et al., Frontiers in Cell and Developmental Biology (2021) 8, Article 607670; Vousden et al., Cell (2009) 137, 413-431; Bieging et al., Nat. Rev. Cancer (2014) 14, 359-370). TP53 is altered in over 50% of all human cancers, making it the most frequently mutated gene among oncogenes and tumor suppressor genes (Hainaut et al., Adv Cancer Res (2000) 77, 81-137; Joerger et al., Cold Spring Harb. Perspect. Biol. (2010) 2(6), Article a000919). Mutations in TP53 result in loss of its normal function, rendering cells incapable of responding to a variety of cellular stresses such as DNA damage or oncogene activation, making them susceptible to tumorigenesis (Joerger et al., Oncogene (2007) 26, 2226-2242). The great majority of TP53 mutations are missense mutations, located within or proximal to its DNA-binding domain (Baugh et al., Cell Death & Differentiation
(2018) 25, 154-160). Mutations leading to p53 loss of function can be categorized into two main types: (1) DNA contact mutations, where the mutant protein loses its ability to bind DNA; (2) structural mutations, which destabilize the p53 protein (Brosh et al., Nat. Rev. Cancer (2009) 9, 701-713; Hollstein et al., Science (1991) 253, 49-53). Both classes of mutations prevent p53-driven transcriptional activation, thus abrogating p53-mediated tumor suppression (Zhu et al., Frontiers in Oncology (2020) 10, Article 595187).
Reactivation of the mutant p53 protein emerges as an attractive approach to treat TP53 mutant cancers (Degtjarik et al., Nature Communications (2021) 12, Article 7057; Bykov et al., FEBS Letters (2014) 588, 2622-2627). Theoretically, mutant p53 reactivation will restore its tumor suppressive functions, stimulating p53-dependent arrest or apoptosis and resulting in efficient elimination of tumor cells (Selivanova et al., Oncogene (2007) 26, 2243-2254). The p53Y220C mutation occurs in -1% of human cancers; -100,000 new cancer cases per year worldwide (Joerger et al., Annu. Rev. Biochem. (2016) 85, 375-404; Bouaoun et al., Hum. Mutat. (2016) 37, 865-876). Stabilization of the mutant protein may restore and/or maintain the functional conformation of the protein (Baud et al., Eur J Med Chem. (2018) 25, 101-114; Rauf et al., Protein J (2013) 32, 68- 74). In some instances, such as the Y200C mutation, there is a small molecule binding pocket far away from the binding interface between p53 and DNA, such that small molecule engagement at this pocket will not disrupt DNA binding (Bauer et al., Future Med. Chem. (2019) 11, 2491-2504).
SUMMARY
Some embodiments provide a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X1 is CR1 or N;
R1 is hydrogen, halogen, cyano, -OR4, -NR4R5, -C(=O)R4, -OC(=O)R4, -C(=O)OR4, -C(=O)NR4R5, -SR4, -S(=O)R4, -S(O2)R4, -NR4C(=O)R5, -R4C(-O)R5, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;
each of X2, X3, X4, and X5 are CH, N, CR2 or CR3, wherein two or more of X2, X3, X4, and X5 are independently CH, CR2, or CR3; each of Y1, Y2, and Y3 are C or N, wherein one of Y1, Y2, and Y3 is N; RA is hydrogen, –OR6, -NR6R7, -C(=O)R6, -R6C(=O)R7, -OC(=O)R6, -OC(=O)NR6, –C(=O)OR6, –NR6C(=O)OR7, –C(=O)NR6R7, –SR6, –S(=O)R6, –S(O2)R6, –S(O2)NR6, –NR6S(O2)R7, -NR6C(=O)R7, -NR6C(=O)NR7, -SiR6R7R8, optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; RB is halogen, cyano, hydroxyl, –NR8R9, -OR8, –C(=O)NR8R9, –C(=O)R8, -C(=O)OR8, -NR8C(=O)OR9, –OC(=O)R8, –OC(=O)NR8, –C(=O)NR8R9, –NR8C(=O)R9, –NR8C(=O)NR9, –SR8, –S(=O)R8, –S(O2)R8, –S(O2)NR8, –NR8S(O2)R9, -R8C(=O)R9, -NR8C(=O)R9, -NR8C(=O)NR9, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each R2 is Z1 is a bo
ally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or an optionally substituted C3-C4 cycloalkylene; Z2 is CR2C, N, O, or a bond; wherein when Z2 is O, R2B is absent, and when Z1 is a bond and Z2 is a bond, R2B is absent and R2A is directly connected to Formula (I) via Z1; R2A and R2B are independently hydrogen, –C(=O)R10, –C(=O)OR10, –C(=O)NR10R11, –S(=O)R10, –S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; or R2A and R2B together with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted
5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl; or Z2 is O and R2B is absent;
R2C is hydrogen, halogen, or C1-C6 alkyl; each R3 is independently halogen, cyano, -NR12R13, -OR12, -C(=O)NR12R13, -C(=O)R12, -C(=O)OR12, -OC(=O)R12, -NR12(C=O)NR13R14, -SR12, -S(=O)R12, -S(O2)R12, -S(O2)NR12R13, -NR12S(O2)NR13R14, -R1 =O)R -NR12C(=O)R13, optionally substituted Cl- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl;
L is an optionally substituted 4-6 membered heterocyclylene or an optionally substituted 5-6 membered heteroarylene; m is 0, 1, or 2; and each R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
Provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
Provided herein is a method of treating a p53-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a p53-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition as provided herein.
This disclosure also provides a method of treating a p53-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a p53 -associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
Further provided herein is a method of treating a p53-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a p53-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
This disclosure also provides a method of treating a p53-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a p53 -associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
Provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
This disclosure also provides a method for restoring p53 function in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Other embodiments include those described in the Detailed Description and/or in the claims.
Additional Definitions
To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications,
and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.
The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and/or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range.
The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
The phrase “therapeutically effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a p53 protein-associated cancer, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular cancer or (iii) delay the onset of one or more symptoms of the particular cancer, described herein.
The term “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe etal., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.
The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In
some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.
As used herein, the “subject” refers to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the cancer to be treated.
As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a cancer, diminishment of the extent of the cancer, stabilized (i.e., not worsening) state of disease, delay or slowing of cancer progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the cancer), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.
Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “substituted” the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally
substituted” or “substituted” group may be substituted with one or more individually and independently selected group(s) that are stable and chemically acceptable for the group being substituted. Non-limiting examples of optional substituents are halogen, cyano, hydroxyl, nitro, nitroso, azido, sulfhydryl, acyl, alkyl, hydroxyalkyl, aminoalkyl, alkoxyamino, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, hydroxyalkoxy, alkoxyalkoxy, alkenoxy, alkynoxy, haloalkoxy, haloalkenoxy, haloalkynoxy, cycloalkyl, halocycloalkyl, cycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, aralkyl, cycloalkylalkyl, heteroaralkyl, alkoxyalkyl, heterocyclylalkyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, alkoxycarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, sulfenyl, halosulfenyl, sulfonyl, sulfinyl, sulfoximino, sulfonimidamido, phosphine oxide, C-carboxy, O- carboxy, arylalkoxy, cycloalkylalkoxy, carboxaldehyde, iminyl, trihalomethanesulfonyl, trihalomethanesulfonamido, phosphityl, phosphonityl, phosphorothioityl, phophoamidityl, phosphonamidityl, phosphinityl, phosphinyl, phosphonothioityl, phosphorodiamidityl, phosphinamidityl, phosphorodithioityl, phosphonodiamidityl, phosphorotriamidityl, phosphatyl, phosphinatyl, phosphonatyl, phosphoroamidatyl, phosphorodiamidatyl, phosphonodiamidatyl, phosphonamidatyl, phosphinamidatyl, phosphorotriamidatyl, phosphorothiatyl, dithiophosphinatyl, phosphorodithioatyl, phosphonothioatyl, thiophosphatyl, thiophosphinatyl, phosphorodithiatyl, thiophosphonatyl, phosphorofluoridatyl, bisphosphonatyl, triphosphatyl, pyrophosphatyl, tetraphosphatyl, and ureido. The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls. The term "hydroxyl" refers to an -OH radical. The term “sulfhydryl” refers to a –SH radical. The term "cyano" refers to a -CN radical. The term “azido” refers to a –N3 radical. The term “nitro” refers to a –NO2 radical. The term “nitroso” refers to a –N=O radical. The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-C10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can
either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, /e/7-butyl, w-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.
The term “acyl” refers to a -C(=O)alkyl radical (e.g., acetyl), or a -C(=O)alkenyl radical
(e.g., -C(=0)-CH=CH2), or -C(=O)alkynyl radical (e.g., Acyl groups can be
substituted with cyano or with 1-3 independently selected halogens.
As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. An alkenyl group may be unsubstituted or substituted.
As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. An alkynyl group may be unsubstituted or substituted.
The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.
The term “cycloalkyl” as used herein refers to cyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[l.l. l]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2. l]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane,
spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms.
The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, S, P, B, and Si and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e g., tetrahydroquinolinyl). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-J]pyrimidinyl, pyrrolo[2,3-/>]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3- c]pyridinyl, pyrazolo[3,4-Z>]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-Z>]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[Z>][l,4]dioxine, benzo[d][l,3]dioxole, 2,3 -dihydrobenzofuran, tetrahydroquinoline, 2,3- dihydrobenzo[/>][l,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more
or and imidazolone (e.g., wherein each ring nitrogen adjacent to a
carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring).
The term “heterocyclyl” refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, P, S, B, or Si (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, P, S, B, or Si if monocyclic, bicyclic, or tricyclic, respectively), wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an S-oxide, or an S,S-dioxide), valence permitting; and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by 1-2 substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, di hydrofuranyl, dihydrothiophenyl, oxaphosphinanyl oxide, azaphosphinanyl oxide, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2- azabicyclo[l.l.l]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3- azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7- azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2- azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2- oxabicyclo[2.1.0]pentane, 2-oxabicyclo[l . l.l]pentane, 3-oxabicyclo[3.1.0]hexane, 5- oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7- oxabicyclo[2.2. l]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2- oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4- azaspiro[2.5]octane, l-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2- azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane
2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4- oxaspiro[2.5]octane, l-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2- oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, l,7-dioxaspiro[4.5]decane, 2,5- dioxaspiro[3.6]decane, l-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9- azaspiro[5.5]undecane and the like.
As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.
The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
The term “halocycloalkyl” refers to a cycloalkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
The term “hydroxyalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with hydroxyl.
The term “haloalkenyl” refers to an alkenyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
The term “haloalkynyl” refers to an alkynyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3).
The term “alkoxyalkyl” refers to an alkyl, in which one or two hydrogen atoms is/are replaced with an independently selected alkoxy (e.g., methoxy ethyl).
The term “hydroxyalkoxy” refers to an alkoxy group, in which one or two hydrogen atoms is/are replaced with hydroxy.
The term “alkoxyalkoxy” refers to an alkoxy group, in which one or two hydrogen atoms is/are replaced with an independently selected alkoxy.
The term “alkoxyamino” refers to an -O-amino radical (e.g., -OCH2CH2N(CH3)2).
The term “haloalkoxy” refers to an -O-haloalkyl radical (e g., -OCF3).
The term “alkenoxy” refers to an -O-alkenyl radical (e.g., -O-allyl).
The term “haloalkenoxy” refers to an -O-haloalkenyl radical. The term “alkynoxy” refers to an -O-alkynyl radical (e.g., -O-propargyl). The term “haloalkynoxy” refers to an -O-haloalkynyl radical.
The term “cycloalkoxy” refers to an -O-cycloalkyl radical (e.g., -O-cyclopropyl).
The term “aryloxy” refers to an -O-aryl radical (e.g., phenoxy).
The term “heteroaryloxy” refers to an -O-heteroaryl radical (e.g., pyridinoxy).
The term “heterocyclyloxy” refers to an -O-heterocyclyl radical (e.g., -O-pyrrolidinyl or -O-oxetanyl).
The term “aralkyl” refer to an aryl group connected, as a substituent, via an alkyl group (e.g., benzyl).
The term “cycloalkylalkyl” refers to a cycloalkyl group connected, as a substituent, via an alkyl group (e.g., ethylcyclobutyl).
The term “heteroaralkyl” refers to a heteroaryl group connected, as a substituent, via an alkyl group (e.g., methylpyrimidinyl).
The term “heterocyclylalkyl” refers to a heterocyclyl group connected, as a substituent, via an alkyl group (e.g., methyloxetanyl).
The term “aralkoxy” refers to an aryl group connected, as a substituent, via an alkoxy group (e.g., benzyl oxy).
The term “cycloalkylalkoxy” refers to a cycloalkyl connected, as a substituent, via an alkoxy group (e.g., methoxycyclopropyl).
The term “aminoalkyl” refers to an amino group connected, as a substituent, via an alkyl group (e.g., methyl(dimethylamino)).
A “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
A “halosulfenyl” group refers to a sulfenyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen (e.g., -S(CFs) or -S(CHF2)).
A “sulfinyl” group refers to an “-S(=O)” group in which R can be the same as defined with respect to sulfenyl.
A “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl.
A “sulfoximine” group refers to an -S(=O)(=NR)R’, where R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl; and where R’ alkyl,
haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
A “sulfonimidamido” group refers to an -S(=O)(=NR)NR’R” where R, R’, and R” are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl; and where R’ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
An “O-carboxy” group refers to a “RC(=O)O-” group in which R can be hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
The terms “ester” and “C-carboxy” refer to a “-C(=O)OR” group in which R can be the same as defined with respect to O-carboxy.
A “thiocarbonyl” group refers to a “-C(=S)R” group in which R can be the same as defined with respect to O-carboxy.
A “trihalomethanesulfonyl” group refers to an “X3CSO2-” group wherein each X is a halogen.
A “trihalomethanesulfonamido” group refers to an “X3CS(O)2N(R’)-” group wherein each X is a halogen, and R’ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
An “S-sulfonamido” group refers to a “-S02N(RR’)” group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
An “N-sulfonamido” group refers to a “RS02N(R’)-” group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
An “O-carbamyl” group refers to a “-OC(=O)N(RR’)” group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
An “N-carbamyl” group refers to an “ROC(=O)N(R’)-” group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
An “O-thiocarbamyl” group refers to a “-OC(=S)N(RR’)” group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
An “N-thiocarbamyl” group refers to an “ROC(=S)N(R’) — ” group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
A “C-amido” group refers to a “-C(=O)N(RR’)” group in which R and R’ are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
An “N-amido” group refers to a “RC(=O)N(R’)” group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
The terms “ureido” or “urea” refer to an -NR(C=O)NR’R”” group, in which R, R’, and R” are independently hydrogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
The term “carboxaldehyde” refers to a -C(=O)H radical.
The term “imine” or “imino” refers to a -N=R radical, in which R is hydrogen, hydroxyl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
The term “amino” refers to a -NRR’ radical, where R and R’ are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. In some instances, an amino group is -NH2, a mono-alkyl amine (R is hydrogen and R’ is alkyl) or a dialkylamine (R and R’ are independently selected alkyl).
The term “phosphine oxide” refers to a -P(=O)RR’ radical, where R and R’ are independently alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.
As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.
For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms
(e.g., [x.x.O] ring systems, in which 0 represents a zero atom bridge (e.g.,
)); (ii) a single ring atom (spiro-fused ring systems) (e.g.,
, a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,
In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same
atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13C and 14C.
In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety: encompasses the tautomeric form containing the moiety: H 5 Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
The compounds provided herein may encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry (e.g., a “flat” structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and/or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound.
The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims.
DETAILED DESCRIPTION
This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and/or symptoms and/or progression of the disease (e.g., cancer) in a subject (e.g., a human).
Formulae (I) Compounds
Some embodiments provide a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X1 is CR1 or N;
R1 is hydrogen, halogen, cyano, -OR4, -NR4R5, -C(=O)R4, -OC(=O)R4, -C(=O)OR4, C(=O)NR4R5, -SR4, S(=O)R4, -S(O2)R4, -NR4C(=O)R5, -R4C(-O)R5, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each of X2, X3, X4, and X’ are CH, N, CR2 or CR3, wherein two or more of X2, X3, X4, and X5 are independently CH, CR2, or CR3; each of Y1, Y2, and Y3 are C or N, wherein one of Y1, Y2, and Y3 is N;
RA is hydrogen, -OR6, -NR6R7, -C(=O)R6, -R6C(=O)R7, -OC(=O)R6, -OC(=O)NR6, -C(=O)OR6, -NR6C(=O)OR7, -C(=O)NR6R7, -SR6, -S(=O)R6, -S(O2)R6, -S(O2)NR6, -NR6S(O2)R7, -NR6C(=O)R7, -NR6C(=O)NR7, -SiR6R7R8, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;
RB is halogen, cyano, hydroxyl, -NR8R9, -OR8, -C(=O)NR8R9, -C(=O)R8, -C(=O)OR8, -NR8C(=O)OR9, -OC(=O)R8, -OC(=O)NR8, -C(=O)NR8R9, -NR8C(=O)R9, -NR8C(=O)NR9, -SR8, -S(=O)R8, -S(O2)R8, -S(O2)NR8, -NR8S(O2)R9, -R8C(=O)R9, -NR8C(=O)R9, -NR8C(=O)NR9, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; c R2A
^-Z1-Z2'
, , . X R2B each R is ;
Z1 is a bond, -C=O-, -S(O2)-optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or an optionally substituted C3-C4 cycloalkylene; Z2 is CR2C, N, O, or a bond; wherein when Z2 is O, R2B is absent, and when Z1 is a bond and Z2 is a bond, R2B is absent and R2A is directly connected to Formula (I) via Z1; R2A and R2B are independently hydrogen, –C(=O)R10, –C(=O)OR10, –C(=O)NR10R11, –S(=O)R10, –S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; or R2A and R2B together with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl; or Z2 is O and R2B is absent; R2C is hydrogen, halogen, or C1-C6 alkyl; each R3 is independently halogen, cyano, –NR12R13, -OR12, –C(=O)NR12R13, –C(=O)R12, -C(=O)OR12, –OC(=O)R12, –NR12(C=O)NR13R14, –SR12, –S(=O)R12, –S(O2)R12, –S(O2)NR12R13, –NR12S(O2)NR13R14, -R12C(=O)R13, -NR12C(=O)R13, optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl; L is an optionally substituted 4-6 membered heterocyclylene or an optionally substituted 5-6 membered heteroarylene; m is 0, 1, or 2; and each R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
a pharmaceutically acceptable salt of any of the foregoing.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: pharmaceutically acceptable salt of any of the foregoing.
In some embodiments, one of X2, X3, X4, and X5 is N.
In some embodiments, two of X2, X3, X4, and X5 are N.
In some embodiments, X1 is CR1.
In some embodiments, R1 is hydrogen.
In some embodiments, R1 is halogen.
In some embodiments, R1 is cyano.
In some embodiments, R1 is -OR4.
In some embodiments, R1 is -NR4R5.
In some embodiments, R1 is -C(=O)R4.
In some embodiments, R1 is -OC(=O)R4.
In some embodiments, R1 is -C(=O)OR4.
In some embodiments, R1 is -C(=O)NR4R5.
In some embodiments, R1 is -SR4.
In some embodiments, R1 is -S(=O)R4.
In some embodiments, R1 is -S(O2)R4.
In some embodiments, R1 is -NR4C(=O)R3.
In some embodiments, R1 is -R4C(:::OHV.
In some embodiments, R4 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, R4 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
In some embodiments, R4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, R4 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
In some embodiments, R4 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R4 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
In some embodiments, R5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, R5 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
In some embodiments, R’ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, R5 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
In some embodiments, R5 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R5 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
In some embodiments, when R4 and R3 are attached to the same nitrogen atom, R4 and R5 are the same. In some embodiments, when R4 and R5 are attached to the same nitrogen atom, R4 and R5 are different. In some embodiments, when R4 and R3 are attached to the same nitrogen atom, R4 and R5 are each hydrogen. In some embodiments, when R4 and R3 are attached to the same nitrogen atom, R4 and R5 are each an independently selected C1-C6 alkyl.
In some embodiments, when R4 and R5 are attached to the same nitrogen atom, one of R4 and R5 is hydrogen and the other of R4 and R5 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, when R4 and R5 are attached to the same nitrogen atom, one of R4 and R3 is hydrogen and the other of R4 and R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, R1 is optionally substituted C1-C6 alkyl. In some embodiments, R1 is C1-C6 alkyl. In some embodiments, Rx is methyl or ethyl.
In some embodiments, R1 is optionally substituted C2-C6 alkenyl. In some embodiments, R1 is C2-C6 alkenyl. In some embodiments, Rx is optionally substituted C2-C3 alkenyl. In some embodiments, Rx is C2-C3 alkenyl.
In some embodiments, R1 is optionally substituted C2-C6 alkynyl. In some embodiments, R1 is C2-C6 alkynyl. In some embodiments, R4 is optionally substituted C2-C3 alkynyl. In some embodiments, Rx is C2-C3 alkynyl.
In some embodiments, R1 is optionally substituted C3-C6 cycloalkyl. In some embodiments, Rx is C3-C6 cycloalkyl.
In some embodiments, R1 is optionally substituted phenyl. In some embodiments, R1 is phenyl.
In some embodiments, R1 is optionally substituted 4-6 membered heterocyclyl. In some embodiments, R1 is 4-6 membered heterocyclyl.
In some embodiments, R1 is optionally substituted 5-6 membered heteroaryl. In some embodiments, R1 is 5-6 membered heteroaryl.
In some embodiments, X1 is N.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
U), or a pharmaceutically acceptable salt of any of the foregoing.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: a pharmaceutically acceptable salt of any of the foregoing.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
ADa), and (I-AEa), or a pharmaceutically acceptable salt of any of the foregoing.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
AA1), or a pharmaceutically acceptable salt of any of the foregoing.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of
AA2), or a pharmaceutically acceptable salt of any of the foregoing.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of
acceptable salt of any of the foregoing.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
AA21), (I-AC21),
(I-AE21), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a
S-— . pharmaceutically acceptable salt thereof, is "CF3 (I-V21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is
CF3 (I-W21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is (I-X21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is
(I-Y21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is (I-Z21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is
(I-AA21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is
(I-AC21). In some embodiments, the compound of Formula (I), or a
R2 R1 pharmaceutically acceptable salt thereof, is (I-AD21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of
AA5), or a pharmaceutically acceptable salt of any of the foregoing, wherein R2B is hydrogen or an optionally substituted C1-C6 alkyl.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of
AA6), or a pharmaceutically acceptable salt of any of the foregoing, wherein R2B is hydrogen or an optionally substituted C1-C6 alkyl.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
AA7), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of
(I-AA8),
(I-AC8), pharmaceutically acceptable salt of any of the foregoing, wherein R2B is hydrogen or an optionally substituted C1-C6 alkyl.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
(I-W9),
(I-Y9),
(I-AA9),
(I-AC9), or a pharmaceutically acceptable salt of any of the foregoing, wherein R2B is hydrogen or an optionally substituted C1-C6 alkyl.
In some embodiments, RA is hydrogen.
In some embodiments, RA is -OR6.
In some embodiments, RA is -NR6R7.
In some embodiments, RA is -C(=O)R6.
In some embodiments, RA is -R6C(=O)R7.
In some embodiments, RA is -OC(=O)R6.
In some embodiments, RA is -OC(=O)NR6.
In some embodiments, RA is -C(=O)OR6.
In some embodiments, RA is -NR6C(=O)OR7.
In some embodiments, RA is -C(=O)NR6R7.
In some embodiments, RA is -SR6.
In some embodiments, RA is -S(=O)R6.
In some embodiments, RA is -S(O2)R6.
In some embodiments, RA is -S(O2)NR6
In some embodiments, RA is -NR6S(O2)R7.
In some embodiments, RA is -NR6C(=O)R7.
In some embodiments, RA is -NR6C(=O)NR7.
In some embodiments, RA is -SiR6R7R8.
In some embodiments, R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, R6 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
In some embodiments, R6 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, R6 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
In some embodiments, R6 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R6 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
In some embodiments, R7 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, R7 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
In some embodiments, R7 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, R7 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
In some embodiments, R7 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R7 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
In some embodiments, when R6 and R7 are attached to the same nitrogen atom, R6 and R7 are the same. In some embodiments, when R6 and R7 are attached to the same nitrogen atom, R6 and R7 are different. In some embodiments, when R6 and R7 are attached to the same nitrogen atom, R6 and R7 are each hydrogen. In some embodiments, when R6 and R7 are attached to the same nitrogen atom, R6 and R7 are each an independently selected C1-C6 alkyl.
In some embodiments, when R6 and R7 are attached to the same nitrogen atom, one of R6 and R7 is hydrogen and the other of R6 and R7 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, when R6 and R7 are attached to the same nitrogen atom, one of R6 and R7 is hydrogen and the other of R6 and R7 is optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R6 and R7 are attached to the same nitrogen atom, one of R6 and R7 is hydrogen and the other of R6 and R7 is substituted phenyl or optionally 5-10 membered heteroaryl.
In some embodiments, when R6 and R7 are attached to the same nitrogen atom, one of R6 and R7 is hydrogen and the other of R6 and R7 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, R8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, R8 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
In some embodiments, R8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, R8 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
In some embodiments, R8 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. In some embodiments, R8 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
In some embodiments, RA is optionally substituted C1-C6 alkyl. In some embodiments, RA is C1-C6 alkyl. In some embodiments, RA is methyl, ethyl, or n-propyl.
In some embodiments, RA is C1-C6 haloalkyl. In some embodiments, RA is C1-C3 haloalkyl. In some embodiments, RA is trifluoromethyl.
In some embodiments, RA is optionally substituted C2-C6 alkenyl. In some embodiments, RA is C2-C6 alkenyl. In some embodiments, RA is optionally substituted C2-C3 alkenyl. In some embodiments, RA is C2-C3 alkenyl.
In some embodiments, RA is optionally substituted C2-C6 alkynyl. In some embodiments, RA is C2-C6 alkynyl. In some embodiments, RA is optionally substituted C2-C3 alkynyl. In some embodiments, RA is C2-C3 alkynyl.
In some embodiments, RA is optionally substituted C3-C10 cycloalkyl. In some embodiments, RA is optionally substituted C3-C6 cycloalkyl. In some embodiments, RA is C3- C10 cycloalkyl. In some embodiments, RA is C3-C6 cycloalkyl.
In some embodiments, RA is optionally substituted phenyl. In some embodiments, RA is phenyl.
In some embodiments, RA is optionally substituted 3-12 membered heterocyclyl. In some embodiments, RA is optionally substituted 4-8 membered heterocyclyl. In some embodiments, RA is 3-12 membered heterocyclyl. In some embodiments, RA is 4-8 membered heterocyclyl.
In some embodiments, RA is optionally substituted 5-10 membered heteroaryl. In some embodiments, RA is optionally substituted 5-6 membered heteroaryl. In some embodiments, RA is 5-10 membered heteroaryl. In some embodiments, RA is 5-6 membered heteroaryl. In some embodiments, RA is an optionally substituted 9-10 membered heteroaryl. In some embodiments, RA is a 9-10 membered heteroaryl.
In some embodiments, RA is phenyl optionally substituted with 1-3 independently selected RAi. In some embodiments, RAis pyridinyl, pyrimidinyl, pyridizinyl, orpyrazinyl, each optionally substituted with 1-3 independently selected RA2. In some embodiments, RA is a 9 membered heteroaryl optionally substituted with 1-3 independently selected RA3.
In some embodiments, each RA1 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkyl, (hydroxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3amino, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphoxide, and C-carboxy.
In some embodiments, each RA2 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkyl, (hydroxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkoxy, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphine oxide, and C-carboxy.
In some embodiments, each RA3 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkyl, (hydroxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkoxy, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphine oxide, and C-carboxy.
In some embodiments, each RA1, RA2 and RA3 is independently selected from halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkyl, (hydroxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3amino, 4-5 membered heterocyclyloxy, -C(=O)NRR’, -CO2H, -SO2(C1-C3 alkyl), -S(=O)C1-C3 alkyl, -SO2NRR’, -
S(=O)(=NR)NRR’, or -P(=O)(C1-C3 alkyl)2, wherein each R and R’ are independently hydrogen or Cl -C 3 alkyl.
In some embodiments, each RA1 is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, 4-5 membered heterocyclyloxy, -SCh(Cl-C3 alkyl), -SO2NRR’, or -P(=O)(C1-C3 alkyl)2, wherein R and R’ are independently hydrogen or C1-C3 alkyl.
39
, , , , .or . In some embodiments, RA is , , , , , , , , , , , , , , , , , , , , , , , ,
In some embodiments, RAis
In some embodiments, RA is ° , ° , 0 , 0 o o o o o o o o o o o o o O O O O o or o n some embodiments, RB is halogen. In some embodiments, RB is fluoro or chloro.
In some embodiments, RB is cyano.
In some embodiments, RB is hydroxyl. In some embodiments, RB is -NR8R9.
In some embodiments, RB is -OR8.
In some embodiments, RB is -C(=O)NR8R9.
In some embodiments, RB is -C(=O)R8.
In some embodiments, RB is -C(=O)OR8. In some embodiments, RB is -NR8C(=O)OR9
In some embodiments, RB is -OC(=O)R8.
In some embodiments, RB is -OC(=O)NR8.
In some embodiments, RB is -C(=O)NR8R9.
In some embodiments, RB is -NR8C(=O)R9.
In some embodiments, RB is -NR8C(=O)NR9.
In some embodiments, RB is -SR8.
In some embodiments, RB is -S(=O)R8.
In some embodiments, RB is -S(O2)R8.
In some embodiments, RB is -S(O2)NR8.
In some embodiments, RB is -NR8S(Ch)R9.
In some embodiments, RB is -R8C(:::;O)R9.
In some embodiments, RB is -NR8C(=O)R9.
In some embodiments, RB is -NR8C(=O)NR9.
In some embodiments, R8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, R8 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
In some embodiments, R8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, R8 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
In some embodiments, R8 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. In some embodiments, R8 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
In some embodiments, R9 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, R9 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6
cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
In some embodiments, R9 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, R9 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
In some embodiments, R9 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R9 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
In some embodiments, when R8 and R9 are attached to the same nitrogen atom, R8 and R9 are the same. In some embodiments, when R8 and R9 are attached to the same nitrogen atom, R8 and R9 are different. In some embodiments, when R8 and R9 are attached to the same nitrogen atom, R8 and R9 are each hydrogen. In some embodiments, when R8 and R9 are attached to the same nitrogen atom, R8 and R9 are each an independently selected C1-C6 alkyl.
In some embodiments, when R8 and R9 are attached to the same nitrogen atom, one of R8 and R9 is hydrogen and the other of R8 and R9 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, when R8 and R9 are attached to the same nitrogen atom, one of R8 and R9 is hydrogen and the other of R8 and R9 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, RB is optionally substituted C1-C6 alkyl. In some embodiments, RB is C1-C6 alkyl. In some embodiments, RB is methyl, ethyl, or n-propyl.
In some embodiments, RB is C1-C6 haloalkyl. In some embodiments, RB is C1-C3 haloalkyl. In some embodiments, RB is a C1-C3 fluoroalkyl. In some embodiments, RB is trifluoromethyl or 2,2,2-trifluoroethyl. In some embodiments, RB is 2,2,2-trifluoroethyl.
In some embodiments, RB is optionally substituted C2-C6 alkenyl. In some embodiments, RB is C2-C6 alkenyl. In some embodiments, RB is optionally substituted C2-C3 alkenyl. In some embodiments, RB is C2-C3 alkenyl.
In some embodiments, RB is optionally substituted C2-C6 alkynyl. In some embodiments, RB is C2-C6 alkynyl. In some embodiments, RB is optionally substituted C2-C3 alkynyl. In some embodiments, RB is C2-C3 alkynyl.
In some embodiments, RB is optionally substituted C3-C10 cycloalkyl. In some embodiments, RB is optionally substituted C3-C6 cycloalkyl. In some embodiments, RB is C3- C10 cycloalkyl. In some embodiments, RB is C3-C6 cycloalkyl.
In some embodiments, RB is optionally substituted phenyl. In some embodiments, RB is phenyl.
In some embodiments, RB is optionally substituted 3-12 membered heterocyclyl. In some embodiments, RB is optionally substituted 4-8 membered heterocyclyl. In some embodiments, RB is 3-12 membered heterocyclyl. In some embodiments, RB is 4-8 membered heterocyclyl.
In some embodiments, RB is optionally substituted 5-10 membered heteroaryl. In some embodiments, RB is optionally substituted 5-6 membered heteroaryl. In some embodiments, RB is 5-10 membered heteroaryl. In some embodiments, RB is 5-6 membered heteroaryl.
In some embodiments, RB is methyl, ethyl, or n-propyl.
F F
-|-O— ( -|-O— ^-F
In some embodiments, RB is hydroxyl, F , or F .
In some embodiments, RB is or . In some embodiments, RB is ,
In some embodiments, RB is CF3 , . In some embodiments, RB is CFs , f o p
X CF3 X , or
In some embodiments, RB is In some embodiments, RB is
T R2A
|-Z1-Z2'
7 •
In some embodiments, each R is XR2B .
In some embodiments, one of X2, X3, X4, and X5 is CR2 and the remaining X2, X3, X4, and X5 are CH, N, or CR3.
In some embodiments, Z1 is a bond.
In some embodiments, Z1 is -C=O-.
In some embodiments, Z1 is -S(O2)-.
In some embodiments, Z1 is optionally substituted C1-C6 alkylene. In some embodiments, Z1 is optionally substituted C1-C3 alkylene. In some embodiments, Z1 is C1-C6 alkylene. In some embodiments, Z1 is C1-C3 alkylene. In some embodiments, Z1 is methylene or ethylene.
In some embodiments, Z1 is optionally substituted C2-C6 alkenylene. In some embodiments, Z1 is optionally substituted C2-C3 alkenylene. In some embodiments, Z1 is C2-C6 alkenylene. In some embodiments, Z1 is C2-C3 alkenylene.
In some embodiments, Z1 is optionally substituted C2-C6 alkynylene. In some embodiments, Z1 is optionally substituted C2-C3 alkynylene. In some embodiments, Z1 is C2-C6 alkynylene. In some embodiments, Z1 is C2-C3 alkynylene.
In some embodiments, Z1 is an optionally substituted C3-C4 cycloalkylene. In some embodiments, Z1 is C3-C4 cycloalkylene.
In some embodiments, Z2 is N.
In some embodiments, Z2 is O and R2B is absent.
In some embodiments, Z2 is a bond.
In some embodiments, Z2 is CR2C.
In some embodiments, R2C is hydrogen.
In some embodiments, R2C is halogen. In some embodiments, R2C is fluoro or chloro.
In some embodiments, R2C is C1-C6 alkyl. In some embodiments, R2C is C1-C3 alkyl. In some embodiments, R2C is methyl.
In some embodiments, when Z1 is a bond and Z2 is a bond, R2B is absent and R2A is directly connected to Formula (I) via Z1. In some embodiments, when Z2 is a bond, R2B is absent and R2A is directly connected to Z1. In some embodiments, Z2 is O and R2B is absent.
In some embodiments, R2 is -NR2AR2B, i.e., Z1 is a bond and Z2 is N. In some embodiments, R2 is R2B, i.e., Z1 and Z2 are both a bond, R2A is absent and R2B is directly connected to Formula (I) via Z1.
In some embodiments, when Z1 is a not a bond and Z2 is a bond, R2B is absent and R2A is directly connected to Z1.
In some embodiments, R2A is hydrogen.
In some embodiments, R2A is -C(=O)R10.
In some embodiments, R2A is -C(=O)OR10.
In some embodiments, R2A is -C(=O)NR10Rn.
In some embodiments, R2A is -S(=O)R10.
In some embodiments, R2A is -S(O2)R10.
In some embodiments, R10 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, R10 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
In some embodiments, R10 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, R10 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
In some embodiments, R10 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R10 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl.
In some embodiments, R11 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, R11 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
In some embodiments, Ru is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, R11 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
In some embodiments, R11 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R11 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
In some embodiments, when R10 and R11 are attached to the same nitrogen atom, R10 and R11 are the same. In some embodiments, when R10 and R11 are attached to the same nitrogen atom, R10 and R11 are different. In some embodiments, when R10 and R11 are attached to the same nitrogen atom, R10 and R11 are each hydrogen. In some embodiments, when R10 and R11 are attached to the same nitrogen atom, R10 and Rn are each an independently selected C1-C6 alkyl.
In some embodiments, when R10 and R11 are attached to the same nitrogen atom, one of R10 and R11 is hydrogen and the other of R10 and R11 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, when R10 and R11 are attached to the same nitrogen atom, one of R10 and R11 is hydrogen and the other of R10 and R11 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, R2A is optionally substituted C1-C6 alkyl. In some embodiments, R2Ais C1-C6 alkyl. In some embodiments, R2Ais methyl or ethyl.
In some embodiments, R2A is C1-C6 haloalkyl. In some embodiments, R2A is C1-C3 haloalkyl. In some embodiments, R2Ais trifluoromethyl.
In some embodiments, R2Ais optionally substituted C2-C6 alkenyl. In some embodiments, R2Ais C2-C6 alkenyl. In some embodiments, R2Ais optionally substituted C2-C3 alkenyl. In some embodiments, R2Ais C2-C3 alkenyl.
In some embodiments, R2Ais optionally substituted C2-C6 alkynyl. In some embodiments, R2A is C2-C6 alkynyl. In some embodiments, R2A is optionally substituted C2-C3 alkynyl. In some embodiments, R2Ais C2-C3 alkynyl.
In some embodiments, R2A is optionally substituted C3-C10 cycloalkyl. In some embodiments, R2Ais optionally substituted C3-C6 cycloalkyl. In some embodiments, R2A is C3- C10 cycloalkyl. In some embodiments, R2Ais C3-C6 cycloalkyl.
In some embodiments, R2Ais optionally substituted phenyl. In some embodiments, R2Ais phenyl.
In some embodiments, R2Ais optionally substituted 3-12 membered heterocyclyl. In some embodiments, R2A is optionally substituted 4-8 membered heterocyclyl. In some embodiments, R2Ais 3-12 membered heterocyclyl. In some embodiments, R2Ais 4-8 membered heterocyclyl.
In some embodiments, R2A is optionally substituted 5-10 membered heteroaryl. In some embodiments, R2Ais optionally substituted 5-6 membered heteroaryl. In some embodiments, R2A is 5-10 membered heteroaryl. In some embodiments, R2Ais 5-6 membered heteroaryl.
In some embodiments, R2B is hydrogen.
In some embodiments, R2B is -C(=O)R10.
In some embodiments, R2B is -C(=O)OR10.
In some embodiments, R2B is -C(=O)NR10R11.
In some embodiments, R2B is -S(=O)R10.
In some embodiments, R2B is -S(O2)R10.
In some embodiments, R2B is optionally substituted C1-C6 alkyl. In some embodiments, R2B is C1-C6 alkyl. In some embodiments, R2B is methyl or ethyl.
In some embodiments, R2B is C1-C6 haloalkyl. In some embodiments, R2B is C1-C3 haloalkyl. In some embodiments, R2B is trifluoromethyl.
In some embodiments, R2Bis optionally substituted C2-C6 alkenyl. In some embodiments, R2B is C2-C6 alkenyl. In some embodiments, R2B is optionally substituted C2-C3 alkenyl. In some embodiments, R2B is C2-C3 alkenyl.
In some embodiments, R2Bis optionally substituted C2-C6 alkynyl. In some embodiments, R2Bis C2-C6 alkynyl. In some embodiments, R2Bis optionally substituted C2-C3 alkynyl. In some embodiments, R2B is C2-C3 alkynyl.
In some embodiments, R2B is optionally substituted C3-C10 cycloalkyl. In some embodiments, R2B is optionally substituted C3-C6 cycloalkyl. In some embodiments, R2B is C3- C10 cycloalkyl. In some embodiments, R2Bis C3-C6 cycloalkyl.
