NZ749590A - Pyrimidine-based antiproliferative agents - Google Patents
Pyrimidine-based antiproliferative agentsInfo
- Publication number
- NZ749590A NZ749590A NZ749590A NZ74959017A NZ749590A NZ 749590 A NZ749590 A NZ 749590A NZ 749590 A NZ749590 A NZ 749590A NZ 74959017 A NZ74959017 A NZ 74959017A NZ 749590 A NZ749590 A NZ 749590A
- Authority
- NZ
- New Zealand
- Prior art keywords
- formula
- alkylene
- compound
- alkyl
- cancer
- Prior art date
Links
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 title abstract description 14
- 230000001028 anti-proliferant Effects 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 427
- -1 heterocyclo Chemical group 0.000 claims description 195
- 239000000203 mixture Substances 0.000 claims description 105
- 239000011780 sodium chloride Substances 0.000 claims description 90
- 150000003839 salts Chemical class 0.000 claims description 89
- 125000000217 alkyl group Chemical group 0.000 claims description 83
- 125000003118 aryl group Chemical group 0.000 claims description 57
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 34
- 239000000651 prodrug Substances 0.000 claims description 33
- 229940002612 prodrugs Drugs 0.000 claims description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 30
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 30
- 125000004429 atoms Chemical group 0.000 claims description 27
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 24
- 125000003342 alkenyl group Chemical group 0.000 claims description 21
- 230000000155 isotopic Effects 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 125000000304 alkynyl group Chemical group 0.000 claims description 16
- 125000001188 haloalkyl group Chemical group 0.000 claims description 15
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 15
- 150000002431 hydrogen Chemical group 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 125000005842 heteroatoms Chemical group 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000004043 oxo group Chemical group O=* 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 150000007574 3-membered cyclic compounds Chemical class 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 abstract description 82
- 201000010099 disease Diseases 0.000 abstract description 63
- 206010028980 Neoplasm Diseases 0.000 abstract description 44
- 230000002159 abnormal effect Effects 0.000 abstract description 26
- 230000035755 proliferation Effects 0.000 abstract description 23
- 230000001413 cellular Effects 0.000 abstract description 19
- 230000002401 inhibitory effect Effects 0.000 description 92
- 235000002639 sodium chloride Nutrition 0.000 description 88
- 239000003112 inhibitor Substances 0.000 description 87
- 210000004027 cells Anatomy 0.000 description 77
- 239000003814 drug Substances 0.000 description 54
- 239000003795 chemical substances by application Substances 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- 150000001412 amines Chemical class 0.000 description 41
- 230000015572 biosynthetic process Effects 0.000 description 39
- 239000002585 base Substances 0.000 description 35
- 238000003786 synthesis reaction Methods 0.000 description 34
- 230000002194 synthesizing Effects 0.000 description 34
- 125000004452 carbocyclyl group Chemical group 0.000 description 30
- 206010025323 Lymphomas Diseases 0.000 description 27
- 239000002253 acid Substances 0.000 description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 26
- 230000001225 therapeutic Effects 0.000 description 26
- 101700008359 CDK4 Proteins 0.000 description 25
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- 210000001744 T-Lymphocytes Anatomy 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- 238000000034 method Methods 0.000 description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 23
- 206010025310 Other lymphomas Diseases 0.000 description 22
- 239000002246 antineoplastic agent Substances 0.000 description 22
- 230000000670 limiting Effects 0.000 description 22
- 125000004432 carbon atoms Chemical group C* 0.000 description 21
- 229940079593 drugs Drugs 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 208000003950 B-Cell Lymphoma Diseases 0.000 description 20
- 206010006187 Breast cancer Diseases 0.000 description 20
- 102000000551 Syk Kinase Human genes 0.000 description 20
- 108010016672 Syk Kinase Proteins 0.000 description 20
- 239000000543 intermediate Substances 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 20
- 230000000975 bioactive Effects 0.000 description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 19
- 238000004519 manufacturing process Methods 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 241000282414 Homo sapiens Species 0.000 description 17
- 108090001123 antibodies Proteins 0.000 description 17
- 102000004965 antibodies Human genes 0.000 description 17
- 239000000725 suspension Substances 0.000 description 17
- 206010000880 Acute myeloid leukaemia Diseases 0.000 description 16
- 239000000969 carrier Substances 0.000 description 16
- 239000002552 dosage form Substances 0.000 description 16
- 239000003937 drug carrier Substances 0.000 description 16
- 150000002118 epoxides Chemical class 0.000 description 16
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 16
- 206010012818 Diffuse large B-cell lymphoma Diseases 0.000 description 15
- 208000007046 Leukemia, Myeloid, Acute Diseases 0.000 description 15
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 15
- 239000008194 pharmaceutical composition Substances 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 210000001519 tissues Anatomy 0.000 description 15
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
- 150000002500 ions Chemical class 0.000 description 14
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
- 230000000269 nucleophilic Effects 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 208000008456 Leukemia, Myelogenous, Chronic, BCR-ABL Positive Diseases 0.000 description 13
- 239000002841 Lewis acid Substances 0.000 description 13
- 206010042971 T-cell lymphoma Diseases 0.000 description 13
- 230000027455 binding Effects 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- 201000006934 chronic myeloid leukemia Diseases 0.000 description 13
- 150000007517 lewis acids Chemical class 0.000 description 13
- 239000012071 phase Substances 0.000 description 13
- 230000002062 proliferating Effects 0.000 description 13
- 238000007363 ring formation reaction Methods 0.000 description 13
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-Aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 12
- FPGGTKZVZWFYPV-UHFFFAOYSA-M Tetra-n-butylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 12
- 201000005510 acute lymphocytic leukemia Diseases 0.000 description 12
- 150000001408 amides Chemical group 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 12
- 238000011161 development Methods 0.000 description 12
- 230000018109 developmental process Effects 0.000 description 12
- 150000003951 lactams Chemical class 0.000 description 12
- 239000003446 ligand Substances 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 241000894007 species Species 0.000 description 12
- 206010003816 Autoimmune disease Diseases 0.000 description 11
- 210000003719 B-Lymphocytes Anatomy 0.000 description 11
- 206010024324 Leukaemias Diseases 0.000 description 11
- 206010029592 Non-Hodgkin's lymphomas Diseases 0.000 description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 11
- 230000002829 reduced Effects 0.000 description 11
- 102100011141 ALK Human genes 0.000 description 10
- 108010005474 Anaplastic Lymphoma Kinase Proteins 0.000 description 10
- 102100019398 CDK4 Human genes 0.000 description 10
- 102000003903 Cyclin-Dependent Kinases Human genes 0.000 description 10
- 108090000266 Cyclin-Dependent Kinases Proteins 0.000 description 10
- LXNAVEXFUKBNMK-UHFFFAOYSA-N acetic acid;palladium Chemical group [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 238000002512 chemotherapy Methods 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 230000001076 estrogenic Effects 0.000 description 10
- 201000009277 hairy cell leukemia Diseases 0.000 description 10
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 10
- 230000036961 partial Effects 0.000 description 10
- 238000006467 substitution reaction Methods 0.000 description 10
- QDMPMBFLXOWHRY-UHFFFAOYSA-N 5-(4-methylpiperazin-1-yl)pyridin-2-amine Chemical compound C1CN(C)CCN1C1=CC=C(N)N=C1 QDMPMBFLXOWHRY-UHFFFAOYSA-N 0.000 description 9
- 101700025368 ERBB2 Proteins 0.000 description 9
- 102100016662 ERBB2 Human genes 0.000 description 9
- 102100019764 PDCD1 Human genes 0.000 description 9
- 206010060862 Prostate cancer Diseases 0.000 description 9
- 206010039491 Sarcoma Diseases 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- 125000002950 monocyclic group Chemical group 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 9
- 102100006400 CSF2 Human genes 0.000 description 8
- 241000229754 Iva xanthiifolia Species 0.000 description 8
- 101700081293 LMX1A Proteins 0.000 description 8
- 210000003491 Skin Anatomy 0.000 description 8
- 206010057644 Testis cancer Diseases 0.000 description 8