In some embodiments, R2B is optionally substituted phenyl. In some embodiments, R2B is phenyl.
In some embodiments, R2B is optionally substituted 3-12 membered heterocyclyl. In some embodiments, R2B is optionally substituted 4-8 membered heterocyclyl. In some embodiments, R2B is 3-12 membered heterocyclyl. In some embodiments, R2B is 4-8 membered heterocyclyl.
In some embodiments, R2B is optionally substituted 5-10 membered heteroaryl. In some embodiments, R2B is optionally substituted 5-6 membered heteroaryl. In some embodiments, R2B is 5-10 membered heteroaryl. In some embodiments, R2B is 5-6 membered heteroaryl.
In some embodiments, R2B is -C(=O)R10, -C(=O)OR10, -C(=O)NR10Ru, -S(=O)R10, -S(C>2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; and R2B is hydrogen.
In some embodiments, one of R2A and R2B is hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl, and the other of R2A and R2B is hydrogen, -C(=O)R10, -C(=O)OR10, -C(=O)NR10Rn, -S(=O)R10, -S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl.
In some embodiments, one of R2A and R2B is hydrogen and the other of R2A and R2B is an optionally substituted 4-12 membered heterocyclyl or an optionally substituted 5-6 membered heteroaryl. In some embodiments, one of R2A and R2B is hydrogen and the other of R2A and R2B
is an optionally substituted 4-12 membered heterocyclyl. In some embodiments, one of R2A and R2B is hydrogen and the other of R2A and R2B is a substituted 4-12 membered heterocyclyl.
In some embodiments, R2A and R2B together with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl.
R2A
In some embodiments, R2 is or CF’ , i.e., Z1 is optionally
R2A
R2A
N-R2B substituted alkylene and Z2 is N. In some embodiments, R2 is
R2A R2A R2A N'R2B V<R R2B N'R2B 2B /yR
F CF3 , or CF NH 3 . In some embodiments, R2 is NHz , or
H N.
R2B
, i.e., Z1 is optionally substituted alkylene, Z2 is a bond, and R2A is absent. In some
>OR2B </R2B ^R2B /^R2B
NH embodiments, R2 is NHz , RH2 , /NH , x R2B , or R2B O In some embodiments, R2A is hydrogen.
F F
OH
In some embodiments, R2B is , or . In some
OH
OH embodiments, R2B is , or '
F. F. F. F,
10
In some embodiments, R2B is
10
10
10
I
In some embodiments, R2 as defined herein, comprises an a, P-unsaturated system or an electrophilic group.
In some embodiments, X3 is CR2 and R2 as defined herein comprises an a, 0-unsaturated system or an electrophilic group, as described herein.
In some embodiments, one of X2, X3, X4, and X5 is CR2, one of X2, X3, X4, and X5 is CR3, and the remaining X2, X3, X4, and X5 are CH or N.
In some embodiments, one of X2, X3, X4, and X5 is CR2, one of X2, X3, X4, and X5 is CR3, and the remaining X2, X3, X4, and X3 are CH.
In some embodiments, R3 is halogen. In some embodiments, R3 is fluoro. In some embodiments, R3 is chloro.
In some embodiments, R3 is cyano.
In some embodiments, R3 is -NR12R13.
In some embodiments, R3 is -OR12.
In some embodiments, R3 is -C(=O)NR12R13.
In some embodiments, R3 is -C(=O)R12.
In some embodiments, R3 is -C(=O)OR12.
In some embodiments, R3 is -OC(=O)R12.
In some embodiments, R3 is NR12(C=O)NR12R13.
In some embodiments, R3 is -SR12.
In some embodiments, R3 is -S(=O)R12.
In some embodiments, R3 is -S(O2)R12.
In some embodiments, R3 is -S(O2)NR12R13.
In some embodiments, R3 is -NR12S(O2)NR13R14.
In some embodiments, R3 is -R!2C(=O)R13.
In some embodiments, R3 is -NR12C(=O)R13.
In some embodiments, R12 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, R12 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
In some embodiments, R12 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, R12 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
In some embodiments, R12 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R12 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
In some embodiments, R13 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, Rlj is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
In some embodiments, R13 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, R13 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
In some embodiments, R13 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R13 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
In some embodiments, R14 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, R14 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.
In some embodiments, R14 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, R14 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.
In some embodiments, R14 is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R14 is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.
In some embodiments, when R12 and R13 are attached to the same nitrogen atom, R12 and R13 are the same. In some embodiments, when R12 and R13 are attached to the same nitrogen atom, R12 and R13 are different. In some embodiments, when R12 and R13 are attached to the same nitrogen atom, R12 and R13 are each hydrogen. In some embodiments, when R12 and R13 are attached to the same nitrogen atom, R12 and R13 are each an independently selected C1-C6 alkyl.
In some embodiments, when R12 and R13 are attached to the same nitrogen atom, one of R12 and R13 is hydrogen and the other of R12 and R13 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, when R12 and R13 are attached to the same nitrogen atom, one of R12 and R13 is hydrogen and the other of R12 andR13 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, when R13 and R14 are attached to the same nitrogen atom, R13 and R14 are the same. In some embodiments, when R13 and R14 are attached to the same nitrogen atom, R13 and R14 are different. In some embodiments, when R13 and R14 are attached to the same nitrogen atom, R13 and R14 are each hydrogen. In some embodiments, when R13 and R14 are attached to the same nitrogen atom, R13 and R14 are each an independently selected C1-C6 alkyl.
In some embodiments, when R13 and R14 are attached to the same nitrogen atom, one of R13 and R14 is hydrogen and the other of R13 and R14 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.
In some embodiments, when Rlj and R14 are attached to the same nitrogen atom, one of R13 and R14 is hydrogen and the other of R13 andR14 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.
In some embodiments, R3 is optionally substituted C1-C6 alkyl. In some embodiments, R3 is C1-C6 alkyl. In some embodiments, R3 is methyl or ethyl.
In some embodiments, R3 is optionally substituted C2-C6 alkenyl. In some embodiments, R3 is C2-C6 alkenyl. In some embodiments, R3 is optionally substituted C2-C3 alkenyl. In some embodiments, R3 is C2-C3 alkenyl.
In some embodiments, R3 is optionally substituted C2-C6 alkynyl. In some embodiments, R3 is C2-C6 alkynyl. In some embodiments, R3 is optionally substituted C2-C3 alkynyl. In some embodiments, R3 is C2-C3 alkynyl.
In some embodiments, R3 is optionally substituted C3-C6 cycloalkyl. In some embodiments, R3 is C3-C6 cycloalkyl.
In some embodiments, R3 is optionally substituted phenyl. In some embodiments, R3 is phenyl.
In some embodiments, R3 is optionally substituted 4-6 membered heterocyclyl. In some embodiments, R3 is 4-6 membered heterocyclyl.
In some embodiments, R3 is optionally substituted 5-6 membered heteroaryl. In some embodiments, R3 is 5-6 membered heteroaryl.
In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.
In some embodiments, L is an optionally substituted 5-6 membered heteroarylene. In some embodiments, L is a 5-6 membered heteroarylene. In some embodiments, L is a substituted 6 membered heteroarylene. In some embodiments, L is a 5 membered heteroarylene. In some embodiments, L is a 2,5-(l,3,4-oxadiazolyl)ene, a 2,5-(l,3,4-thiadiazolyl)ene, or a 3,5-(l,2,4- oxadiazolyl)ene. In some embodiments, L is
N-N
, wherein each represents a bond to either the cabon of the 5 -membered ring of
Formula (I) or the CH2 or RA of Formula (I).
In some embodiments, L is an optionally substituted 4-6 membered heterocyclylene. In some embodiments, L is a 4-6 membered heterocyclylene. In some embodiments, L is a 4 membered heterocyclylene.
Non-Limiting Exemplary Compounds
In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table 1, or a pharmaceutically acceptable salt thereof. w Table 1
Example
Structure
No.
1
X X ..-J /\
X . ' —A
XT A -
2 f . / 1
X:. 'sxz N-:”’ X ..A X X', /
r r" T
< / \ * / y
* > - ; y
■ J
HA7 Q €i > x iv
/ f X
\ K
^
■; ‘!
Z . L
Z J / Z 7 f I > L J
J X X
\ Y . _ xM J
'if
F 6 x/ X
f^YW V .=;X 1 ^.Xx xx j? X. -
F- _ /
/ \
I - yj ^ — X X X
J 1
1 1 r w u/
J x A/ J X
X' --X
K,fl r : r : v> _- / v i ’C \
X X/ N. // \ K-- ,-1 H X ! \
,s I ' t--^/ (>
\ rK ,/x x xx XNX
J
X x X,, s o .
1 : i ;i< A : ■ /
-x >- x.^x /Z'-^z' KN V \ \ r r w ii " u 'z xx N. 'x /;/ \ O'- _N
$
/ f/ 1
X r rw 1 r\ .
X/M s 11 \
F->_ "x /
FK ^S-- Xr ,xz
'X-'■’ i ti " \ -i r \ \
X-x ' W:::-\ .„M X \
It f F
\ /K / 'X--
\
FK /V
HN^ x-X
L hj // \ J H / \
V:""\ -'■ 1 N—./ r f V -'- \
Z<v•N-- J V. / K■ "0 b
L %..- L;P r--^ K'- AX. H n /-X (-.
/xj" J v
L J J . U. A ri.„
1 "" r%/ S
,-y x J N- f f \ . / '?
L X / \ -i « i ''
In some embodiments, the compound is selected from the group consisting of the compounds delineated in List 1, or a pharmaceutically acceptable salt thereof.
List 1
N-((3-(8-(((3S,4R)-3 -fluoro- l-methylpiperidin-4-yl)amino)-3-vinylimidazo[l,2-a]pyridin-2-yl)- l,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-vinylpyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH- pyrazole-4-carb oxami de; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-vinyl-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; 1- (tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-vinylimidazo[l,2- a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3- (8-(((3 S,4R)-3 -fluoro- 1 -methylpiperidin-4-yl)amino)-3-vinylimidazo[ 1 ,2-a]pyri din-2 -yl)- 1 ,2,4- oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-vinylpyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-vinylpyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3- carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2- yl)- 1 ,3 ,4-thiadiazol-2-yl)methyl)cyclopropanecarboxamide; N-((5-(8-(((3 S,4R)-3 -fluoro- 1 - methylpiperidin-4-yl)amino)-3-vinylimidazo[l,2-a]pyridin-2-yl)-l,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; N-((5-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-
yl )amino)-3 -viny 1 pyrazol o[ 1 , 5 -a]pyri din-2-yl )- 1 , 3 ,4-thi adi azol -2- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)-l,3,4-thiadiazol-2-yl)methyl)-lH- pyrazol e-4-carb oxami de; 1 -(tert-butyl)-N-((5 -(7-(((3 S,4R)-3 -fluoro- 1 -methylpiperidin-4- yl)amino)-3-vinyl-2H-indazol-2-yl)-l,3,4-thiadiazol-2-yl)methyl)-lH-pyrrole-3-carboxamide; 1- (tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-vinylimidazo[l,2- a]pyridin-2-yl)-l,3,4-thiadiazol-2-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5- (8-(((3 S,4R)-3 -fluoro- 1 -methylpiperidin-4-yl)amino)-3-vinylimidazo[ 1 ,2-a]pyri din-2 -yl)- 1,3,4- thiadiazol-2-yl)methyl)-lH-pyrrole-3-carboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-vinylpyrazolo[l,5-a]pyridin-2-yl)-l,3,4-thiadiazol-2-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-vinylpyrazolo[l,5-a]pyridin-2-yl)-l,3,4-thiadiazol-2-yl)methyl)-lH-pyrrole-3- carboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-vinyl-2H- indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3-(8-(((3S,4R)-3- fluoro- 1 -methylpiperidin-4-yl)amino)-3 -vinylimidazof 1 ,2-a]pyrazin-2-yl)- 1 ,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3 -fluoro- 1-methylpiperi din-4- yl)amino)-3 -vinylpyrazolof 1 ,5 -a]pyrazin-2-yl)- 1 ,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(5-amino-7-(((3 S,4R)-3-fluoro- 1-methylpiperi din-4- yl)amino)-3-vinyl-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-l-(tert-butyl)-lH-pyrazole-4- carboxamide; N-((3-(5-amino-7-(((3 S,4R)-3-fluoro- 1-methylpiperi din-4-yl)amino)-3-vinyl-2H- indazol-2-yl)- 1 ,2,4-oxadiazol-5-yl)methyl)- 1 -(tert-butyl)- lH-pyrrole-3 -carboxamide; 1 -(tert- butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-vinylimidazo[l,2-a]pyrazin- 2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8- (((3 S,4R)-3-fluoro- 1-methylpiperi din-4-yl)amino)-3 -vinylimidazof l,2-a]pyrazin-2-yl)- 1,2,4- oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-vinylpyrazolo[l,5-a]pyrazin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-vinylpyrazolo[l,5-a]pyrazin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3- carboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-vinyl-2H- indazol-2-yl)-l,3,4-thiadiazol-2-yl)methyl)cyclopropanecarboxamide; N-((5-(8-(((3S,4R)-3- fluoro- 1-methylpiperi din-4-yl)amino)-3-vinylimidazo[l,2-a]pyrazin-2-yl)- 1,3, 4-thiadiazol-2-
yl)methyl)cyclopropanecarboxamide; N-((5-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-vinylpyrazolo[l,5-a]pyrazin-2-yl)-l,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3 -vinyl -2H-indazol-2-yl)-l, 3, 4-thiadiazol-2-yl)m ethyl)- 1 -(tert-butyl)- lH-pyrazole-4- carboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-vinyl-2H- indazol-2-yl)-l,3,4-thiadiazol-2-yl)methyl)-l-(tert-butyl)-lH-pyrrole-3-carboxamide; l-(tert- butyl)-N-((5-(8-(((3S,4R)-3 -fluoro- l-methylpiperidin-4-yl)amino)-3-vinylimidazo[l,2-a]pyrazin-
2-yl)-l,3,4-thiadiazol-2-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(8- (((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-vinylimidazo[l,2-a]pyrazin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrrole-3 -carboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-vinylpyrazolo[l,5-a]pyrazin-2-yl)-l,3,4-thiadiazol-2-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-vinylpyrazolo[l,5-a]pyrazin-2-yl)-l,3,4-thiadiazol-2-yl)methyl)-lH-pyrrole-3- carboxamide; N-((3-(5-fluoro-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-vinyl-2H- indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(5- fluoro-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(5-fluoro-7-(((3S,4R)-
3-fluoro-l-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)- lH-pyrrole-3-carboxamide; N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-vinyl-2H-indazol-2-yl)-l,3,4-thiadiazol-2-yl)methyl)cyclopropanecarboxamide; 1- (tert-butyl)-N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-vinyl-2H- indazol-2-yl)-l,3,4-thiadiazol-2-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(5- fluoro-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)- 1,3,4- thiadiazol-2-yl)methyl)-lH-pyrrole-3 -carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(prop-l-en-2-yl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3 -(prop- l-en-2-yl)imidazo[l,2-a]pyridin-2-yl)- 1,2, 4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3 -fluoro- l-methylpiperidin-4- yl)amino)-3 -(prop- 1 -en-2-yl)pyrazolo[ 1 ,5-a]pyridin-2-yl)- 1 ,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(prop-l -en-2-yl)-2H-indazol -2-yl)- 1,2, 4-oxadiazol-5-yl)methyl)-
lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-(prop-l-en-2-yl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-(prop- l-en-2-yl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-(prop-
1-en-2-yl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide;
1 -(tert-butyl)-N-((3 -(7-(((3 S,4R)-3 -fluoro- 1 -methylpiperidin-4-yl)amino)-3 -(prop- 1 -en-2- yl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; 1- (tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-(prop-l-en-2- yl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; N-((3- (7-(((3 S,4R)-3 -fluoro- 1 -methylpiperidin-4-yl)amino)-3-( 1 -fluorovinyl)-2H-indazol-2-yl)- 1 ,2,4- oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3-(8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(l-fluorovinyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-(l-fluorovinyl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- rnethylpiperidin-4-yl)amino)-3-(l-fluorovinyl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)rnethyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-(l-fluorovinyl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-(l- fluorovinyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-(l- fluorovinyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3- carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-(l- fluorovinyl)pyrazolo[ 1 , 5-a]pyridin-2-yl)- 1 ,2,4-oxadiazol-5-yl)methyl)- lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-(l- fluorovinyl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3- carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-((E)-prop-l-en-l- yl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3-(8-
(((3 S,4R)-3-fluoro- 1 -methylpiperidin-4-yl)amino)-3 -((E)-prop- 1 -en- 1 -yl)imidazo[ 1 ,2-a]pyridin-
2-yl)-l,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l-
methylpiperidin-4-yl)amino)-3-((E)-prop-l-en-l-yl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-((E)-prop-l-en-l-yl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3 -((E)-prop- 1 -en- 1 -yl)-2H-indazol-2-yl)- 1 ,2,4-oxadiazol-5- yl)methyl)-lH-pyrrole-3-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3 -((E)-prop- 1 -en- 1 -yl)imidazo[ 1 ,2-a]pyri din-2 -yl)- 1 ,2,4-oxadiazol- 5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3 -((E)-prop- 1 -en- 1 -yl)imidazo[ 1 ,2-a]pyri din-2 -yl)- 1 ,2,4-oxadiazol- 5-yl)methyl)-lH-pyrrole-3-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3 -((E)-prop- 1 -en- 1 -yl)pyrazolo[ 1 ,5-a]pyridin-2-yl)- 1 ,2,4- oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro- 1 -methylpiperidin-4-yl)amino)-3 -((E)-prop- 1 -en- 1 -yl)pyrazolo[ 1 , 5-a]pyridin-2-yl)- 1 ,2,4- oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; N-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3- fluoro- 1 -methylpiperidin-4-yl)amino)-2H-indazol-2-yl)- 1 ,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(3-(2,2-difluorovinyl)-8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3- fluoro- 1 -methylpiperidin-4-yl)amino)-2H-indazol-2-yl)- 1 ,2,4-oxadiazol-5-yl)methyl)- 1H- pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3- carboxamide; l-(tert-butyl)-N-((3-(3-(2,2-difluorovinyl)-8-(((3S,4R)-3-fluoro-l-rnethylpiperidin- 4-yl)amino)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(3-(2,2-difluorovinyl)-8-(((3S,4R)-3-fluoro-l-methylpiperidin- 4-yl)amino)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3- carboxamide; l-(tert-butyl)-N-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3-fluoro-l-methylpiperidin- 4-yl)amino)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3-fluoro-l-methylpiperidin- 4-yl)amino)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lE[-pyrrole-3-
carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-(l,2,2- trifluorovinyl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3- (8-(((3 S,4R)-3 -fluoro- 1 -methylpiperidin-4-yl)amino)-3-( 1 ,2,2-trifluorovinyl)imidazo[ 1 ,2- a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3- fluoro- 1 -methylpiperidin-4-yl)amino)-3 -( 1 ,2,2-trifluorovinyl)pyrazolo[ 1 ,5 -a]pyri din-2 -yl)- 1 ,2,4- oxadiazol-5-yl)methyl)cyclopropanecarboxamide; 2-(5-((((l-(tert-butyl)-lH-pyrazol-4-yl)(12- fluoraneylidene)methyl)amino)methyl)-l,2,4-oxadiazol-3-yl)-N-((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)-3-(l,2,2-trifluorovinyl)-2H-indazol-7-amine; l-(tert-butyl)-N-((3-(7- (((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)arnino)-3-(l,2,2-trifluorovinyl)-2H-indazol-2-yl)- l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3- fluoro- 1 -methylpiperidin-4-yl)amino)-3 -( 1 ,2,2-trifluorovinyl)imidazo[ 1 ,2-a]pyridin-2-yl)- 1 ,2,4- oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3 -(1,2, 2-trifluorovinyl)imidazo[l,2-a]pyridin-2-yl)- 1,2,4- oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(l,2,2-trifluorovinyl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(l,2,2-trifluorovinyl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-((R)-oxiran-2-yl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-((S)-oxiran-2-yl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-((R)-oxiran-2-yl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-((S)-oxiran-2-yl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-((S)-oxiran-2-yl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-((R)- oxiran-2-yl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-((S)- oxiran-2-yl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3-
carboxamide; l -(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-((R)- oxiran-2-yl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-((R)- oxiran-2-yl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3- carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-((S)-oxiran-2-yl)- 2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3-(8-(((3S,4R)-3- fluoro-l-methylpiperidin-4-yl)amino)-3-((R)-oxiran-2-yl)imidazo[l,2-a]pyridin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-((S)-oxiran-2-yl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-((R)-oxiran-2-yl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-((R)-oxiran-2-yl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-((S)- oxiran-2-yl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-((R)- oxiran-2-yl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3- carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-((S)- oxiran-2-yl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3- carboxamide; N-((3-(6-acrylamido-8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)imidazo[ 1 ,2-a]pyridin-2-yl)- 1 ,2,4-oxadiazol-5-yl)methyl)- 1 -(tert-butyl)- 1H- pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-6-methacrylamido-3 -(2,2,2-trifluoroethyl)imidazo[ 1 ,2-a]pyridin-2-yl)- 1 ,2,4- oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(6-((E)-4- (dimethylamino)but-2-enamido)-8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3 -fluoro- l-methylpiperidin-4-yl)amino)-6-((E)-4- (4-methylpiperazin-l-yl)but-2-enamido)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)- l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3- fluoro-l-methylpiperidin-4-yl)amino)-6-(4-(methylamino)but-2-ynamido)-3 -(2,2,2- trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4-
carboxamide; l -(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-6-(2- fluoroacrylamido)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5- yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-6-propiolamido-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)- l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3- fluoro-l-methylpiperidin-4-yl)amino)-6-((E)-4-(methylamino)but-2-enamido)-3-(2,2,2- trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3 -fluoro- l-methylpiperidin-4-yl)amino)-6-((E)-4- morpholinobut-2-enamido)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol- 5-yl)methyl)-lH-pyrazole-4-carboxamide; N-((3-(6-(but-2-ynamido)-8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol- 5-yl)methyl)-l-(tert-butyl)-lH-pyrazole-4-carboxamide; N-((3-(6-((E)-but-2-enamido)-8- (((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyridin- 2 -yl)-l, 2, 4-oxadiazol-5-yl)methyl)-l -(tert-butyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N- ((3-(6-((E)-4-(3,3-difluoroazetidin-l-yl)but-2-enamido)-8-(((3S,4R)-3-fluoro-l-methylpiperidin-
4-yl)amino)-3 -(2,2,2-trifluoroethyl)imidazo[ 1 ,2-a]pyridin-2-yl)- 1 ,2,4-oxadiazol-5-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(6-(4-(dimethylamino)but-2-ynamido)-8-
(((3 S,4R)-3-fluoro- 1 -methylpiperidin-4-yl)amino)-3 -(2,2,2-trifluoroethyl)imidazo[ 1 ,2-a]pyridin- 2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S/lR)-3 -fluoro- l-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)- lH-pyrrole-3 -carboxamide; 1 -(tert-butyl)-N-((3 -(8-(((3 S,4R)-3-fluoro- 1 - methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-
5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-
methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)-l ,2,4-oxadiazol- 5-yl)methyl)-lH-pyrrole-3-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,3,4-thiadiazol-2- yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,3,4-thiadiazol-2- yl)methyl)-lH-pyrrole-3-carboxamide; N-((5-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)-l,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrrole-3 -carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[l,5-a]pyridin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[l,5-a]pyridin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[l,5-a]pyridin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrrole-3 -carboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3 -(2, 2, 2-trifluoroethyl)-2H-indazol-2-yl)-l, 2, 4-oxadiazol-5-yl)methyl)-l -(tert-butyl)- lH-pyrazole-4-carboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3 -(2, 2, 2-trifluoroethyl)-2H-indazol-2-yl)-l, 2, 4-oxadiazol-5-yl)methyl)-l -(tert-butyl)- lH-pyrrole-3-carboxamide; N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)imidazo[ 1 ,2-a]pyrazin-2-yl)- 1 ,2,4-oxadiazol-5-
yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l - methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyrazin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyrazin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[l,5-a]pyrazin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[l,5-a]pyrazin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[l,5-a]pyrazin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,3,4-thiadiazol-2-yl)methyl)-l-(tert-butyl)- lH-pyrrole-3-carboxamide; N-((5-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)imidazo[l,2-a]pyrazin-2-yl)-l,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyrazin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyrazin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrrole-3 -carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[l,5-a]pyrazin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)cyclopropanecarboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,3,4-thiadiazol-2- yl)methyl)-l -(tert-butyl)- lH-pyrazole-4-carboxami de; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[l,5-a]pyrazin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[l,5-a]pyrazin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrrole-3 -carboxamide; N-((3-(5-fluoro-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(5-fluoro-7-(((3S,4R)-3 -fluoro- 1-
methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(5-fluoro-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)-lH-pyrrole-3-carboxamide; N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-l-methylpiperidin- 4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,3,4-thiadiazol-2- yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,3,4-thiadiazol-2- yl)methyl)-lH-pyrrole-3-carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3- carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3- (perfluoroethyl)pyrazolo[l,5-a]pyridin-2-yl)-l,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(perfluoroethyl)pyrazolo[l,5-a]pyridin-2-yl)-l,3,4-thiadiazol-2- yl)methyl)-lH-pyrazole-4-carboxamide; and l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(perfluoroethyl)pyrazolo[l,5-a]pyridin-2-yl)-l,3,4-thiadiazol-2- yl)methyl)-lH-pyrrole-3-carboxamide.
Pharmaceutical Compositions
Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
Methods of Treatment
Provided herein are methods for restoring p53 function, encoded by TP53 gene. For example, provided herein are compounds that restore p53 function that are useful for treating or
preventing diseases associated with dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same (i.e., a p53 -associated disease), such as cancer (e.g., p53-associated cancer).
The terms “restore” or “restoration of’ means to increase the activity and/or function of the specified target by a measurable amount. For example, restoration of a mutant p53 with a compound of Formula (I) refers to increasing the function of the mutant p53 in the presence of the compound to a higher level than the function of the mutant p53 in the absence of the compound.
The ability of test compounds to act as a p53 restorer may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as p53 restorers can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine activation of the protein and/or a change in its conformation. Potency of a p53 restorer as provided herein can be determined by EC50 value. A compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent p53 restorer relative to a compound with a higher EC50 value.
Indications
Compounds of Formula (I), or pharmaceutically acceptable salts thereof, are useful for treating diseases which can be treated with a p53 restorer, such as p53-associated diseases, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors). In some embodiments, the p53 -associated disease or disorder is Li -Fraumeni syndrome.
Some embodiments provide a method of treating cancer in a subject in need thereof, compirising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is a p53 -associated cancer.
Some embodiments provide a method of treating cancer in a subj ect that has been identified or diagnosed as having a p53 -associated cancer, compirising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the p53 -associated cancer harbors a Y220C mutation.
Some embodiments provide a method of treating a p53 -associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any
one of the compound of Examples 1 -1 10, or a pharmaceutically acceptable salt thereof. In some embodiments, the p53-associated cancer harbors a Y220C mutation.
Some embodiments provide a method of treating cancer in a subject in need thereof, comprising (a) determing that the subject has a p53 -associated cancer, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, compirising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject that has been identified or diagnosed as having Li-Fraumeni syndrome, compirising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising (a) determing that the subject has Li-Fraumeni syndrome, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered prophylactically to a subject with Li-Fraumeni syndrome. In some embodiments, a therapeutically effective amount of Formula (I), or a pharmaceutically acceptable salt thereof, is administered prophylactically to a subject with Li-Fraumeni syndrome.
The term “p53 -associated disease” as used herein refers to diseases associated with or having a dysregulation of a TP53 gene, a p53 protein, or the activity of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a TP53 gene, or a p53 protein, or the activity of any of the same described herein). Non-limiting examples of a p53-associated disease include, for example, cancer (e.g., p53-associated cancer).
The term “p53 -associated cancer” as used herein refers to cancers associated with or having a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. Non-limiting examples of p53-associated cancers are described herein.
The term “wild type” or “wild-type” describes a nucleic acid (e.g., a TP53 gene or a p53 mRNA) or protein (e.g., a p53) sequence that is typically found in a subject that does not have a cancer related to the reference nucleic acid or protein.
Provided herein is a method of treating cancer (e.g., a p53-associated cancer) in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating p53- associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of TP53 gene, a p53 protein, or the activity of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same includes one or more a p53 protein substitutions/point mutations/insertions. Non-limiting examples of p53 protein substitutions/insertions/deletions are described in Table 1.
In some embodiments, the p53 protein substitution / insertion / deletion is Y220X, where X is any amino acid other than Y. In some embodiments, the p53 protein substitution/insertion/deletion is selected from the group consisting of Y220C, Y220S, Y220N, Y220D, and combinations thereof. In some embodiments, the p53 protein substitution/insertion/deletion is selected from the group consisting of Y220C or Y220S, or a combination thereof. In some embodiments, the p53 protein substitution/insertion/deletion is Y220C. In some embodiments, the p53 protein substitution/insertion/deletion is Y220S.
In some embodiments, the dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, includes at least one point mutation in a TP53 gene that results in the production of a p53 protein that has one or more amino acid substitutions or insertions or deletions in a TP53 gene that results in the production of a p53 protein that has one or more amino acids inserted or removed, as compared to the wild type p53 protein. In some cases, the resulting mutant p53 protein has reduced function, as compared to a wild type p53 protein or a p53 protein not including the same mutation. In some embodiments, the compounds described herein restore the resulting mutant p53 protein function relative to the mutant p53 protein function in the absence of the compounds described herein, for example, by stabilizing the mutant protein into an active conformation.
Exemplary Sequence of Human p53 (UniProtKB entry P04637-1) (SEQ ID NO: 1)
MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGP DEAPRMPE AAPP VAPAP AAPTP AAPAPAP S WPL S S S VP SQKTYQGS YGFRLGFLHSGTA KSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCP HHERC SD SDGL APPQHLIRVEGNLRVEYLDDRNTFRHS VVVP YEPPE VGSDCTTIHYNY MCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPH HELPPGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAG KEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD
In some embodiments, compounds of Formula (I), or pharmaceutically acceptable thereof, are useful for treating a cancer that has been identified as having one or more p53 mutations. Accordingly, provided herein are methods for treating a subject diagnosed with (or identified as having) a cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Also provided herein are methods for treating a subject identified or diagnosed as having a p53 -associated cancerthat include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject that has been identified or diagnosed as having a p53 -associated cancer through the use of a regulatory agency-approved, e.g., FDA- approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject or by performing any of the nonlimiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an p53-associated cancer.
Also provided are methods for treating cancer in a subject in need thereof, the method comprising: (a) detecting a p53-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., an immunotherapy). In some embodiments, the subj ect was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy. In some embodiments, the subject is determined to have a p53-associated cancer through the use of a regulatory agency- approved, e.g., FDA-approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject or by
performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an p53-associated cancer.
Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a p53-associated cancer in a subject identified or diagnosed as having a p53 -associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, where the presence of a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, identifies that the subject has a p53-associated cancer.
Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer in a subject in need thereof, or a subject identified or diagnosed as having a p53-associated cancer. Also provided is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having a p53 -associated cancer. In some embodiments, a subject is identified or diagnosed as having a p53-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject. As provided herein, a p53-associated cancer includes those described herein and known in the art.
In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed as having a cancer with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject can be a subject with a tumor(s) that is positive for a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject can be a subject whose tumors have a dysregulation of a TP 53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject is suspected of having a p53-associated cancer. In some embodiments, provided herein are methods for treating a p53 -associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same in a sample from the subject; and b) administering a
therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same includes one or more p53 protein point mutations/insertions/deletions, as described herein. In some embodiments, the cancer with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments, the tumor with a dysregulation of a TP 53 gene, a p53 protein, or activity of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a TP 53 gene, a p53 protein, or activity of any of the same. Also provided are methods of treating a subject that include administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a clinical record that indicates that the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.
Also provided is a method for restoring p53 function in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant p53 function. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a p53-associated cancer cell. As used herein, the term "contacting" refers to the bringing together of indicated moi eties in an in vitro system or an in vivo system. For example, "contacting" a p53 protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a p53 protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the p53 protein.
Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
Further provided herein is a method of increase cell death, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject. The method comprises administering to the subject an effective compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.
In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is selected from a hematological cancer and a solid tumor.
In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is a hematological cancer. In some embodiments, the hematological cancer is a leukemia. In some embodiments, the hematological cancer is a lymphoma. In some embodiments, the hematological cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or hairy cell leukemia (HCL). In some embodiments, the hematological cancer is acute myeloid leukemia (AML).
In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is selected from brain cancer, bladder cancer, breast cancer, colorectal cancer, skin cancer, esophageal cancer, lung cancer, gastric cancer, kidney cancer, uterine cancer, ovarian cancer, liver cancer, pancreatic cancer, prostate cancer, leiomyosarcoma, and head and neck squamous cell carcinoma.
In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is selected from colorectal cancer, ovarian cancer, pancreatic cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, endometrial cancer, and bladder cancer.
In some embodiments, the brain cancer is astrocytoma, oligoastrocytoma, oligodendroglioma, or glioblastoma multiforme.
In some embodiments, the bladder cancer is bladder urothelial carcinoma.
In some embodiments, the esophageal cancer is esophageal adenocarcinoma or esophageal squamous cell carcinoma.
In some embodiments, the skin cancer is cutaneous melanoma.
In some embodiments, the lung cancer is small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is small cell lung cancer (SCLC).
In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is lung adenocarcinoma or lung squamous cell carcinoma.
In some embodiments, the gastric cancer is mucinous stomach adenocarcinoma or intestinal type stomach adenocarcinoma.
In some embodiments, the breast cancer is breast invasive ductal carcinoma.
In some embodiments, the uterine cancer is uterine mixed endometrial carcinoma, uterine endometrioid carcinoma, uterine serous carcinoma, or uterine papillary serous carcinoma.
In some embodiments, the ovarian cancer is serous ovarian cancer.
In some embodiments, the kidney cancer is chromophobe renal cell carcinoma.
In some embodiments, the colorectal cancer is colon adenocarcinoma.
In some embodiments, the liver cancer is hepatocellular carcinoma.
In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma.
In some embodiments, the cancer is prostate cancer.
In some embodiments of any of the methods or uses described herein, the p53-associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the p53 -associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is lung cancer.
In some embodiments of any of the methods or uses described herein, the p53-associated cancer is selected from the cancers described in Table 1.