- 150000001336 alkenes Chemical class 0.000 description 8
- 125000002947 alkylene group Chemical group 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 201000008937 atopic dermatitis Diseases 0.000 description 8
- 239000002775 capsule Substances 0.000 description 8
- 125000004122 cyclic group Chemical group 0.000 description 8
- 239000001064 degrader Substances 0.000 description 8
- 239000003085 diluting agent Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 238000000132 electrospray ionisation Methods 0.000 description 8
- 239000000262 estrogen Substances 0.000 description 8
- 230000012010 growth Effects 0.000 description 8
- 150000002576 ketones Chemical class 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 230000003000 nontoxic Effects 0.000 description 8
- 231100000252 nontoxic Toxicity 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 230000004224 protection Effects 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 201000003120 testicular cancer Diseases 0.000 description 8
- AOJJSUZBOXZQNB-TZSSRYMLSA-N ADRIAMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 7
- 208000009956 Adenocarcinoma Diseases 0.000 description 7
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 description 7
- 102100009312 BTK Human genes 0.000 description 7
- 210000000481 Breast Anatomy 0.000 description 7
- 102100006130 CDK6 Human genes 0.000 description 7
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 7
- 229960004679 Doxorubicin Drugs 0.000 description 7
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 7
- KTUFNOKKBVMGRW-UHFFFAOYSA-N Imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 7
- HPJKCIUCZWXJDR-UHFFFAOYSA-N Letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 7
- 206010035226 Plasma cell myeloma Diseases 0.000 description 7
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 7
- 229960001603 Tamoxifen Drugs 0.000 description 7
- 229940035295 Ting Drugs 0.000 description 7
- 230000003078 antioxidant Effects 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 7
- 230000001419 dependent Effects 0.000 description 7
- 239000003995 emulsifying agent Substances 0.000 description 7
- 229960005167 everolimus Drugs 0.000 description 7
- 230000003176 fibrotic Effects 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 200000000018 inflammatory disease Diseases 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 7
- 229960003881 letrozole Drugs 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- 150000003457 sulfones Chemical class 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- HWBIQJOWCBKZJW-UHFFFAOYSA-N $l^{1}-silanyloxysilicon Chemical compound [Si]O[Si] HWBIQJOWCBKZJW-UHFFFAOYSA-N 0.000 description 6
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 6
- 102100013894 BCL2 Human genes 0.000 description 6
- 108060000885 BCL2 Proteins 0.000 description 6
- 102000001765 Bcl-2-Like Protein 11 Human genes 0.000 description 6
- 108010040168 Bcl-2-Like Protein 11 Proteins 0.000 description 6
- 206010008958 Chronic lymphocytic leukaemia Diseases 0.000 description 6
- STQGQHZAVUOBTE-VGBVRHCVSA-N DAUNOMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 6
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 6
- 102100016692 ESR1 Human genes 0.000 description 6
- 108090000394 Erythropoietin Proteins 0.000 description 6
- 102000003951 Erythropoietin Human genes 0.000 description 6
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 6
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 206010020243 Hodgkin's disease Diseases 0.000 description 6
- 208000000429 Leukemia, Lymphocytic, Chronic, B-Cell Diseases 0.000 description 6
- 210000004072 Lung Anatomy 0.000 description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 6
- 150000001204 N-oxides Chemical class 0.000 description 6
- 208000002154 Non-Small-Cell Lung Carcinoma Diseases 0.000 description 6
- 101710027499 Os03g0268000 Proteins 0.000 description 6
- 206010033128 Ovarian cancer Diseases 0.000 description 6
- 108091000081 Phosphotransferases Proteins 0.000 description 6
- 102000001253 Protein Kinases Human genes 0.000 description 6
- 208000000587 Small Cell Lung Carcinoma Diseases 0.000 description 6
- 229940083542 Sodium Drugs 0.000 description 6
- 229940091252 Sodium supplements Drugs 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 6
- HJUGFYREWKUQJT-UHFFFAOYSA-N Tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 6
- 108010010691 Trastuzumab Proteins 0.000 description 6
- 206010046766 Uterine cancer Diseases 0.000 description 6
- 239000003098 androgen Substances 0.000 description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 201000009030 carcinoma Diseases 0.000 description 6