Table 1. p53 Protein Amino Acid Substitutions/Insertions/DeletionsA
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
1 Ml Head and Neck Squamous Cell Carcinoma (translation start site)
4 P4L Mucinous Stomach Adenocarcinoma
10 XIO splice (splice site) Acute Myeloid Leukemia
11 Ell* (nonsense mutation) Breast Invasive Ductal Carcinoma E11K Renal Clear Cell Carcinoma
20 S20* Bladder Urothelial Carcinoma S20Qfs*24 Intestinal Type Stomach Adenocarcinoma (frame shift, additional amino acids)
22 L22Yfs*22 Bladder Urothelial Carcinoma
23 W23* Cervical Squamous Cell Carcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
25 X25_splice Adrenocortical Carcinoma
Head and Neck Squamous Cell Carcinoma Tubular Stomach Adenocarcinoma
27 P27L Adrenocortical Carcinoma P27Lfs*17 Astrocytoma P27S Breast Invasive Ductal Carcinoma
Chromophobe Renal Cell Carcinoma
Colon Adenocarcinoma
Cutaneous Melanoma
Head and Neck Squamous Cell Carcinoma
Mucinous Carcinoma
Pancreatic Adenocarcinoma
Serous Ovarian Cancer
Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian
Tumor
30 N30del Colon Adenocarcinoma (in frame deletion)
32 L32Cfs*12 Astrocytoma
X32_splice Chromophobe Renal Cell Carcinoma Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma Head and Neck Squamous Cell Carcinoma Lung Squamous Cell Carcinoma Oligoastrocytoma
Renal Clear Cell Carcinoma
33 S33Ffs*10 Astrocytoma
X33_splice Bladder Urothelial Carcinoma
Breast Invasive Ductal Carcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Prostate Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
35 L35Cfs*9 Bladder Urothelial Carcinoma
L35Ffs*7 Colon Adenocarcinoma
L35Ffs*8 Lung Adenocarcinoma
L35Pfs*10 Lung Squamous Cell Carcinoma Pancreatic Adenocarcinoma Papillary Stomach Adenocarcinoma Rectal Adenocarcinoma
Tubular Stomach Adenocarcinoma Uterine Endometrioid Carcinoma
36 P36Wfs*4 Serous Ovarian Cancer
37 S37Vfs*6 Lung Squamous Cell Carcinoma
38 Q38* Colon Adenocarcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Q38Kfs*6 Head and Neck Squamous Cell Carcinoma
Lung Squamous Cell Carcinoma
Pancreatic Adenocarcinoma
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
40 M40Lfs*7 Acute Myeloid Leukemia
42 D42Ifs*2 Esophageal Squamous Cell Carcinoma
43 L43* Hepatocellular Carcinoma
L43Afs*7 Serous Ovarian Cancer
Uterine Endometrioid Carcinoma
44 M44Ifs*79 Bladder Urothelial Carcinoma
M44Tfs*75 Lung Squamous Cell Carcinoma
46 S46* Lung Squamous Cell Carcinoma
S46Tfs*5
47 P47Rfs*76 Serous Ovarian Cancer
48 D48Gfs*4 Cutaneous Melanoma D48N Head and Neck Squamous Cell Carcinoma D48Nfs*72 Lung Adenocarcinoma D48Tfs*75 Lung Squamous Cell Carcinoma
49 D49Sfs*69 Lung Squamous Cell Carcinoma
51 E51* Breast Invasive Ductal Carcinoma
E51Gfs*6 Esophageal Adenocarcinoma Serous Ovarian Cancer
52 Q52* Breast Invasive Ductal Carcinoma
Head and Neck Squamous Cell Carcinoma Lung Adenocarcinoma
53 W53* Bladder Urothelial Carcinoma
W53Cfs*4 Diffuse Type Stomach Adenocarcinoma
W53Mfs*4 Glioblastoma Multiforme
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
54 F54Sfs*69 Lung Adenocarcinoma
56 E56* Adrenocortical Carcinoma
E56Kfs*67 Breast Invasive Ductal Carcinoma
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Lung Squamous Cell Carcinoma
57 D57Kfs*67 Lung Adenocarcinoma
D57N Pancreatic Adenocarcinoma
58 P58Qfs*65 Head and Neck Squamous Cell Carcinoma
61 D61* Uterine Endometrioid Carcinoma
D61G Uterine Mixed Endometrial Carcinoma
62 E62* Cervical Squamous Cell Carcinoma
E62K Lung Squamous Cell Carcinoma
E62Kfs*61 Pancreatic Adenocarcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Serous Ovarian Cancer
64 P64Qfs*84 Esophageal Squamous Cell Carcinoma
P64Sfs*59 Lung Squamous Cell Carcinoma
P64T Uterine Endometrioid Carcinoma
65 R65* Head and Neck Squamous Cell Carcinoma
R65Efs*58 Lung Adenocarcinoma
R65Qfs*84 Lung Squamous Cell Carcinoma
66 M66Tfs*60 Serous Ovarian Cancer
67 P67S Uterine Endometrioid Carcinoma
68 E68* Bladder Urothelial Carcinoma
Head and Neck Squamous Cell Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
69 A69Gfs*80 Lung Adenocarcinoma
72 P72Rfs*51 Cutaneous Melanoma
P72S Diffuse Type Stomach Adenocarcinoma
Lung Adenocarcinoma
73 V73Rfs*76 Adrenocortical Carcinoma
V73Wfs*50 Colon Adenocarcinoma
Head and Neck Squamous Cell Carcinoma
Leiomyosarcoma
Lung Squamous Cell Carcinoma
Pancreatic Adenocarcinoma
Rectal Adenocarcinoma
Tubular Stomach Adenocarcinoma
74 A74T Prostate Adenocarcinoma
75 P75Lfs*48 Lung Squamous Cell Carcinoma
76 A76Hfs*47 Serous Ovarian Cancer
77 P77Cfs*73 Breast Invasive Ductal Carcinoma
P77Gfs*65 Lung Adenocarcinoma
P77L
79 A79Pfs*70 Colon Adenocarcinoma
A79V Head and Neck Squamous Cell Carcinoma
82 P82L Prostate Adenocarcinoma P82Rfs*41 Stomach Adenocarcinoma
83 A83Gfs*66 Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
84 A84Pfs*39 Head and Neck Squamous Cell Carcinoma Lung Squamous Cell Carcinoma
85 P85Lfs*38 Head and Neck Squamous Cell Carcinoma
86 A86Cfs*63 Breast Invasive Ductal Carcinoma
A86Pfs*34 Prostate Adenocarcinoma
A86Vfs*55 Serous Ovarian Cancer
I ll
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
90 S90Ffs*53 Astrocytoma
S90Pfs*33 Breast Invasive Ductal Carcinoma
S90Pfs*34 Head and Neck Squamous Cell Carcinoma
S90Vfs*55 Hepatocellular Carcinoma
Lung Adenocarcinoma
Prostate Adenocarcinoma
Serous Ovarian Cancer
Uterine Endometrioid Carcinoma
91 W91* Astrocytoma
Bladder Urothelial Carcinoma
Breast Invasive Ductal Carcinoma
Colon Adenocarcinoma
Esophageal Adenocarcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Papillaty Renal Cell Carcinoma
Stomach Adenocarcinoma
92 P92Afs*57 Bladder Urothelial Carcinoma
P92S Uterine Endometrioid Carcinoma
93 L93Vfs*55 Breast Invasive Ductal Carcinoma
94 S94* Bladder Urothelial Carcinoma S94Cfs*30 Colon Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Rectal Adenocarcinoma
Stomach Adenocarcinoma
96 S96Ffs*25 Diffuse Type Stomach Adenocarcinoma
97 V97D Cutaneous Melanoma
V97Efs*48 Hepatocellular Carcinoma
V97Sfs*26 Tubular Stomach Adenocarcinoma
Uterine Endometrioid Carcinoma
98 P98Afs*51 Stomach Adenocarcinoma
99 S99Rfs*23 Head and Neck Squamous Cell Carcinoma Serous Ovarian Cancer
100 Q100* Colon Adenocarcinoma Q100Gfs*37 Lung Squamous Cell Carcinoma
Serous Ovarian Cancer
Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian
Tumor
101 K101* Head and Neck Squamous Cell Carcinoma
102 T102Pfs*21 Glioblastoma Multiforme Serous Ovarian Cancer
103 Y103* Head and Neck Squamous Cell Carcinoma
Y103Lfs*46 Hepatocellular Carcinoma
Y103Tfs*20 Lung Squamous Cell Carcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Stomach Adenocarcinoma
104 Q104* Esophageal Adenocarcinoma
Q104H Head and Neck Squamous Cell Carcinoma
Q104Tfs*20 Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Pancreatic Adenocarcinoma
Serous Ovarian Cancer
105 G105C Bladder Urothelial Carcinoma G105D Glioblastoma Multiformc G105R Head and Neck Squamous Cell Carcinoma G105S Lung Adenocarcinoma
G105V Lung Squamous Cell Carcinoma
Serous Ovarian Cancer
106 S106R Esophageal Squamous Cell Carcinoma Head and Neck Squamous Cell Carcinoma Hepatocellular Carcinoma Lung Squamous Cell Carcinoma
107 Y107Cfs*16 Breast Invasive Ductal Carcinoma
Y107D Colon Adenocarcinoma
Stomach Adenocarcinoma
108 G108Ffs*40 Breast Invasive Ductal Carcinoma G108S Glioblastoma Multiforme G108Vfs*15 Uterine Endometrioid Carcinoma
109 F109C Colon Adenocarcinoma
F109Lfs*36 Esophageal Squamous Cell Carcinoma
F109S Lung Adenocarcinoma
F109V Lung Squamous Cell Carcinoma
Oligoastrocytoma
Oligodendroglioma
Rectal Adenocarcinoma
110 R110_G112del Bladder Urothelial Carcinoma
R110C Breast Invasive Ductal Carcinoma RllOdel Cutaneous Melanoma
R110L Esophageal Squamous Cell Carcinoma
R110P Head and Neck Squamous Cell Carcinoma
R110Sfs*14 Lung Adenocarcinoma R110Vfs*13 Lung Squamous Cell Carcinoma R110Wfs*12 Oligoastrocytoma
Pancreatic Adenocarcinoma Serous Ovarian Cancer
111 L111P Bladder Urothelial Carcinoma
L111Q Breast Invasive Ductal Carcinoma
L111R Diffuse Type Stomach Adenocarcinoma Lung Squamous Cell Carcinoma Papillary Renal Cell Carcinoma
113 F113C Astrocytoma F113del Breast Invasive Carcinoma (NOS) F113L Breast Invasive Ductal Carcinoma F113V Colon Adenocarcinoma Esophageal Adenocarcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Leiomyosarcoma
Oligodendroglioma
114 L114* Breast Invasive Carcinoma (NOS)
115 H115Ifs*8 Breast Invasive Ductal Carcinoma
118 T118Dfs*31 Breast Invasive Ductal Carcinoma
T118Qfs*5 Head and Neck Squamous Cell Carcinoma Serous Ovarian Cancer
120 K120E Cutaneous Melanoma
K120Sfs*3 Lung Adenocarcinoma
K120Tfs*2 Lung Squamous Cell Carcinoma
Oligoastrocytoma
Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous
Histiocytoma/High-Grade Spindle Cell Sarcoma
121 S121Cfs*27 Bladder Urothelial Carcinoma
S121Y Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
122 V122Cfs*27 V122Dfs*26 Astrocytoma
V122Lfs*25 Breast Invasive Ductal Carcinoma Colon Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Leiomyosarcoma
Oligoastrocytoma
Oligodendroglioma
Pancreatic Adenocarcinoma Rectal Adenocarcinoma Serous Ovarian Cancer
123 T123Dfs*26 Glioblastoma Multiforme
T123Lfs*47 Pancreatic Adenocarcinoma
T123Rfs*48 Serous Ovarian Cancer
124 C124* Breast Invasive Ductal Carcinoma C124Afs*46 Colon Adenocarcinoma C124G Esophageal Squamous Cell Carcinoma C124Wfs*25 Prostate Adenocarcinoma
Serous Ov arian Cancer
125 T125= Acute Myeloid Leukemia (splice region) Adrenocortical Carcinoma
Astrocytoma
T125M Bladder Urothelial Carcinoma
T125P Breast Invasive Ductal Carcinoma
X125_splice Colon Adenocarcinoma
Cutaneous Melanoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Mucinous Adenocarcinoma of the Colon and Rectum
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Mucinous Stomach Adenocarcinoma
Oligoastrocytoma
Oligodendroglioma
Pancreatic Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Tubular Stomach Adenocarcinoma
Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous
Histiocytoma/High-Grade Spindle Cell Sarcoma
Uterine Endometrioid Carcinoma
Uterine Serous Carcinoma/U terine Papillary Serous Carcinoma
126 Y126_M133del Acute Myeloid Leukemia
Y126C Breast Invasive Ductal Carcinoma
Y126D Cutaneous Melanoma
Y126H Esophageal Squamous Cell Carcinoma
Y126N Glioblastoma Multiforme Y126S Head and Neck Squamous Cell Carcinoma X126_splice Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Mucinous Stomach Adenocarcinoma
Oligodendroglioma
Pancreatic Adenocarcinoma
Prostate Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Signet Ring Cell Carcinoma of the Stomach
Stomach Adenocarcinoma
Tubular Stomach Adenocarcinoma
Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian
Tumor
Uterine Endometrioid Carcinoma
127 S127C Astrocytoma
S127F Breast Invasive Ductal Carcinoma
S127P Colon Adenocarcinoma
S127T Cutaneous Melanoma
S127Y Glioblastoma Multiforme S127Yfs*43 Head and Neck Squamous Cell Carcinoma
Lung Adenocarcinoma
Pancreatic Adenocarcinoma
Serous Ovarian Cancer
Uterine Endometrioid Carcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
128 P128del Astrocytoma P128Lfs*42 Breast Invasive Ductal Carcinoma Esophageal Squamous Cell Carcinoma Head and Neck Squamous Cell Carcinoma Lung Squamous Cell Carcinoma
129 A129Vfs*20 Lung Squamous Cell Carcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
130 L130Cfs*20 Astrocytoma
L130F Breast Invasive Lobular Carcinoma
L130P Colon Adenocarcinoma
L130R Diffuse Type Stomach Adenocarcinoma
L130V Esophageal Squamous Cell Carcinoma Glioblastoma Multiforme
Lung Adenocarcinoma
Serous Ovarian Cancer
Tubular Stomach Adenocarcinoma
Uterine Mixed Endometrial Carcinoma
131 N131del Astrocytoma N131I Breast Invasive Ductal Carcinoma N131Kfs*39 Lung Adenocarcinoma
N131Qfs*17 Lung Squamous Cell Carcinoma N131S Pancreatic Adenocarcinoma N131Tfs*39 Serous Ovarian Cancer
Stomach Adenocarcinoma
Uterine Mixed Endometrial Carcinoma
132 K132E Adrenocortical Carcinoma
K132M Astrocytoma K132N Bladder Urothelial Carcinoma K132Q Breast Invasive Ductal Carcinoma K132R Cervical Squamous Cell Carcinoma
K132T Colon Adenocarcinoma K132Vfs*15 Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Pleural Mesothelioma, Epithelioid Type
Serous Ovarian Cancer
Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous
Histiocytoma/High-Grade Spindle Cell Sarcoma
Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian Tumor
133 M133K Breast Invasive Carcinoma (NOS)
M133R Head and Neck Squamous Cell Carcinoma
Mucinous Adenocarcinoma of the Colon and Rectum
134 F134L Cutaneous Melanoma
F134V Esophageal Squamous Cell Carcinoma Head and Neck Squamous Cell Carcinoma Serous Ovarian Cancer
Tubular Stomach Adenocarcinoma
Uterine Endometrioid Carcinoma
135 C135* Adrenocortical Carcinoma
C135Afs*35 Bladder Urothelial Carcinoma C135F Breast Invasive Ductal Carcinoma
C135Lfs*14 Colon Adenocarcinoma
C135R Diffuse Type Stomach Adenocarcinoma
C135W Esophageal Adenocarcinoma C135Y Esophageal Squamous Cell Carcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Pancreatic Adenocarcinoma
Papillary Stomach Adenocarcinoma
Prostate Adenocarcinoma
Serous Ovarian Cancer
Tubular Stomach Adenocarcinoma
Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous Histiocytoma/High-Grade Spindle Cell Sarcoma
Uterine Endometrioid Carcinoma
136 Q136* Astrocytoma Q136_C141del Breast Invasive Ductal Carcinoma Q136del Glioblastoma Multiforme Q136E Head and Neck Squamous Cell Carcinoma Q136H Hepatocellular Carcinoma Q136P Intestinal Type Stomach Adenocarcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Metaplastic Breast Cancer
Mucinous Stomach Adenocarcinoma
Oligodendroglioma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
137 L137Pfs*32 Head and Neck Squamous Cell Carcinoma L137Q
138 A138_L145dcl Breast Invasive Ductal Carcinoma
A138_P142del Esophageal Adenocarcinoma
A138Cfs*27 Glioblastoma Multiforme
A138T Lung Adenocarcinoma
A138V Rectal Adenocarcinoma Serous Ovarian Cancer Uterine Endometrioid Carcinoma
139 K139_P142del Bladder Urothelial Carcinoma K139_P142delinsT Breast Invasive Carcinoma (NOS) K139Afs*5 Esophageal Squamous Cell Carcinoma K139Cfs*6 Glioblastoma Multiforme K139N Head and Neck Squamous Cell Carcinoma K139Nfs*9 Hepatocellular Carcinoma K139Rfs*31 Lung Adenocarcinoma
Uterine Endometrioid Carcinoma
140 T140Mfs*28 Serous Ovarian Cancer
141 C141* Acute Myeloid Leukemia C141Afs*29 Astrocytoma C141F Bladder Urothelial Carcinoma C141G Breast Invasive Ductal Carcinoma
C141R Chromophobe Renal Cell Carcinoma C141S Colon Adenocarcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
C141W Cutaneous Melanoma
C141Y Head and Neck Squamous Cell Carcinoma
Intrahepatic Cholangiocarcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Prostate Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Uterine Endometrioid Carcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
142 P142del Lung Squamous Cell Carcinoma P142L Oligoastrocytoma P142Lfs*28 Uterine Mixed Endometrial Carcinoma
143 V143A Bladder Urothelial Carcinoma V143Afs*29 Colon Adenocarcinoma V143E Cutaneous Melanoma V143G Esophageal Adenocarcinoma V143M Head and Neck Squamous Cell Carcinoma V143Rfs*18 Hepatocellular Carcinoma
Oligoastrocytoma
Pancreatic Adenocarcinoma
Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian
Tumor
144 Q144* Bladder Urothelial Carcinoma Q144_L145dup Breast Invasive Lobular Carcinoma Q144Afs*16 Colon Adenocarcinoma Q144Gfs*24 Head and Neck Squamous Cell Carcinoma Q144H Hepatocellular Carcinoma Q144L Lung Adenocarcinoma Q144Lfs*5 Lung Squamous Cell Carcinoma Q144P Prostate Adenocarcinoma Q144Tfs*5 Serous Ovarian Cancer
Stomach Adenocarcinoma
Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma
145 L145P Colon Adenocarcinoma
L145Q Oligoastrocytoma
L145R Serous Ovarian Cancer
Signet Ring Cell Carcinoma of the Stomach
146 W146* Astrocytoma
W146S Bladder Urothelial Carcinoma
W146Vfs*3 Esophageal Squamous Cell Carcinoma
Head and Neck Squamous Cell Carcinoma
Intestinal Type Stomach Adenocarcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligodendroglioma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Uterine Endometrioid Carcinoma
Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
147 V147_D148dup Breast Invasive Ductal Carcinoma V147G Esophageal Adenocarcinoma V147Lfs*23 Serous Ovarian Cancer
148 D148Ifs*22 Bladder Urothelial Carcinoma
D148N Lung Adenocarcinoma
149 S149Ffs*32 Pancreatic Adenocarcinoma
S149Pfs*21 Prostate Adenocarcinoma Serous Ovarian Cancer
150 T150Afs*16 Stomach Adenocarcinoma
151 P151A Astrocytoma
P151H Bladder Urothelial Carcinoma
P151L Breast Invasive Ductal Carcinoma
P151R Colon Adenocarcinoma
P151Rfs*27 Cutaneous Melanoma
P151S Esophageal Squamous Cell Carcinoma
P151T Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Pancreatic Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Tubular Stomach Adenocarcinoma
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
Uterine Mixed Endometrial Carcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
152 P152Afs*14 Astrocytoma P152L Bladder Urothelial Carcinoma P152Lfs*18 Breast Invasive Ductal Carcinoma P152Q Cutaneous Melanoma P152Rfs*18 Diffuse Type Stomach Adenocarcinoma P152S Glioblastoma Multiforme P152Wfs*10 Head and Neck Squamous Cell Carcinoma Intestinal Type Stomach Adenocarcinoma Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Pancreatic Adenocarcinoma
Serous Ovarian Cancer
Signet Ring Cell Carcinoma of the Stomach Tubular Stomach Adenocarcinoma
153 P153Afs*28 Bladder Urothelial Carcinoma
P153Rfs* 18 Lung Squamous Cell Carcinoma Oligoastrocytoma
Stomach Adenocarcinoma
154 G154Afs*16 Bladder Urothelial Carcinoma
G154Rfs*27 Esophageal Squamous Cell Carcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
G154V Head and Neck Squamous Cell Carcinoma
G154Wfs*10 Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligodendroglioma
Pancreatic Adenocarcinoma Serous Ovarian Cancer
155 T155_A161dcl Astrocytoma T155_R156del Bladder Urothelial Carcinoma
T155_R156delinsN Breast Invasive Ductal Carcinoma T155_R158del Colon Adenocarcinoma
T155_R158delinsC Glioblastoma Multiforme T155I Head and Neck Squamous Cell Carcinoma T155N Lung Adenocarcinoma T155P Lung Squamous Cell Carcinoma
Oligoastrocytoma
Serous Ovarian Cancer
156 R156Afs*12 Astrocytoma R156C Bladder Urothelial Carcinoma R156del Breast Invasive Ductal Carcinoma R156G Glioblastoma Multiforme R156H Head and Neck Squamous Cell Carcinoma R156Hfs*26 Hepatocellular Carcinoma R156P Leiomyosarcoma
R156Pfs*13 Lung Adenocarcinoma
Serous Ovarian Cancer
Uterine Serous Carcinoma/Uterine Papil la ry Serous Carcinoma
157 V157_P177del Breast Invasive Ductal Carcinoma V157_R158dup Colon Adenocarcinoma V157Afs*24 Esophageal Squamous Cell Carcinoma V157D Glioblastoma Multiformc V157F Head and Neck Squamous Cell Carcinoma V157G Hepatocellular Carcinoma V157Hfs*21 Lung Adenocarcinoma
V157L Lung Squamous Cell Carcinoma
V157Pfs*23 Oligodendroglioma V157Sfs*13 Prostate Adenocarcinoma
Serous Ovarian Cancer
Uterine Endometrioid Carcinoma
Uterine Mixed Endometrial Carcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
158 R158Afs*12 Astrocytoma
R158C Bladder Urothelial Carcinoma R158G Breast Invasive Ductal Carcinoma R158H Colon Adenocarcinoma R158L Diffuse Type Stomach Adenocarcinoma R158P Esophageal Squamous Cell Carcinoma
R158S Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma Leiomyosarcoma
Lung Adenocarcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Lung Squamous Cell Carcinoma Oligoastrocytoma Oligodendroglioma
Prostate Adenocarcinoma Stomach Adenocarcinoma Uterine Endometrioid Carcinoma
159 A159P Astrocytoma
A159V Bladder Urothelial Carcinoma
Cervical Squamous Cell Carcinoma
Chromophobe Renal Cell Carcinoma
Colon Adenocarcinoma
Cutaneous Melanoma
Head and Neck Squamous Cell Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Uterine Endometrioid Carcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
160 M160I Lung Squamous Cell Carcinoma
161 A161_H62del Astrocytoma A161D Bladder Urothelial Carcinoma A161Gfs*3 Breast Invasive Ductal Carcinoma A161P Colon Adenocarcinoma A161S Cutaneous Melanoma A161T Head and Neck Squamous Cell Carcinoma A161V Hepatocellular Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Serous Ovarian Cancer
162 I162_Y163delinsN Breast Invasive Ductal Carcinoma
I162dup Colon Adenocarcinoma I162F Lung Squamous Cell Carcinoma I162Hfs*12 Tubular Stomach Adenocarcinoma I162N Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma I162Tfs*8 I162Wfs*10
163 Y163* Astrocytoma
Y163D Breast Invasive Ductal Carcinoma
Y163H Colon Adenocarcinoma Y163Lfs*18 Esophageal Squamous Cell Carcinoma
Y163N Head and Neck Squamous Cell Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Malignant Peripheral Nerve Sheath Tumor
Oligoas trocy to ma
Prostate Adenocarcinoma
Serous Ovarian Cancer
Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian
Tumor
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
164 K164E Esophageal Squamous Cell Carcinoma
K164Sfs*5 Glioblastoma Multiforme
K164Sfs*6 Lung Squamous Cell Carcinoma Mucinous Carcinoma Rectal Adenocarcinoma Serous Ovarian Cancer
165 Q165* Breast Invasive Ductal Carcinoma Q165Afs*6 Lung Adenocarcinoma Q165Hfs*17 Prostate Adenocarcinoma
166 S166* Head and Neck Squamous Cell Carcinoma
Lung Adenocarcinoma
Pancreatic Adenocarcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
167 Q167* Bladder Urothelial Carcinoma Q167Hfs*3 Breast Invasive Ductal Carcinoma Q167Tfs*14 Esophageal Adenocarcinoma
Head and Neck Squamous Cell Carcinoma
Lung Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous Histiocytoma/High-Grade Spindle Cell Sarcoma
Uterine Endometrioid Carcinoma
168 H168Cfs*8 Adrenocortical Carcinoma
H168L Breast Invasive Ductal Carcinoma
H168P Esophageal Squamous Cell Carcinoma
H168R Head and Neck Squamous Cell Carcinoma Lung Adenocarcinoma Stomach Adenocarcinoma
169 M169I Bladder Urothelial Carcinoma
M169T Breast Invasive Lobular Carcinoma Stomach Adenocarcinoma
171 E171* Bladder Urothelial Carcinoma
E171Gfs*3 Breast Invasive Ductal Carcinoma
E171Gfs*4 Cutaneous Melanoma
E171K Diffuse Large B-Cell Lymphoma, NOS
E171Lfs*2 Glioblastoma Multiforme
E171Rfs*3 Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Pleural Mesothelioma. Epithelioid Type
Rectal Adenocarcinoma
172 V172D Esophageal Adenocarcinoma
V172F Glioblastoma Multiforme
V172G Head and Neck Squamous Cell Carcinoma
V172Lfs*2 Lung Squamous Cell Carcinoma
Pleural Mesothelioma, Epithelioid Type
173 V173* Acute Myeloid Leukemia
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
V173_R175del Adrenocortical Carcinoma V173A Astrocytoma V173Afs*69 Breast Invasive Ductal Carcinoma
V173dup Colon Adenocarcinoma V173Efs*7 Esophageal Adenocarcinoma V173G Head and Neck Squamous Cell Carcinoma V173L Lung Adenocarcinoma V173M Lung Squamous Cell Carcinoma
Oligoastrocytoma
Oligodendroglioma
Pancreatic Adenocarcinoma
Serous Ovarian Cancer
Signet Ring Cell Carcinoma of the Stomach
Stomach Adenocarcinoma
Tubular Stomach Adenocarcinoma
Uterine Mixed Endometrial Carcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
174 R174Sfs*73 Breast Invasive Ductal Carcinoma
R174W Esophageal Squamous Cell Carcinoma Hepatocellular Carcinoma
Uterine Endometrioid Carcinoma
175 R175C Astrocytoma
R175G Bladder Urothelial Carcinoma
R175H Breast Invasive Ductal Carcinoma
R175L Colon Adenocarcinoma
Cutaneous Melanoma
Diffuse Type Stomach Adenocarcinoma
Esophageal Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Mucinous Adenocarcinoma of the Colon and Rectum
Mucinous Stomach Adenocarcinoma
Oligoastrocytoma
Pancreatic Adenocarcinoma
Prostate Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Tubular Stomach Adenocarcinoma
Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous
Histiocytoma/High-Grade Spindle Cell Sarcoma
Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian
Tumor
Uterine Endometrioid Carcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
176 C176* Acute Myeloid Leukemia
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
C176dup Bladder Urothelial Carcinoma C176F Breast Invasive Carcinoma (NOS) C176G Breast Invasive Ductal Carcinoma C176R Chromophobe Renal Cell Carcinoma C176S Colon Adenocarcinoma C176Sfs*71 Diffuse Type Stomach Adenocarcinoma C176W Esophageal Adenocarcinoma C176Y Esophageal Squamous Cell Carcinoma
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Mucinous Stomach Adenocarcinoma
Oligoastrocytoma
Oligodendroglioma
Prostate Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Tubular Stomach Adenocarcinoma
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
177 P177_C182del Astrocytoma
P177_H178del Colon Adenocarcinoma
P177H Cutaneous Melanoma
P177L Esophageal Adenocarcinoma
P177R Head and Neck Squamous Cell Carcinoma
P177S Lung Adenocarcinoma
P177T Prostate Adenocarcinoma
Serous Ovarian Cancer
178 H178_S183del Bladder Urothelial Carcinoma
H178D Chromophobe Renal Cell Carcinoma H178Pfs*3 Colon Adenocarcinoma H178Pfs*70 Glioblastoma Multiforme
H178Q Head and Neck Squamous Cell Carcinoma H178Qfs*3 Lung Adenocarcinoma H178Sfs*69 Lung Squamous Cell Carcinoma
H178Tfs*69 Pancreatic Adenocarcinoma
Renal Clear Cell Carcinoma Stomach Adenocarcinoma Uterine Endometrioid Carcinoma
179 H179D Acute Myeloid Leukemia H179L Astrocytoma H179N Bladder Urothelial Carcinoma H179P Breast Invasive Ductal Carcinoma H179Q Colon Adenocarcinoma H179R Cutaneous Melanoma H179Y Diffuse Type Stomach Adenocarcinoma
Esophageal Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Oligodendroglioma
Pancreatic Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous
Histiocytoma/High-Grade Spindle Cell Sarcoma
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
Uterine Endometrioid Carcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
180 E180* Adrenocortical Carcinoma
E180_D184del Bladder Urothelial Carcinoma
E180_S185del Head and Neck Squamous Cell Carcinoma
E180K Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Rectal Adenocarcinoma
181 R181C Astrocytoma
R181H Bladder Urothelial Carcinoma
R181P Colon Adenocarcinoma
Lung Squamous Cell Carcinoma
Prostate Adenocarcinoma
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
Uterine Endometrioid Carcinoma
183 S183* Bladder Urothelial Carcinoma
Breast Invasive Ductal Carcinoma
Cervical Squamous Cell Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
184 D184Afs*62 Head and Neck Squamous Cell Carcinoma
186 D186Vfs*61 Pancreatic Adenocarcinoma
187 G187S Bladder Urothelial Carcinoma X187_splice Breast Invasive Carcinoma (NOS) Breast Invasive Ductal Carcinoma Chromophobe Renal Cell Carcinoma Colon Adenocarcinoma Cutaneous Melanoma
Esophageal Squamous Cell Carcinoma Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma Oligoastrocytoma
Pancreatic Adenocarcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Rectal Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous
Histiocytoma/High-Grade Spindle Cell Sarcoma
Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian Tumor
Uterine Endometrioid Carcinoma
188 L188Gfs*20 Lung Squamous Cell Carcinoma
L188Tfs*21 Serous Ovarian Cancer
189 A189Dfs*14 Bladder Urothelial Carcinoma
A189Pfs*58 Leiomyosarcoma
Lung Squamous Cell Carcinoma
190 P190L Astrocytoma
P190R Chromophobe Renal Cell Carcinoma
Colon Adenocarcinoma
Glioblastoma Multiforme
Lung Squamous Cell Carcinoma
191 P191del Astrocytoma P191L Colon Adenocarcinoma P191Qfs*51 Cutaneous Melanoma
Diffuse Type Stomach Adenocarcinoma
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Lung Adenocarcinoma
Oligodendroglioma
Serous Ovarian Cancer
Stomach Adenocarcinoma
192 Q192* Bladder Urothelial Carcinoma Q192_H193del Breast Invasive Ductal Carcinoma Q192del Cervical Squamous Cell Carcinoma Q192R Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Pancreatic Adenocarcinoma
Papillary Thyroid Cancer
Serous Ovarian Cancer
Tubular Stomach Adenocarcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
193 H193D Acute Myeloid Leukemia H193L Astrocytoma H193N Bladder Urothelial Carcinoma H193P Breast Invasive Carcinoma (NOS) H193R Breast Invasive Ductal Carcinoma H193Y Esophageal Squamous Cell Carcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Metaplastic Breast Cancer
Oligoastrocytoma
Papillary Renal Cell Carcinoma
Prostate Adenocarcinoma
Renal Clear Cell Carcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Tubular Stomach Adenocarcinoma
Uterine Carcinosarcoma/Utcrinc Malignant Mixed Mullerian
Tumor
Uterine Endometrioid Carcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
194 L194Efs*51 Bladder Urothelial Carcinoma
L194F Breast Invasive Ductal Carcinoma
L194H Endometrioid Carcinoma
L194P Glioblastoma Multiforme
L194Pfs*13 Head and Neck Squamous Cell Carcinoma
L194R Hepatocellular Carcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Pancreatic Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Thymoma
Uterine Serous Carcinoma/Uterine Papillary' Serous Carcinoma
195 I195F Acute Myeloid Leukemia I195Ffs*52 Astrocytoma 1195Lfs*53 Breast Invasive Ductal Carcinoma
I195M Colon Adenocarcinoma
I195N Cutaneous Melanoma I195Nfs*14 Esophageal Squamous Cell Carcinoma
I195S Glioblastoma Multiforme
I195Sfs*52 Head and Neck Squamous Cell Carcinoma
I195T Hepatocellular Carcinoma I195Yfs*14 Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Oligodendroglioma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Tubular Stomach Adenocarcinoma
Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian
Tumor
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
196 R196* Astrocytoma
R196P Breast Invasive Carcinoma (NOS)
Breast Invasive Ductal Carcinoma
Cervical Squamous Cell Carcinoma
Chromophobe Renal Cell Carcinoma
Colon Adenocarcinoma
Cutaneous Melanoma
Esophageal Adenocarcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Intestinal Type Stomach Adenocarcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Mucinous Adenocarcinoma of the Colon and Rectum
Oligodendroglioma
Pancreatic Adenocarcinoma
Pleural Mesothelioma. Epithelioid Type
Rectal Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Tubular Stomach Adenocarcinoma
Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma
197 V197G Breast Invasive Ductal Carcinoma V197Ifs*42 Esophageal Squamous Cell Carcinoma V197L Head and Neck Squamous Cell Carcinoma V197M Hepatocellular Carcinoma
Lung Squamous Cell Carcinoma
Pancreatic Adenocarcinoma
Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma
198 E198* Breast Invasive Ductal Carcinoma
E198Gfs*ll Colon Adenocarcinoma
Cutaneous Melanoma
Esophageal Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Serous Ovarian Cancer
Tubular Stomach Adenocarcinoma
199 G199* Bladder Urothelial Carcinoma
G199Efs*48 Breast Invasive Ductal Carcinoma
G1991fs*47 Colon Adenocarcinoma
G199V Head and Neck Squamous Cell Carcinoma
Pancreatic Adenocarcinoma
Prostate Adenocarcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Uterine Endometrioid Carcinoma
200 N2001fs*47 Head and Neck Squamous Cell Carcinoma Oligoastrocytoma
201 L201* Breast Invasive Ductal Carcinoma L201Ffs*8 Head and Neck Squamous Cell Carcinoma
202 R202 L206del Head and Neck Squamous Cell Carcinoma
203 V203Gfs*44 Head and Neck Squamous Cell Carcinoma
V203Gfs*5 Leiomyosarcoma
V203L Mucinous Adenocarcinoma of the Colon and Rectum V203Wfs*44 Prostate Adenocarcinoma
204 E204* Bladder Urothelial Carcinoma
E204D Breast Invasive Ductal Carcinoma
E204Q Esophageal Squamous Cell Carcinoma
E204Sfs*43 Head and Neck Squamous Cell Carcinoma
E204Vfs*4 Hepatocellular Carcinoma Lung Squamous Cell Carcinoma Serous Ovarian Cancer
Uterine Endometrioid Carcinoma
Uterine Mixed Endometrial Carcinoma
205 Y205* Astrocytoma Y205C Breast Invasive Ductal Carcinoma Y205D Chromophobe Renal Cell Carcinoma Y205F Colon Adenocarcinoma Y205H Esophageal Squamous Cell Carcinoma
Y205N Glioblastoma Multiforme Y205S Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Pancreatic Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian
Tumor
Uterine Endometrioid Carcinoma
Uterine Mixed Endometrial Carcinoma
Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma
206 L206Wfs*41 Head and Neck Squamous Cell Carcinoma
207 D207Ffs*35 Lung Squamous Cell Carcinoma D207Mfs*40
208 D208G Bladder Urothelial Carcinoma
D208N Breast Invasive Ductal Carcinoma
D208V Oligoastrocytoma
Serous Ovarian Cancer
209 R209* Bladder Urothelial Carcinoma R209Hfs*5 Breast Invasive Carcinoma (NOS) R209I Breast Invasive Ductal Carcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
R209K Esophageal Adenocarcinoma R209Kfs*6 Esophageal Squamous Cell Carcinoma Head and Neck Squamous Cell Carcinoma Leiomyosarcoma
Lung Adenocarcinoma
Prostate Adenocarcinoma
Serous Ovarian Cancer
Signet Ring Cell Carcinoma of tire Stomach Uterine Endometrioid Carcinoma
210 N210Tfs*37 Serous Ovarian Cancer
211 T211_H214del Breast Invasive Carcinoma (NOS) T211A Breast Invasive Ductal Carcinoma T211Ffs*4 Colon Adenocarcinoma T211I Glioblastoma Multiforme T211Lfs*36 Head and Neck Squamous Cell Carcinoma
Lung Squamous Cell Carcinoma
Rectal Adenocarcinoma
Uterine Endometrioid Carcinoma
212 F212Sfs*3 Astrocytoma F212Yfs*34 Breast Invasive Ductal Carcinoma Glioblastoma Multiforme Lung Squamous Cell Carcinoma
213 R213* Adrenocortical Carcinoma R213Dfs*34 Astrocytoma R213G Bladder Urothelial Carcinoma R213L Breast Invasive Carcinoma (NOS) R213P Breast Invasive Ductal Carcinoma
R213Q Chromophobe Renal Cell Carcinoma
Colon Adenocarcinoma
Cutaneous Melanoma
Dedifferentiated Liposarcoma
Diffuse Type Stomach Adenocarcinoma
Esophageal Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Mucinous Adenocarcinoma of the Colon and Rectum
Myxofibrosarcoma
Oligoastrocytoma
Oligodendroglioma
Pancreatic Adenocarcinoma
Rectal Adenocarcinoma
Renal Clear Cell Carcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous
Histiocytoma/High-Grade Spindle Cell Sarcoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian Tumor
Uterine Endometrioid Carcinoma
214 H214L Astrocytoma H214Qfs*33 Bladder Urothelial Carcinoma H214R Chromophobe Renal Cell Carcinoma
Colon Adenocarcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Pancreatic Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous
Histiocytoma/High-Grade Spindle Cell Sarcoma
Uterine Serous Carcinoma/Uterine Papi 1 la ry Serous Carcinoma
215 S215G Acute Myeloid Leukemia
S215I Astrocytoma
S215Kfs*7 Breast Invasive Ductal Carcinoma
S215N Colon Adenocarcinoma
S215R Cutaneous Melanoma
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Pancreatic Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Uterine Endometrioid Carcinoma
216 V216E Astrocytoma
V216G Breast Invasive Ductal Carcinoma
V216L Colon Adenocarcinoma V216M Esophageal Adenocarcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Pleural Mesothelioma, Biphasic Type
Serous Ovarian Cancer
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma
217 V217Gfs*31 Pancreatic Adenocarcinoma
218 V218Cfs*29 Bladder Urothelial Carcinoma V218del Cutaneous Melanoma V218E Head and Neck Squamous Cell Carcinoma V218G Lung Squamous Cell Carcinoma
Serous Ovarian Cancer
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
219 P219Afs*3 Bladder Urothelial Carcinoma
P219Lfs*2 Head and Neck Squamous Cell Carcinoma
P219T Rectal Adenocarcinoma
220 Y220* Astrocytoma
Y220C Bladder Urothelial Carcinoma
Y220D Breast Invasive Carcinoma (NOS)
Y220H Breast Invasive Ductal Carcinoma Y220Mfs*27 Cervical Squamous Cell Carcinoma Y220S Chromophobe Renal Cell Carcinoma
Colon Adenocarcinoma
Cutaneous Melanoma
Dedifferentiated Liposarcoma
Esophageal Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Mucinous Stomach Adenocarcinoma
Oligoastrocytoma
Oligodendroglioma
Pancreatic Adenocarcinoma
Papillary Renal Cell Carcinoma
Serous Ovarian Cancer
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
Uterine Endometrioid Carcinoma
Uterine Mixed Endometrial Carcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
221 E221* Bladder Urothelial Carcinoma E221Afs*2 Breast Invasive Ductal Carcinoma
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Lung Squamous Cell Carcinoma
Serous Ovarian Cancer
223 P223* Acute Myeloid Leukemia P223Rfs*4 Serous Ovarian Cancer X223_splice Tubular Stomach Adenocarcinoma
Uterine Serous Carcinoma/Uterine Papillary' Serous Carcinoma
224 E224* Astrocytoma
E224D Bladder Urothelial Carcinoma E224Gfs*4 Breast Invasive Ductal Carcinoma X224 splice Colon Adenocarcinoma
Cutaneous Melanoma
Diffuse Type Stomach Adenocarcinoma Esophageal Squamous Cell Carcinoma Head and Neck Squamous Cell Carcinoma Hepatocellular Carcinoma Leiomyosarcoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Myxofibrosarcoma
Oligoastrocytoma
Serous Ovarian Cancer
Tubular Stomach Adenocarcinoma
225 V225Rfs*23 Acute Myeloid Leukemia
X225_splice Astrocytoma
Breast Invasive Ductal Carcinoma
Chromophobe Renal Cell Carcinoma
Esophageal Squamous Cell Carcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Pleural Mesothelioma, Epithelioid Type
Serous Ovarian Cancer
Uterine Endometrioid Carcinoma
Uterine Mixed Endometrial Carcinoma
Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma
226 G226Afs*21 Serous Ovarian Cancer
Tubular Stomach Adenocarcinoma
227 S227* Oligoastrocytoma
228 D228* Bladder Urothelial Carcinoma
D228E Hepatocellular Carcinoma
D228N Serous Ovarian Cancer D228Vfs*18 Tubular Stomach Adenocarcinoma
229 C229* Bladder Urothelial Carcinoma C229_I232del Chromophobe Renal Cell Carcinoma C229Lfs*18 Colon Adenocarcinoma C229Yfs*10 Esophageal Squamous Cell Carcinoma
Head and Neck Squamous Cell Carcinoma
Lung Adenocarcinoma
Serous Ovarian Cancer
230 T230_T231del Hepatocellular Carcinoma
T230Hfs*9 Lung Squamous Cell Carcinoma T230P Oligoastrocytoma
232 I232F Astrocytoma
I232N Breast Invasive Ductal Carcinoma
I232S Colon Adenocarcinoma
I232T Diffuse Large B-Cell Lymphoma, NOS
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Uterine Endometrioid Carcinoma
234 Y234* Adrenocortical Carcinoma
Y234C Astrocytoma
Y234H Breast Invasive Ductal Carcinoma
Y234N Colon Adenocarcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Y234Pfs*7 Glioblastoma Multiforme Y234S Head and Neck Squamous Cell Carcinoma Y234Tfs*ll Intrahepatic Cholangiocarcinoma
Leiomyosarcoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Pleural Mesothelioma. Biphasic Type
Rectal Adenocarcinoma
Renal Clear Cell Carcinoma
Serous Ovarian Cancer
236 Y236* Astrocytoma Y236C Bladder Urothelial Carcinoma Y236D Colon Adenocarcinoma Y236del Head and Neck Squamous Cell Carcinoma
Y236H Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Serous Ovarian Cancer
Uterine Mixed Endometrial Carcinoma
Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma
237 M237_N239del Astrocytoma M237Cfs*10 Bladder Urothelial Carcinoma M237Gfs*20 Breast Invasive Ductal Carcinoma M237I Colon Adenocarcinoma M237K Dedifferentiated Liposarcoma M237L Esophageal Adenocarcinoma M237V Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Intrahepatic Cholangiocarcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Myxofibrosarcoma
Oligoastrocytoma
Prostate Adenocarcinoma
Serous Ovarian Cancer
Tubular Stomach Adenocarcinoma
Uterine Endometrioid Carcinoma
Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma
238 C238* Astrocytoma C238_M243del Bladder Urothelial Carcinoma C238_N239delinsY Breast Invasive Ductal Carcinoma C238F Endocervical Adenocarcinoma C238G Esophageal Squamous Cell Carcinoma
C238Lfs*9 Glioblastoma Multiforme
C238R Head and Neck Squamous Cell Carcinoma C238S Hepatocellular Carcinoma C238W Intestinal Type Stomach Adenocarcinoma C238Y Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma Oligodendroglioma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Pancreatic Adenocarcinoma
Pleural Mesothelioma, Epithelioid Type
Rectal Adenocarcinoma
Serous Ovarian Cancer
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
Uterine Endometrioid Carcinoma
239 N239* Astrocytoma
N239_S240del Breast Invasive Ductal Carcinoma
N239_S241del Chromophobe Renal Cell Carcinoma
N239D Colon Adenocarcinoma
N239Qfs*24 Esophageal Adenocarcinoma
N239S Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Lung Adenocarcinoma
Pancreatic Adenocarcinoma
Prostate Adenocarcinoma
Serous Ovarian Cancer
Tubular Stomach Adenocarcinoma
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
Uterine Endometrioid Carcinoma
240 S240 C242del Bladder Urothelial Carcinoma S240G Colon Adenocarcinoma
S240Gfs*20 Head and Neck Squamous Cell Carcinoma
S240Kfs*24 Stomach Adenocarcinoma
S240R Uterine Endometrioid Carcinoma
241 S241A Bladder Urothelial Carcinoma S241C Breast Invasive Ductal Carcinoma S241dup Cervical Squamous Cell Carcinoma S241F Cutaneous Melanoma S241P Esophageal Adenocarcinoma S241Pfs*6 Glioblastoma Multiforme
S241Y Head and Neck Squamous Cell Carcinoma
Invasive Breast Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Pancreatic Adenocarcinoma
Pancreatic Adenocarcinoma
Papillary Renal Cell Carcinoma
Papillary Stomach Adenocarcinoma
Perihilar Cholangiocarcinoma
Serous Ovarian Cancer
Serous Ovarian Cancer
Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous
Histiocytoma/High-Grade Spindle Cell Sarcoma
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian Tumor
Uterine Endometrioid Carcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
242 C242* Bladder Urothelial Carcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
C242Afs*5 Breast Invasive Ductal Carcinoma
C242F Colon Adenocarcinoma C242G Diffuse Type Stomach Adenocarcinoma C242R Esophageal Adenocarcinoma C242S Esophageal Squamous Cell Carcinoma
C242Y Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Intestinal Type Stomach Adenocarcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Pancreatic Adenocarcinoma
Pancreatic Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous
Histiocytoma/High-Grade Spindle Cell Sarcoma
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian Tumor
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
243 M243I Bladder Urothelial Carcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Serous Ovarian Cancer
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
244 G244* Colon Adenocarcinoma G244C Glioblastoma Multiforme G244D Head and Neck Squamous Cell Carcinoma
G244S Leiomyosarcoma G244V Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Pleural Mesothelioma, Epithelioid Type
Serous Ovarian Cancer
Tubular Stomach Adenocarcinoma
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
Uterine Endometrioid Carcinoma
Uterine Serous Carcinoma/Uterine Papillary' Serous Carcinoma
245 G245C Astrocytoma G245D Bladder Urothelial Carcinoma G245R Breast Invasive Ductal Carcinoma G245S Colon Adenocarcinoma
G245V Esophageal Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Oligodendroglioma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Pancreatic Adenocarcinoma
Pleural Mesothelioma, Epithelioid Type
Prostate Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Signet Ring Cell Carcinoma of the Stomach
Stomach Adenocarcinoma
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
Uterine Endometrioid Carcinoma
246 M246I Bladder Urothelial Carcinoma
M246R Breast Invasive Lobular Carcinoma
M246T Chromophobe Renal Cell Carcinoma
M246V Esophageal Adenocarcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Oligoastrocytoma
Pancreatic Adenocarcinoma
Tubular Stomach Adenocarcinoma
Uterine Mixed Endometrial Carcinoma
247 N247I Breast Invasive Ductal Carcinoma Lung Adenocarcinoma
248 R248G Acute Myeloid Leukemia R248Hfs*13 Astrocytoma R248L Bladder Urothelial Carcinoma R248P Breast Invasive Carcinoma (NOS)
R248Q Breast Invasive Ductal Carcinoma R248W Cholangiocarcinoma
Colon Adenocarcinoma
Cutaneous Melanoma
Diffuse Large B-Cell Lymphoma, NOS
Diffuse Type Stomach Adenocarcinoma
Esophageal Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Mucinous Adenocarcinoma of the Colon and Rectum
Oligoastrocytoma
Oligodendroglioma
Pancreatic Adenocarcinoma
Prostate Adenocarcinoma
Rectal Adenocarcinoma
Renal Clear Cell Carcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Thymoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Tubular Stomach Adenocarcinoma
Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian
Tumor
Uterine Endometrioid Carcinoma
Uterine Mixed Endometrial Carcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
249 R249Ffs*96 Astrocytoma R249G Bladder Urothelial Carcinoma R249Gfs*96 Esophageal Squamous Cell Carcinoma R249M Glioblastoma Multiforme R249S Head and Neck Squamous Cell Carcinoma R249T Hepatocellular Carcinoma R249W Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Mucinous Adenocarcinoma of the Colon and Rectum
Prostate Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
250 P250_I251delinsL Astrocytoma
P250Hfs*13 Breast Invasive Ductal Carcinoma
P250L Chromophobe Renal Cell Carcinoma
P250R Esophageal Squamous Cell Carcinoma Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Mucinous Stomach Adenocarcinoma
Oligoastrocytoma
Pancreatic Adenocarcinoma
Rectal Adenocarcinoma Serous Ovarian Cancer
251 125 IF Breast Invasive Ductal Carcinoma
125 IN Head and Neck Squamous Cell Carcinoma
125 IS Hepatocellular Carcinoma I251Sfs*94 Lung Squamous Cell Carcinoma
Serous Ov arian Cancer
252 L252_I254del Breast Invasive Ductal Carcinoma L252_T253delinsP Esophageal Squamous Cell Carcinoma L252del Lung Squamous Cell Carcinoma L252P Myxofibrosarcoma L252Sfs*93 Uterine Mixed Endometrial Carcinoma
253 T253A Breast Invasive Ductal Carcinoma T253dup Esophageal Adenocarcinoma T253Hfs*ll Hepatocellular Carcinoma T253I Papillary Stomach Adenocarcinoma T253N Serous Ovarian Cancer
254 I254S Glioblastoma Multiforme
Intestinal Type Stomach Adenocarcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Pancreatic Adenocarcinoma
255 1255del Breast Invasive Lobular Carcinoma I255F Esophageal Adenocarcinoma I255N Esophageal Squamous Cell Carcinoma I255S Glioblastoma Multiforme I255T Glioblastoma Multiforme
Lung Adenocarcinoma
Oligodendroglioma
Pancreatic Adenocarcinoma
Papillary Renal Cell Carcinoma
256 T256del Breast Invasive Ductal Carcinoma T256Hfs*8 Head and Neck Squamous Cell Carcinoma T256I Prostate Adenocarcinoma T256Ifs*90 Serous Ovarian Cancer T256Nfs*8 Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous
Histiocytoma/High-Grade Spindle Cell Sarcoma
Uterine Endometrioid Carcinoma
257 L257P Bladder Urothelial Carcinoma L257Pfs*7 Breast Invasive Ductal Carcinoma L257Q Esophageal Adenocarcinoma L257R Hepatocellular Carcinoma Serous Ovarian Cancer
258 E258* Bladder Urothelial Carcinoma
E258A Breast Invasive Ductal Carcinoma
E258D Esophageal Adenocarcinoma
E258G Head and Neck Squamous Cell Carcinoma
E258K Hepatocellular Carcinoma
E258Q Lung Adenocarcinoma E258Qfs*3 Lung Squamous Cell Carcinoma X258_splice Prostate Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
259 D259Efs*86 Bladder Urothelial Carcinoma
D259N Colon Adenocarcinoma
D259V Head and Neck Squamous Cell Carcinoma
D259Y Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Pancreatic Adenocarcinoma
Tubular Stomach Adenocarcinoma
260 S260_L264dup Serous Ovarian Cancer S260Lfs*4
261 S261Vfs*84 Breast Invasive Ductal Carcinoma
X261_splicc Esophageal Adenocarcinoma Esophageal Squamous Cell Carcinoma Head and Neck Squamous Cell Carcinoma Intestinal Type Stomach Adenocarcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma Oligoastrocytoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Renal Clear Cell Carcinoma
Serous Ovarian Cancer
Signet Ring Cell Carcinoma of the Stomach
Stomach Adenocarcinoma
Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian
Tumor
262 G262dcl Head and Neck Squamous Cell Carcinoma G262V Hepatocellular Carcinoma G262Vfs*83 Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Uterine Endometrioid Carcinoma
263 N263Ifs*82 Hepatocellular Carcinoma N263Kfs*9 Oligoastrocytoma N263Sfs*8
264 L264Yfs*81 Glioblastoma Multiforme
265 L265P Astrocytoma
L265R Bladder Urothelial Carcinoma
L265Tfs*7 Breast Invasive Ductal Carcinoma
Head and Neck Squamous Cell Carcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Serous Ov arian Cancer
Tubular Stomach Adenocarcinoma
266 G266* Breast Invasive Ductal Carcinoma G266Dfs*79 Colon Adenocarcinoma
G266E Cutaneous Melanoma
G266R Glioblastoma Multiforme
G266V Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligodendroglioma
Pancreatic Adenocarcinoma
Prostate Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
Uterine Mixed Endometrial Carcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
267 R267G Astrocytoma R267L Chromophobe Renal Cell Carcinoma R267P Colon Adenocarcinoma R267Q Glioblastoma Multiforme R267W Head and Neck Squamous Cell Carcinoma
Lung Adenocarcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Lung Squamous Cell Carcinoma
Mucinous Adenocarcinoma of the Colon and Rectum
Oligoastrocytoma
Tubular Stomach Adenocarcinoma
Uterine Endometrioid Carcinoma
268 N268* Head and Neck Squamous Cell Carcinoma N268_R273dcl Lung Squamous Cell Carcinoma N268Kfs*77 Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous N268Tfs*77 Histiocytoma/High-Grade Spindle Cell Sarcoma
Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian Tumor
269 S269_E271delinsK Oligodendroglioma
S269Ifs*2 Pancreatic Adenocarcinoma
270 F270C Astrocytoma
F270I Breast Invasive Ductal Carcinoma
F270L Head and Neck Squamous Cell Carcinoma
F270Lfs*2 Intestinal Type Stomach Adenocarcinoma
F270S Leiomyosarcoma
F270V Lung Adenocarcinoma
Oligodendroglioma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Tubular Stomach Adenocarcinoma
271 E271* Bladder Urothelial Carcinoma
E271K Breast Invasive Ductal Carcinoma
E271Q Colon Adenocarcinoma
E271V Endometrioid Carcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Prostate Adenocarcinoma
Serous Ovarian Cancer
Tubular Stomach Adenocarcinoma
272 V272A Astrocytoma
V272Cfs*73 Breast Invasive Carcinoma (NOS)
V272G Breast Invasive Ductal Carcinoma V272L Cervical Squamous Cell Carcinoma V272M Colon Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Head and Neck Squamous Cell Carcinoma
Intestinal Type Stomach Adenocarcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Pancreatic Adenocarcinoma
Rectal Adenocarcinoma
Renal Clear Cell Carcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
273 R273C Acute Myeloid Leukemia
R273G Adrenocortical Carcinoma
R273H Astrocytoma
R273L Bladder Urothelial Carcinoma R273Lfs*72 Breast Invasive Carcinoma (NOS)
R273P Breast Invasive Ductal Carcinoma
R273S Colon Adenocarcinoma
Diffuse Large B-Cell Lymphoma, NOS
Esophageal Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Intestinal Type Stomach Adenocarcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Mucinous Adenocarcinoma of the Colon and Rectum
Oligoastrocytoma
Oligodendroglioma
Pancreatic Adenocarcinoma
Pleural Mesothelioma, Biphasic Type
Prostate Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Thymoma
Tubular Stomach Adenocarcinoma
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
Uterine Endometrioid Carcinoma
Uterine Mixed Endometrial Carcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
274 V274_C275dup Astrocytoma V274_G279del Breast Invasive Ductal Carcinoma V274D Colon Adenocarcinoma V274dup Esophageal Adenocarcinoma V274F Esophageal Squamous Cell Carcinoma V274G Head and Neck Squamous Cell Carcinoma V274L Intestinal Type Stomach Adenocarcinoma Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Pancreatic Adenocarcinoma Serous Ovarian Cancer
275 C275* Adrenocortical Carcinoma C275_R282delinsW Astrocytoma C275F Bladder Urothelial Carcinoma C275G Breast Invasive Ductal Carcinoma C275Lfs*67 Chromophobe Renal Cell Carcinoma C275Lfs*70 Colon Adenocarcinoma C275R Cutaneous Melanoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
C275S Esophageal Squamous Cell Carcinoma
C275Vfs*70 Glioblastoma Multiforme
C275W Head and Neck Squamous Cell Carcinoma C275Y Hepatocellular Carcinoma
Leiomyosarcoma
Low-Grade Glioma (NOS)
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Pancreatic Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Uterine Serous Carcinoma/U terine Papillary Serous Carcinoma
276 A276D Breast Invasive Ductal Carcinoma
A276G Cutaneous Melanoma
A276Lfs*29 Head and Neck Squamous Cell Carcinoma
A276Lfs*31 Hepatocellular Carcinoma
A276P Lung Squamous Cell Carcinoma
Pleural Mesothelioma, Biphasic Type
Serous Ovarian Cancer
Uterine Serous Carcinoma/Uterine Papillary' Serous Carcinoma
277 C277* Astrocytoma
C277dup Bladder Urothelial Carcinoma
C277F Head and Neck Squamous Cell Carcinoma
C277G Lung Adenocarcinoma
C277Vfs*68 Oligoastrocytoma
C277W Oligodendroglioma
C277Y Serous Ovarian Cancer
Serous Ovarian Cancer
278 P278A Astrocytoma
P278H Bladder Urothelial Carcinoma P278L Breast Invasive Ductal Carcinoma P278Lfs*67 Colon Adenocarcinoma P278Lfs*68 Cutaneous Melanoma
P278R Esophageal Squamous Cell Carcinoma P278S Head and Neck Squamous Cell Carcinoma P278T Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Metaplastic Breast Cancer
Mucinous Adenocarcinoma of the Colon and Rectum
Mucinous Carcinoma
Myxofibrosarcoma
Pancreatic Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Uterine Serous Carcinoma/Uterine Papillary' Serous Carcinoma
279 G279E Bladder Urothelial Carcinoma G279Pfs*69 Breast Invasive Ductal Carcinoma G279R Lung Squamous Cell Carcinoma Oligoastrocytoma
Prostate Adenocarcinoma Serous Ovarian Cancer
Uterine Endometrioid Carcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
280 R280* Acute Myeloid Leukemia R280Efs*65 Astrocytoma R280G Bladder Urothelial Carcinoma R280I Breast Invasive Carcinoma (NOS) R280K Breast Invasive Ductal Carcinoma R280Kfs*59 Cervical Squamous Cell Carcinoma R280S Cutaneous Melanoma R280T Esophageal Adenocarcinoma
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Metaplastic Breast Cancer
Oligoastrocytoma
Oligodendroglioma
Serous Ovarian Cancer
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
281 D281A Astrocytoma
D281Afs*62 Bladder Urothelial Carcinoma
D281Afs*64 Breast Invasive Ductal Carcinoma
D281Afs*66 Diffuse Type Stomach Adenocarcinoma
D281E Glioblastoma Multiforme
D281Efs*26 Head and Neck Squamous Cell Carcinoma
D281Gfs*63 Hepatocellular Carcinoma
D281H Leiomyosarcoma
D281N Lung Adenocarcinoma
D281V Lung Squamous Cell Carcinoma
D281Y Metaplastic Breast Cancer
Renal Clear Cell Carcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Thymoma
Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian
Tumor
Uterine Serous Carcinoma/Uterine Papillary' Serous Carcinoma
282 R282_R283del Astrocytoma R282G Bladder Urothelial Carcinoma R282Gfs*63 Breast Invasive Carcinoma (NOS) R282Q Breast Invasive Ductal Carcinoma R282W Cervical Squamous Cell Carcinoma
Chromophobe Renal Cell Carcinoma
Colon Adenocarcinoma
Diffuse Type Stomach Adenocarcinoma
Esophageal Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Intestinal Type Stomach Adenocarcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Mucinous Adenocarcinoma of the Colon and Rectum
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Mucinous Stomach Adenocarcinoma
Oligoastrocytoma
Oligodendroglioma
Pancreatic Adenocarcinoma
Prostate Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Signet Ring Cell Carcinoma of tire Stomach
Stomach Adenocarcinoma
Uterine Endometrioid Carcinoma
Uterine Mixed Endometrial Carcinoma
Uterine Serous Carcinoma/U terine Papillary Serous Carcinoma
283 R283Afs*62 Bladder Urothelial Carcinoma
R283H Head and Neck Squamous Cell Carcinoma
R283P Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Pancreatic Adenocarcinoma
284 T284Hfs*22 Serous Ovarian Cancer
T284Kfs*61 Tubular Stomach Adenocarcinoma
T284Qfs*61
285 E285* Bladder Urothelial Carcinoma
E285K Breast Invasive Ductal Carcinoma
E285Q Breast Invasive Lobular Carcinoma E285Rfs*54 Cervical Squamous Cell Carcinoma
E285V Colon Adenocarcinoma
Diffuse Type Stomach Adenocarcinoma Esophageal Squamous Cell Carcinoma Head and Neck Squamous Cell Carcinoma Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Mucinous Carcinoma
Pheochromocytoma
Prostate Adenocarcinoma
Rectal Adenocarcinoma
Stomach Adenocarcinoma
286 E286* Acute Myeloid Leukemia E286_E287del Bladder Urothelial Carcinoma E286A Breast Invasive Carcinoma (NOS) E286G Breast Invasive Ductal Carcinoma E286K Colon Adenocarcinoma E286Q Cutaneous Melanoma E286V Diffuse Type Stomach Adenocarcinoma
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligoastrocytoma
Pancreatic Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous Histiocytoma/High-Grade Spindle Cell Sarcoma
Uterine Endometrioid Carcinoma
287 E287* Bladder Urothelial Carcinoma
E287D Breast Invasive Ductal Carcinoma
E287Pfs*9 Cervical Squamous Cell Carcinoma
E287Q Lung Squamous Cell Carcinoma Rectal Adenocarcinoma
288 N288Efs*18 Astrocytoma
N288Kfs*59 Myxofibrosarcoma
289 L289F Breast Invasive Ductal Carcinoma
290 R290C Colon Adenocarcinoma
R290Kfs*53 Cutaneous Melanoma
R290Sfs*56 Head and Neck Squamous Cell Carcinoma
291 K291Sfs*51 Lung Squamous Cell Carcinoma
292 K292* Breast Invasive Ductal Carcinoma K292Gfs*52 Chromophobe Renal Cell Carcinoma Hepatocellular Carcinoma
294 E294* Astrocytoma E294Sfs*51 Bladder Urothelial Carcinoma
Breast Invasive Ductal Carcinoma
Esophageal Squamous Cell Carcinoma
Head and Neck Squamous Cell Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Pancreatic Adenocarcinoma
Serous Ovarian Cancer
Tubular Stomach Adenocarcinoma
Uterine Endometrioid Carcinoma
296 H296Tfs*49 Lung Adenocarcinoma
297 H297Pfs*48 Astrocytoma
Head and Neck Squamous Cell Carcinoma
298 E298* Bladder Urothelial Carcinoma
Head and Neck Squamous Cell Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Pancreatic Adenocarcinoma
Prostate Adenocarcinoma
Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous
Histiocytoma/High-Grade Spindle Cell Sarcoma
299 L299Afs*7 Breast Invasive Ductal Carcinoma
301 P301Qfs*44 Bladder Urothelial Carcinoma P301T Colon Adenocarcinoma
Cutaneous Melanoma
Lung Squamous Cell Carcinoma
Stomach Adenocarcinoma
302 G302Afs*31 Colon Adenocarcinoma
G302Efs*3 Glioblastoma Multiforme
G302Rfs*4 Head and Neck Squamous Cell Carcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Hepatocellular Carcinoma Pancreatic Adenocarcinoma
303 S303Afs*42 Breast Invasive Ductal Carcinoma
304 T3041fs*41 Breast Invasive Ductal Carcinoma
305 K3O5* Head and Neck Squamous Cell Carcinoma K305Efs*39 Lung Adenocarcinoma X305_splice Lung Squamous Cell Carcinoma
Serous Ovarian Cancer
306 R306* Astrocytoma R306Afs*31 Bladder Urothelial Carcinoma
Breast Invasive Lobular Carcinoma
Colon Adenocarcinoma
Esophageal Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Lung Squamous Cell Carcinoma
Mucinous Adenocarcinoma of the Colon and Rectum
Mucinous Stomach Adenocarcinoma
Oligoastrocytoma
Pancreatic Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Uterine Endometrioid Carcinoma
307 X307_splice Adrenocortical Carcinoma
Astrocytoma
Breast Invasive Carcinoma (NOS)
Chromophobe Renal Cell Carcinoma
Colon Adenocarcinoma
Diffuse Type Stomach Adenocarcinoma
Esophageal Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Prostate Adenocarcinoma
Serous Ovarian Cancer
308 L308Afs*28 Breast Invasive Ductal Carcinoma
L308Qfs*27 Esophageal Adenocarcinoma
310 N310Tfs*35 Diffuse Type Stomach Adenocarcinoma
313 S313Afs*32 Glioblastoma Multiforme
Lung Adenocarcinoma
Uterine Endometrioid Carcinoma
315 S315C Lung Squamous Cell Carcinoma
S315Lfs*30 Uterine Endometrioid Carcinoma
316 P316Sfs*21 Serous Ovarian Cancer
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
317 Q317* Acute Myeloid Leukemia Q317Afs*19 Astrocytoma Q317Pfs*20 Bladder Urothelial Carcinoma
Cutaneous Melanoma
Esophageal Squamous Cell Carcinoma
Head and Neck Squamous Cell Carcinoma
Intestinal Type Stomach Adenocarcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Serous Ovarian Cancer
Uterine Serous Carcinoma/U terine Papillary Serous Carcinoma
318 P318Tfs*15 Breast Invasive Ductal Carcinoma
319 K319* Bladder Urothelial Carcinoma K319Afs*19 Cervical Squamous Cell Carcinoma
K319N Prostate Adenocarcinoma K319Rfs*26 Rectal Adenocarcinoma
320 K320E Head and Neck Squamous Cell Carcinoma
K320Gfs*22 Lung Squamous Cell Carcinoma
K320Nfs*19 Serous Ovarian Cancer
K320Rfs*25
321 K321* Astrocytoma K321Efs*16 Serous Ovarian Cancer
322 P322Hfs*23 Colon Adenocarcinoma
325 G325* Esophageal Adenocarcinoma
327 Y327* Cutaneous Melanoma Glioblastoma Multiforme Serous Ovarian Cancer
328 F328Sfs*17 Breast Invasive Ductal Carcinoma Hepatocellular Carcinoma
329 T329Hfs*8 Head and Neck Squamous Cell Carcinoma
T329Rfs*14 Hepatocellular Carcinoma
330 L33OFfs*15 Cutaneous Melanoma
L330I Head and Neck Squamous Cell Carcinoma
L330R Serous Ovarian Cancer
331 Q331* Astrocytoma
Q331H Bladder Urothelial Carcinoma
Q331Sfs*6 Breast Invasive Ductal Carcinoma
X331_splice Colon Adenocarcinoma
Cutaneous Melanoma
Head and Neck Squamous Cell Carcinoma
Intestinal Type Stomach Adenocarcinoma
Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Mucinous Adenocarcinoma of the Colon and Rectum
Mucinous Carcinoma
Pancreatic Adenocarcinoma
Pleural Mesothelioma, Epithelioid Type
Prostate Adenocarcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Rectal Adenocarcinoma
Serous Ovarian Cancer
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
332 I332F Astrocytoma X332_splice Diffuse Large B-Cell Lymphoma, NOS
Esophageal Squamous Cell Carcinoma
Head and Neck Squamous Cell Carcinoma
Hepatocellular Carcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Mucinous Adenocarcinoma of the Colon and Rectum
Oligoastrocytoma
Serous Ovarian Cancer
Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous
Histiocytoma/High-Grade Spindle Cell Sarcoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
333 R333C Breast Invasive Ductal Carcinoma R333Vfs*12 Cervical Squamous Cell Carcinoma
Mucinous Adenocarcinoma of the Colon and Rectum
Serous Ovarian Cancer
334 G334V Lung Adenocarcinoma
G334W Lung Squamous Cell Carcinoma
Seminoma
Uterine Serous Carcinoma/Uterine Papillary' Serous Carcinoma
335 R335Lfs*10 Adrenocortical Carcinoma R335Qfs*2 Colon Adenocarcinoma
R335Vfs*10 Oligoastrocytoma
Rectal Adenocarcinoma
Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous
Histiocytoma/High-Grade Spindle Cell Sarcoma
336 E336* Bladder Urothelial Carcinoma E336 R337del Colon Adenocarcinoma E336Afs*10 Head and Neck Squamous Cell Carcinoma
E336Sfs*9 Leiomyosarcoma
Lung Adenocarcinoma
337 R337C Acute Myeloid Leukemia R337H Adrenocortical Carcinoma R337L Bladder Urothelial Carcinoma R337P Cervical Squamous Cell Carcinoma
R337S Chromophobe Renal Cell Carcinoma Colon Adenocarcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma Intestinal Type Stomach Adenocarcinoma Leiomyosarcoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Oligodendroglioma
Pancreatic Adenocarcinoma
Prostate Adenocarcinoma
Rectal Adenocarcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Stomach Adenocarcinoma
338 F3381 Chromophobe Renal Cell Carcinoma
F338Lfs*7 Serous Ovarian Cancer
339 E339* Adrenocortical Carcinoma
E339Afs*8 Breast Invasive Ductal Carcinoma
E339Rfs*6 Head and Neck Squamous Cell Carcinoma
Lung Adenocarcinoma
Oligodendroglioma
Stomach Adenocarcinoma
340 M340Sfs*8 Serous Ovarian Cancer
341 F341Efs*7 Head and Neck Squamous Cell Carcinoma
F341L Hepatocellular Carcinoma
F341V Lung Adenocarcinoma
342 R342* Acute Myeloid Leukemia
R342Efs*2 Astrocytoma
R342Efs*3 Breast Invasive Ductal Carcinoma
R342P Colon Adenocarcinoma
Cutaneous Melanoma
Esophageal Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Glioblastoma Multiforme
Head and Neck Squamous Cell Carcinoma
Intestinal Type Stomach Adenocarcinoma
Lung Adenocarcinoma
Lung Squamous Cell Carcinoma
Myxofibrosarcoma
Oligoastrocytoma
Pancreatic Adenocarcinoma
Prostate Adenocarcinoma
Rectal Adenocarcinoma
Serous Ovarian Cancer
Stomach Adenocarcinoma
Uterine Endometrioid Carcinoma
Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
343 E343* Esophageal Squamous Cell Carcinoma E343Gfs*2 Head and Neck Squamous Cell Carcinoma Lung Adenocarcinoma Serous Ovarian Cancer
345 N345D Mucinous Stomach Adenocarcinoma
N345Mfs*25 Serous Ovarian Cancer
N345Sfs*2 Tubular Stomach Adenocarcinoma
346 E346* Lung Adenocarcinoma Oligoastrocytoma
347 A347V Uterine Mixed Endometrial Carcinoma
348 L348* Head and Neck Squamous Cell Carcinoma
L348F Lung Squamous Cell Carcinoma
L348S Serous Ovarian Cancer L348Wfs*22
351 K351* Leiomyosarcoma
K351E Lung Adenocarcinoma
Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)
Lung Squamous Cell Carcinoma
354 Q354* Lung Adenocarcinoma
355 A355T Lung Adenocarcinoma
367 X367_splice Bladder Urothelial Carcinoma
Head and Neck Squamous Cell Carcinoma
Uterine Mixed Endometrial Carcinoma
375 Q375* Bladder Urothelial Carcinoma
Q375K Glioblastoma Multiforme Papillary Thyroid Cancer
376 S376C Cervical Squamous Cell Carcinoma
379 R379C Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma
382 K382Nfs*40 Bladder Urothelial Carcinoma
Oligoastrocytoma
Uterine Endometrioid Carcinoma Uterine Mixed Endometrial Carcinoma
383 L383Cfs*38 Head and Neck Squamous Cell Carcinoma
385 F385L Bladder Urothelial Carcinoma
390 P390Qfs*32 Esophageal Squamous Cell Carcinoma
392 S392Tfs*76 Intestinal Type Stomach Adenocarcinoma
A Unless noted otherwise, the mutations of Table 1 are found in cBioPortal database derived from Cerami et al. The eBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 2012 2; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pH (2013).
Combinations
In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each subject with cancer. In medical oncology the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as kinase inhibitors, signal transduction inhibitors and/or monoclonal antibodies, or combinations of any of the foregoing. For example, a surgery may be open surgery or minimally invasive surgery. Compounds of Formula (I), or pharmaceutically acceptable salts thereof, therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by a different mechanism of action. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and under one or more rounds of radiation therapy. In some embodiments, the treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.
In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a multikinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy. In some embodiments, a subject has undergone prior therapy. In some embodiments, a subject is naive to p53 restoration therapy. In some embodiments, a subject is not naive to p53 restoration therapy. In some embodiments, a subject is kinase inhibitor naive. In some embodiments, a subject is not kinase inhibitor naive.
In some embodiments of any the methods described herein, the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents described herein. For example, in some embodiments, the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with one, two, or three independently selected additional therapeutic agents as described herein.
Non-limiting examples of additional therapeutic agents include small molecules, antibodies, and antibody-drug conjugates such as EGFR inhibitors, HER2 inhibitors, RAS pathway targeted therapeutic agents (as described herein), PARP inhibitors, CDK4/6 inhibitors, FGFR inhibitors, ALK inhibitors, NTRK/ROS inhibitors, MET inhibitors, RET inhibitors, other
kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents (e.g., multi-kinase inhibitors)), selective estrogen receptor modulators or degraders (SERMs / SERDs), antiandrogens, checkpoint inhibitors; cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy.
In some embodiments, the CDK4/6 inhibitor is palbociclib (IBRANCE®, PD-0332991), ribociclib (KISQALI®, LEE-011), abemaciclib (VERZENIO®, LY-2835219), trilaciclib (COSELA™, G1T28), lerociclib (G1T38), dalpiciclib (SHR-6390), or BPI-16350.
In some embodiments, the FGFR inhibitor is pemigatinib (PEMAZYRE®, INCB-054828), infigratinib (TRUSELTIQ®, BGJ-398, NVP-BGJ398), futibatinib (LYTGOBI®, TAS- 120), erdafitinib (BAL VERSA®, JNJ-42756493), AZD4547, derazantinib (ARQ-087), AZD4547, ferulic acid-13C3, FGFR-IN-7, PP58, FGFR3-IN-1, ENMD-2076 tartrate, R1530, FGFR3-IN-3, ryrosine kinase-IN-1, SU4984, roblitinib (FGF-401), PD173074, FGFR4-IN-8, lucitanib (E-3810), masitinib (AB1010), zoligratinib (debio 1347, CH5183284), FGFR4-IN-4, BLU9931, SMI-71, TG 100801, FGFR1 inhibitor-6, or TG 100572.
In some embodiments, the ALK inhibitor is crizotinib (X.kl.KORI®. PF-02341066), ceritinib (ZYKADIA®, LDK-378), alectinib (ALECENSA®, CH5424802, RO5424802, AF802), brigatinib (ALUNBRIG®, AP-26113), lorlatinib (LORBRENA®, PF-06463922), entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), ASP3026, TSR-01 L PF-06463922, ensartinib (X- 396), or CEP-37440.
In some embodiments, the NTRK/ROS inhibitor is entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), taletrectinib (DS-6051b, AB-106), or repotrectinib (TPX-0005),
In some embodiments, the MET inhibitor is capmatinib (TABRECTA®, INC280; INCB28060), tepotinib (TEPMETKO®), tivantinib (ARQ197), savolitinib (ORPATHYS®, Volitinib, HMPL-504, AZD-6094), foretinib (XL880, GSK1363089, GSK089, EXEL-2880), pamufetinib (TAS-115), c-Met-IN-2, PHA-665752, SU11274, SYN1143, or amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride).
In some embodiments, the RET inhibitor is selpercatinib (RETEVMO®, LOXO-292), zeteletinib (BOS- 172738, DS-5010), GSK3179106, amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride), TPX-0046, or pralsetinib (GAVRETO®, BLU-667).
In some embodiments, the EGFR inhibitor is osimertinib (AZD9291, merelectinib, TAGRISSOTM), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®),
necitumumab (PORTRAZZATM, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS-816), mavelertinib (PF-06747775), icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetyl shikonin, P,P-dimethylacrylshikonin and acetylalkannin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM- 151, AZD3759, ZD6474, PF-06459988, varlintinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, Modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG 595, BDTX-189, avatinib, Disruptin, CL-387785, EGFRBi-Armed Autologous T Cells, and EGFR CAR-T Therapy. In some embodiments, the EGFR-targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.
Exemplary HER2 inhibitors include trastuzumab (e g., TRAZIMERA™, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S- 22261 1, and AEE-788.
A “RAS pathway targeted therapeutic agent” as used herein includes any compound exhibiting inactivation activity of any protein in a RAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a RAS pathway include any one of the proteins in the RAS-RAF-MAPK pathway or PI3K/AKT pathway such as RAS (e g., KRAS, HRAS, and NRAS), RAF (ARAF, BRAF, CRAF), MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a RAS pathway modulator can be
selective for a protein in a RAS pathway, e.g., the RAS pathway modulator can be selective for RAS (also referred to as a RAS modulator). In some embodiments, a RAS modulator is a covalent inhibitor. In some embodiments, a RAS pathway targeted therapeutic agent is a “KRAS pathway modulator.” A KRAS pathway modulator includes any compound exhibiting inactivation activity of any protein in a KRAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or PI3K/AKT pathway such as KRAS, RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a KRAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the KRAS pathway modulator can be selective for KRAS (also referred to as a KRAS modulator). In some embodiments, a KRAS modulator is a covalent inhibitor.
Non-limiting examples of a KRAS-targeted therapeutic agents (e.g., KRAS inhibitors) include sotorasib (AMG510, LUMAKRAS®), BI 1701963, BI 1823911, ARS-853, ARS-3248, ARS-1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, GDC-6036, D-1553, AA12, JDQ443, and adagrasib (MRTX-849).
Further non-limiting examples of RAS-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVI®), BMS-908662 (XL281), sorafenib, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof.
In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK 162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI 1040 (PD 184352), hypothemycin, or a combination thereof.
In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-1 le, 25-OH-D3-3- BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ- 13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5- 7-Oxozeaenol, 5 -iodotuberci din, GDC0994, ONC201, or a combination thereof.
In some embodiments, the PI3K inhibitor is selected from buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ- 235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI- 103, rigosertib, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, GSK2636771, or a combination thereof.
In some embodiments, the AKT inhibitor is selected from miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, 2-[4-(2- aminoprop-2-yl)phenyl]-3 -phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphophocholine, erufosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine (Triciribine Phosphate Monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2- aminopyridin-3-yl)-3H-imidazo[4,5-b] pyridin-3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY 1125976, 3-oxo-tirucallic acid, lactoquinomycin, boc-Phe-vinyl ketone, Perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or a combination thereof.
In some embodiments, the mTOR inhibitor is selected from MLN0128, vistusertib (AZD- 2014), onatasertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), ridaforolimus (MK-8669), or a combination thereof.
In some embodiments, a chemotherapeutic agent includes an anthracycline, a topoisomerase inhibitors, an antimetabolite, an alkylating agent, a taxane, a platinum-based agent, mitomycin, eribulin (HALAVEN™), or combinations thereof.
In some embodiments, the topoisomerase inhibitor is irinotecan (CAMPTOSAR®), camptothecin, topotecan, etoposide, or teniposide.
In some embodiments, the alkylating agent is cyclophosphamide, Melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, or busulfan. In some embodiments, the alkylating agent is cyclophosphamide.
In some embodiments, the antimetabolite is methotrexate, pemetrexed (ALIMTA®), 5- fluorouracil (5-FU), 6-Mercaptopurine (6-MP), capecitabine (XELODA®), cytarabine (Ara-C®), floxuridine, fludarabine, gemcitabine (GEMZAR®), hydroxycarbamide, phototrexate, or a combination of any of the foregoing. In some embodiments, the antimetabolite is methotrexate, pemetrexed, or 5-FU.
Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere.
In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, aclarubicin, and combinations thereof.
In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin and combinations thereof.
Non-limiting examples of P ARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF- 01367338, INO-1001, and JPI-289.
Non-limiting examples of selective estrogen receptor modulators or degraders (SERMs / SERDs) include tamoxifen, fulvestrant, brilanestrant, elacestrant, giredestrant, amcenestrant (SAR439859), AZD9833, rintodestrant, LSZ102, LY3484356, ZN-c5, D-0502, and SHR9549.
Non-limiting examples of anti-androgens include enzalutamide (XTANDI®), leuprolide (LUPRON®, ELIGARD®), goserelin (ZOLDEX®), triptorelin (TRELSTAR®), leuprolide mesylate (CAMCEVI®), flutamide (EULEXIN®), bicalutamide (CASXODEX®), nilutamide (NILANDRON®), degarelix (FIRMAGON®), relugolix (ORGOVYX®), and abiraterone (ZYTIGA®).
Non-limiting examples of immunotherapy include immune checkpoint therapies, such as inhibitors that target CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodimetnts the CTLA-4 inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostarlimab (JEMPERLI®), vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IB 1308), tislelizumab (BGB-A317), toripalimab (JS 001), INCMGA00012, AMP-224, AMP-514 (MEDI0680), or combinations thereof. In some embodiments, the PD-L1 inhibitor is
selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), KN035, cosibelimab (CK-301), AUNP12, CA-170, BMS-986189, or combinations thereof. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI-444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is INJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, for example, Marin- Acevedo, et al., J Hematol Oncol. 11: 39 (2018).
In some embodiments, the additional therapy or therapeutic agent is selected from 5-FU, irinotecan, cisplatin, carboplatin, oxaliplatin, doxorubicin, epirubicin, gemcitabine, methotrexate, pemetrexed, cyclophosphamide, olaparib, rucaparib, niraparib, pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostarlimab (JEMPERLI®), atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), radiation therapy, and combinations of any of the foregoing.
In some embodiments, additional therapeutic agents may also be administereted to treat potential side-effects for particular anticancer therapies and/or as palliative therapy, for example, opioids and corticosteroids.
EXAMPLES
Compound Preparation
The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents.
Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis,
John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure.
The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.
The compounds described herein can be synthesized, for example, using the procedure shown in Scheme 1, Scheme 2, or Scheme 3 below, using different coupling partners from diversifiable intermediate 8, intermediate 16, or intermediate 29.
Example 1 - Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3-
[(trifluoromethyl)sulfanyl] imidazo [1 ,2-a] pyridin-2-yl)- 1 ,2,4-oxadiazol-5- yl]methyl}cyclopropanecarboxamide
Step 1: To a stirred solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2- a]pyridine-2-carboxylic acid (1.00 g, 2.93 mmol, 1.00 equiv) in DMF (3.00 mL) was added HATU (1.67 g, 4.39 mmol, 1.50 equiv), NaHCCh (1.23 g, 14.66 mmol, 5.00 equiv) and NFhCl (470.5 mg, 8.79 mmol, 3.00 equiv). The resulting mixture was stirred for 1 h at room temperature. The resulted solution was purified reverse flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) to afford 8-
bromo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridine-2-carboxamide (800 mg, 80.23%) as a white solid. LC-MS: [M+H]+ found found 339.9.