- 230000000973 chemotherapeutic Effects 0.000 description 6
- 230000001684 chronic Effects 0.000 description 6
- YZCKVEUIGOORGS-OUBTZVSYSA-N deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 6
- 229940105423 erythropoietin Drugs 0.000 description 6
- 108010038795 estrogen receptors Proteins 0.000 description 6
- 239000003102 growth factor Substances 0.000 description 6
- 201000008064 heavy chain disease Diseases 0.000 description 6
- 230000001965 increased Effects 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000002502 liposome Substances 0.000 description 6
- 201000004044 liver cirrhosis Diseases 0.000 description 6
- 239000000314 lubricant Substances 0.000 description 6
- 201000005202 lung cancer Diseases 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 201000001441 melanoma Diseases 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 230000000051 modifying Effects 0.000 description 6
- 229960000060 monoclonal antibodies Drugs 0.000 description 6
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 6
- 201000009251 multiple myeloma Diseases 0.000 description 6
- 201000005962 mycosis fungoide Diseases 0.000 description 6
- MIMNFCVQODTQDP-NDLVEFNKSA-N oblimersen Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(S)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)CO)[C@@H](O)C1 MIMNFCVQODTQDP-NDLVEFNKSA-N 0.000 description 6
- 125000002524 organometallic group Chemical group 0.000 description 6
- 125000004430 oxygen atoms Chemical group O* 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 239000003755 preservative agent Substances 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 230000001603 reducing Effects 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 125000004434 sulfur atoms Chemical group 0.000 description 6
- 201000010874 syndrome Diseases 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 6
- 125000003944 tolyl group Chemical group 0.000 description 6
- 229960000575 trastuzumab Drugs 0.000 description 6
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 6
- YOVVNQKCSKSHKT-HNNXBMFYSA-N (2S)-1-[4-[[2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl]piperazin-1-yl]-2-hydroxypropan-1-one Chemical compound C1CN(C(=O)[C@@H](O)C)CCN1CC1=C(C)C2=NC(C=3C=NC(N)=NC=3)=NC(N3CCOCC3)=C2S1 YOVVNQKCSKSHKT-HNNXBMFYSA-N 0.000 description 5
- NRUKOCRGYNPUPR-QBPJDGROSA-N (5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-thiophen-2-yl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 5
- 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 5
- 102100004323 ASPG Human genes 0.000 description 5
- 206010003571 Astrocytoma Diseases 0.000 description 5
- 206010004146 Basal cell carcinoma Diseases 0.000 description 5
- 206010009944 Colon cancer Diseases 0.000 description 5
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytosar Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 5
- 206010012438 Dermatitis atopic Diseases 0.000 description 5
- 206010014733 Endometrial cancer 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
- 229960005420 Etoposide Drugs 0.000 description 5
- VJJPUSNTGOMMGY-MRVIYFEKSA-N Etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 5
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 5
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 5
- 102100018758 IL3 Human genes 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- RCINICONZNJXQF-MZXODVADSA-N Intaxel Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 5
- 102000015696 Interleukins Human genes 0.000 description 5
- 108010063738 Interleukins Proteins 0.000 description 5
- 210000000822 Killer Cells, Natural Anatomy 0.000 description 5
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 5
- 208000003002 Lymphoma, T-Cell, Peripheral Diseases 0.000 description 5
- 206010025650 Malignant melanoma Diseases 0.000 description 5
- VIUAUNHCRHHYNE-JTQLQIEISA-N N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)pyridine-4-carboxamide Chemical compound OC[C@@H](O)CNC(=O)C1=CC=NC=C1NC1=CC=C(I)C=C1F VIUAUNHCRHHYNE-JTQLQIEISA-N 0.000 description 5
- HHZIURLSWUIHRB-UHFFFAOYSA-N Nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 5
- 108009000071 Non-small cell lung cancer Proteins 0.000 description 5
- 208000008589 Obesity Diseases 0.000 description 5
- 229960001592 Paclitaxel Drugs 0.000 description 5
- 208000003476 Primary Myelofibrosis Diseases 0.000 description 5
- RJKFOVLPORLFTN-STHVQZNPSA-N Progesterone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC(=O)CC4)CC3)CC2)CC1 RJKFOVLPORLFTN-STHVQZNPSA-N 0.000 description 5
- 229950003687 Ribociclib Drugs 0.000 description 5
- QFJCIRLUMZQUOT-HPLJOQBZSA-N Sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 5
- 206010041067 Small cell lung cancer Diseases 0.000 description 5
- RJKFOVLPORLFTN-LEKSSAKUSA-N Syngestrets Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 5
- JBWKIWSBJXDJDT-UHFFFAOYSA-N Triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 230000033115 angiogenesis Effects 0.000 description 5
- 239000000427 antigen Substances 0.000 description 5
- 108091007172 antigens Proteins 0.000 description 5
- 102000038129 antigens Human genes 0.000 description 5
- 229910052805 deuterium Inorganic materials 0.000 description 5
- 239000012039 electrophile Substances 0.000 description 5
- 239000000328 estrogen antagonist Substances 0.000 description 5
- 238000005755 formation reaction Methods 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- 230000003394 haemopoietic Effects 0.000 description 5
- 229960002411 imatinib Drugs 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 5
- 230000003211 malignant Effects 0.000 description 5
- 239000002609 media Substances 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 239000011859 microparticle Substances 0.000 description 5
- 201000003793 myelodysplastic syndrome Diseases 0.000 description 5
- 239000002105 nanoparticle Substances 0.000 description 5
- 235000020824 obesity Nutrition 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 238000007911 parenteral administration Methods 0.000 description 5
- 201000007923 peripheral T-cell lymphoma Diseases 0.000 description 5
- CDRPUGZCRXZLFL-OWOJBTEDSA-N piceatannol Chemical compound OC1=CC(O)=CC(\C=C\C=2C=C(O)C(O)=CC=2)=C1 CDRPUGZCRXZLFL-OWOJBTEDSA-N 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 230000002335 preservative Effects 0.000 description 5
- 229960003387 progesterone Drugs 0.000 description 5
- 239000000186 progesterone Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000006884 silylation reaction Methods 0.000 description 5
- 229960002930 sirolimus Drugs 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 5
- 230000001629 suppression Effects 0.000 description 5
- VWUXBMIQPBEWFH-WCCTWKNTSA-N (7R,8R,9S,13S,14S,17S)-13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 4
- JOVVKPCDUDNVPP-UHFFFAOYSA-N 6-(1,4-dihydroxy-3-methyl-6,7-dioxo-5-propan-2-ylnaphthalen-2-yl)-5,8-dihydroxy-7-methyl-1-propan-2-ylnaphthalene-2,3-dione Chemical compound CC1=C(O)C2=C(C(C)C)C(=O)C(=O)C=C2C(O)=C1C1=C(O)C2=CC(=O)C(=O)C(C(C)C)=C2C(O)=C1C JOVVKPCDUDNVPP-UHFFFAOYSA-N 0.000 description 4
- 108060005293 AGA Proteins 0.000 description 4
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 description 4
- YBBLVLTVTVSKRW-UHFFFAOYSA-N Anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 4
- 206010059512 Apoptosis Diseases 0.000 description 4
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 4
- 206010003210 Arteriosclerosis Diseases 0.000 description 4
- 208000006673 Asthma Diseases 0.000 description 4
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Belustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 4
- 108010005144 Bevacizumab Proteins 0.000 description 4
- 210000004204 Blood Vessels Anatomy 0.000 description 4
- UBPYILGKFZZVDX-UHFFFAOYSA-N Bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 4
- 206010055113 Breast cancer metastatic Diseases 0.000 description 4
- 208000009899 Burkitt Lymphoma Diseases 0.000 description 4
- 208000002458 Carcinoid Tumor Diseases 0.000 description 4
- 108010022830 Cetuximab Proteins 0.000 description 4
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 4
- 229960000684 Cytarabine Drugs 0.000 description 4
- BUROJSBIWGDYCN-GAUTUEMISA-N Deforolimus Chemical compound C1C[C@@H](OP(C)(C)=O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 BUROJSBIWGDYCN-GAUTUEMISA-N 0.000 description 4
- 206010013774 Dry eye Diseases 0.000 description 4
- 208000005679 Eczema Diseases 0.000 description 4
- 229960001433 Erlotinib Drugs 0.000 description 4
- 229960002258 Fulvestrant Drugs 0.000 description 4
- 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 4
- JNWBBCNCSMBKNE-UHFFFAOYSA-N HATU Chemical compound F[P-](F)(F)(F)(F)F.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JNWBBCNCSMBKNE-UHFFFAOYSA-N 0.000 description 4
- 210000003128 Head Anatomy 0.000 description 4
- 206010019641 Hepatic cirrhosis Diseases 0.000 description 4
- 208000006454 Hepatitis Diseases 0.000 description 4
- 201000006743 Hodgkin's lymphoma Diseases 0.000 description 4
- 108020001267 IL3 Proteins 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 208000007766 Kaposi Sarcoma Diseases 0.000 description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 4