Step 2: A solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridine-2- carboxamide (780.0 mg, 2.29 mmol, 1.00 equiv) in POCh (5 mb) was stirred for 30 min at 110°C. The solvent was removed under vacuum. The residue was quenched by ice and basified to pH 7 with saturated NaHCCh at 0°C. The resulted mixture was poured into water and extracted with EA. The organic layer was washed with brine, dried over Na2SOr and evaporated to give 8-bromo-3- [(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridine-2-carbonitrile (700 mg, 94.76%) as a yellow solid. LC-MS: [M+H]+ found found 321.8.
Step 3: To a solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridine-2- carbonitrile (500.0 mg, 1.55 mmol, 1.00 equiv) in EtOH (5.00 mL) was added hydroxylamine (50%, 205.1 mg, 3.10 mmol, 2.00 equiv). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. This resulted in 8-bromo-N'- hydroxy-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridine-2-carboximidamide (500 mg, 90.7%) as a white solid. LC-MS: [M+H]+ found found 354.9.
Step 4: To a stirred solution of 8-bromo-N'-hydroxy-3-
[(trifhioromethyl)sulfanyl]imidazo[l,2-a]pyridine-2-carboximidamide (500.0 mg, 1.40 mmol, 1.00 equiv) in DMF (6.0 mL) were added (tert-butoxycarbonyl)glycine (369.3 mg, 2.11 mmol, 1.50 equiv), HATU (801.8 mg, 2.11 mmol, 1.50 equiv) and TEA (569.9 mg, 5.63 mmol, 4.00 equiv). After stirring at room temperature for 1 h, the reaction mixture was heated at 100°C for another 4 h. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in tert-butyl N-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl}-l,2,4-oxadiazol-5-yl)methyl]carbamate (300 mg, 43.11%) as a yellow solid. LC-MS: [M+H] found 494.1.
Step 5: To a stirred solution of tert-butyl N-[(3-{8-bromo-3-
[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl}-l,2,4-oxadiazol-5-yl)methyl]carbamate (280.0 mg, 0.56 mmol, 1.00 equiv) in THF (3.0 mL) were added (3 S,4R)-3 -fluoro- 1- methylpiperidin-4-amine dihydrochloride (232.4 mg, 1.13 mmol, 2.00 equiv), tBuXPhos Pd G3 (90.0 mg, 0.11 mmol, 0.20 equiv) and t-BuONa (272.2 mg, 2.83 mmol, 5.00 equiv). The resulting mixture was stirred for 2 h at 65°C under nitrogen atmosphere, then purified by reverse flash
chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in tert-butyl N-{ [3-(8-{[(3S,4R)-3-fluoro- l-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)-l,2,4- oxadiazol-5-yl]methyl}carbamate (40 mg, 12.94%) as a yellow oil. LC-MS: [M+H]+ found 546.3.
Step 6: To a stirred solution of tert-butyl N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5- yl]methyl} carbamate (40.0 mg, 0.06 mmol, 1.00 equiv) in MeOH (1.00 mL) was added HC1 (4M in dioxane, 3.00 mL). The resulting mixture was stirred for 1 h at room temperature. The solvent was removed under vacuum. This resulted in (3S,4R)-N-{2-[5-(aminomethyl)-l,2,4-oxadiazol-3- yl]-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-8-yl}-3-fluoro-l-methylpiperidin-4-amine hydrochloride (40 mg, crude) as a yellow solid. LC-MS: [M+H]+ found 446.1.
Step 7: To a stirred solution of (3S,4R)-N-{2-[5-(aminomethyl)-l,2,4-oxadiazol-3-yl]-3- [(trifluoromethyl)sulfanyl] imidazo[l,2-a]pyridin-8-yl}-3-fluoro-l-methylpiperidin-4-amine hydrochloride (40.0 mg, 0.09 mmol, 1.00 equiv) in DMF (3.0 mL) were added cyclopropanecarboxylic acid (10.5 mg, 0.12 mmol, 1.30 equiv), HATU (45.6 mg, 0.12 mmol, 1.30 equiv) and NaHCCh (47.1 mg, 0.55 mmol, 6 equiv). The resulting mixture was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (Column: XBridge Prep OBD Cl 8 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NFh H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 23% B to 53% B in 7min; Wave Length: 254nm/220nm nm; RT(min): 6.75). This resulted in N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5- yl]methyl}cyclopropanecarboxamide (12.8 mg, 26.24%) as a white solid. LC-MS: [M+H]+ found 514.25. XH NMR (400 MHz, DMSO-tA) 8 9.02 (t, J= 5.8 Hz, 1H), 8.05 (d, J= 6.7 Hz, 1H), 7.13 (t, J= 7.2 Hz, 1H), 6.72 (d, J= 7.7 Hz, 1H), 5.62 (d, J= 9.1 Hz, 1H), 4.89 (d, J = 49.3 Hz, 1H), 4.70 (d, J= 5.7 Hz, 2H), 3.81 (dt, J = 27.0, 8.4 Hz, 1H), 3.08 (t, J = 11.5 Hz, 1H), 2.80 (d, J= 10.8 Hz, 1H), 2.36-2.23 (m, 1H), 2.21 (s, 3H), 2.13 (td, J= 10.9, 4.0 Hz, 1H), 1.88 (td, J= 10.5, 4.0 Hz, 2H), 1.68 (m, 1H), 0.79-0.67 (m, 4H).
Example 3 - Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5- yl]methyl}cyclopropanecarboxamide
HN
> O H N
,S
Step 1 : A mixture of ethyl 8-bromoindolizine-2-carboxylate (2 g, 7.46 mmol, 1 equiv), 2- [(trifluoromethyl) sulfanyl]isoindole-l, 3-dione (2.21 g, 8.95 mmol, 1.20 equiv), NaCl (87.19 mg, 1.49 mmol, 0.2 equiv) in DMF (10 mb) was stirred for 4 h at 90°C under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (100 mb), washed with brine, and dried over anhydrous Na2SO-r After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (100:1) to afford ethyl 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carboxylate (1.8 g, 65.54%) as a light yellow solid. LC-MS: (M+H)+ found 368.1.
Step 2: A solution of ethyl 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carboxylate (1.8 g, 4.89 mmol, 1 equiv) and caustic soda (1 g, 24.45 mmol, 5 equiv) in MeOH (7 mL)/THF (7 mL)/H20 (6 mb) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 2 with HC1 (3N). The precipitated solids were collected by filtration and dried under vacuum to afford 8-bromo-3- [(trifluoromethyl)sulfanyl]indolizine-2-carboxylic acid (1.8 g) as a light yellow solid. LC-MS: (M+H)+ found 340.1.
Step 3: To a stirred solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2- carboxylic acid (1 g, 2.94 mmol, 1 equiv), EtsN (0.89 g, 8.82 mmol, 3 equiv), and NH-iCl (1.57 g, 29.40 mmol, 10 equiv) in DMF (10 mL) was added HATU (1.68 g, 4.41 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with ethyl acetate (100 mL), then washed with 3*100 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vaccum. The residue was washed with
MeOH (3 mL) and filtered to give 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2- carboxamide (850 mg, 85.25%) as a white solid. LC-MS: (M+H)+ found 339.2.
Step 4: A mixture of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carboxamide (1 g, 2.95 mmol, 1 equiv) and POCh (0.99 g, 6.49 mmol, 2.2 equiv) in toluene (10 mL) was stirred at 110 °C for 1 h. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (10: 1) to afford 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carbonitrile (0.8 g, 84.49%) as a white solid. LC-MS: (M+H)+ found 321.1.
Step 5: A mixture of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carbonitrile (1 g, 3.11 mmol, 1 equiv), NH2OHHCI (770 mg, 4.67 mmol, 1.5 equiv) and EtsN (0.95 g, 9.34 mmol, 3 equiv) in EtOH (10 mL) was stirred for 1 h at 80 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford (Z)-8-bromo-N'-hydroxy-3-[(trifluoromethyl)sulfanyl]indolizine-2- carboximidamide (700 mg, 63.47%) as a white solid. LC-MS: (M+H)+ found 354.2.
Step 6: To a stirred solution of (Z)-8-bromo-N'-hydroxy-3- [(trifluoromethyl)sulfanyl]indolizine-2-carboximidamide (2 g, 5.65 mmol, 1 equiv), DIEA (7.30 g, 56.47 mmol, 10 equiv), and [(tert-butoxycarbonyl)amino]acetic acid (1.19 g, 6.77 mmol, 1.2 equiv) in DMF (20 mL) were added HOBT (1.53 g, 11.29 mmol, 2 equiv) and EDCI (2.17 g, 11.29 mmol, 2 equiv) at 0°C. The reaction mixture was stirred at room temperature for 1 h and then 80°C for 16 h. The mixture was purified by reversed-phase flash chromatography directly (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm) to give tert-butyl N-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-l,2,4- oxadiazol-5-yl)methyl] carbamate (1.8 g, 64.61%) as a white solid. LC-MS: (M+H)+ found 493.3.
Step 7: A mixture of tert-butyl N-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}-l,2,4-oxadiazol-5-yl)methyl]carbamate vanadium (500 mg, 0.92 mmol, 1 equiv), (3S,4R)-3- fluoro-l-methylpiperidin-4-amine dihydrochloride (283 mg, 1.38 mmol, 1.5 equiv), RAC-BINAP- PD-G3 (183 mg, 0.18 mmol, 0.2 equiv), BINAP (228 mg, 0.37 mmol, 0.4 equiv), and CS2CO3 (1.5 g, 4.59 mmol, 5 equiv) in dioxane (5 mL) were added was stirred for 6 h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10: 1) to afford tertbutyl N-{[3-(8-{[(3S)-3-fluoro-l-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)
sulfanyl]indolizin-2-yl)-l ,2,4-oxadiazol-5-yl]methyl)carbamate (300 mg, 59.96%) as a light brown solid. LC-MS: (M+H)+ found 545.2.
Step 8: A solution of tert-butyl N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-l, 2, 4-oxadiazol-5-yl]methyl (carbamate (280 mg, 0.51 mmol, 1 equiv) and 4M HC1 (gas) in 1,4-dioxane (0.6 mL) in DCM (3 mL) was stirred for 0.5 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford crude product 2-[5-(aminomethyl)-l,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro- l-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (280 mg, crude) as a brown solid. LC-MS: (M+H)+ found 454.2.
Step 9: To a stirred solution of cyclopropanecarboxylic acid (14.5 mg, 0.17 mmol, 1.5 equiv), 2-[5-(aminomethyl)-l,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]- 3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), and DIEA (0.10 mL, 0.56 mmol, 5 equiv) in DMF (1 mL) was added HATU (64.2 mg, 0.17 mmol, 1.5 equiv) at 0°C. The resulting solution was stirred for additional 1 h at room temperature, then diluted with EtOAc (20 mL) and washed with brine (2*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CILCh/MeOHM 0: 1) and Prep-HPLC (Column: XB ridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HC03+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 32% B to 57% B in 8 min; Wave Length: 220nm nm; RTl(min): 7.73) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5- yl]methyl}cyclopropanecarboxamide (20.4 mg, 35.10%) as a light yellow solid. LC-MS: (M+H)+ found 513.15. 'HNMR (400 MHz, DMSO-i/s) 8 8.99 (t, J = 5.8 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.79 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.29 (d, J= 8.0 Hz, 1H), 6.21 (d, J= 7.6 Hz, 1H), 4.87 (d, J = 49.5 Hz, 1H), 4.67 (d, J= 5.7 Hz, 2H), 3.63 (d, J= 29.1 Hz, 1H), 3.05 (t, J= 11.2 Hz, 1H), 2.83 (s, 1H), 2.20 (s, 4H), 2.08 (t, J= 8.9 Hz, 2H), 1.76 - 1.60 (m, 2H), 0.73 (m, 4H).
Example 4 - Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-thiadiazol-5- yl] methyl} cyclopropanecarboxamide
Step 1 : A solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carboxamide (2 g, 5.89 mmol, 1 equiv) and chloro(chlorosulfanyl)methanone (803.3 mg, 6.13 mmol, 1.04 equiv) in THF (20 mL) was stirred for 1 h at 65°C. The resulting solution was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (100: 1) to afford 5-{8-bromo- 3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-l,3,4-oxathiazol-2-one (800 mg, 34.15%) as a light yellow solid. LC-MS: (M+H)+ found 397.3.
Step 2: A solution of 5-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-l,3,4- oxathiazol-2-one (800 mg, 2.01 mmol, 1 equiv) and 2-ethoxy-2-oxoacetonitrile (399.2 mg, 4.03 mmol, 2.00 equiv) in M-xylene (4 mL) was irradiated with microwave radiation for 15 min at 180°C. The solution was allowed to cool down to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/ EA (10:1) to afford ethyl 3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-l,2,4-thiadiazole-5- carboxylate (600 mg, 65.87%) as a light yellow solid. LC-MS: (M+H)+ found 451.1.
Step 3: A mixture of NaBEh (501.9 mg, 13.27 mmol, 10 equiv) in THF (5 mL) was stirred for 5 min at 0°C. To the above mixture was added ethyl 3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}-l,2,4-thiadiazole-5-carboxylate (600 mg, 1.33 mmol, 1 equiv) in portions. The resulting mixture was stirred overnight at room temperature, then quenched with MeOH at 0°C and concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography (column, C18 silica gel; mobile phase, MeOH in water (0.1% FA), 0% to 70% gradient in 20 min; detector, UV 254 nm) to afford (3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}-l,2,4-thiadiazol-5-yl)methanol (400 mg, 73.50%) as a light yellow solid. LC-MS: (M+H)+ found 410.2.
Step 4: A solution of (3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-l ,2,4- thiadiazol-5-yl)methanol (400 mg, 0.98 mmol, 1 equiv), TEA (296.0 mg, 2.93 mmol, 3 equiv) and TsCl (185.9 mg, 0.98 mmol, 1 equiv) in DCM (3 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous NaiSOu After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (3 mL) and added to a stirred NHs(g) in MeOH (6 mL) at room temperature. The resulting solution was stirred for 3 h at 40°C under, then concentrated under reduced pressure to afford 1 -(3 -{8-bromo-3 -[(trifluoromethyl) sulfanyl]indolizin-2-yl}-l,2,4-thiadiazol-5-yl)methanamine (300 mg, 75.18%) as a light yellow solid. LC-MS: (M+H)+ found 409.1.
Step 5: A solution of l-(3-{8-bromo-3-[(trifhioromethyl)sulfanyl]indolizin-2-yl}-l,2,4- thiadiazol-5-yl)methanamine (100 mg, 0.24 mmol, 1 equiv), cyclopropanecarboxylic acid (25.2, 0.29 mmol, 1.2 equiv), DIEA (94.8 mg, 0.73 mmol, 3.00 equiv) and HATU (92.9 mg, 0.244 mmol, 1.00 equiv) in DMF (1 mL) was stirred for Ih at room temperature. The resulting solution was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na2SO-i. After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2CI2 / MeOH 15 : 1 ) to afford N-[(3-{ 8-bromo- 3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-l,2,4-thiadiazol-5- yl)methyl]cyclopropanecarboxamide (80 mg, 68.59%) as a light brown solid. LC-MS: (M+H)+ found 477.1.
Step 6: A mixture of N-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-l,2,4- thiadiazol-5-yl)methyl] cyclopropanecarboxamide (80 mg, 0.17 mmol, 1 equiv), (3S,4R)-3-fluoro- l-methylpiperidin-4-amine dihydrochloride (68.8 mg, 0.34 mmol, 2 equiv), Pd-PEPPSLIHeptCl 3 -chloropyridine (81.6 mg, 0.08 mmol, 0.5 equiv) and CS2CO3 (327.6 mg, 1.01 mmol, 6 equiv) in dioxane (1 mL) was stirred for 2 h at 100°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2CI2 / (7 M NH3 in MeOH = 20/1) and Prep- HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HC03+0.05% NH3 H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 36% B to 61% B in 8 min; Wave Length: 220nm nm; RTl(min): 7.4) to afford N-{[3- (8-{[(3S,4R)-3-fhjoro-l-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-
yl)-l,2,4-thiadiazol-5-yl]methyl}cyclopropanecarboxamide (3.4 mg, 3.84%) as a light yellow solid. LC-MS: (M+H)+ found 529.15. ^ NMR ^OO MHz, DMSO4) 8 9.17 (t, J= 5.8 Hz, 1H), 8.02 (d, J= 6.9 Hz, 1H), 7.84 (s, 1H), 6.82 (t, J= 7.2 Hz, 1H), 6.19 (t, J= 8.9 Hz, 2H), 5.02 - 4.69 (m, 3H), 3.63 (d, J= 29.8 Hz, 1H), 3.05 (t, J= 11.3 Hz, 1H), 2.83 (s, 1H), 2.20 (s, 4H), 2.10 (d, J = 8.3 Hz, 2H), 1.69 m, 2H), 0.77 (d, J= 5.2 Hz, 4H).
Example 55 - Preparation of N-[(lS)-l-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl] amino}-3- [(trifluor omethyl)sulfanyl] indolizin-2-yl)- 1 ,2, 4-oxadiazol-5-yl] -2- hydroxyethyljcyclopropanecarboxamide y—O OH
S HN
Step 1 : A mixture of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carbonitrile (1 g,
3.11 mmol, 1 equiv), (3S,4R)-3-fluoro-l-methylpiperidin-4-amine dihydrochloride (958.1 mg, 4.67 mmol, 1.5 equiv), CS2CO3 (5.07 g, 15.57 mmol, 5 equiv) and Pd-PEPPSI-IHeptCl 3- chloropyridine (303.3 mg, 0.31 mmol, 0.1 equiv) in 1,4-dioxane (10 mL) was stirred for 4 h at 100°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (15: 1) to afford 8-{[(3S,4R)-3- fluoro-l-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizine-2-carbonitrile (1.2 g, 103.48%) as a yellow solid. LC-MS: (M+H)+ found 373.2.
Step 2: A solution of 8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizine-2-carbonitrile (1.2 g, 3.22 mmol, 1 equiv), TEA (1.63 g,
16.11 mmol, 5 equiv) and NH2OHHCI (0.67 g, 9.67 mmol, 3 equiv) in EtOH (10 mL) was stirred for 3 h at 80°C under nitrogen atmosphere. The solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (1.1g) was used in the next step directly without further purification. LC-MS: (M+H)+ found 406.3.
Step 3: A solution of (Z)-8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-N'- hydroxy-3 -[(trifluoromethyl) sulfanyl]indolizine-2-carboximidamide (300 mg, 0.74 mmol, 1 equiv), (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoic acid (182.2 mg, 0.89 mmol, 1.2 equiv), HOBT (200 mg, 1.48 mmol, 2 equiv), EDCI (283.7 mg, 1.48 mmol, 2 equiv) and DIEA (956.4 mg, 7.40 mmol, 10 equiv) in DMF (6 mL) was stirred for 3 h at room temperature under nitrogen atmosphere. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2CI2 / MeOH 15: 1) to afford tert-butyl N-[(lS)-l-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl]indolizin-2-yl)-l, 2, 4-oxadiazoL5-yl]-2-hydroxy ethylcarbamate (190 mg, 44.69%) as a yellow solid. LC-MS: (M+H)+ found 575.2.
Step 4: To a stirred solution of tert-butyl N-[(lS)-l-[3-(8-{[(3S,4R)-3-fluoro-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5-yl]- 2-hydroxyethyl]carbamate (190 mg, 0.33 mmol, 1 equiv) in DCM (5 mL) were added HC1 (gas) in 1,4-dioxane (0.5 mL) dropwise at room temperature. The resulting mixture was stirred for 0.5 h at room temperature, then basified to pH 8 with sat.NaHCOi. The resulting mixture was extracted with CH2CI2. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (170 mg) was used in the next step directly without further purification. LC-MS: (M+H)+ found 409.1.
Step 5: A solution of (2S)-2-amino-2-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl]amino}-3-[(triftaoromethyl) sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5-yl]ethanol (170 mg, 0.36 mmol, 1 equiv), cyclopropanecarboxylic acid (37.0 mg, 0.43 mmol, 1.2 equiv), PyBOP (223.7 mg, 0.43 mmol, 1.2 equiv) and DIEA (231.5 mg, 1.79 mmol, 5 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting solution was extracted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2CI2 / 7 M NH3 in MeOH 15: 1) (Column: CHIRALPAKIC-34.6*50mm, 3.0um; Mobile Phase A: Hex(0.2%DEA): (EtOH: DCM=1 : l)=60: 40; Gradient: isocratic ; Injection Volume: 5.0L mL) to afford N-[(lS)-l-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3-
[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5-yl]-2- hydroxyethyl]cyclopropanecarboxamide (17.2 mg, 8.85%) as a light yellow solid. LC-MS:
(M+H)+ found 543.15. XH NMR (400 MHz, DMSO-fifc) 8 8.96 (d, J= 7.2 Hz, 1H), 8.08 (d, J= 6.9 Hz, 1H), 7.77 (s, 1H), 6.90 (t, J= 7.2 Hz, 1H), 6.52 (d, J= 7.8 Hz, 1H), 6.25 (d, J= 7.7 Hz, 1H), 5.38 (s, 1H), 5.34 - 5.02 (m, 2H), 4.09 - 3.66 (m, 4H), 3.47 (s, 2H), 3.12 (s, 1H), 2.80 (s, 3H), 2.39 - 2.18 (m, 1H), 1.99 (d, J= 13.9 Hz, 1H), 1.85 - 1.70 (m, 1H), 0.72 (m, 4H).
Example 53 - Preparation of N-[(lR)-l-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-l,2,4-oxadiazol-5-yl]-2- hydroxyethyljcyclopropanecarboxamide
Step 1 : A solution of (Z)-8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-N'- hydroxy-3 -[(trifluoromethyl) sulfanyl]indolizine-2-carboximidamide (400 mg, 0.99 mmol, 1 equiv), HOBT (266.6 mg, 1.97 mmol, 2 equiv), EDCI (378.3 mg, 1.97 mmol, 2 equiv) and DIEA (1.28 g, 9.87 mmol, 10 equiv) in DMF (5 mL) was stirred for 3 h at room temperature, then stirred overnight at 80°C. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2CI2 / MeOH 15: 1) to afford tert-butyl N-[(lR)-l-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5-yl]-2-hydroxyethyl]carbamate (188 mg, 33.16%) as a light yellow solid. LC-MS: (M+Hf found 575.2.
Step 2: To a stirred solution of tert-butyl N-[(lR)-l-[3-(8-{[(3S,4R)-3-fluoro-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5-yl]- 2-hydroxyethyl]carbamate (188 mg, 0.33 mmol, 1 equiv) in DCM (5 mL) was added HC1 (gas) in 1,4-dioxane (0.5 mL) dropwise at room temperature. The resulting mixture was stirred for 0.5 h at room temperature, then basified to pH 8 with sat.NaHCOs. The resulting mixture was extracted with CH2CI2. The combined organic layers were dried over anhydrous Na2SO4. After filtration,
the filtrate was concentrated under reduced pressure. The residue (140 mg) was used in the next step directly without further purification. LC-MS: (M+H)+ found 409.1.
Step 3: A solution of (2R)-2-amino-2-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5-yl]ethanol (140 mg, 0.30 mmol, 1 equiv), cyclopropanecarboxylic acid (27.9 mg, 0.33 mmol, 1.10 equiv), PyBOP (184.3 mg, 0.35 mmol, 1.2 equiv) and DIEA (190.7 mg, 1.48 mmol, 5 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (CH2CI2 / 7 MNH3 in MeOH 15: 1) and Prep-HPLC (Column: CHIRALPAKIC-34.6*50mm, 3.0um; Mobile Phase A: Hex(0.2%DEA): (EtOH: DCM=1 : 1) = 60: 40; Gradient: isocratic ; Injection Volume: 5.0 L mL) to afford N-[(lR)-l-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-l,2,4-oxadiazol-5-yl]-2- hydroxyethyl]cyclopropanecarboxamide (37 mg, 23.11%) as a light yellow solid. LC-MS: (M+H) found 543.30. ‘HNMR (400 MHz, DMSO-rL) 5 8.94 (d, J= 7.5 Hz, 1H), 8.03 (d, J= 6.9 Hz, 1H), 7.79 (s, 1H), 6.86 (t, J= 7.2 Hz, 1H), 6.32 (d, J= 8.1 Hz, 1H), 6.21 (d, J= 7.6 Hz, 1H), 5.35 (t, J = 5.7 Hz, 1H), 5.24 (m 1H), 4.88 (d, J = 49.2 Hz, 1H), 3.99 - 3.78 (m, 2H), 3.64 (d, J = 29.0 Hz, 1H), 3.06 (s, 1H), 2.85 (s, 1H), 2.21 (s, 4H), 2.11 (d, J = 9.1 Hz, 2H), 1.74 (m 2H), 0.72 (m 4H).
Example 51 - Preparation of N-[(lR*)-l-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5- yl] ethyl] cyclopropanecarboxamide
Step 1 : To a stirred mixture of (Z)-8-bromo-N'-hydroxy-3-
[(trifluoromethyl)sulfanyl]indolizine-2-carboximidamide (1 g, 2.82 mmol, 1 equiv), (2R)-2-[(tert- butoxycarbonyl)amino]propanoic acid (801.4 mg, 4.24 mmol, 1.5 equiv) and DIEA (3.65 g,
28.240 mmol, 10 equiv) in DMF (1 mL) were added HOBT (763.1 mg, 5.65 mmol, 2 equiv) and EDCI (1.08 g, 5.65 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 3 h at room temperature and then overnight at 80°C. The resulting mixture was diluted with EA (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6: 1) to afford tert-butyl N-[(lR)-l-(3-{ 8- bromo-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl}-l,2,4-oxadiazol-5-yl)ethyl]carbamate (350 mg, 24.43%, 88 ee%) as a white solid. LC-MS: (M+H)+ found 507.1.
Step 2: A mixture of tert-butyl N-[(lR)-l-(3-{8-bromo-3-
[(trifluoromethyl)sulfanyl]indolizin-2-yl}-l ,2,4-oxadiazol-5-yl)ethyl]carbamate (460 mg, 0.91 mmol, 1 equiv), (3 S,4R)-3 -fluoro- l-methylpiperidin-4-amine dihydrochloride (279 mg, 1.36 mmol, 1.50 equiv), BINAP (282.3 mg, 0.45 mmol, 0.50 equiv), CS2CO3 (1.48 g, 4.54 mmol, 5 equiv) and RAC-BINAP-PD-G3 (90 mg, 0.09 mmol, 0.10 equiv) in dioxane (4 mL) was stirred for 4 h at 100°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ACN. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) and Prep-TLC (CH2CI2 / MeOH 20: 1) to afford tert-butyl N-[(lR)-l-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5-yl]ethyl] carbamate (120 mg, 23.69%, 45 ee%) as a grey solid. LC-MS: (M+H)+ found 559.2.
Step 3: To a stirred solution of tert-butyl N-[(lR)-l-[3-(8-{[(3S,4R)-3-fluoro-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5- yl]ethyl]carbamate (120 mg, 0.21 mmol, 1 equiv) in DCM (2 mL) were added TFA (0.4 mL) at room temperature. The resulting solution was stirred for 0.5 h at room temperature, then basified to pH 8 with sat.NaHCOs. The resulting mixture was extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-{5-[(lR)-l-aminoethyl]-l,2,4-oxadiazol-3-yl}-N- [(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (120 mg, crude) as a yellow oil. LC-MS: (M+H)+ found 459.2.
Step 4: A solution of 2-{5-[(1R)-1-aminoethyl]-1,2,4-oxadiazol-3-yl}-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (120 mg, 0.26 mmol, 1 equiv), cyclopropanecarboxylic acid (27.0 mg, 0.31 mmol, 1.2 equiv), DIEA (169.1 mg, 1.31 mmol, 5.00 equiv) and PyBOP (163.4 mg, 0.31 mmol, 1.20 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting solution was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) and Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH 20:1) to afford N- [(1R)-1-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]ethyl]cyclopropanecarboxamide (42 mg, 30.48%, 45 ee%) as a off-white solid. LC-MS: (M+H)+ found 527.2. Step 5: The crude product (42 mg) was purified by Prep-HPLC (Column: CHIRALPAKIA3; Mobile Phase A: Hex(0.2%DEA): (EtOH: DCM=1: 1)=80: 20; Flow rate: 1mL/min mL/min; Gradient: isocratic ; Injection Volume: 3μL mL) to afford N-[(1R*)-1-[3-(8- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)- 1,2,4-oxadiazol-5-yl]ethyl]cyclopropanecarboxamide (18.7 mg, 44.52%, 100 ee%) as a white solid. LC-MS: (M+H)+ found 527.15.1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J = 7.3 Hz, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.78 (s, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.33 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 7.7 Hz, 1H), 5.27 (m, 1H), 4.89 (d, J = 49.2 Hz, 1H), 3.83 – 3.57 (m, 1H), 3.11 (s, 1H), 2.89 (d, J = 10.4 Hz, 1H), 2.49 – 1.98 (m, 6H), 1.75 – 1.69 (m, 1H), 1.69 – 1.44 (m, 4H), 0.84 – 0.57 (m, 4H). Example 52 – Preparation of N-[(1S)-1-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]ethyl]cyclopropanecarboxamide
Step 1: A solution of (Z)-8-bromo-N'-hydroxy-3-[(trifluoromethyl)sulfanyl]indolizine-2- carboximidamide (1 g, 2.82 mmol, 1 equiv), (2S)-2-[(tert-butoxycarbonyl)amino]propanoic acid (0.64 g, 3.39 mmol, 1.2 equiv), HOBT (0.76 g, 5.65 mmol, 2 equiv), EDCI (1.08 g, 5.65 mmol, 2 equiv) and DIEA (3.65 g, 28.24 mmol, 10 equiv) in DMF (10 mL) was stirred for 1 h at room temperature. Then the solution was heated at 80°C for 5 h. The reaction was diluted with EA (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6:1) to afford tert-butyl N-[(1S)-1-(3-{8- bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-1,2,4-oxadiazol-5-yl)ethyl]carbamate (1.152 g, 80.42%, 89.4 ee%) as a white solid. LC-MS: (M+H)+ found 507.1. Step 2: A solution of tert-butyl N-[(1S)-1-(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}-1,2,4-oxadiazol-5-yl)ethyl]carbamate (1 g, 1.97 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (0.61 g, 2.96 mmol, 1.5 equiv), RAC-BINAP-PD-G3 (0.39 g, 0.39 mmol, 0.2 equiv), BINAP (0.61 g, 0.99 mmol, 0.5 equiv) and Cs2CO3 (3.21 g, 9.86 mmol, 5 equiv) in dioxane (10 mL) was stirred for 1 h at 100°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was washed with brine (50 mL), then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 50 min; detector, UV 254 nm). This resulted in tert-butyl N-[(1S)-1-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (600 mg, 54.49%) as a yellow solid. LC-MS: (M+H)+ found 559.2. Step 3: A solution of tert-butyl N-[(1S)-1-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]ethyl]carbamate (300 mg, 0.54 mmol, 1 equiv) and TFA (0.6 mL, 8.08 mmol, 15.04 equiv) in DCM (3 mL) was stirred for 1 h at room temperature. The mixture was basified to pH 7 with saturated NaHCO3, and then extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / 7 M NH3 in MeOH (25:1) to
afford 2-{5-[(1S)-1-aminoethyl]-1,2,4-oxadiazol-3-yl}-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (68 mg, 27.62%) as a yellow solid. LC-MS: (M+H)+ found 459.2. Step 4: A solution of 2-{5-[(1S)-1-aminoethyl]-1,2,4-oxadiazol-3-yl}-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (55 mg, 0.12 mmol, 1 equiv), cyclopropanecarboxylic acid (12.4 mg, 0.14 mmol, 1.2 equiv), PyBOP (81.2 mg, 0.16 mmol, 1.3 equiv) and DIEA (77.5 mg, 0.60 mmol, 5 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EA (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 38% B to 63% B in 8 min; Wave Length: 220nm nm; RT1(min): 6.85) to afford N-[(1S)-1-[3-(8-{[(3S,4R)-3-fluoro- 1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]ethyl]cyclopropanecarboxamide (26 mg, 40.72%, 8 ee%) as a white solid. LC-MS: (M+H)+ found 527.15. Step 5: The crude product (26 mg) was purified by CHIRAL-HPLC (Column: CHIRALPAKIA3; Mobile Phase A: Hex(0.2%DEA): (EtOH: DCM=1: 1)=80: 20; Flow rate: 1mL/min mL/min; Gradient: isocratic ; Injection Volume: 3μL mL) to afford N-[(1S)-1-[3-(8- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)- 1,2,4-oxadiazol-5-yl]ethyl]cyclopropanecarboxamide (8.3 mg, 31.92%, 100 ee%) as a light brown solid. LC-MS: (M+H)+ found 527.15.1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J = 7.3 Hz, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.78 (s, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.41 – 6.29 (m, 1H), 6.21 (d, J = 7.6 Hz, 1H), 5.27 (m, 1H), 4.90 (d, J = 49.2 Hz, 1H), 3.66 (d, J = 28.5 Hz, 1H), 3.13 (s, 1H), 2.90 (d, J = 10.2 Hz, 1H), 2.47 – 1.93 (m, 6H), 1.73 (d, J = 10.8 Hz, 1H), 1.64 (m, 1H), 1.57 (d, J = 7.1 Hz, 3H), 0.79 – 0.62 (m, 4H). Example 54 – Preparation of 6-({[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}amino)- N-methylpyridine-3-carboxamide
Step 1 : A mixture of ethyl 8-bromoindolizine-2-carboxylate (2 g, 7.46 mmol, 1 equiv), 2- [(trifhioromethyl)sulfanyl] isoindole- 1,3-dione (2.21 g, 8.95 mmol, 1.20 equiv), NaCl (87.19 mg, 1.49 mmol, 0.2 equiv) in DMF (10 mb) was stirred for 4 h at 90°C under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (100 mb), washed with brine, and dried over anhydrous Na2SO-L After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (100:1) to afford ethyl 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carboxylate (1.8 g, 65.54%) as a light yellow solid. LC-MS: (M+H)+ found 368.1.
Step 2: A solution of ethyl 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carboxylate (1.8 g, 4.89 mmol, 1 equiv) and caustic soda (1 g, 24.45 mmol, 5 equiv) in MeOH (7 mL)/THF (7 mL)/H20 (6 mb) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 2 with HC1 (3N). The precipitated solids were collected by filtration and dried under vacuum to afford 8-bromo-3- [(trifluoromethyl)sulfanyl]indolizine-2-carboxylic acid (1.8 g) as a light yellow solid. LC-MS: (M+H)+ found 340.1.
Step 3: To a stirred solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2- carboxylic acid (1 g, 2.94 mmol, 1 equiv), EtsN (0.89 g, 8.82 mmol, 3 equiv), and NH4CI (1.57 g, 29.40 mmol, 10 equiv) in DMF (10 mb) was added HATU (1.68 g, 4.41 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with ethyl acetate (100 mL), then washed with 3*100 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vaccum. The residue was washed with MeOH (3 mL) and filtered to give 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2- carboxamide (850 mg, 85.25%) as a white solid. LC-MS: (M+H)+ found 339.2.
Step 4: A mixture of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carboxamide (1 g, 2.95 mmol, 1 equiv) and POCh (0.99 g, 6.49 mmol, 2.2 equiv) in toluene (10 mb) was stirred at 110 °C for 1 h. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carbonitrile (0.8 g, 84.49%) as a white solid. LC-MS: (M+H)+ found 321.1.
Step 5: A mixture of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carbonitrile (1 g, 3.11 mmol, 1 equiv), NH2OHHCI (770 mg, 4.67 mmol, 1.5 equiv) and EtsN (0.95 g, 9.34 mmol, 3 equiv) in EtOH (10 mb) was stirred for 1 h at 80 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford (Z)-8-bromo-N'-hydroxy-3-[(trifluoromethyl)sulfanyl]indolizine-2- carboximidamide (700 mg, 63.47%) as a white solid. LC-MS: (M+H)+ found 354.2.
Step 6: To a stirred solution of (Z)-8-bromo-N'-hydroxy-3- [(trifluoromethyl)sulfanyl]indolizine-2-carboximidamide (2 g, 5.65 mmol, 1 equiv), DIEA (7.30 g, 56.47 mmol, 10 equiv), and [(tert-butoxycarbonyl)amino]acetic acid (1.19 g, 6.77 mmol, 1.2 equiv) in DMF (20 mL) were added HOBT (1.53 g, 11.29 mmol, 2 equiv) and EDCI (2.17 g, 11.29 mmol, 2 equiv) at 0°C. The reaction mixture was stirred at room temperature for 1 h and then 80°C for 16 h. The mixture was purified by reversed-phase flash chromatography directly (column, Cl 8 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm) to give tert-butyl N-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-l,2,4- oxadiazol-5-yl)methyl] carbamate (1.8 g, 64.61%) as a white solid. LC-MS: (M+H)+ found 493.3.
Step 7: A mixture of tert-butyl N-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}-l,2,4-oxadiazol-5-yl)methyl]carbamate vanadium (500 mg, 0.92 mmol, 1 equiv), (3S,4R)-3- fluoro-l-methylpiperidin-4-amine dihydrochloride (283 mg, 1.38 mmol, 1.5 equiv), RAC -BINAP - PD-G3 (183 mg, 0.18 mmol, 0.2 equiv), BINAP (228 mg, 0.37 mmol, 0.4 equiv), and CS2CO3 (1.5 g, 4.59 mmol, 5 equiv) in dioxane (5 mL) were added was stirred for 6 h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10: 1) to afford tertbutyl N-{[3-(8-{[(3S)-3-fluoro-l-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)
sulfanyl]indolizin-2-yl)-l ,2,4-oxadiazol-5-yl]methyl(carbamate (300 mg, 59.96%) as a light brown solid. LC-MS: (M+H)+ found 545.2.
Step 8: A solution of tert-butyl N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l, 2, 4-oxadiazol-5-yl]methyl (carbamate (280 mg, 0.51 mmol, 1 equiv) and 4M HC1 (gas)in 1,4-dioxane (0.6 mL) in DCM (3 mL) was stirred for 0.5 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford crude product 2-[5-(aminomethyl)-l,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro- l-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (280 mg, crude) as a brown solid. LC-MS: (M+H)+ found 445.2.
Step 9: A solution of 2-[5-(aminomethyl)-l,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-l- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (80 mg, 0.18 mmol, 1 equiv), TEA (54.6 mg, 0.54 mmol, 3 equiv) and methyl 6-fluoropyridine-3 -carboxylate (41.9 mg, 0.27 mmol, 1.5 equiv) in NMP (2 mL) was stirred overnight at 90°C. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH4HCO3), 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford methyl 6-({[3-(8-{[(3S,4R)-3- fluoro- 1-methylpiperi din-4-yl]amino(-3-[(tri fluoromethyl)sulfanyl]indolizin-2-yl)- 1,2,4- oxadiazol-5-yl]methyl( amino)pyridine-3-carboxylate (40 mg, 35.28%) as ayellow solid. LC-MS: (M+H)+ found 580.2.
Step 10: A solution of methyl 6-({ [3 -(8- {[(3 S,4R)-3 -fluoro- 1-methylpiperi din-4- yl]amino(-3-[(trifhioromethyl) sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5- yl]methyl(amino)pyridine-3-carboxylate (40 mg, 0.07 mmol, 1 equiv) and NaOH (13.8 mg, 0.35 mmol, 5 equiv) in THF (0.2 mL)/MeOH (0.4 mL)/H20 (0.4 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with water (10 mL) and acidfied to pH 5 with IM HC1, then extracted with EtOAc (3*10 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 6-({[3-(8-{[(3S,4R)- 3-fluoro- 1-methylpiperi din-4-yl]amino(-3-[(tri fhioromethyl)sulfanyl]indolizin-2-yl)-l, 2,4- oxadiazol-5-yl]methyl( amino)pyridine-3-carboxylic acid (35 mg) as a white solid. LC-MS: (M+H)+ found 566.0.