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 4
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 4
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 4
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 4
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 4
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 4
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 4
- 208000002490 Leukemia, Myelomonocytic, Juvenile Diseases 0.000 description 4
- 229960004338 Leuprorelin Drugs 0.000 description 4
- 210000004698 Lymphocytes Anatomy 0.000 description 4
- 208000008968 Lymphoma, Large-Cell, Anaplastic Diseases 0.000 description 4
- 206010061232 Lymphoproliferative disease Diseases 0.000 description 4
- 229960004296 Megestrol Acetate Drugs 0.000 description 4
- 206010028537 Myelofibrosis Diseases 0.000 description 4
- 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 4
- 108010019706 Nivolumab Proteins 0.000 description 4
- 102100011593 PSMA7 Human genes 0.000 description 4
- 101710033516 PSMA7 Proteins 0.000 description 4
- 229960004390 Palbociclib Drugs 0.000 description 4
- AHJRHEGDXFFMBM-UHFFFAOYSA-N Palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 4
- 208000008443 Pancreatic Carcinoma Diseases 0.000 description 4
- 108010061219 Panitumumab Proteins 0.000 description 4
- KASDHRXLYQOAKZ-OLHLVPFQSA-N Pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C\C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-OLHLVPFQSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- SHGAZHPCJJPHSC-YCNIQYBTSA-N Retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 4
- 206010039073 Rheumatoid arthritis Diseases 0.000 description 4
- 230000036191 S Phase Effects 0.000 description 4
- 230000018199 S phase Effects 0.000 description 4
- 206010040767 Sjogren's syndrome Diseases 0.000 description 4
- 206010062113 Splenic marginal zone lymphoma Diseases 0.000 description 4
- WINHZLLDWRZWRT-ATVHPVEESA-N Sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 4
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 4
- 229960001278 Teniposide Drugs 0.000 description 4
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N [(8R,9S,10R,13S,14S,17R)-17-acetyl-6,10,13-trimethyl-3-oxo-2,8,9,11,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 4
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 4
- 229960002932 anastrozole Drugs 0.000 description 4
- 230000001833 anti-estrogenic Effects 0.000 description 4
- 239000000051 antiandrogen Substances 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 201000001320 atherosclerosis Diseases 0.000 description 4
- 229960000397 bevacizumab Drugs 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 238000004166 bioassay Methods 0.000 description 4
- 238000006065 biodegradation reaction Methods 0.000 description 4
- 239000004305 biphenyl Substances 0.000 description 4
- 229960003736 bosutinib Drugs 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- 125000002837 carbocyclic group Chemical group 0.000 description 4
- 230000032823 cell division Effects 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 229960005395 cetuximab Drugs 0.000 description 4
- 230000001767 chemoprotection Effects 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 229960002448 dasatinib Drugs 0.000 description 4
- 201000009910 diseases by infectious agent Diseases 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 229960000255 exemestane Drugs 0.000 description 4
- 201000003444 follicular lymphoma Diseases 0.000 description 4
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 4
- 229960002584 gefitinib Drugs 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 230000003463 hyperproliferative Effects 0.000 description 4
- 239000007943 implant Substances 0.000 description 4
- 238000001764 infiltration Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 201000005992 juvenile myelomonocytic leukemia Diseases 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 4
- 201000007270 liver cancer Diseases 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 230000001404 mediated Effects 0.000 description 4
- 229960000485 methotrexate Drugs 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 229960001346 nilotinib Drugs 0.000 description 4
- 150000002829 nitrogen Chemical group 0.000 description 4
- 229960003301 nivolumab Drugs 0.000 description 4
- 238000005935 nucleophilic addition reaction Methods 0.000 description 4
- 229960000435 oblimersen Drugs 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 201000002528 pancreatic cancer Diseases 0.000 description 4
- 229960001972 panitumumab Drugs 0.000 description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 4
- 125000004193 piperazinyl group Chemical group 0.000 description 4
- 125000005936 piperidyl group Chemical group 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- 150000003212 purines Chemical class 0.000 description 4
- 230000001850 reproductive Effects 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229960003787 sorafenib Drugs 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 230000002459 sustained Effects 0.000 description 4
- 229930003347 taxol Natural products 0.000 description 4
- 229960000235 temsirolimus Drugs 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- LXZZYRPGZAFOLE-UHFFFAOYSA-L transplatin Chemical compound [H][N]([H])([H])[Pt](Cl)(Cl)[N]([H])([H])[H] LXZZYRPGZAFOLE-UHFFFAOYSA-L 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- ZROHGHOFXNOHSO-BNTLRKBRSA-L (1R,2R)-cyclohexane-1,2-diamine;oxalate;platinum(2+) Chemical compound [H][N]([C@@H]1CCCC[C@H]1[N]1([H])[H])([H])[Pt]11OC(=O)C(=O)O1 ZROHGHOFXNOHSO-BNTLRKBRSA-L 0.000 description 3
- KCOYQXZDFIIGCY-CZIZESTLSA-N (3E)-4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1,3-dihydrobenzimidazol-2-ylidene]quinolin-2-one Chemical compound C1CN(C)CCN1C1=CC=C(N\C(N2)=C/3C(=C4C(F)=CC=CC4=NC\3=O)N)C2=C1 KCOYQXZDFIIGCY-CZIZESTLSA-N 0.000 description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17 Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
- OMJKFYKNWZZKTK-UXBLZVDNSA-N (5E)-5-(dimethylaminohydrazinylidene)imidazole-4-carboxamide Chemical compound CN(C)N\N=C1\N=CN=C1C(N)=O OMJKFYKNWZZKTK-UXBLZVDNSA-N 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- RCLQNICOARASSR-SECBINFHSA-N 3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione Chemical compound FC=1C(=O)N(C)C=2N=CN(C[C@@H](O)CO)C(=O)C=2C=1NC1=CC=C(I)C=C1F RCLQNICOARASSR-SECBINFHSA-N 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N 5-flurouricil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- 102100007495 AR Human genes 0.000 description 3
- 229940009456 Adriamycin Drugs 0.000 description 3
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N Altretamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 3
- 206010002412 Angiocentric lymphomas Diseases 0.000 description 3
- 206010073360 Appendix cancer Diseases 0.000 description 3
- 206010004593 Bile duct cancer Diseases 0.000 description 3
- WTEOIRVLGSZEPR-UHFFFAOYSA-N Boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 3
- 201000004085 CLL/SLL Diseases 0.000 description 3
- TXNMZIBTVJSDEY-UHFFFAOYSA-N CN1CCN(CC1)C=1C=CC(=NC=1)NC=1N=CC=2N=C3N(C=2N=1)C1(CNC3=O)CCCCC1 Chemical compound CN1CCN(CC1)C=1C=CC(=NC=1)NC=1N=CC=2N=C3N(C=2N=1)C1(CNC3=O)CCCCC1 TXNMZIBTVJSDEY-UHFFFAOYSA-N 0.000 description 3
- 229960005069 Calcium Drugs 0.000 description 3
- 210000003169 Central Nervous System Anatomy 0.000 description 3
- 206010008342 Cervix carcinoma Diseases 0.000 description 3
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 3
- 208000006990 Cholangiocarcinoma Diseases 0.000 description 3
- 208000005243 Chondrosarcoma Diseases 0.000 description 3
- 206010008943 Chronic leukaemia Diseases 0.000 description 3
- AMLYAMJWYAIXIA-VWNVYAMZSA-N Cilengitide Chemical compound N1C(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C(C)C)N(C)C(=O)[C@H]1CC1=CC=CC=C1 AMLYAMJWYAIXIA-VWNVYAMZSA-N 0.000 description 3
- NGSLYYBESOYVMN-UHFFFAOYSA-N ClC1=NC=C(C(=N1)NC1(CCCCC1)CNC(OC(C)(C)C)=O)[N+](=O)[O-] Chemical compound ClC1=NC=C(C(=N1)NC1(CCCCC1)CNC(OC(C)(C)C)=O)[N+](=O)[O-] NGSLYYBESOYVMN-UHFFFAOYSA-N 0.000 description 3
- BSMCAPRUBJMWDF-KRWDZBQOSA-N Cobimetinib Chemical compound C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F BSMCAPRUBJMWDF-KRWDZBQOSA-N 0.000 description 3
- 229960002271 Cobimetinib Drugs 0.000 description 3
- 206010009900 Colitis ulcerative Diseases 0.000 description 3
- 206010011401 Crohn's disease Diseases 0.000 description 3
- 108010036949 Cyclosporine Proteins 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229960000640 Dactinomycin Drugs 0.000 description 3
- 108010092160 Dactinomycin Proteins 0.000 description 3
- 229960000975 Daunorubicin Drugs 0.000 description 3
- UREBDLICKHMUKA-CXSFZGCWSA-N Dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 3
- BMKDZUISNHGIBY-ZETCQYMHSA-N Dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 description 3
- 206010012601 Diabetes mellitus Diseases 0.000 description 3
- AXRCEOKUDYDWLF-UHFFFAOYSA-N Enzastaurin Chemical compound C12=CC=CC=C2N(C)C=C1C(C(NC1=O)=O)=C1C(C1=CC=CC=C11)=CN1C(CC1)CCN1CC1=CC=CC=N1 AXRCEOKUDYDWLF-UHFFFAOYSA-N 0.000 description 3