Step 11: A solution of 6-({[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl](methyl)amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}amino)pyridine-3-carboxylic acid (40 mg, 0.07 mmol, 1 equiv), methanamine, hydrochloride (14.0 mg, 0.21 mmol, 3 equiv), HATU (31.5 mg, 0.08 mmol, 1.2 equiv) and TEA (34.9 mg, 0.35 mmol, 5 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with CH2Cl (2*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 27% B to 54% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.77) to afford 6-({[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}amino)-N- methylpyridine-3-carboxamide (6.3 mg, 15.45%) as a white solid. LC-MS: (M+H)+ found 579.35. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 2.3 Hz, 1H), 8.15 (d, J = 4.7 Hz, 1H), 8.01 (d, J = 6.9 Hz, 1H), 7.94 – 7.83 (m, 2H), 7.74 (s, 1H), 6.84 (t, J = 7.2 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H), 6.21 (dd, J = 16.2, 7.9 Hz, 2H), 4.97 – 4.72 (m, 3H), 3.62 (d, J = 28.9 Hz, 1H), 3.04 (t, J = 11.3 Hz, 1H), 2.84 (dd, J = 14.9, 6.6 Hz, 1H), 2.72 (d, J = 4.5 Hz, 3H), 2.19 (s, 4H), 2.13 – 2.00 (m, 2H), 1.68 (d, J = 10.4 Hz, 1H). Example 50 – Preparation of 2-({[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}amino)- N-methylpyrimidine-5-carboxamide Step 1: A mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (130 mg, 0.29 mmol, 1
equiv), methyl 2-chloropyrimidine-5-carboxylate (55.5 mg, 0.32 mmol, 1.1 equiv), and KF (34.0 mg, 0.58 mmol, 2 equiv) in DMSO (1 mL) stirred for 40 min at room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (2*50 mL). The combined organic layers were dried over anhydrous NaiSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CFLCh/MeOHMO: !) to afford methyl 2-({[3-(8-{ [(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-l,2,4-oxadiazol-5-yl]methyl}amino)pyrimidine-5-carboxylate (90 mg, 53.00%) as a yellow solid. LC-MS: (M+H)+ found 581.2.
Step 2: To a stirred solution of methyl 2-({[3-(8-{[(3S,4R)-3-fhioro-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l ,2,4-oxadiazol-5- yl]methyl}amino)pyrimidine-5-carboxylate (40 mg, 0.07 mmol, 1 equiv) in THF (1 mL)/H20 (0.25 mL) was added LiOH (10 mg, 0.08 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature, then acidified to pH 5 with HC1 (aq.). The resulting solution was extracted with DCM (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-({[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5-yl]methyl}amino)pyrimidine-5- carboxylic acid (23 mg, 58.92%) as a brown oil. LC-MS: (M+H)+ found 567.1.
Step 3: A solution of 2-({[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluorom ethyl) sulfanyl]indolizin-2-yl)- 1 ,2,4-oxadiazol-5-yl]methyl } amino)pyrimidine-5 - carboxylic acid (50 mg, 0.09 mmol, 1 equiv), methanamine hydrochloride (7.8 mg, 0.11 mmol, 1.3 equiv), DIEA (57.0 mg, 0.44 mmol, 5 equiv), and HATU (43.6 mg, 0.11 mmol, 1.3 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting solution purified by Prep- HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NHIHC03+0.05%NH3 H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7min; Wave Length: 254nm/220nm nm; RTl(min): 6.7; Number Of Runs: 2) to afford 2-({[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3-
[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5-yl]methyl}amino)-N- methylpyrimidine-5-carboxamide (4.9 mg, 9.48%) as a white solid. LC-MS: (M+H)+ found 580.35. 'H NMR (400 MHz, DMSO-d6) 5 8.72 (d, J= 29.1 Hz, 2H), 8.51 (t, J= 6.0 Hz, 1H), 8.33
(m, 1H), 8.01 (d, J= 6.9 Hz, 1H), 7.74 (s, 1H), 6.84 (t, J= 7.2 Hz, 1H), 6.23 (dd, J= 26.3, 7.9 Hz, 2H), 4.98 - 4.74 (m, 3H), 3.62 (d, J= 28.8 Hz, 1H), 3.04 (t, J= 11.1 Hz, 1H), 2.83 (d, J= 8.3 Hz, 1H), 2.74 (d, J= 4.5 Hz, 3H), 2.39 - 2.26 (m, 1H), 2.19 (s, 3H), 2.10 - 2.01 (m, 2H), 1.68 (d, J = 9.5 Hz, 1H).
Example 2 - Preparation of l-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fluoro-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5- yljmethyl}pyrazole-4-carboxamide
Step 1 : To a stirred solution of l-tert-butylpyrazole-4-carboxylic acid (29 mg, 0.17 mmol, 1.5 equiv), DIEA (0.20 mL, 1.12 mmol, 10 equiv), and 2-[5-(aminomethyl)-l,2,4-oxadiazol-3-yl]- N-[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv) in DMF (1 mL) was added HATU (65 mg, 0.17 mmol, 1.5 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature, then diluted with EtOAc (20 mL) and washed with brine (2*30 mL). The organic layer was dried over anhydrous Na2SO4. After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2C12/MeOH=10: 1) and Prep-HPLC (Column: XB ridge Prep OBD C 18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HC03+0.05% NH3 H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 36% B to 61% B in 8 min; Wave Length: 220nm nm; RTl(min): 7.62) to afford l-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fluoro-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5- yl]methyl}pyrazole-4-carboxamide (25.8 mg, 38.45%) as a light yellow solid. LC-MS: (M+H)~ found 595.20. E NMR (400 MHz, DMSO-e/e) S 8.98 (t, J = 5.7 Hz, 1H), 8.34 (s, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.93 (s, 1H), 7.76 (s, 1H), 6.85 (t, J= 7.2 Hz, 1H), 6.28 (d, J= 8.1 Hz, 1H), 6.20
(d, J= 7.7 Hz, 1H), 4.96 - 4.75 (m, 3H), 3.62 (d, J= 28.4 Hz, 1H), 3.04 (t, J= 11 .3 Hz, 1H), 2.83 (d, J= 8.1 Hz, 1H), 2.19 (s, 4H), 2.07 (t, J= 10.9 Hz, 2H), 1.68 (d, J= 10.3 Hz, 1H), 1.54 (s, 9H).
Example 7 - Preparation of l-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fluoro-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5- yl] methyl} pyrrole-3-carboxamide
N-0 ' u H
N
S F-V
Step 1 : To a stirred solution of l-tert-butylpyrrole-3 -carboxylic acid (29 mg, 0.17 mmol, 1.5 equiv), 2-[5-(aminomethyl)- 1 ,2,4-oxadiazol-3 -yl]-N-[(3 S,4R)-3 -fluoro- 1 -methylpiperidin-4- yl]-3-[(trifluoromethyl) sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv) and DIEA (0.20 mb, 1.12 mmol, 10 equiv) in DMF (1 mL) was added HATU (64.2 mg, 0.17 mmol, 1.5 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (20 mL) and washed with brine (2*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHiCh/MeOHMOT) and Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HC03+0.05%NH3 H20), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 42% B to 62% B in 7min; Wave Length: 254nm/220 nm nm; RTl(min): 6.67; Number Of Runs: 2) to afford l-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fhroro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5-yl]methyl}pyrrole-3-carboxamide (19.7 mg, 29.26%) as a light yellow solid. LC-MS: (M+H)+ found 594.25. 'H NMR (400 MHz, DMSO-tA) 8 8.66 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.76 (s, 1H), 7.55 (t, J= 2.1 Hz, 1H), 6.99 (t, J = 2.7 Hz, 1H), 6.85 (t, J= 7.2 Hz, 1H), 6.50 (dd, J= 3.0, 1.8 Hz, 1H), 6.24 (dd, J = 30.8, 7.9 Hz, 2H), 4.98 - 4.66 (m, 3H), 3.62 (d, J= 28.7 Hz, 1H), 3.12 - 2.97 (m, 1H), 2.87 - 2.78 (m, 1H), 2.19 (s, 4H), 2.13 - 2.01 (m, 2H), 1.73 - 1.64 (m, 1H), 1.49 (s, 9H).
Example 27 - Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl]amino}-3- [(trifluoromethyl) sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5-yl]methyl}-l,2- thiazole-5-carboxamide
Step 1 : To a stirred solution of 2-[5-(aminomethyl)-l,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- fluoro-l-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), l,2-thiazole-5-carboxylic acid (29.1 mg, 0.22 mmol, 2 equiv) and DIEA (145.4 mg, 1.12 mmol, 10 equiv) in DMF (1 mL) was added HATU (51.3 mg, 0.13 mmol, 1.2 equiv) at room temperature. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (30 mL) and washed with brine (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HC03)+0.05%NH3H20, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 35% B to 60% B in 7min; Wave Length: 254nm/220nm nm; RTl(min): 7.48) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluorom ethyl) sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5-yl]methyl }-l,2-thiazole-5- carboxamide (17.7 mg, 28.26%) as a white solid. LC-MS: (M+H)+ found 556.30. NMR (400 MHz, DMSO4) 5 9.87 (t, J= 5.7 Hz, 1H), 8.72 (d, J= 1.8 Hz, 1H), 8.07 - 7.94 (m, 2H), 7.77 (d, J= 0.8 Hz, 1H), 6.85 (t, J= 7.2 Hz, 1H), 6.24 (dd, J= 29.7, 7.9 Hz, 2H), 4.95 - 4.72 (m, 3H), 3.63 (d, J= 29.2 Hz, 1H), 3.04 (t, J = 11.2 Hz, 1H), 2.83 (d, J= 8.0 Hz, 1H), 2.19 (s, 4H), 2.14 - 1.94 (m, 2H), 1.68 (d, J= 10.5 Hz, 1H).
Example 30 - Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-l,2,4-oxadiazol-5-yl]methyl}-3- methylthiophene-2-carboxamide
Step 1: To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), 3-methylthiophene-2-carboxylic acid (32.0 mg, 0.22 mmol, 2 equiv) and DIEA (145.4 mg, 1.12 mmol, 10 equiv) in DMF (1 mL) was added HATU (51.3 mg, 0.13 mmol, 1.2 equiv) at room temperature. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (30 mL) and washed with brine (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 41% B to 66% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.5) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3- methylthiophene-2-carboxamide (17.5 mg, 27.30%) as a white solid. LC-MS: (M+H)+ found 569.30.1H NMR (400 MHz, DMSO-d6) δ 8.80 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.66 (d, J = 5.0 Hz, 1H), 7.01 (d, J = 5.0 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.27 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 7.6 Hz, 1H), 4.92– 4.78 (m, 3H), 3.63 (d, J = 28.0 Hz, 1H), 3.13 – 2.98 (m, 1H), 2.83 (d, J = 7.6 Hz, 1H), 2.46 (s, 3H), 2.34 – 2.19 (m, 4H), 2.07 (t, J = 10.7 Hz, 2H), 1.69 (d, J = 9.2 Hz, 1H). Example 13 – Preparation of 2-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}-1,3-oxazole-5-carboxamide
l)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1-
methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), 2-tert-butyl-1,3-oxazole-5-carboxylic acid (22.8 mg, 0.13 mmol, 1.2 equiv), HATU (64.1 mg, 0.17 mmol, 1.5 equiv) and DIEA (145.4 mg, 1.12 mmol, 10 equiv) in DMF (1.5 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with 3*50 mL of brine. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (CH2Cl2 / MeOH 20:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 40% B to 65% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.28) to afford 2-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1,3- oxazole-5-carboxamide (11 mg, 16.14%) as a off-white solid. LC-MS: (M+H)+ found 596.15.1H NMR (400 MHz, DMSO-d6) δ 9.41 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.83 – 7.68 (m, 2H), 6.85 (t, J = 7.2 Hz, 1H), 6.27 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 4.97 – 4.76 (m, 3H), 3.62 (d, J = 28.8 Hz, 1H), 3.04 (t, J = 11.2 Hz, 1H), 2.83 (d, J = 8.1 Hz, 1H), 2.19 (s, 4H), 2.06 (t, J = 11.1 Hz, 2H), 1.68 (d, J = 9.9 Hz, 1H), 1.37 (s, 9H). Example 14 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-5- methyl-4-oxo-3H-thieno[2,3-d]pyrimidine-6-carboxamide
o[2,3-d]pyrimidine-6-carboxylic
acid (47.3 mg, 0.23 mmol, 1 equiv), HATU (102.6 mg, 0.27 mmol, 1.2 equiv), DIEA (116.3 mg, 0.90 mmol, 4 equiv) in DMF (2 mL) was added 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N- [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (100 mg, 0.23 mmol, 1 equiv) at room temperature. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 28% B to 53% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.82) to afford N-{[3-(8- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)- 1,2,4-oxadiazol-5-yl]methyl}-5-methyl-4-oxo-3H-thieno[2,3-d]pyrimidine-6-carboxamide (13.6 mg, 9.36%) as a yellow solid. LC-MS: (M+H)+ found 637.10.1H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 9.06 (t, J = 5.6 Hz, 1H), 8.18 (s, 1H), 8.03 (d, J = 6.9 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 17.0, 7.9 Hz, 2H), 4.98 – 4.74 (m, 3H), 3.63 (d, J = 27.8 Hz, 1H), 3.04 (t, J = 11.2 Hz, 1H), 2.78 (s, 4H), 2.19 (s, 4H), 2.07 (t, J = 11.2 Hz, 2H), 1.69 (d, J = 9.8 Hz, 1H). Example 16 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2-oxo- 1,3-dihydroindole-6-carboxamide
zol-3-yl]-N-[(3S,4R)-3-fluoro-1-
methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (80 mg, 0.18 mmol, 1 equiv), 2-oxo-1,3-dihydroindole-6-carboxylic acid (31.9 mg, 0.18 mmol, 1 equiv), DIEA (93.1 mg, 0.72 mmol, 4 equiv), and HATU (88.9 mg, 0.23 mmol, 1.3 equiv) in DMF (4 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (50 mL) and washed with briner (2*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2/MeOH=8:1) and Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 55% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.47; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}-2-oxo-1,3-dihydroindole-6-carboxamide (11.7 mg, 10.47%) as a light yellow solid. LC-MS: (M+H)+ found 604.10.1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.38 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.76 (d, J = 0.9 Hz, 1H), 7.53 (dd, J = 7.8, 1.6 Hz, 1H), 7.40 – 7.30 (m, 2H), 6.85 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 8.0 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.95 – 4.76 (m, 3H), 3.56 (s, 3H), 3.11 – 2.98 (m, 1H), 2.82 (d, J = 8.2 Hz, 1H), 2.41 – 1.96 (m, 6H).1.68 (d, J = 10.1 Hz, 1H). Example 17 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2-oxo- 1,3-dihydroindole-7-carboxamide
aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- flu
oro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (120 mg, 0.27 mmol, 1 equiv), DIEA (0.24 mL, 1.35 mmol, 5 equiv), and 2-oxo-1,3-dihydroindole-7-carboxylic acid (52.6 mg, 0.30 mmol, 1.1 equiv) in DMF (2 mL) was added HATU (154.0 mg, 0.41 mmol, 1.5 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 34% B to 59% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.57) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2-oxo-1,3- dihydroindole-7-carboxamide (23.7 mg, 14.24%) as a white solid. LC-MS: (M+H)+ found 604.15. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.48 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.75 (dd, J = 7.3, 1.0 Hz, 2H), 7.44 – 7.38 (m, 1H), 7.08 (dd, J = 8.1, 7.3 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.22 (dd, J = 15.3, 7.8 Hz, 2H), 4.95 – 4.77 (m, 3H), 3.55 (s, 3H), 3.04 (t, J = 11.2 Hz, 1H), 2.82 (d, J = 8.5 Hz, 1H), 2.33 – 1.95 (m, 6H), 1.68 (d, J = 10.5 Hz, 1H). Example 18 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2-oxo- 1,3-dihydroindole-5-carboxamide
Step 1: To a stirred solution of 2-oxo-1,3-dihydroindole-5-carboxylic acid (35.9 mg, 0.20 mmol, 1 equiv), DIEA (130.9 mg, 1.01 mmol, 5 equiv) and 2-[5-(aminomethyl)-1,2,4-oxadiazol- 3-yl]-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8- amine (90 mg, 0.20 mmol, 1 equiv) in DMF (1.5 mL) was added PyBOP (115.9 mg, 0.22 mmol, 1.1 equiv) at 0°C. The mixture was stirred at 25°C for 30 min. The resulting solution was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 53% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.77; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2-oxo-1,3- dihydroindole-5-carboxamide (20.4 mg, 16.36%) as an off-white solid. LC-MS: (M+H)+ found 604.35.1H NMR (400 MHz, DMSO-d6) 10.67 (s, 1H), 9.23 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.85-7.73 (m, 3H), 6.93-6.81 (m, 2H), 6.23 (dd, J = 22.5, 7.8 Hz, 2H), 4.96-4.71 (m, 3H), 3.56 (s, 3H), 3.04 (t, J = 11.1 Hz, 1H), 2.83 (d, J = 8.7 Hz, 1H),2.35- 2.19 (m, 4H), 2.14-1.99 (m, 2H), 1.68 (d, J = 11.0 Hz, 1H). Example 19 – Preparation of 3-cyano-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1H- indole-5-carboxamide
Step 1: To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (100 mg, 0.23 mmol, 1 equiv), DIEA (290.8 mg, 2.25 mmol, 10 equiv) and 3-cyano-1H-indole-5-carboxylic acid (20.9 mg, 0.11 mmol, 0.5 equiv) in DMF (1 mL) was added PyBOP (175.6 mg, 0.34 mmol, 1.5 equiv) at 0 °C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 35% B to 60% B in 8 min; Wave Length: 220 nm nm; RT1(min): 7.78) to afford 3-cyano-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1H-indole-5- carboxamide (27.2 mg, 19.73%) as an off-white solid. LC-MS: (M+H)+ found 613.40. 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.51 (t, J = 5.6 Hz, 1H), 8.41 – 8.33 (m, 2H), 8.02 (d, J = 6.8 Hz, 1H), 7.88 (dd, J = 8.7, 1.7 Hz, 1H), 7.77 (d, J = 0.9 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 23.3, 7.9 Hz, 2H), 4.94 – 4.77 (m, 3H), 3.61 (d, J = 28.5 Hz, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.82 (d, J = 8.4 Hz, 1H), 2.18 (s, 4H), 2.05 (t, J = 11.3 Hz, 2H), 1.66 (s, 1H). Example 20 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2- (morpholin-4-yl)-1,3-thiazole-4-carboxamide
Step 1: A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (100 mg, 0.23 mmol, 1 equiv), 2-(morpholin-4-yl)-1,3-thiazole-4-carboxylic acid (33.7 mg, 0.16 mmol, 0.7 equiv), HATU (85.5 mg, 0.23 mmol, 1 equiv) and DIEA (145.4 mg, 1.13 mmol, 5 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (20 mL) and washed with brine (3*20 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (CH2Cl2/MeOH 10:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 57% B to 82% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.77; Number Of Runs: 4) to afford N-{[3-(8-{[(3S,4R)-3-fluoro- 1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}-2-(morpholin-4-yl)-1,3-thiazole-4-carboxamide (18.8 mg, 12.72%) as a off-white solid. LC-MS: (M+H)+found 641.15. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (t, J = 6.0 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (d, J = 0.9 Hz, 1H), 7.55 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 28.4, 7.9 Hz, 2H), 4.96 – 4.74 (m, 3H), 3.74 (t, J = 4.9 Hz, 4H), 3.62 (d, J = 29.4 Hz, 1H), 3.48 (t, J = 4.9 Hz, 4H), 3.04 (t, J = 11.1 Hz, 1H), 2.83 (d, J = 8.3 Hz, 1H), 2.19 (s, 4H), 2.07 (t, J = 11.2 Hz, 2H), 1.68 (d, J = 10.9 Hz, 1H). Example 32 – Preparation of 3-fluoro-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}thiophene-2-carboxamide
Step 1: A mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (60 mg, 0.14 mmol, 1 equiv), 3-fluorothiophene-2-carboxylic acid (23.7 mg, 0.16 mmol, 1.2 equiv), DIEA (87.2 mg, 0.67 mmol, 5 equiv) and HATU (77mg, 020 mmol, 1.5 equiv) in DMF (1.5 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 20:1) and Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 40% B to 65% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.4; Number Of Runs: 2) to afford 3-fluoro-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}thiophene- 2-carboxamide (18.4 mg, 23.52%) as a off-white solid. LC-MS: (M+H)+ found 573.10.1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.87 (dd, J = 5.5, 4.0 Hz, 1H), 7.77 (d, J = 0.9 Hz, 1H), 7.16 (d, J = 5.5 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.28 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 4.95 – 4.74 (m, 3H), 3.62 (d, J = 29.1 Hz, 1H), 3.04 (t, J = 10.7 Hz, 1H), 2.82 (s, 1H), 2.19 (s, 4H), 2.13 – 2.00 (m, 2H), 1.68 (d, J = 10.0 Hz, 1H). Example 43 – Preparation of 2-(4-cyanophenoxy)-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}acetamide
Step 1: A mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (60 mg, 0.14 mmol, 1 equiv), P-cyanophenoxyacetic acid (28.7 mg, 0.16 mmol, 1.2 equiv), HATU (77.0 mg, 0.20 mmol, 1.5 equiv) and DIEA (87.2 mg, 0.67 mmol, 5 equiv) in DMF (1.5 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 20:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 37% B to 62% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.85) to afford 2-(4-cyanophenoxy)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}acetamide (17 mg, 20.59%) as a yellow solid. LC-MS: (M+H)+ found 604.10.1H NMR (400 MHz, DMSO-d6) δ 9.10 (t, J = 5.8 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.88 – 7.71 (m, 3H), 7.25 – 7.09 (m, 2H), 6.86 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 7.7 Hz, 1H), 4.87 (d, J = 49.5 Hz, 1H), 4.80 – 4.71 (m, 4H), 3.63 (d, J = 28.4 Hz, 1H), 3.05 (t, J = 11.4 Hz, 1H), 2.82 (s, 1H), 2.20 (s, 4H), 2.07 (t, J = 10.2 Hz, 2H), 1.70 (d, J = 9.5 Hz, 1H). Example 23 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1- methyl-3-oxo-2,4-dihydroquinoxaline-6-carboxamide
Step 1: A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (100 mg, 0.225 mmol, 1 equiv) in DMF (1 mL) was treated with DIEA (203.6 mg, 1.58 mmol, 7 equiv) and PyBOP (175.6 mg, 0.34 mmol, 1.5 equiv) for 2 min at 0°C followed by the addition of 1-methyl-3-oxo-2,4- dihydroquinoxaline-6-carboxylic acid (46.4 mg, 0.23 mmol, 1 equiv) at room temperature. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with water (30 mL) and extracted with DCM (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 40% B to 60% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.70) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1-methyl-3-oxo-2,4- dihydroquinoxaline-6-carboxamide (29.8 mg, 20.94%) as an off-white solid. LC-MS: (M+H)+ found 633.15.1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.10 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (d, J = 0.9 Hz, 1H), 7.54 (dd, J = 8.5, 2.1 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 6.26 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.78 (d, J = 5.6 Hz, 3H), 3.79 (s, 2H), 3.62 (d, J = 30.2 Hz, 1H), 3.04 (t, J = 10.3 Hz, 1H), 2.86 (s, 4H), 2.19 (s, 4H), 2.14 – 2.01 (m, 2H), 1.68 (d, J = 11.0 Hz, 1H). Example 31 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3-(1- methylcyclopropyl)prop-2-ynamide
Step 1: To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (90 mg, 0.20 mmol, 1 equiv), 3-(1-methylcyclopropyl) prop-2-ynoic acid (25.1 mg, 0.20 mmol, 1 equiv) and DIEA (0.18 mL, 1.01 mmol, 5 equiv) in DMF (1 mL) was added PyBOP (137.0 mg, 0.26 mmol, 1.3 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was diluted with water (30 mL) and extracted with DCM (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2/MeOH=10:1) and Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 44% B to 62% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.42; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3-(1- methylcyclopropyl)prop-2-ynamide (29 mg, 25.80%) as a light yellow solid. LCMS: (M+H)+ found 551.40.1H NMR (400 MHz, DMSO-d6) δ 9.32 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.77 (s, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.25 (dd, J = 34.0, 7.9 Hz, 2H), 4.87 (d, J = 48.8 Hz, 1H), 4.65 (d, J = 5.8 Hz, 2H), 3.63 (d, J = 29.3 Hz, 1H), 3.10 – 2.99 (m, 1H), 2.83 (s, 1H), 2.30 – 2.20 (m, 4H), 2.14 – 2.03 (m, 2H), 1.70 (d, J = 9.0 Hz, 1H), 1.28 (s, 3H), 0.98 (m, 2H), 0.80 (m, 2H). Example 33 – Preparation of 3-amino-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}thiophene-2-carboxamide
Step 1: A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (40 mg, 0.09 mmol, 1 equiv), 3-aminothiophene-2-carboxylic acid (12.9 mg, 0.09 mmol, 1 equiv), HATU (34.2 mg, 0.09 mmol, 1 equiv) and DIEA (34.9 mg, 0.27 mmol, 3 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7M NH3 in MeOH 20:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 53% B to 77% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.78; Number Of Runs: 5) to afford 3-amino-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}thiophene-2-carboxamide (3.1 mg, 6.05%) as a white solid. LC-MS: (M+H)+ found 570.10.1H NMR (400 MHz, DMSO-d6) δ 8.34 (t, J = 5.5 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (s, 1H), 7.46 (d, J = 5.3 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 5.3 Hz, 1H), 6.51 (s, 2H), 6.28 (d, J = 8.2 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.86 (d, J = 49.2 Hz, 1H), 4.69 (d, J = 5.5 Hz, 2H), 3.62 (d, J = 28.5 Hz, 1H), 3.04 (t, J = 11.1 Hz, 1H), 2.82 (s, 1H), 2.19 (s, 4H), 2.07 (t, J = 9.8 Hz, 2H), 1.69 (s, 1H). Example 34 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl] methyl}-6- methoxyquinoline-2-carboxamide
Step 1: A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), 6-methoxyquinoline-2-carboxylic acid (22.9 mg, 0.11 mmol, 1 equiv), PyBOP (70.3 mg, 0.13 mmol, 1.2 equiv) and DIEA (72.7 mg, 0.56 mmol, 5.00 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 15:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 45% B to 70% B in 8 min; Wave Length: 220nm nm; RT1(min): 8.17) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl] methyl}-6-methoxyquinoline-2- carboxamide (10.9 mg, 15.39%) as a white solid. LC-MS: (M+H)+ found 630.20. 1H NMR (400 MHz, DMSO-d6) δ 9.69 (t, J = 6.1 Hz, 1H), 8.47 (d, J = 8.5 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 9.1 Hz, 1H), 8.01 (d, J = 6.8 Hz, 1H), 7.75 (s, 1H), 7.55 – 7.51 (m, 2H), 6.84 (t, J = 7.2 Hz, 1H), 6.21 (m 2H), 5.10 – 4.58 (m, 3H), 3.95 (s, 3H), 3.61 (d, J = 29.3 Hz, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.81 (d, J = 9.7 Hz, 1H), 2.18 (s, 4H), 2.11 – 1.90 (m, 2H), 1.66 (d, J = 11.8 Hz, 1H). Example 37 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-4- methoxythiophene-2-carboxamide
Step 1: To a stirred solution of 4-methoxythiophene-2-carboxylic acid (32.0 mg, 0.20 mmol, 1 equiv) in DMF (1.5 mL) was added PyBOP (158.1 mg, 0.30 mmol, 1.5 equiv), DIEA (130.9 mg, 1.01 mmol, 5 equiv) and 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoro-methyl) sulfanyl]indolizin-8-amine (90 mg, 0.20 mmol, 1 equiv) at 0°C. The reaction solution was stirred at r.t. for 1 h. The resulting mixture was diluted with water (30 mL) and extracted with DCM (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 42% B to 62% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.57; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}-4-methoxythiophene-2-carboxamide (43.3 mg, 36.54%) as an off-white solid. LC-MS: (M+H)+ found 585.30.1H NMR (400 MHz, DMSO-d6) 9.39 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (d, J = 0.9 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 6.98-6.81 (m, 2H), 6.23 (dd, J = 23.1, 7.9 Hz, 2H), 4.96- 4.77 (m, 3H), 3.78 (s, 3H), 3.63 (d, J = 28.4 Hz, 1H), 3.04 (t, J = 11.1 Hz, 1H), 2.82 (d, J = 7.9 Hz, 1H), 2.19 (s, 4H), 2.07 (t, J = 10.8 Hz, 2H), 1.68 (d, J = 9.7 Hz, 1H). Example 38 – Preparation of 4-cyano-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl} thiophene-2-carboxamide
Attorney Docket No.50006-0109WO1 Step 1: To a stirred solution of 4-cyanothiophene-2-carboxylic acid (33 mg, 0.22 mmol, 1.2 equiv), 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]-3-[(trifluoromethyl) sulfanyl]indolizin-8-amine (80 mg, 0.18 mmol, 1 equiv), and DIEA (0.16 mL, 0.90 mmol, 5 equiv) in DMF (1 mL) was added PyBOP (112 mg, 0.22mmol, 1.2 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature, then diluted with EtOAc (20 mL) and washed with brine (3*20 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH=10:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 38% B to 63% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.7) to afford 4-cyano-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl} thiophene-2-carboxamide (36.2 mg, 34.70%) as a light yellow solid. LC-MS: (M+H)+ found 580.00.1H NMR (400 MHz, DMSO-d6) δ 9.70 (t, J = 5.7 Hz, 1H), 8.80 (d, J = 1.3 Hz, 1H), 8.18 (d, J = 1.3 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.27 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 4.97 – 4.78 (m, 3H), 3.63 (d, J = 28.9 Hz, 1H), 3.04 (t, J = 11.0 Hz, 1H), 2.92 – 2.78 (m, 1H), 2.19 (s, 4H), 2.12 – 1.97 (m, 2H), 1.68 (d, J = 9.5 Hz, 1H). Example 39 – Preparation of 5-cyano-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}thiophene-2-carboxamide
Attorney Docket No.50006-0109WO1 Step 1: To a stirred solution of 5-cyanothiophene-2-carboxylic acid (31.0 mg, 0.20 mmol, 1 equiv) in DMF (1.5 mL) was added PyBOP (126.5 mg, 0.24 mmol, 1.2 equiv), DIEA (130.9 mg, 1.01 mmol, 5 equiv) and 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoro-methyl) sulfanyl]indolizin-8-amine (90 mg, 0.20 mmol, 1 equiv) at 0°C. The reaction solution was stirred at r.t. for 1 h. The resulting solution was diluted with water (30 mL) and extracted with DCM (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 42% B to 62% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.73; Number Of Runs: 2) to afford 5-cyano-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}thiophene-2-carboxamide (37.5 mg, 31.63%) as a yellow solid. LC-MS: (M+H)+ found 580.30.1H NMR (400 MHz, DMSO-d6) 9.85 (t, J = 5.6 Hz, 1H), 8.07-7.99 (m, 2H), 7.95 (d, J = 4.1 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 23.5, 7.9 Hz, 2H), 4.94- 4.73 (m, 3H), 3.62 (d, J = 28.1 Hz, 1H), 3.04 (t, J = 11.0 Hz, 1H), 2.83 (d, J = 8.4 Hz, 1H), 2.19 (s, 4H), 2.07 (t, J = 11.6 Hz, 2H), 1.68 (d, J = 10.3 Hz, 1H). Example 41 – Preparation of 3-(difluoromethoxy)-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}thiophene-2-carboxamide
Attorney Docket No.50006-0109WO1 Step 1: To a stirred solution of 3-(difluoromethoxy)thiophene-2-carboxylic acid (48.1 mg, 0.25 mmol, 1.1 equiv), PyBOP (140.5 mg, 0.27 mmol, 1.2 equiv) and DIEA (0.20 mL, 1.13 mmol, 5 equiv) in DMF (1 mL) was added 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl) sulfanyl]indolizin-8-amine (100 mg, 0.23 mmol, 1 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature. The reaction was quenched by the addition of water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 42% B to 67% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.62) to afford 3-(difluoromethoxy)-N-{[3-(8- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)- 1,2,4-oxadiazol-5-yl]methyl}thiophene-2-carboxamide (32.4 mg, 23.18%) as a white solid. LC- MS: (M+H)+ found 621.00.1H NMR (400 MHz, DMSO-d6) δ 8.52 (t, J = 5.8 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.90 (d, J = 5.5 Hz, 1H), 7.76 (d, J = 0.9 Hz, 1H), 7.54 – 7.16 (m, 2H), 6.85 (t, J = 7.3 Hz, 1H), 6.27 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.94 – 4.74 (m, 3H), 3.63 (d, J = 29.1 Hz, 1H), 3.04 (t, J = 11.2 Hz, 1H), 2.83 (d, J = 7.5 Hz, 1H), 2.19 (s, 4H), 2.15 – 1.99 (m, 2H), 1.68 (d, J = 10.4 Hz, 1H). Example 44 – Preparation of tert-butyl N-{1-[2-({[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}carbamoyl)eth-1-yn-1-yl]cyclopropyl}carbamate
Attorney Docket No.50006-0109WO1 Step 1: A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (80 mg, 0.18 mmol, 1 equiv), 3-{1-[(tert-butoxycarbonyl) amino]cyclopropyl}prop-2-ynoic acid (40.5 mg, 0.18 mmol, 1 equiv), PyBOP (121.8 mg, 0.23 mmol, 1.3 equiv) and DIEA (116.3 mg, 0.90 mmol, 5 equiv) in DMF (1 mL) was stirred for 1 h at r.t.. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 41% B to 66% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.68) to afford tert-butyl N-{1-[2-({[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}carbamoyl)eth-1-yn-1- yl]cyclopropyl}carbamate (14.1 mg, 11.77%) as a white solid. LC-MS: (M+H)+ found 652.30.1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.76 (d, J = 18.5 Hz, 2H), 6.85 (t, J = 7.2 Hz, 1H), 6.31 (d, J = 7.9 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.97 – 4.76 (m, 1H), 4.66 (d, J = 5.8 Hz, 2H), 3.63 (d, J = 28.8 Hz, 1H), 3.05 (t, J = 10.9 Hz, 1H), 2.84 (d, J = 7.0 Hz, 1H), 2.20 (s, 4H), 2.08 (t, J = 9.4 Hz, 2H), 1.70 (s, 1H), 1.39 (s, 9H), 1.24 – 1.16 (m, 2H), 1.14 – 1.06 (m, 2H). Example 56 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-5-(2H- pyrazol-3-yl)thiophene-2-carboxamide
Attorney Docket No.50006-0109WO1 Step 1: A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (100 mg, 0.23 mmol, 1 equiv) in DMF (1.2 mL) was treated with DIEA (203.6 mg, 1.58 mmol, 7 equiv) and PyBOP (175.6 mg, 0.34 mmol, 1.5 equiv) for 2 min at 0 °C followed by the addition of 5-(2H-pyrazol-3- yl)thiophene-2-carboxylic acid (30.6 mg, 0.16 mmol, 0.7 equiv). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3) +0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 34% B to 58% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.77) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-5-(2H-pyrazol-3- yl)thiophene-2-carboxamide (40.5 mg, 29.00%) as an off-white solid. LC-MS: (M+H)+ found 621.10.1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 9.40 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.85 – 7.75 (m, 3H), 7.45 (d, J = 3.9 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.71 (t, J = 2.1 Hz, 1H), 6.24 (dd, J = 29.1, 7.9 Hz, 2H), 4.96 – 4.75 (m, 3H), 3.62 (d, J = 28.7 Hz, 1H), 3.04 (t, J = 11.0 Hz, 1H), 2.82 (d, J = 7.6 Hz, 1H), 2.19 (s, 4H), 2.13 – 1.98 (m, 2H), 1.68 (d, J = 10.7 Hz, 1H). Example 59 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}acetamide
Attorney Docket No.50006-0109WO1 Step 1: To a stirred mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (70 mg, 0.16 mmol, 1 equiv) in DCM (0.7 mL) were added TEA (0.04 mL, 0.31 mmol, 2 equiv) and acetic anhydride (48.2 mg, 0.47 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred for 1 h at 0°C. The resulting solution was diluted with EA (30 mL) and washed with sat.NaHCO3 (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 28% B to 53% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.5) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}acetamide (29.6 mg, 38.21%) as a light yellow solid. LCMS: (M+H)+ found 487.15. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.78 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.24 (dd, J = 28.5, 7.8 Hz, 2H), 4.87 (d, J = 49.7 Hz, 1H), 4.62 (d, J = 5.7 Hz, 2H), 3.63 (d, J = 29.2 Hz, 1H), 3.05 (t, J = 11.2 Hz, 1H), 2.84 (d, J = 7.1 Hz, 1H), 2.20 (s, 4H), 2.09 (d, J = 8.6 Hz, 2H), 1.93 (s, 3H), 1.70 (d, J = 8.7 Hz, 1H). Example 10 – Preparation of 3,3-difluoro-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}cyclobutane-1-carboxamide
Attorney Docket No.50006-0109WO1 Step 1: To a stirred mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (2.00 mL) were added PyBOP (81.1 mg, 0.15 mmol, 1.50 equiv), DIEA (134.4 mg, 1.04 mmol, 10.00 equiv) and 3,3-difluorocyclobutane-1-carboxylic acid (17.0 mg, 0.12 mmol, 1.20 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 35% B in 7 min; Wave Length: 254nm/220nm; RT(min): 6.3). This resulted in 3,3-difluoro-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}cyclobutane-1-carboxamide (FA salt; 17.5 mg, 29.4%) as a light yellow solid. LC-MS: (M+H)+ found 563.10.1H NMR (400 MHz, DMSO-d6) δ 8.98 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 7.6 Hz, 1H), 4.87 (d, J = 48.0 Hz, 1H), 4.68 (d, J = 5.7 Hz, 2H), 3.75-3.58 (m, 1H), 3.08-2.96 (m, 2H), 2.84 (s, 1H), 2.81-2.70 (m, 4H), 2.21 (s, 4H), 2.13-2.03 (m, 2H), 1.70 (d, J = 11.0 Hz, 1H). Example 15 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3,3- dimethyl-2-oxo-1H-indole-5-carboxamide
Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), 3,3-dimethyl-2-oxo-1H-indole-5-carboxylic acid (23.1 mg, 0.11 mmol, 1 equiv), PyBOP (70.3 mg, 0.13 mmol, 1.2 equiv), and DIEA (87.2 mg, 0.67 mmol, 6 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (50mL) and washed with brine (2*50mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 55% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.47; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-dimethyl-2-oxo-1H- indole-5-carboxamide (41.9 mg, 58.73%) as a white solid. LC-MS: (M+H)+ found 632.35. 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.25 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.84 – 7.72 (m, 2H), 6.94 (d, J = 8.1 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 8.0 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 4.98 – 4.71 (m, 3H), 3.62 (d, J = 27.7 Hz, 1H), 3.04 (t, J = 11.2 Hz, 1H), 2.82 (d, J = 8.4 Hz, 1H), 2.19 (s, 4H), 2.13 – 2.03 (m, 2H), 1.69 (s, 1H), 1.29 (s, 6H). Example 21 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-5- methoxy-1H-indazole-3-carboxamide
Attorney Docket No.50006-0109WO1 To a solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl) sulfanyl] indolizin-8-amine hydrochloride (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (1.00 mL) were added 5-methoxy-1H-indazole-3-carboxylic acid 5 (21.6 mg, 0.11 mmol, 1.00 equiv), DIEA (145.4 mg, 1.12 mmol, 10.00 equiv) and PyBOP (87.8 mg, 0.17 mmol, 1.50 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: MeOH; Flow rate: 25 mL/min; Gradient: 58% B to 83% B in 10min; Wave Length: 254nm/220nm; RT(min): 9.73; Number Of Runs: 3). This resulted in N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-5-methoxy-1H-indazole- 3-carboxamide (17.7 mg, 24.54%) as a white solid. LC-MS: (M+H)+ found 619.35.1H NMR (400 MHz, DMSO-d6) δ 13.64 (s, 1H), 9.20 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.78-7.73 (m, 1H), 7.59-7.51 (m, 2H), 7.08 (dd, J = 9.0, 2.5 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 8.1 Hz, 1H), 6.19 (d, J = 7.6 Hz, 1H), 5.10-4.46 (m, 3H), 3.79 (s, 3H), 3.40 (d, J = 11.2 Hz, 1H), 3.01 (d, J = 11.2 Hz, 1H), 2.81 (d, J = 8.6 Hz, 1H), 2.38-2.18 (m, 4H), 2.17-1.85 (m, 2H), 1.66 (d, J = 10.4 Hz, 1H). Example 22 – Preparation of tert-butyl N-[1-({[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}carbamoyl)cyclopropyl]carbamate
Attorney Docket No.50006-0109WO1 To a stirred mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (2.00 mL) were added PyBOP (81.1 mg, 0.15 mmol, 1.50 equiv), DIEA (134.4 mg, 1.0 mmol, 10.00 equiv) and 1-[(tert-butoxycarbonyl)amino]cyclopropane-1-carboxylic acid (25.1 mg, 0.12 mmol, 1.20 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 22% B to35% B in 7 min; Wave Length: 254nm/220nm; RT(min): 6.9). This resulted in tert-butyl N-[1-({[3-(8-{[(3S,4R)- 3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4- oxadiazol-5-yl]methyl}carbamoyl)cyclopropyl]carbamate (FA salt; 14.2 mg, 21.1%) as a light yellow solid. LC-MS: (M+H)+ found 628.15.1H NMR (400 MHz, DMSO-d6) δ 8.82-8.50 (m, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.77 (s, 1H), 7.49-7.19 (m, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.35-6.13 (m, 2H), 4.88 (d, J = 49.6 Hz, 1H), 4.64 (d, J = 5.7 Hz, 2H), 3.75 (s, 1H), 3.06 (t, J = 10.8 Hz, 1H), 2.85 (d, J = 9.2 Hz, 1H), 2.38-2.20 (m, 4H), 2.19-2.00 (m, 2H), 1.75-1.67 (m, 1H), 1.39 (d, J = 10.0 Hz, 9H), 1.27 (m, 2H), 0.94 (m, 2H). Example 24 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl] methyl}-1- hydroxycyclopropane-1-carboxamide
Attorney Docket No.50006-0109WO1 To a solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl) sulfanyl] indolizin-8-amine hydrochloride (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (2.00 mL) were added 1-hydroxycyclopropane-1-carboxylic acid (10.6 mg, 0.10 mmol, 1.00 equiv), PyBOP (81.2 mg, 0.15 mmol, 1.50 equiv) and DIEA (134.4 mg, 1.04 mmol, 10.00 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 55% B in 7min; Wave Length: 254nm/220nm; RT(min): 7.23). This resulted in N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl] methyl}-1-hydroxycyclopropane-1-carboxamide (22.3 mg, 40.26%) as a white solid. LC-MS: (M+H)+ found 529.15.1H NMR (400 MHz, DMSO-d6) δ 8.78 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.78 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.39 (s, 1H), 6.27 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 7.6 Hz, 1H), 4.87 (d, J = 49.4 Hz, 1H), 4.68 (d, J = 5.9 Hz, 2H), 3.63 (d, J = 28.1 Hz, 1H), 3.05 (t, J = 11.0 Hz, 1H), 2.83 (s, 1H), 2.35-2.19 (m, 4H), 2.18- 1.98 (m, 2H), 1.80-1.62 (m, 1H), 1.11-1.00 (m, 2H), 0.91-0.88 (m, 2H). Example 25 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}oxetane- 3-carboxamide
Attorney Docket No.50006-0109WO1 To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (40 mg, 0.09 mmol, 1 equiv), DIEA (0.05 mL, 0.27 mmol, 3 equiv) and oxetane-3-carboxylic acid (9.2 mg, 0.09 mmol, 1 equiv) in DMF (1 mL) was added PyBOP (60.9 mg, 0.12 mmol, 1.3 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with water (30 mL) and extracted with DCM (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 27% B to 54% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.27) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}oxetane-3-carboxamide (8.2 mg, 16.98%) as a light yellow solid. LCMS: (M+H)+ found 529.15. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 0.9 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.24 (dd, J = 21.2, 7.8 Hz, 2H), 4.87 (d, J = 49.5 Hz, 1H), 4.73 – 4.56 (m, 6H), 3.86 (tt, J = 8.5, 6.6 Hz, 1H), 3.63 (d, J = 28.7 Hz, 1H), 3.06 (dt, J = 12.2, 6.5 Hz, 1H), 2.84 (d, J = 7.9 Hz, 1H), 2.30 – 2.20 (m, 4H), 2.14 – 2.00 (m, 2H), 1.70 (d, J = 9.7 Hz, 1H). Example 26 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1- methoxycyclopropane-1-carboxamide
Attorney Docket No.50006-0109WO1 To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv) in DMF (1.5 mL) was added 1-methoxycyclopropane-1-carboxylic acid (19.6 mg, 0.17 mmol, 1.5 equiv), DIEA (72.7 mg, 0.56 mmol, 5 equiv) and PyBOP (87.8 mg, 0.17 mmol, 1.5 equiv) at 0°C. The reaction solution was stirred at room temperature for 1 h. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 37% B to 60% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.67; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}-1-methoxycyclopropane-1-carboxamide (24.9 mg, 40.47%) as an off-white solid. LC- MS: (M+H)+ found 543.15.1H NMR (400 MHz, DMSO-d6) 8.94 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 16.0, 7.9 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.70 (d, J = 5.9 Hz, 2H), 3.63 (d, J = 28.3 Hz, 1H), 3.34 (s, 3H), 3.05 (t, J = 11.1 Hz, 1H), 2.84 (d, J = 8.0 Hz, 1H), 2.20 (s, 4H), 2.08 (t, J = 10.9 Hz, 2H), 1.70 (d, J = 9.5 Hz, 1H), 1.08 (m, 4H). Example 28 – Preparation of 1-cyano-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}cyclopropane-1-carboxamide
Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv) in DMF (1.5 mL) was treated with DIEA (72.7 mg, 0.56 mmol, 5 equiv) and PyBOP (87.8 mg, 0.17 mmol, 1.5 equiv) for 2 min at 0 °C followed by the addition of 1-cyanocyclopropane-1- carboxylic acid (12.5 mg, 0.11 mmol, 1 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resultingsolution was diluted with water (30 mL) and extracted with DCM (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 35% B to 60% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.78) to afford 1-cyano-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}cyclopropane-1- carboxamide (18.4 mg, 30.43%) as an off-white solid. LC-MS: (M+H)+ found 538.35. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.78 (s, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.25 (dd, J = 30.1, 7.9 Hz, 2H), 4.87 (d, J = 49.5 Hz, 1H), 4.68 (d, J = 5.5 Hz, 2H), 3.63 (d, J = 30.6 Hz, 1H), 3.05 (t, J = 11.2 Hz, 1H), 2.84 (d, J = 6.7 Hz, 1H), 2.30 (d, J = 13.1 Hz, 1H), 2.20 (s, 3H), 2.14 – 2.01 (m, 2H), 1.68 (m, 3H), 1.56 (m, 2H). Example 35 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-6- methoxy-1-methylindole-2-carboxamide
Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (60 mg, 0.14 mmol, 1 equiv), 6-methoxy-1-methylindole-2-carboxylic acid (30.5 mg, 0.15 mmol, 1.1 equiv), PyBOP (84.3 mg, 0.16 mmol, 1.2 equiv) and DIEA (87.2 mg, 0.68 mmol, 5 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (15 mL) and washed with brine (4*10 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2/MeOH=20:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 45% B to 70% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.8) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-6-methoxy-1- methylindole-2-carboxamide (23.7 mg, 27.65%) as a off-white solid. LC-MS: (M+H)+found 632.15.1H NMR (400 MHz, DMSO-d6) δ 9.26 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.78 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.20 (s, 1H), 7.04 (d, J = 2.2 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.77 (dd, J = 8.7, 2.2 Hz, 1H), 6.26 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 4.97 – 4.74 (m, 3H), 3.98 (s, 3H), 3.84 (s, 3H), 3.62 (d, J = 28.4 Hz, 1H), 3.04 (t, J = 11.5 Hz, 1H), 2.81 (s, 1H), 2.19 (s, 4H), 2.06 (t, J = 11.4 Hz, 2H), 1.68 (d, J = 10.3 Hz, 1H). Example 36 – Preparation of 4-fluoro-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl} oxane- 4-carboxamide
Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (70 mg, 0.16 mmol, 1 equiv), PyBOP (98.4 mg, 0.19 mmol, 1.2 equiv), DIEA (0.14 mL, 0.79 mmol, 5 equiv) and 4- fluorooxane-4-carboxylic acid (25.7 mg, 0.17 mmol, 1.1 equiv) in DMF (0.7 mL) was stirred for 0.5 h at room temperature. The solution was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 35% B to 60% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.2) to afford 4-fluoro-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl} oxane-4-carboxamide (17.7 mg, 19.34%) as a white solid. LC-MS: (M+H)+ found 575.15.1H NMR (400 MHz, DMSO- d6) δ 9.09 (td, J = 5.8, 2.4 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 14.8, 7.9 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.69 (d, J = 5.7 Hz, 2H), 3.83 (m, 2H), 3.59 (td, J = 11.8, 2.3 Hz, 3H), 3.05 (t, J = 11.0 Hz, 1H), 2.84 (d, J = 10.1 Hz, 1H), 2.20 (s, 4H), 2.18 – 1.97 (m, 4H), 1.83 – 1.64 (m, 3H). Example 40 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1,3- benzothiazole-6-carboxamide
Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), 1,3-benzothiazole-6-carboxylic acid (22.2 mg, 0.12 mmol, 1.1 equiv), PyBOP (70.3 mg, 0.13 mmol, 1.2 equiv) and DIEA (72.7 mg, 0.56 mmol, 5 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 15:1) and Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 37% B to 60% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.67; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1,3-benzothiazole-6- carboxamide (18.0 mg, 26.42%) as a light yellow solid. LC-MS: (M+H)+ found 606.05.1H NMR (400 MHz, DMSO-d6) δ 9.58 (d, J = 7.8 Hz, 2H), 8.76 (d, J = 1.7 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.09 (m, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.77 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 8.0 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.98 – 4.73 (m, 3H), 3.62 (d, J = 28.2 Hz, 1H), 3.05 (d, J = 11.2 Hz, 1H), 2.82 (d, J = 8.8 Hz, 1H), 2.19 (s, 4H), 2.05 (t, J = 11.4 Hz, 2H), 1.67 (d, J = 11.0 Hz, 1H). Example 42 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-4- methanesulfonylbenzamide
Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (60 mg, 0.14 mmol, 1 equiv), P-methylsulfonylbenzoic acid (29.7 mg, 0.15 mmol, 1.1 equiv), PyBOP (84.3 mg, 0.16 mmol, 1.2 equiv) and DIEA (87.2 mg, 0.68 mmol, 5 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (15 mL) and washed with brine (4*10 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 /MeOH=20:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 34% B to 59% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.6) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-4- methanesulfonylbenzamide (21.6 mg, 25.41%) as a off-white solid. LC-MS: (M+H)+found 627.05. 1H NMR (400 MHz, DMSO-d6) δ 9.72 (t, J = 5.6 Hz, 1H), 8.21 – 8.13 (m, 2H), 8.13 – 8.06 (m, 2H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.27 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 4.97 – 4.72 (m, 3H), 3.71 – 3.54 (m, 1H), 3.29 (s, 3H), 3.04 (t, J = 11.4 Hz, 1H), 2.82 (d, J = 7.5 Hz, 1H), 2.19 (s, 4H), 2.06 (t, J = 11.2 Hz, 2H), 1.68 (d, J = 10.3 Hz, 1H). Example 45 – Preparation of tert-butyl N-[3-({[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}carbamoyl)bicyclo[1.1.1]pentan-1-yl]carbamate
Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (80 mg, 0.18 mmol, 1 equiv), 3-[(tert-butoxycarbonyl) amino]bicyclo[1.1.1]pentane-1-carboxylic acid (40.9 mg, 0.18 mmol, 1 equiv), PyBOP (112.4 mg, 0.22 mmol, 1.2 equiv) and DIEA (116.3 mg, 0.90 mmol, 5 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with water (30 mL) and extracted with DCM (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 60% B to 83% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.27) to afford tert-butyl N-[3-({[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}carbamoyl)bicyclo[1.1.1]pentan-1-yl]carbamate (16.5 mg, 13.69%) as a white solid. LC-MS: (M+H)+ found 654.45.1H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 5.8 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.77 (s, 1H), 7.60 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.24 (dd, J = 19.7, 7.8 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.61 (d, J = 5.7 Hz, 2H), 3.63 (d, J = 29.8 Hz, 1H), 3.05 (t, J = 11.2 Hz, 1H), 2.83 (s, 1H), 2.20 (s, 4H), 2.11 (s, 8H), 1.70 (d, J = 9.3 Hz, 1H), 1.38 (s, 9H). Example 46 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1-(4- fluorophenyl)cyclopropane-1-carboxamide
Attorney Docket No.50006-0109WO1 To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (90 mg, 0.20 mmol, 1 equiv), PyBOP (126.5 mg, 0.24 mmol, 1.2 equiv) and DIEA (130.9 mg, 1.01 mmol, 5 equiv) in DMF (1.0 mL) was added 1-(4-fluorophenyl)cyclopropane-1-carboxylic acid (40.1 mg, 0.22 mmol, 1.1 equiv) at 0°C. The resulting solution was stirred for 0.5 h at room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 47% B to 74% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.02) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1-(4- fluorophenyl)cyclopropane-1-carboxamide (40.4 mg, 32.46%) as a white solid. LC-MS: (M+H)+ found 607.15.1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 6.8 Hz, 1H), 7.76 (d, J = 0.9 Hz, 1H), 7.67 (t, J = 5.7 Hz, 1H), 7.48 – 7.41 (m, 2H), 7.25 – 7.17 (m, 2H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 13.6, 7.9 Hz, 2H), 4.87 (d, J = 49.5 Hz, 1H), 4.54 (d, J = 5.7 Hz, 2H), 3.64 (d, J = 28.8 Hz, 1H), 3.05 (t, J = 11.1 Hz, 1H), 2.88 – 2.78 (m, 1H), 2.20 (s, 4H), 2.08 (t, J = 11.1 Hz, 2H), 1.70 (d, J = 9.7 Hz, 1H), 1.40 (m, 2H), 1.05 (m, 2H). Example 47 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl] methyl}-1- (trifluoromethyl)cyclopropane-1-carboxamide
Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (70 mg, 0.16 mmol, 1 equiv), 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (24.3 mg, 0.16 mmol, 1 equiv), PyBOP (98.4 mg, 0.19 mmol, 1.2 equiv) and DIEA (101.8 mg, 0.79 mmol, 5 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 44% B to 68% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.25) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl] methyl}-1- (trifluoromethyl)cyclopropane-1-carboxamide (35.5 mg, 38.67%) as a white solid. LC-MS: (M+H)+ found 581.30.1H NMR (400 MHz, DMSO-d6) δ 8.65 (t, J = 5.5 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 0.9 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 18.6, 7.8 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.66 (d, J = 5.6 Hz, 2H), 3.64 (d, J = 28.9 Hz, 1H), 3.05 (t, J = 11.2 Hz, 1H), 2.84 (d, J = 7.6 Hz, 1H), 2.20 (s, 4H), 2.08 (t, J = 10.8 Hz, 2H), 1.70 (d, J = 9.8 Hz, 1H), 1.38 (d, J = 7.5 Hz, 2H), 1.36 – 1.27 (m, 2H). Example 49 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2- hydroxy-2-methylpropanamide
Attorney Docket No.50006-0109WO1 To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (80 mg, 0.18 mmol, 1 equiv) in anhydrous DMF (1 mL) was added acetonate (28.1 mg, 0.27 mmol, 1.5 equiv), PyBOP (140.5 mg, 0.27 mmol, 1.5 equiv) and DIEA (116.3 mg, 0.90 mmol, 5 equiv) at 0°C. The reaction solution was stirred at room temperature for 1 h at room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 31% B to 56% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.18) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2-hydroxy-2- methylpropanamide (42.1 mg, 42.67%) as a yellow solid. LC-MS: (M+H)+ found 531.40.1H NMR (400 MHz, DMSO-d6) 8.55 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.76 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.22 (t, J = 8.8 Hz, 2H), 5.53 (s, 1H), 4.87 (d, J = 49.5 Hz, 1H), 4.63 (d, J = 5.9 Hz, 2H), 3.63 (d, J = 28.3 Hz, 1H), 3.05 (t, J = 11.1 Hz, 1H), 2.83 (d, J = 7.8 Hz, 1H), 2.20 (s, 4H), 2.08 (t, J = 11.0 Hz, 2H), 1.70 (d, J = 9.6 Hz, 1H), 1.30 (s, 6H). Example 57 – Preparation of N1-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-N4- methylbenzene-1,4-dicarboxamide
Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), 4-(methylcarbamoyl)benzoic acid (22.2 mg, 0.12 mmol, 1.1 equiv), PyBOP (70.3 mg, 0.13 mmol, 1.2 equiv) and DIEA (72.7 mg, 0.56 mmol, 5 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 15:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 31% B to 56% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.23) to afford N1-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-N4-methylbenzene-1,4- dicarboxamide (15.7 mg, 23.04%) as a white solid. LC-MS: (M+H)+ found 606.15.1H NMR (400 MHz, DMSO-d6) δ 9.54 (t, J = 5.6 Hz, 1H), 8.60 (d, J = 4.7 Hz, 1H), 8.16 – 7.83 (m, 5H), 7.77 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 5.00 – 4.71 (m, 3H), 3.62 (d, J = 29.4 Hz, 1H), 3.04 (t, J = 11.4 Hz, 1H), 2.81 (d, J = 4.5 Hz, 4H), 2.19 (s, 4H), 2.14 – 1.97 (m, 2H), 1.68 (d, J = 9.9 Hz, 1H). Example 58 – Preparation of N1-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-N3- methylbenzene-1,3-dicarboxamide
Attorney Docket No.50006-0109WO1 Step 1: A mixture of isophthalic acid, methyl ester (1 g, 5.55 mmol, 1 equiv), HATU (3.2 g, 8.32 mmol, 1.5 equiv) CH3NH2.HCl (0.5 g, 6.66 mmol, 1.2 equiv) and DIEA (2.9 g, 22.20 mmol, 4 equiv) in DMF (5 mL) was stirred for 1 h at room temperature. The resulting solution was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0 to 100% gradient in 20 min; detector, UV 254 nm) to afford methyl 3- (methylcarbamoyl)benzoate (1 g, 93.25%) as a off-white solid. LC-MS: (M+H)+ found 193.2. Step 2: A mixture of methyl 3-(methylcarbamoyl)benzoate (1 g, 5.18 mmol, 1 equiv) and NaOH (2.1 g, 51.76 mmol, 10 equiv) in H2O (10 mL)/MeOH (20 mL) was stirred for 2 h at room temperature. The resulting mixture was diluted with water (50 mL) and acidified to pH 2 with 1M HCl. The aqueous layer was extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-(methylcarbamoyl)benzoic acid (820 mg, 88.42%) as a off-white solid. LC-MS: (M+H)+ found 179.1. Step 3: A mixture of 3-(methylcarbamoyl)benzoic acid (24.2 mg, 0.13 mmol, 1.2 equiv), 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3- [(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1.00 equiv), PyBOP (87.8 mg, 0.17 mmol, 1.5 equiv) and DIEA (72.7 mg, 0.56 mmol, 5 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting solution was purified by Prep-TLC (CH2Cl2 / MeOH 10:1) and Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 55% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.75; Number Of Runs: 2) to afford N1-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-N3-methylbenzene-1,3- dicarboxamide (15.6 mg, 22.90%) as a yellow solid. LC-MS: (M+H)+ found 606.15.1H NMR (400
Attorney Docket No.50006-0109WO1 MHz, DMSO-d6) δ 9.55 (t, J = 5.6 Hz, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.39 (d, J = 1.9 Hz, 1H), 8.12 – 7.92 (m, 3H), 7.76 (s, 1H), 7.61 (t, J = 7.7 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.96 – 4.73 (m, 3H), 3.62 (d, J = 28.7 Hz, 1H), 3.04 (t, J = 11.1 Hz, 1H), 2.80 (d, J = 4.5 Hz, 4H), 2.19 (s, 4H), 2.06 (t, J = 11.5 Hz, 2H), 1.68 (d, J = 10.4 Hz, 1H). Example 60 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2- methylpropanamide A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (100 mg, 0.23 mmol, 1 equiv) in DMF (1.5 mL) was treated with DIEA (145.4 mg, 1.13 mmol, 5 equiv) and PyBOP (175.6 mg, 0.34 mmol, 1.5 equiv) for 2 min at 0 °C followed by the addition of isobutyric acid (19.8 mg, 0.23 mmol, 1 equiv). The resulting solution was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 35% B to 60% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.78) to afford N-{[3- (8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl)-1,2,4-oxadiazol-5-yl]methyl}-2-methylpropanamide (28.3 mg, 24.45%) as an off-white solid. LC-MS: (M+H)+ found 515.35.1H NMR (400 MHz, DMSO-d6) δ 8.67 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 0.9 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 16.8, 7.8 Hz, 2H), 4.87 (d, J = 49.5 Hz, 1H), 4.62 (d, J = 5.7 Hz, 2H), 3.63 (d, J = 29.3 Hz, 1H), 3.05 (t, J = 11.3 Hz, 1H), 2.83 (s, 1H), 2.50 – 2.42 (m, 1H), 2.20 (s, 4H), 2.16 – 2.00 (m, 2H), 1.70 (d, J = 10.4 Hz, 1H), 1.06 (d, J = 6.8 Hz, 6H).
Attorney Docket No.50006-0109WO1 Example 61 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2- methoxy-2-methylpropanamide A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), 2-methoxy-2-methylpropanoic acid (13.3 mg, 0.11 mmol, 1 equiv), pybop (76.1 mg, 0.15mmol, 1.3 equiv) and DIEA (0.06 mL, 0.34 mmol, 3 equiv) in DMF (1 mL) was stirred for 1 at room temperature. The resultingsolution was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 37% B to 60% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.13; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2-methoxy-2- methylpropanamide (18.1 mg, 29.49%) as a light yellow solid. LCMS: (M+H)+ found 545.20.1H NMR (400 MHz, DMSO-d6) δ 8.68 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 12.2, 7.9 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.64 (d, J = 5.9 Hz, 2H), 3.64 (d, J = 28.1 Hz, 1H), 3.23 (s, 3H), 3.05 (t, J = 11.1 Hz, 1H), 2.84 (d, J = 7.7 Hz, 1H), 2.30 (d, J = 13.2 Hz, 1H), 2.20 (s, 3H), 2.13 – 2.01 (m, 2H), 1.70 (d, J = 9.7 Hz, 1H), 1.31 (s, 6H). Example 63 – Preparation of (3R)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3- hydroxybutanamide
Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (60 mg, 0.14 mmol, 1 equiv), (-)-3-hydroxybutyric acid (15.5 mg, 0.15 mmol, 1.1 equiv), PyBOP (84.3 mg, 0.16 mmol, 1.2 equiv) and DIEA (87.2 mg, 0.68 mmol, 5 equiv) in DMF (1 mL) was stirred for 30 min at room temperature. The resulting mixture was diluted with EtOAc (10 mL) and washed with brine (4*10 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 26% B to 53% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.37) to afford (3R)-N- {[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin- 2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3-hydroxybutanamide (16.5 mg, 22.65%) as a light yellow solid. LC-MS: (M+H)+found 531.15.1H NMR (400 MHz, DMSO-d6) δ 8.71 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.79 – 7.73 (m, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.22 (dd, J = 11.2, 7.9 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.75 – 4.55 (m, 3H), 4.00 (dt, J = 12.0, 6.2 Hz, 1H), 3.63 (d, J = 28.8 Hz, 1H), 3.05 (s, 1H), 2.83 (d, J = 8.0 Hz, 1H), 2.41 – 2.28 (m, 1H), 2.22 (d, J = 19.4 Hz, 5H), 2.16 – 1.99 (m, 2H), 1.70 (d, J = 9.9 Hz, 1H), 1.10 (d, J = 6.1 Hz, 3H). Example 64 – Preparation of (3S)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3- hydroxybutanamide
Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), (S)-3-hydroxybutanoic acid (14.1 mg, 0.13 mmol, 1.2 equiv), PyBOP (70.3 mg, 0.13 mmol, 1.2 equiv) and DIEA (72.7 mg, 0.56 mmol, 5 equiv) in DMF (1 mL) was stirred for 1 h at room temperature under. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 26% B to 50% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.75) to afford (3S)-N- {[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin- 2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3-hydroxybutanamide (19.6 mg, 32.84%) as a light yellow solid. LC-MS: (M+H)+ found 531.15.1H NMR (400 MHz, DMSO-d6) δ 8.71 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.22 (m, 2H), 4.86 (d, J = 49.3 Hz, 1H), 4.76 – 4.55 (m, 3H), 4.00 (m, 1H), 3.63 (d, J = 28.9 Hz, 1H), 3.05 (t, J = 11.2 Hz, 1H), 2.83 (d, J = 8.1 Hz, 1H), 2.34 (m, 1H), 2.22 (d, J = 19.5 Hz, 5H), 2.08 (t, J = 10.9 Hz, 2H), 1.70 (d, J = 9.6 Hz, 1H), 1.10 (d, J = 6.1 Hz, 3H). Example 65 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3- hydroxy-3-methylbutanamide
Attorney Docket No.50006-0109WO1 To a stirred mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), 3-hydroxyisovaleric acid (14.6 mg, 0.12 mmol, 1.1 equiv) and DIEA (72.7 mg, 0.56 mmol, 5 equiv) in DMF (1 mL) was added PyBOP (70.3 mg, 0.13 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 1h at room temperature. The resulting solution was diluted with EtOAc (30 mL) and washed with brine (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 31% B to 56% B in 8 min; Wave Length: 220nm nm; RT1(min): 6.98) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3-hydroxy-3- methylbutanamide (9.9 mg, 15.79%) as a white solid. LC-MS: (M+H)+ found 545.15. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.22 (t, J = 9.2 Hz, 2H), 4.87 (d, J = 49.5 Hz, 1H), 4.74 (s, 1H), 4.66 (d, J = 5.7 Hz, 2H), 3.64 (d, J = 29.7 Hz, 1H), 3.06 (t, J = 11.3 Hz, 1H), 2.84 (d, J = 8.5 Hz, 1H), 2.32 (s, 2H), 2.20 (s, 3H), 2.08 (t, J = 11.3 Hz, 2H), 1.70 (d, J = 10.5 Hz, 1H), 1.20 (s, 6H). Example 8 – Preparation of (1r,3r)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl] amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3- hydroxycyclobutane-1-carboxamide
Attorney Docket No.50006-0109WO1 To a solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl) sulfanyl] indolizin-8-amine hydrochloride (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (1.00 mL) were added trans-3-hydroxycyclobutanecarboxylic acid (12.8 mg, 0.01 mmol, 1.00 equiv), PyBOP (75.4 mg, 0.15 mmol, 1.50 equiv) and DIEA (124.9 mg, 0.97 mmol, 10.00 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 27% B to 52% B in 8 min; Wave Length: 220 nm; RT(min): 7.17). This resulted in (1r,3r)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3- [(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3-hydroxycyclobutane- 1-carboxamide (20.2 mg, 38.10%) as a white solid. LC-MS: (M+H)+ found 543.10.1H NMR (400 MHz, DMSO-d6) δ 8.64 (t, J = 5.8 Hz, 1H), 8.03 (d, J = 6.9 Hz, 1H), 7.76 (s, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.28-6.10 (m, 2H), 5.06 (d, J = 6.2 Hz, 1H), 4.92 (d, J = 49.0 Hz, 1H), 4.63 (d, J = 5.7 Hz, 2H), 4.26 (t, J = 6.8 Hz, 1H), 3.68 (d, J = 29.2 Hz, 1H), 3.28 (s, 1H), 2.98-2.87 (m, 2H), 2.42- 2.20 (m, 6H), 2.19-1.95 (m, 4H), 1.90-1.60 (m, 1H). Example 9 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2-(5- methoxy-1H-indazol-3-yl)acetamide
Attorney Docket No.50006-0109WO1 To a stirred mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine hydrochloride (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (2.0 mL) were added PyBOP (81.2 mg, 0.15 mmol, 1.50 equiv), DIEA (134.4 mg, 1.04 mmol, 10.00 equiv) and (5-methoxy-1H-indazol-3-yl)acetic acid (25.7 mg, 0.12 mmol, 1.20 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 60% B in 7min; Wave Length: 254 nm/220 nm; RT1(min): 7.68). This resulted in N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2-(5-methoxy-1H- indazol-3-yl)acetamide (28.5 mg, 43.0%) as an off-white solid. LC-MS: (M+H)+ found 633.20.1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 9.02 (t, J = 5.8 Hz, 1H), 8.03 (d, J = 6.9 Hz, 1H), 7.75 (d, J = 0.9 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 6.98 (dd, J = 9.0, 2.4 Hz, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.26-6.21 (m, 2H), 4.87 (d, J = 49.6 Hz, 1H), 4.69 (d, J = 5.7 Hz, 2H), 3.88 (s, 2H), 3.76 (s, 3H), 3.75-3.56 (m, 1H), 3.05 (t, J = 11.1 Hz, 1H), 2.84 (d, J = 7.4 Hz, 1H), 2.35-2.18 (m, 4H), 2.08 (t, J = 9.7 Hz, 2H), 1.71 (d, J = 9.4 Hz, 1H). Example 11 – Preparation of (2S)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl] methyl}-1,4- dioxane-2-carboxamide
Attorney Docket No.50006-0109WO1 To a solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] indolizin-8-amine hydrochloride (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (1.00 mL) were added (2S)-1,4-dioxane-2-carboxylic acid (13.7 mg, 0.10 mmol, 1.00 equiv), PyBOP (81.2 mg, 0.16 mmol, 1.50 equiv) and DIEA (134.4 mg, 1.04 mmol, 10.00 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 31% B to 57% B in 7min; Wave Length: 254nm/220nm; RT(min): 7.52). This resulted in (2S)-N- {[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl] methyl}-1,4-dioxane-2-carboxamide (11.6 mg, 19.94%) as a white solid. LC-MS: (M+H)+ found 559.10.1H NMR (400 MHz, DMSO-d6) δ 8.74 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.35-6.10 (m, 2H), 4.87 (d, J = 49.5 Hz, 1H), 4.73-4.58 (m, 2H), 4.16 (dd, J = 9.4, 3.1 Hz, 1H), 3.89 (td, J = 11.1, 10.7, 2.9 Hz, 2H), 3.76-3.65 (m, 3H), 3.62-3.42 (m, 2H), 3.05 (t, J = 11.2 Hz, 1H), 2.84 (d, J = 7.9 Hz, 1H), 2.40-2.18 (m, 4H), 2.17-2.02 (m, 2H), 1.70 (d, J = 9.4 Hz, 1H). Example 12 – Preparation of 2-(dimethylamino)-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}-1,3-oxazole-5-carboxamide
Attorney Docket No.50006-0109WO1 Step 1: A mixture of ethyl 2-amino-1,3-oxazole-5-carboxylate (400 mg, 2.56 mmol, 1 equiv), dimethylamine hydrochloride (626.7 mL, 7.69 mmol, 3 equiv) and K2CO3 (1.77 g, 12.81 mmol, 5 equiv) in ACN (10 mL) was stirred for 2 h at room temperature. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in ethyl 2-(dimethylamino)-1,3-oxazole-5-carboxylate (400 mg, 84.77%) as a light yellow oil. LC-MS: (M+H)+ found 185.1. Step 2: To a stirred mixture of ethyl 2-(dimethylamino)-1,3-oxazole-5-carboxylate (500 mg, 2.72 mmol, 1 equiv) in THF (2 mL)/H2O (2 mL) was added NaOH (108.6 mg, 2.72 mmol, 1 equiv) at 0°C. The resulting mixture was stirred for 2 h at room temperature, then acidified to pH 3 with 1 M HCl. The resulting solution was extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-(dimethylamino)-1,3-oxazole-5-carboxylic acid (400 mg, 94.37%) as an off-white solid. LC-MS: (M+H)+ found 157.1. Step 3: A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (60 mg, 0.14 mmol, 1.00 equiv), DIEA (122.1 mg, 0.95 mmol, 7 equiv), 2-(dimethylamino)-1,3-oxazole-5-carboxylic acid (42.2 mg, 0.27 mmol, 2 equiv) and PyBOP (105.4 mg, 0.20 mmol, 1.5 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (20 mL) and washed with briner (3*20 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 35% B to 60% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.78 ) to afford 2-
Attorney Docket No.50006-0109WO1 (dimethylamino)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1,3-oxazole-5- carboxamide (26.6 mg, 33.82%) as a off-white solid. LC-MS: (M+H)+ found 583.20. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (t, J = 5.8 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.79 – 7.74 (m, 1H), 7.53 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.28 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 4.98 – 4.68 (m, 3H), 3.62 (d, J = 29.0 Hz, 1H), 3.07 (s, 7H), 2.83 (d, J = 7.5 Hz, 1H), 2.19 (s, 4H), 2.07 (t, J = 10.2 Hz, 2H), 1.68 (d, J = 9.2 Hz, 1H). Example 29 – Preparation of (2R)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1,4- dioxane-2-carboxamide To a solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] indolizin-8-amine hydrochloride (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (1.00 mL) were added (2S)-1,4-dioxane-2-carboxylic acid (13.7 mg, 0.10 mmol, 1.00 equiv), PyBOP (81.2 mg, 0.16 mmol, 1.50 equiv) and DIEA (134.4 mg, 1.04 mmol, 10.00 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 31% B to 57% B in 7min; Wave Length: 254nm/220nm; RT(min): 7.52). This resulted in (2S)-N- {[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl] methyl}-1,4-dioxane-2-carboxamide (11.6 mg, 19.94%) as a white solid. LC-MS: (M+H)+ found 559.10.1H NMR (400 MHz, DMSO-d6) δ 8.74 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.35-6.10 (m, 2H), 4.87
Attorney Docket No.50006-0109WO1 (d, J = 49.5 Hz, 1H), 4.73-4.58 (m, 2H), 4.16 (dd, J = 9.4, 3.1 Hz, 1H), 3.89 (td, J = 11.1, 10.7, 2.9 Hz, 2H), 3.76-3.65 (m, 3H), 3.62-3.42 (m, 2H), 3.05 (t, J = 11.2 Hz, 1H), 2.84 (d, J = 7.9 Hz, 1H), 2.40-2.18 (m, 4H), 2.17-2.02 (m, 2H), 1.70 (d, J = 9.4 Hz, 1H). Example 29 – Preparation of 3-fluoro-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-5 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}bicyclo[1.1.1]pentane-1-carboxamide A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (17.6 mg, 0.13 mmol, 1.2 eq), DIEA (72.7 mg, 0.56 mmol, 5 equiv) and PyBOP (70.3 mg, 0.13 mmol, 1.2 equiv) in DMF (1.5 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (30 mL) and washed with brine (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 37% B to 60% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.52; Number Of Runs: 2) to afford 3-fluoro-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}bicyclo[1.1.1]pentane-1- carboxamide (19.6 mg, 31.02%) as a white solid. LC-MS: (M+H)+ found 557.15.1H NMR (400 MHz, DMSO-d6) δ 8.90 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.78 (s, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.24 (m, 2H), 4.87 (d, J = 49.3 Hz, 1H), 4.65 (d, J = 5.7 Hz, 2H), 3.64 (d, J = 29.0 Hz, 1H), 3.05 (t, J = 11.2 Hz, 1H), 2.84 (d, J = 8.1 Hz, 1H), 2.33 (d, J = 2.6 Hz, 7H), 2.20 (s, 3H), 2.14 – 2.00 (m, 2H), 1.70 (d, J = 9.7 Hz, 1H).
Attorney Docket No.50006-0109WO1 Example 62 – Preparation of (1s,3s)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3- hydroxycyclobutane-1-carboxamide To a stirred mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine hydrochloride (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (2.00 mL) were added PyBOP (81.2 mg, 0.15 mmol, 1.50 equiv), DIEA (134.4 mg, 1.04 mmol, 10.00 equiv) and (1s,3s)-3-hydroxycyclobutane-1-carboxylic acid (14.5 mg, 0.12 mmol, 1.20 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 52% B in 7min; Wave Length: 254nm/220nm; RT(min): 7.63). This resulted in (1s,3s)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3-hydroxycyclobutane- 1-carboxamide (14.9 mg, 25.9%) as an off-white solid. LC-MS: (M+H)+ found 543.15.1H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (s, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.32-6.16 (m, 2H), 5.15 (d, J = 6.9 Hz, 1H), 4.87 (d, J = 49.6 Hz, 1H), 4.62 (d, J = 5.7 Hz, 2H), 3.95 (m, 1H), 3.76-3.57 (m, 1H), 3.05 (t, J = 10.8 Hz, 1H), 2.84 (d, J = 7.7 Hz, 1H), 2.47-2.02 (m, 9H), 1.97 (m, 2H), 1.70 (d, J = 10.0 Hz, 1H). Example 66 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2- (morpholin-4-yl)-1,3-oxazole-5-carboxamide
Attorney Docket No.50006-0109WO1 Step 1: A mixture of ethyl 2-chloro-1,3-oxazole-5-carboxylate (500 mg, 2.85 mmol, 1 equiv), morpholine (496.2 mg, 5.69 mmol, 2 equiv) and K2CO3 (1.18 g, 8.54 mmol, 3 equiv) in MeCN (8 mL) was stirred at 80°C for 2 h. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was diluted with water (30 mL) and washed with brine (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford ethyl 2-(morpholin-4-yl)-1,3-oxazole-5-carboxylate (600 mg, 93.13%) as a yellow oil. LC-MS: (M+H)+ found 227.2. Step 2: To a stirred solution of ethyl 2-(morpholin-4-yl)-1,3-oxazole-5-carboxylate (590 mg, 2.61 mmol, 1 equiv) in THF (4 mL)/water (4 mL) was added NaOH (208.6 mg, 5.22 mmol, 2 equiv). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture concentrated under reduced pressure and then acidified to pH 6 with 1 M HCl. The precipitated solids were collected by filtration to afford 2-(morpholin-4-yl)-1,3-oxazole-5-carboxylic acid (500 mg, 96.74%) as an off-white solid. LC-MS: (M+H)+ found 199.0. Step 3: To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (55 mg, 0.12 mmol, 1 equiv) in DMF (1.5 mL) was added 2-(morpholin-4-yl)-1,3-oxazole-5-carboxylic acid (49.1 mg, 0.25 mmol, 2 equiv), PyBOP (96.6 mg, 0.19 mmol, 1.5 equiv) and DIEA (80.0 mg, 0.62 mmol, 5 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with EA (30 mL) and washed with brine (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 55% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.53) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-
Attorney Docket No.50006-0109WO1 [(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2-(morpholin-4-yl)-1,3- oxazole-5-carboxamide (24.5 mg, 31.19%) as an off-white solid. LC-MS: (M+H)+ found 625.35. 1H NMR (400 MHz, DMSO-d6)9.03 (t, J = 5.8 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (s, 1H), 7.57 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.27 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.94- 4.75 5 (m, 3H), 3.61 (dt, J = 66.7, 4.7 Hz, 9H), 3.05 (t, J = 11.3 Hz, 1H), 2.82 (s, 1H), 2.20 (s, 4H), 2.07 (t, J = 10.8 Hz, 2H), 1.69 (d, J = 9.9 Hz, 1H). Example 67 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}morpholine-4-carboxamide Step 1: To a stirred mixture of triphosgene (120.2 mg, 0.40 mmol, 1.2 equiv) in DCM (2 mL) was added 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl) sulfanyl] indolizin-8-amine (150 mg, 0.34 mmol, 1 equiv) and DIEA (174.5 mg, 1.35 mmol, 4 equiv) dropwise at 0°C. Then the resulting mixture was concentrated under reduced pressure. This resulted in N-[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]-2-[5-(isocyanatomethyl)-1,2,4-oxadiazol-3-yl]-3-[(trifluoromethyl)sulfanyl] indolizin-8- amine (100 mg, 62.98%) as a yellow solid. LC-MS: (M+H)+ found 471.1. Step 2: A solution of N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-2-[5- (isocyanatomethyl)-1,2,4-oxadiazol-3-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv) in DCM (1 mL) was treated with morpholine (18.5 mg, 0.21 mmol, 2 equiv) for 30 min at 0°C .The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7min; Wave Length: 254nm/220nm nm;25 RT1(min): 6.53; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-
Attorney Docket No.50006-0109WO1 yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}morpholine- 4-carboxamide (19.7 mg, 33.24%) as an off-white solid. LC-MS: (M+H)+ found 558.25.1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 6.8 Hz, 1H), 7.78 (d, J = 0.9 Hz, 1H), 7.52 (t, J = 5.5 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.24 (dd, J = 29.1, 7.8 Hz, 2H), 4.87 (d, J = 49.5 Hz, 1H), 4.58 (d, J 5 = 5.4 Hz, 2H), 3.75 – 3.53 (m, 5H), 3.32 (s, 4H), 3.05 (t, J = 11.2 Hz, 1H), 2.83 (d, J = 7.0 Hz, 1H), 2.39 – 2.14 (m, 4H), 2.08 (t, J = 9.3 Hz, 2H), 1.69 (d, J = 7.9 Hz, 1H). Example 68 – Preparation of (3R)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-4- methylmorpholine-3-carboxamide A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), (3R)-4-methylmorpholine-3-carboxylic acid hydrochloride (24.5 mg, 0.13 mmol, 1.2 equiv), DIEA (43.6 mg, 0.34mmol, 3 equiv), and PyBOP (76.1 mg, 0.15 mmol, 1.3 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with brien (2*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 55% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.27; Number Of Runs: 2) to afford (3R)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-4-methylmorpholine-3- carboxamide (38.7 mg, 60.06%) as a white solid. LC-MS: (M+H)+ found 572.30.1H NMR (400 MHz, DMSO-d6) δ 8.80 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.75 (d, J = 0.9 Hz, 1H), 25 6.85 (t, J = 7.2 Hz, 1H), 6.22 (t, J = 7.8 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.75 – 4.53 (m, 2H),
Attorney Docket No.50006-0109WO1 3.79 (dt, J = 10.8, 3.5 Hz, 2H), 3.63 (d, J = 28.7 Hz, 1H), 3.52 (td, J = 11.4, 2.4 Hz, 1H), 3.44 – 3.38 (m, 1H), 3.10 – 3.01 (m, 1H), 2.88 – 2.66 (m, 3H), 2.25 (s, 3H), 2.19 (d, J = 4.7 Hz, 4H), 2.09 (d, J = 8.8 Hz, 3H), 1.70 (d, J = 9.5 Hz, 1H). Example 69 – Preparation of (3S)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- 5 yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-4- methylmorpholine-3-carboxamide To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), (3S)-4-methyl-3-morpholinecarboxylic acid hydrochloride (25 mg, 0.13 mmol, 1.2 equiv) and DIEA (0.10 mL, 0.57 mmol, 5.10 equiv) in DMF (1 mL) was added PyBOP (71 mg, 0.13 mmol, 1.2 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (30 mL) and washed with brine (2*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 55% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.27) to afford (3S)-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}-4-methylmorpholine-3-carboxamide (33.9 mg, 52.35%) as a off-white solid. LC-MS: (M+H)+ found 572.25.1H NMR (400 MHz, DMSO-d6) δ 8.80 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (d, J = 0.9 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.22 (t, J = 8.5 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.73 – 4.56 (m, 2H), 3.79 (dt, J = 11.3, 3.5 Hz, 2H), 3.72 – 3.45 (m, 2H), 3.39 (dd, J = 11.1, 10.1 Hz, 1H), 3.05 (t, J = 11.4 Hz, 1H), 2.89 – 2.61 (m, 3H), 2.36 – 2.14 (m, 8H), 2.13 – 25 2.01 (m, 2H), 1.70 (d, J = 9.9 Hz, 1H).
Attorney Docket No.50006-0109WO1 Example 5 – Preparation of (3S)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-4- methylmorpholine-3-carboxamide Step 1: A mixture of 1-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-1,2,4- thiadiazol-5-yl)methanamine (100 mg, 0.24 mmol, 1 equiv), 1-tert-butylpyrazole-4-carboxylic acid (49.3 mg, 0.29 mmol, 1.2 equiv), HATU (92.9 mg, 0.24 mmol, 1 equiv) and DIEA (94.8 mg, 0.73 mmol, 3 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 2:1) to afford N-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}-1,2,4-thiadiazol-5-yl)methyl]-1-tert-butylpyrazole-4- carboxamide (60 mg, 43.89%) as a light yellow solid. LC-MS: (M+H)+ found 559.3. Step 2: A mixture of N-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-1,2,4- thiadiazol-5-yl)methyl]-1-tert-butylpyrazole-4-carboxamide (60 mg, 0.11 mmol, 1 equiv), Pd- PEPPSI-IHeptCl 3-chloropyridine (52.2 mg, 0.05 mmol, 0.5 equiv) and Cs2CO3 (209.7 mg, 0.64 mmol, 6 equiv) in dioxane (1 mL) was stirred for 2 h at 100°C under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeCN. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 20:1) and Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 40% B to 63% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.47; Number Of Runs: 1) to afford 1-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-thiadiazol-5-25 yl]methyl}pyrazole-4-carboxamide (8.6 mg, 13.13%) as a light yellow solid. to afford 1-tert-butyl-
Attorney Docket No.50006-0109WO1 N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-thiadiazol-5-yl]methyl}pyrazole-4-carboxamide (8.6 mg, 13.13%) as a light yellow solid. LC-MS: (M+H)+ found 611.15. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (t, J = 5.8 Hz, 1H), 8.36 (s, 1H), 8.03 (d, J = 6.9 Hz, 1H), 7.95 (s, 1H), 7.85 (s, 5 1H), 6.82 (t, J = 7.2 Hz, 1H), 6.20 m, 2H), 5.00 – 4.78 (m, 3H), 3.82 – 3.52 (m, 1H), 3.08 (s, 1H), 2.86 (s, 1H), 2.23 (s, 4H), 2.19 – 2.03 (m, 2H), 1.72 (d, J = 11.6 Hz, 1H), 1.54 (s, 9H). Example 6 – Preparation of 1-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-thiadiazol-5- yl]methyl}pyrrole-3-carboxamide Step 1: A mixture of 1-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-1,2,4- thiadiazol-5-yl)methanamine (100 mg, 0.244 mmol, 1 equiv), 1-tert-butylpyrrole-3-carboxylic acid (49.0 mg, 0.29 mmol, 1.20 equiv), HATU (92.91mg, 0.24 mmol, 1.00 equiv) and DIEA (94.8 mg, 0.73 mmol, 3.00 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 2:1) to afford N-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}-1,2,4-thiadiazol-5-yl)methyl]-1-tert-butylpyrazole-4- carboxamide (40 mg, 29.26%) as a light yellow solid. LC-MS: (M+H)+ found 558.3. Step 2: A mixture of N-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-1,2,4- thiadiazol-5-yl)methyl]-1-tert-butylpyrrole-3-carboxamide (40 mg, 0.07 mmol, 1 equiv), Pd- PEPPSI-IHeptCl 3-chloropyridine (34.9 mg, 0.04 mmol, 0.5 equiv) and Cs2CO3 (140.0 mg, 0.43 mmol, 6 equiv) in dioxane (1 mL) was stirred for 2 h at 100°C under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeCN. The filtrate was 25 concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7M NH3
Attorney Docket No.50006-0109WO1 in MeOH 20:1) and Prep-HPLC (Column: Waters Xbridge C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.5%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 43% B to 70% B in 7min; Wave Length: 254/220 nm; RT1(min): 6.28) to afford 1-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- 5 [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-thiadiazol-5-yl]methyl}pyrrole-3-carboxamide (1.5 mg, 3.43%) as a light yellow solid. LC-MS: (M+H)+ found 610.20. 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 5.6 Hz, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.84 (s, 1H), 7.57 (s, 1H), 7.01 (d, J = 2.8 Hz, 1H), 6.82 (t, J = 7.1 Hz, 1H), 6.52 (d, J = 2.7 Hz, 1H), 6.19 (t, J = 8.3 Hz, 2H), 5.05 – 4.69 (m, 3H), 3.72 (m, 1H), 3.06 (s, 1H), 2.85 (s, 1H), 2.21 (s, 4H), 2.09 (d, J = 10.5 Hz, 2H), 1.72 10 (s, 1H), 1.50 (s, 9H). Assays Surface Plasmon Resonance (SPR) Assay Protocol SPR experiments are performed on a Biacore 8K instrument. Biotinylated recombinant p53 Y220C mutant protein (amino acid residues 94-293) is immobilized onto a streptavidin sensor chip (Sensor Chip SA), by flowing the protein solution through the sensor chip at typically 10 ^g/mL concentration, 5 ^L/min flow rate for 70 seconds. Compounds are 2-fold, 7-point serial diluted; the top concentration varies depending on the potency. Compound binding affinities are measured in the multi-cycle kinetics mode, at 30 μL/min flow rate with 60 seconds association time and 120 seconds dissociation time. The running buffer contains 50 mM Tris, pH 7.5, 100 mM NaCl, 1 mM DTT, 0.01% Brij35, 0.05% Tween-20 and 1% DMSO. The assay temperature is maintained at 16 or 20oC and data are fit into the 1:1 binding model using the Biacore Insight Evaluation software. Thermal shift assay protocol 5 ^M recombinant p53 Y220C mutant protein (amino acid residues 94-293) is incubated with 100 ^M compound for 3 hours at 20oC in buffer containing 20 mM HEPES, pH7.4, 100 mM NaCl, 0.01% Pluronic F-127, and 1% DMSO in the presence of 400-fold diluted Sypro Orange (ThermoFisher Scientific catalog number 4461146), on a 384-well PCR plate (Applied Biosystems catalog number 4483285). The volume is 5 ^L/well. The sealed plate is then loaded onto a 30 QuantStudio 7 Flex instrument for melting temperature (TM) measurement. The temperature is
Attorney Docket No.50006-0109WO1 increased from 30 oC to 50oC, at a rate of 0.03oC/second. Data are fit into a Boltzmann two-state model to determine the TM. Luciferase reporter assay protocol 5 Luciferase reporter (Luc) driven by p53 response element (LTV-p53-Luc (SKU#: LTLR007); G&P Biosciences) and inducible p53 Y220C construct (Tet-One inducible expression system; Takara) were stably expressed in NCIH1299 cells by lentiviral transduction. The cells were then used for p53 reporter assay. 5,000 cells were seeded in each well of 384 plate and cultured in 0.5 ug/mL doxycycline (D3072; Sigma) containing medium for 24 hours before 10 compound treatment. After 6 hour of compound treatment, equal volume of One-Glo reagent (E6110; Promega) was added to each well and the plate was incubated for 5 minutes with shaking at room temperature. The luciferase activity was immediately measured with PheraStar microplate reader. Luciferase activity was stimulated by 10 uM of a tool compound as positive control and AC50 was calculated. Cell proliferation assay Inducible p53 Y220C and R273H constructs (Tet-One inducible expression system; Takara) were stably expressed in NCIH1299 cells by lentiviral transduction. NUGC3, A549, BxPC3, T3M4, HuH7, HCC2935, MFE296, NCIH1299, NCIH1299-inducible p53 Y220C, and NCIH1299-inducible p53 R273H cell lines were used for cell proliferation assay. 250-500 cells were seeded in each well of 384 plate and then compounds were dispensed into each well using Echo or Tecan. After 5 days of incubation, equal volume of CellTiter-Glo reagent (G7570; Promega) was added into each well and the plate was incubated at room temperature for 10 minutes with shaking. The luminescent signal was measured by PheraStar microplate reader and IC50 was calculated. Table A shows results of the SPR p53 Y220C Kd_kinetic (nM), TSA p53 Y220C dTM (deg C), Luc p53 Y220C AC50 (nM), CTG H1299 p53 Y220C IC50 (nM), CTG H1299 p53 R273H IC50 (nM), and CTG NUGC3 p53 Y220C IC50 (nM) assays. Activity categories are as follows: 30 • SPR p53 Y220C Kd_kinetic (nM): D ≥ 1000 > C ≥ 100 > B ≥ 10 > A • TSA p53 Y220C dTM (deg C, 100 µM): A ≥ 10 > B ≥ 5 > C ≥ 1 > D
Attorney Docket No.50006-0109WO1 • TSA p53 Y220C dTM (deg C, 10 µM): A ≥ 10 > B ≥ 5 > C ≥ 1 > D • CTG NUGC3 p53 Y220C IC50 (nM): D ≥ 3000 > C ≥ 1500 > B ≥ 750 > A • CTG H1299 p53 Y220C IC50 (nM): D ≥ 3000 > C ≥ 1500 > B ≥ 750 > A • CTG H1299 p53 R273H IC50 (nM): A ≥ 10000 > B ≥ 8000 > C ≥ 5000 > D 5 • Luc p53 Y220C AC50 (nM): D ≥ 3000 > C ≥ 1500 > B ≥ 750 > A Table A Example SPR P53 TSA TSA Luc CTG CTG CTG No. Y220C P53 P53 P53 NUGC3 H1299 H1299 Kd_kinetic Y220C Y220C Y220C P53 P53 P53 (nM) dTM dTM AC50 Y220C Y220C R273H (deg (deg (nM) IC50 IC50 IC50 C) C, 10 (nM) (nM) (nM) uM) 1 B B B D D D A 2 A A A A 3 A A A A 4 B D D D 5 C D D D 6 D D D D 7 A A A A 8 A C C B 9 C D C C 10 B C D D 11 A B B B 12 A A A A 13 A A A A 14 B C B B 15 A A A A 16 A B A B 17 A A A B 18 A B A B 19 B B A A 20 A A A A 21 C C C C 22 B D C D 23 A A A A 24 A A B B 25 A C C C 26 B C C C 27 A A A B
Attorney Docket No.50006-0109WO1 28 A A A A 29 A B B B 30 B B C C 31 A A A A 32 A A A A 33 A A A A 34 B D C C 35 B D C C 36 B C C C 37 A A A A 38 B B A A 39 B B A A 40 B A A A 41 B B B B 42 A A A A 43 B B B B 44 A A B A 45 B D C D 46 C D D D 47 B D D D 48 B D D D 49 B C D C 50 A A B 51 B D D D 52 B D D D 53 B D D 54 A A A A 55 B D D 56 B B A A 57 A A A A 58 A A A A 59 A B B A 60 B C C C 61 B D D D 62 A C C B 63 A C C D 64 B D D D 65 B D D D 66 A A A A 67 A B C B 68 B D D 69 B D D 70 A A A
Attorney Docket No.50006-0109WO1 71 A A A 72 A A A 73 A A B 74 A B C 75 A B B 76 A A B 77 A A A 78 A A A 79 A A A 80 A C C 81 A A B 82 A A A 83 A B B 84 B D D 85 A A A 86 A A 87 A B 88 B A 89 A A A 90 A A 91 A A 92 A A 93 A A A 94 A A A 95 A A 96 A A 97 A A 98 A B B 99 100 101 102 103 104 105 106 107 108 109 110
Claims
Attorney Docket No.50006-0109WO1 WHAT IS CLAIMED IS: 1. A compound of Formula (I) (I) or a pharmaceutically acceptable salt thereof, wherein: 5 X1 is CR1 or N; R1 is hydrogen, halogen, cyano, –OR4, -NR4R5, -C(=O)R4, -OC(=O)R4, –C(=O)OR4, –C(=O)NR4R5, –SR4, –S(=O)R4, –S(O2)R4, -NR4C(=O)R5, –R4C(=O)R5, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each of X2, X3, X4, and X5 are CH, N, CR2 or CR3, wherein two or more of X2, X3, X4, and X5 are independently CH, CR2, or CR3; each of Y1, Y2, and Y3 are C or N, wherein one of Y1, Y2, and Y3 is N; RA is hydrogen, –OR6, -NR6R7, -C(=O)R6, -R6C(=O)R7, -OC(=O)R6, -OC(=O)NR6, –C(=O)OR6, –NR6C(=O)OR7, –C(=O)NR6R7, –SR6, –S(=O)R6, –S(O2)R6, –S(O2)NR6, –NR6S(O2)R7, -NR6C(=O)R7, -NR6C(=O)NR7, -SiR6R7R8, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; RB is halogen, cyano, hydroxyl, –NR8R9, -OR8, –C(=O)NR8R9, –C(=O)R8, -C(=O)OR8, -NR8C(=O)OR9, –OC(=O)R8, –OC(=O)NR8, –C(=O)NR8R9, –NR8C(=O)R9, –NR8C(=O)NR9, –SR8, –S(=O)R8, –S(O2)R8, –S(O2)NR8, –NR8S(O2)R9, -R8C(=O)R9, -NR8C(=O)R9, -NR8C(=O)NR9, optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;
Attorney Docket No.50006-0109WO1 each R2 is ; Z1 is a bond, -C=O-, -S(O2)-optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or an optionally substituted C3-C4 cycloalkylene; 5 Z2 is CR2C, N, O, or a bond; wherein when Z2 is O, R2B is absent; when Z1 is a bond and Z2 is a bond, R2B is absent and R2A is directly connected to Formula (I) via Z1; R2A and R2B are independently hydrogen, –C(=O)R10, –C(=O)OR10, –C(=O)NR10R11, –S(=O)R10, –S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; or R2A and R2B together with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl; or Z2 is O and R2B is absent; R2C is hydrogen, halogen, or C1-C6 alkyl; each R3 is independently halogen, cyano, –NR12R13, -OR12, –C(=O)NR12R13, –C(=O)R12, -C(=O)OR12, –OC(=O)R12, –NR12(C=O)NR13R14, –SR12, –S(=O)R12, –S(O2)R12, –S(O2)NR12R13, –NR12S(O2)NR13R14, -R12C(=O)R13, -NR12C(=O)R13, optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl; L is an optionally substituted 4-6 membered heterocyclylene or an optionally substituted 5-6 membered heteroarylene; m is 0, 1, or 2; and each R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted
Attorney Docket No.50006-0109WO1 C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. 2. The compound of Claim 1, wherein the compound of Formula (I), or a 5 pharmaceutically acceptable salt thereof, is selected from the group consisting of: (I-A), (I-B), and (I-C), or a pharmaceutically acceptable salt of any of the foregoing. 3. The compound of Claim 1 or 2, wherein one of X2, X3, X4, and X5 is N. 4. The compound of Claim 1 or 2, wherein two of X2, X3, X4, and X5 are N. 5. The compound of any one of Claims 1-4, wherein X1 is CR1. 6. The compound of any one of Claims 1-5, wherein R1 is hydrogen. 7. The compound of any one of Claims 1-5, wherein R1 is halogen. 8. The compound of any one of Claims 1-5, wherein R1 is cyano. 9. The compound of any one of Claims 1-5, wherein R1 is –OR4. 10. The compound of any one of Claims 1-5, wherein R1 is -NR4R5. 11. The compound of any one of Claims 1-5, wherein R1 is -C(=O)R4. 12. The compound of any one of Claims 1-5, wherein R1 is -OC(=O)R4.
Attorney Docket No.50006-0109WO1 13. The compound of any one of Claims 1-5, wherein R1 is –C(=O)OR4. 14. The compound of any one of Claims 1-5, wherein R1 is –C(=O)NR4R5. 5 15. The compound of any one of Claims 1-5, wherein R1 is –SR4. 16. The compound of any one of Claims 1-5, wherein R1 is –S(=O)R4. 17. The compound of any one of Claims 1-5, wherein R1 is –S(O2)R4. 10 18. The compound of any one of Claims 1-5, wherein R1 is -NR4C(=O)R5. 19. The compound of any one of Claims 1-5, wherein R1 is –R4C(=O)R5. 20. The compound of any one of Claims 1-5, wherein R1 is optionally substituted C1- C6 alkyl. 21. The compound of any one of Claims 1-5, wherein R1 is optionally substituted C2- C6 alkenyl. 22. The compound of any one of Claims 1-5, wherein R1 is optionally substituted C2- C6 alkynyl. 23. The compound of any one of Claims 1-5, wherein R1 is optionally substituted C3- C10 cycloalkyl. 24. The compound of any one of Claims 1-5, wherein R1 is optionally substituted phenyl. 30 25. The compound of any one of Claims 1-5, wherein R1 is optionally substituted 4-12 membered heterocyclyl.
Attorney Docket No.50006-0109WO1 26. The compound of any one of Claims 1-5, wherein R1 is optionally substituted 5-10 membered heteroaryl. 5 27. The compound of any one of Claims 1-4, wherein X1 is N. 28. The compound of any one of Claims 1-27, wherein RA is hydrogen. 29. The compound of any one of Claims 1-27, wherein RA is –OR6. 10 30. The compound of any one of Claims 1-27, wherein RA is -NR6R7. 31. The compound of any one of Claims 1-27, wherein RA is -C(=O)R6. 32. The compound of any one of Claims 1-27, wherein RA is -R6C(=O)R7. 33. The compound of any one of Claims 1-27, wherein RA is -OC(=O)R6. 34. The compound of any one of Claims 1-27, wherein RA is -OC(=O)NR6. 35. The compound of any one of Claims 1-27, wherein RA is –C(=O)OR6. 36. The compound of any one of Claims 1-27, wherein RA is –NR6C(=O)OR7. 37. The compound of any one of Claims 1-27, wherein RA is –C(=O)NR6R7. 38. The compound of any one of Claims 1-27, wherein RA is –SR6. 39. The compound of any one of Claims 1-27, wherein RA is –S(=O)R6. 40. The compound of any one of Claims 1-27, wherein RA is –S(O2)R6.
Attorney Docket No.50006-0109WO1 41. The compound of any one of Claims 1-27, wherein RA is –S(O2)NR6. 42. The compound of any one of Claims 1-27, wherein RA is –NR6S(O2)R7. 5 43. The compound of any one of Claims 1-27, wherein RA is -NR6C(=O)R7. 44. The compound of any one of Claims 1-27, wherein RA is -NR6C(=O)NR7. 45. The compound of any one of Claims 1-27, wherein RA is -SiR6R7R8. 10 46. The compound of any one of Claims 1-27, wherein RA is optionally substituted C1- C6 alkyl. 47. The compound of any one of Claims 1-27, wherein RA is optionally substituted C2- C6 alkenyl. 48. The compound of any one of Claims 1-27, wherein RA is optionally substituted C2- C6 alkynyl. 49. The compound of any one of Claims 1-27, wherein RA is optionally substituted C3- C10 cycloalkyl. 50. The compound of any one of Claims 1-27, wherein RA is optionally substituted phenyl. 51. The compound of any one of Claims 1-27, wherein RA is optionally substituted 4- 12 membered heterocyclyl. 52. The compound of any one of Claims 1-27, wherein RA is optionally substituted 5- 30 10 membered heteroaryl.
Attorney Docket No.50006-0109WO1 53. The compound of any one of Claims 1-52, wherein RB is halogen. 54. The compound of any one of Claims 1-52, wherein RB is cyano. 5 55. The compound of any one of Claims 1-52, wherein RB is hydroxyl. 56. The compound of any one of Claims 1-52, wherein RB is –NR8R9. 57. The compound of any one of Claims 1-52, wherein RB is -OR8. 10 58. The compound of any one of Claims 1-52, wherein RB is –C(=O)NR8R9. 59. The compound of any one of Claims 1-52, wherein RB is –C(=O)R8. 60. The compound of any one of Claims 1-52, wherein RB is -C(=O)OR8. 61. The compound of any one of Claims 1-52, wherein RB is -NR8C(=O)OR9 62. The compound of any one of Claims 1-52, wherein RB is –OC(=O)R8. 63. The compound of any one of Claims 1-52, wherein RB is –OC(=O)NR8. 64. The compound of any one of Claims 1-52, wherein RB is –C(=O)NR8R9. 65. The compound of any one of Claims 1-52, wherein RB is –NR8C(=O)R9. 66. The compound of any one of Claims 1-52, wherein RB is –NR8C(=O)NR9. 67. The compound of any one of Claims 1-52, wherein RB is –SR8. 30 68. The compound of any one of Claims 1-52, wherein RB is –S(=O)R8.
Attorney Docket No.50006-0109WO1 69. The compound of any one of Claims 1-52, wherein RB is –S(O2)R8. 70. The compound of any one of Claims 1-52, wherein RB is –S(O2)NR8. 5 71. The compound of any one of Claims 1-52, wherein RB is –NR8S(O2)R9. 72. The compound of any one of Claims 1-52, wherein RB is -R8C(=O)R9. 10 73. The compound of any one of Claims 1-52, wherein RB is -NR8C(=O)R9. 74. The compound of any one of Claims 1-52, wherein RB is -NR8C(=O)NR9. 75. The compound of any one of Claims 1-52, wherein RB is optionally substituted C1- C6 alkyl. 76. The compound of any one of Claims 1-52, wherein RB is C1-C6 haloalkyl. 77. The compound of any one of Claims 1-52, wherein RB is optionally substituted C2- C6 alkenyl. 78. The compound of any one of Claims 1-52, wherein RB is optionally substituted C2- C6 alkynyl. 79. The compound of any one of Claims 1-52, wherein RB is optionally substituted C3- C10 cycloalkyl. 80. The compound of any one of Claims 1-52, wherein RB is optionally substituted phenyl. 30
Attorney Docket No.50006-0109WO1 81. The compound of any one of Claims 1-52, wherein RB is optionally substituted 3- 12 membered heterocyclyl. 82. The compound of any one of Claims 1-52, wherein RB is optionally substituted 5- 5 10 membered heteroaryl. 83. The compound of any one of Claims 1-82, wherein each R2 is . 84. The compound of any one of Claims 1-83, wherein one of X2, X3, X4, and X5 is CR2 and the remaining X2, X3, X4, and X5 are CH, N, or CR3. 85. The compound of any one of Claims 1-84, wherein Z1 is a bond. 86. The compound of any one of Claims 1-84, wherein Z1 is -C=O-. 87. The compound of any one of Claims 1-84, wherein Z1 is -S(O2)-. 88. The compound of any one of Claims 1-84, wherein Z1 is optionally substituted C1- C6 alkylene. 89. The compound of any one of Claims 1-84, wherein Z1 is optionally substituted C2- C6 alkenylene. 90. The compound of any one of Claims 1-84, wherein Z1 is optionally substituted C2- C6 alkynylene. 91. The compound of any one of Claims 1-84, wherein Z1 is an optionally substituted C3-C4 cycloalkylene.
Attorney Docket No.50006-0109WO1 92. The compound of any one of Claims 1-91, wherein Z2 is N. 93. The compound of any one of Claims 1-91, wherein Z2 is O and R2B is absent. 5 94. The compound of any one of Claims 1-91, wherein Z2 is a bond. 95. The compound of any one of Claims 1-91, wherein Z2 is CR2C. 96. The compound of any one of Claims 1-91 or 95, wherein R2C is hydrogen. 10 97. The compound of any one of Claims 1-91 or 95, wherein R2C is halogen. 98. The compound of any one of Claims 1-91 or 95, wherein R2C is C1-C6 alkyl. 99. The compound of any one of Claims 1-84, wherein Z1 is a bond and Z2 is a bond, R2B is absent and R2A is directly connected to Formula (I) via Z1. 100. The compound of any one of Claims 1-99, wherein R2A is hydrogen. 101. The compound of any one of Claims 1-99, wherein R2A is -C(=O)R10. 102. The compound of any one of Claims 1-99, wherein R2A is –C(=O)OR10. 103. The compound of any one of Claims 1-99, wherein R2A is –C(=O)NR10R11. 104. The compound of any one of Claims 1-99, wherein R2A is –S(=O)R10. 105. The compound of any one of Claims 1-99, wherein R2A is –S(O2)R10. 30 106. The compound of any one of Claims 1-99, wherein R2A is optionally substituted C1-C6 alkyl.
Attorney Docket No.50006-0109WO1 107. The compound of any one of Claims 1-99, wherein R2A is optionally substituted C2-C6 alkenyl. 5 108. The compound of any one of Claims 1-99, wherein R2A is optionally substituted C2-C6 alkynyl. 109. The compound of any one of Claims 1-99, wherein R2A is optionally substituted C3-C10 cycloalkyl. 10 110. The compound of any one of Claims 1-99, wherein R2A is optionally substituted phenyl. 111. The compound of any one of Claims 1-99, wherein R2A is optionally substituted 4- 12 membered heterocyclyl. 112. The compound of any one of Claims 1-99, wherein R2A is optionally substituted 5- 10 membered heteroaryl. 113. The compound of any one of Claims 1-98 and 100-112, wherein R2B is hydrogen. 114. The compound of any one of Claims 1-98 and 100-112, wherein R2B is -C(=O)R10. 115. The compound of any one of Claims 1-98 and 100-112, wherein R2B is –C(=O)OR10. 116. The compound of any one of Claims 1-98 and 100-112, wherein R2B is –C(=O)NR10R11. 30 117. The compound of any one of Claims 1-98 and 100-112, wherein R2B is –S(=O)R10.
Attorney Docket No.50006-0109WO1 118. The compound of any one of Claims 1-98 and 100-112, wherein R2B is –S(O2)R10. 119. The compound of any one of Claims 1-98 and 100-112, wherein R2B is optionally substituted C1-C6 alkyl. 5 120. The compound of any one of Claims 1-98 and 100-112, wherein R2B is optionally substituted C2-C6 alkenyl. 121. The compound of any one of Claims 1-98 and 100-112, wherein R2B is optionally 10 substituted C2-C6 alkynyl. 122. The compound of any one of Claims 1-98 and 100-112, wherein R2B is optionally substituted C3-C10 cycloalkyl. 123. The compound of any one of Claims 1-98 and 100-112, wherein R2B is optionally substituted phenyl. 124. The compound of any one of Claims 1-98 and 100-112, wherein R2B is optionally substituted 4-12 membered heterocyclyl. 125. The compound of any one of Claims 1-98 and 100-112, wherein R2B is optionally substituted 5-10 membered heteroaryl. 126. The compound of any one of Claims 1-98, wherein one of R2A and R2B is hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl, and the other of R2A and R2B is hydrogen, –C(=O)R10, –C(=O)OR10, –C(=O)NR10R11, –S(=O)R10, –S(O2)R10, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl. 127. The compound of any one of Claims 1-98, wherein R2A and R2B together with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl,
Attorney Docket No.50006-0109WO1 an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl. 128. The compound of any one of Claims 1-127, wherein one of X2, X3, X4, and X5 is 5 CR2, one of X2, X3, X4, and X5 is CR3, and the remaining X2, X3, X4, and X5 are CH or N. 129. The compound of any one of Claims 1-2 or 5-127, wherein one of X2, X3, X4, and X5 is CR2, one of X2, X3, X4, and X5 is CR3, and the remaining X2, X3, X4, and X5 are CH. 10 130. The compound of any one of Claims 1-129, wherein R3 is halogen. 131. The compound of any one of Claims 1-129, wherein R3 is cyano. 132. The compound of any one of Claims 1-129, wherein R3 is –NR12R13. 133. The compound of any one of Claims 1-129, wherein R3 is -OR12. 134. The compound of any one of Claims 1-129, wherein R3 is –C(=O)NR12R13. 135. The compound of any one of Claims 1-129, wherein R3 is –C(=O)R12. 136. The compound of any one of Claims 1-129, wherein R3 is -C(=O)OR12. 137. The compound of any one of Claims 1-129, wherein R3 is –OC(=O)R12. 138. The compound of any one of Claims 1-129, wherein R3 is –NR12(C=O)NR12R13. 139. The compound of any one of Claims 1-129, wherein R3 is –SR12. 140. The compound of any one of Claims 1-129, wherein R3 is –S(=O)R12. 141. The compound of any one of Claims 1-129, wherein R3 is –S(O2)R12.
Attorney Docket No.50006-0109WO1 142. The compound of any one of Claims 1-129, wherein R3 is –S(O2)NR12R13. 143. The compound of any one of Claims 1-129, wherein R3 is –NR12S(O2)NR13R14. 5 144. The compound of any one of Claims 1-129, wherein R3 is -R12C(=O)R13. 145. The compound of any one of Claims 1-129, wherein R3 is -NR12C(=O)R13. 10 146. The compound of any one of Claims 1-129, wherein R3 is optionally substituted C1-C6 alkyl. 147. The compound of any one of Claims 1-129, wherein R3 is optionally substituted C2-C6 alkenyl. 148. The compound of any one of Claims 1-129, wherein R3 is optionally substituted C2-C6 alkynyl. 149. The compound of any one of Claims 1-129, wherein R3 is optionally substituted C3-C6 cycloalkyl. 150. The compound of any one of Claims 1-129, wherein R3 is optionally substituted phenyl. 151. The compound of any one of Claims 1-129, wherein R3 is optionally substituted 4- 6 membered heterocyclyl. 152. The compound of any one of Claims 1-129, wherein R3 is optionally substituted 5- 6 membered heteroaryl. 30 153. The compound of any one of Claims 1-152, wherein m is 0.
Attorney Docket No.50006-0109WO1 154. The compound of any one of Claims 1-152, wherein m is 1. 155. The compound of any one of Claims 1-152, wherein m is 2. 5 156. The compound of any one of Claims 1-155, wherein L is an optionally substituted 5-6 membered heteroarylene. 157. The compound of any one of Claims 1-156, wherein L is a 5-6 membered 10 heteroarylene. 158. The compound of any one of Claims 1-155, wherein L is an optionally substituted 4-6 membered heterocyclylene. 159. The compound of any one of Claims 1-155 or 158, wherein L is a 4-6 membered heterocyclylene. 160. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from the compounds described in List 1, or a pharmaceutically acceptable salt of any of the foregoing. 161. A pharmaceutical composition comprising a compound of any one of Claims 1- 160, or a pharmaceutically acceptable salt thereof. 162. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-160, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 161. 163. A method of treating cancer in a subject previously identified as having one or more p53 mutations, comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-160, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 161.
Attorney Docket No.50006-0109WO1 164. A method of treating cancer in a subject in need thereof, comprising: (a) determining that the subject has one or more p53 mutations, and (b) administering to the subject a therapeutically effective amount of a compound 5 of any one of Claims 1-160, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 161.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202263418102P | 2022-10-21 | 2022-10-21 | |
US63/418,102 | 2022-10-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2024086804A1 true WO2024086804A1 (en) | 2024-04-25 |
Family
ID=89068752
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2023/077433 WO2024086804A1 (en) | 2022-10-21 | 2023-10-20 | Indolizine derivatives for treating cancer |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2024086804A1 (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020051707A1 (en) * | 2018-09-12 | 2020-03-19 | The Governing Council Of The University Of Toronto | Indole-oxadiazole compounds and their therapeutic use |
WO2021231474A1 (en) * | 2020-05-12 | 2021-11-18 | Pmv Pharmaceuticals, Inc. | METHODS AND COMPOUNDS FOR RESTORING MUTANT p53 FUNCTION |
WO2021262484A1 (en) * | 2020-06-24 | 2021-12-30 | Pmv Pharmaceuticals, Inc. | Combination therapy for treatment of cancer |
-
2023
- 2023-10-20 WO PCT/US2023/077433 patent/WO2024086804A1/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020051707A1 (en) * | 2018-09-12 | 2020-03-19 | The Governing Council Of The University Of Toronto | Indole-oxadiazole compounds and their therapeutic use |
WO2021231474A1 (en) * | 2020-05-12 | 2021-11-18 | Pmv Pharmaceuticals, Inc. | METHODS AND COMPOUNDS FOR RESTORING MUTANT p53 FUNCTION |
WO2021262484A1 (en) * | 2020-06-24 | 2021-12-30 | Pmv Pharmaceuticals, Inc. | Combination therapy for treatment of cancer |
Non-Patent Citations (3)
Title |
---|
CHEN ZHENGKAI ET AL: "Metal-Free Mediated C-3 Methylsulfanylation of Imidazo[1,2-a]-pyridines with Dimethyl Sulfoxide as a Methylsulfanylating Agent", SYNLETT, vol. 28, no. 14, 10 May 2017 (2017-05-10), DE, pages 1795 - 1800, XP093118817, ISSN: 0936-5214, DOI: 10.1055/s-0036-1588419 * |
MADDIRALA SHAMBABU JOSEPH ET AL: "Reactions of 3-benzylindole-2-carbohydrazides: Synthesis of new 10-Benzyl-1,2-dihydro-1-oxo-1,2,4-triazino[4,5- a ]indoles and 3-Benzyl-2-(1,3,4-oxadiazol-2-yl)indoles", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 41, no. 1, 1 January 2004 (2004-01-01), US, pages 7 - 11, XP093118841, ISSN: 0022-152X, DOI: 10.1002/jhet.5570410102 * |
RAVI CHITRAKAR ET AL: "N -Chlorosuccinimide-Promoted Regioselective Sulfenylation of Imidazoheterocycles at Room Temperature", ORGANIC LETTERS, vol. 16, no. 11, 16 May 2014 (2014-05-16), US, pages 2978 - 2981, XP093118818, ISSN: 1523-7060, DOI: 10.1021/ol501117z * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6563623B1 (en) | Pyridopyrimidinone CDK2 / 4/6 inhibitor | |
RU2742115C2 (en) | Heterocyclic compounds as ret kinase inhibitors | |
AU2012339499B2 (en) | Aminoquinazoline derivatives and their salts and methods of use | |
AU2016210544B2 (en) | Inhibitors of TrkA kinase | |
JP7277376B2 (en) | Compounds useful as RET inhibitors | |
KR101877187B1 (en) | Substituted dihydroisoquinolinone compounds | |
AU2010310786B2 (en) | AKT inhibitors | |
TWI707855B (en) | Novel imidazopyridazine compounds and their use | |
KR20170031669A (en) | Substituted urea derivatives and pharmaceutical uses thereof | |
CN113061132B (en) | Condensed ring lactam compound, preparation method and application | |
EP4011885A1 (en) | Oxo-pyridine fusion ring derivative and pharmaceutical composition comprising same | |
JP2022526854A (en) | Phosphatidylinositol 3-kinase inhibitor | |
CN113912628B (en) | Triazine compound, composition and application thereof | |
CN115996907A (en) | Inhibitors of MLH1 and/or PMS2 for cancer treatment | |
JP2005120102A (en) | Fused heteroaryl derivative | |
WO2024086804A1 (en) | Indolizine derivatives for treating cancer | |
WO2024086809A1 (en) | Methods for treating cancer | |
KR102607051B1 (en) | Heteroaryl derivative compounds, and uses thereof | |
WO2024077036A1 (en) | Methods for treating cancer | |
CN103748095B (en) | Bicyclic heteroaromatic compounds | |
MX2008004668A (en) | Use of pyrazolo [1 , 5 -a]pyrimidine derivatives for inhibiting protein kinases methods for inhibiting protein kinases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23817259 Country of ref document: EP Kind code of ref document: A1 |