- 206010014967 Ependymoma Diseases 0.000 description 3
- 210000002615 Epidermis Anatomy 0.000 description 3
- 210000002744 Extracellular Matrix Anatomy 0.000 description 3
- 229960002949 Fluorouracil Drugs 0.000 description 3
- MKXKFYHWDHIYRV-UHFFFAOYSA-N Flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 3
- 230000005526 G1 to G0 transition Effects 0.000 description 3
- 206010017758 Gastric cancer Diseases 0.000 description 3
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- SDUQYLNIPVEERB-QPPQHZFASA-N Gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 3
- 229940045109 Genistein Drugs 0.000 description 3
- ZCOLJUOHXJRHDI-CMWLGVBASA-N Genistin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 description 3
- 206010018338 Glioma Diseases 0.000 description 3
- QBKSWRVVCFFDOT-UHFFFAOYSA-N Gossypol Chemical compound CC(C)C1=C(O)C(O)=C(C=O)C2=C(O)C(C=3C(O)=C4C(C=O)=C(O)C(O)=C(C4=CC=3C)C(C)C)=C(C)C=C21 QBKSWRVVCFFDOT-UHFFFAOYSA-N 0.000 description 3
- 210000003958 Hematopoietic Stem Cells Anatomy 0.000 description 3
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 description 3
- 206010027665 Immune disorder Diseases 0.000 description 3
- 206010021425 Immune system disease Diseases 0.000 description 3
- 102100001056 KITLG Human genes 0.000 description 3
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 description 3
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 3
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 3
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 3
- 108060004270 LAG3 Proteins 0.000 description 3
- 102100017213 LAG3 Human genes 0.000 description 3
- 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 3
- 208000006404 Large Granular Lymphocytic Leukemia Diseases 0.000 description 3
- 206010024190 Leiomyosarcomas Diseases 0.000 description 3
- 210000000265 Leukocytes Anatomy 0.000 description 3
- 206010024627 Liposarcoma Diseases 0.000 description 3
- 210000004185 Liver Anatomy 0.000 description 3
- 210000003563 Lymphoid Tissue Anatomy 0.000 description 3
- 208000003543 Lymphoma, T-Cell, Cutaneous Diseases 0.000 description 3
- 208000002780 Macular Degeneration Diseases 0.000 description 3
- 206010026798 Mantle cell lymphomas Diseases 0.000 description 3
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N Melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 3
- 206010027191 Meningioma Diseases 0.000 description 3
- 229960000350 Mitotane Drugs 0.000 description 3
- 206010028576 Myeloproliferative disease Diseases 0.000 description 3
- RDSACQWTXKSHJT-NSHDSACASA-N N-[3,4-difluoro-2-(2-fluoro-4-iodoanilino)-6-methoxyphenyl]-1-[(2S)-2,3-dihydroxypropyl]cyclopropane-1-sulfonamide Chemical compound C1CC1(C[C@H](O)CO)S(=O)(=O)NC=1C(OC)=CC(F)=C(F)C=1NC1=CC=C(I)C=C1F RDSACQWTXKSHJT-NSHDSACASA-N 0.000 description 3
- 210000004693 NK cell Anatomy 0.000 description 3
- JLYAXFNOILIKPP-KXQOOQHDSA-N Navitoclax Chemical compound C([C@@H](NC1=CC=C(C=C1S(=O)(=O)C(F)(F)F)S(=O)(=O)NC(=O)C1=CC=C(C=C1)N1CCN(CC1)CC1=C(CCC(C1)(C)C)C=1C=CC(Cl)=CC=1)CSC=1C=CC=CC=1)CN1CCOCC1 JLYAXFNOILIKPP-KXQOOQHDSA-N 0.000 description 3
- 206010029260 Neuroblastoma Diseases 0.000 description 3
- 208000009905 Neurofibromatosis Diseases 0.000 description 3
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Nitrumon Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 3
- RFTSSZJZXOSICM-VXLYETTFSA-N Obatoclax Chemical compound COC1=CC(C=2NC3=CC=CC=C3C=2)=N\C1=C\C=1NC(C)=CC=1C RFTSSZJZXOSICM-VXLYETTFSA-N 0.000 description 3
- SUDAHWBOROXANE-VIFPVBQESA-N PD 0325901-Cl Chemical compound OC[C@H](O)CONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F SUDAHWBOROXANE-VIFPVBQESA-N 0.000 description 3
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N Pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 3
- 229960002340 Pentostatin Drugs 0.000 description 3
- FPVKHBSQESCIEP-JQCXWYLXSA-N Pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 3
- SZFPYBIJACMNJV-UHFFFAOYSA-N Perifosine Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OC1CC[N+](C)(C)CC1 SZFPYBIJACMNJV-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N Prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 3
- GZUITABIAKMVPG-UHFFFAOYSA-N Raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 3
- 229960004622 Raloxifene Drugs 0.000 description 3
- 206010038038 Rectal cancer Diseases 0.000 description 3
- 208000006265 Renal Cell Carcinoma Diseases 0.000 description 3
- 108010001645 Rituximab Proteins 0.000 description 3
- 101710006487 SSE2 Proteins 0.000 description 3
- CYOHGALHFOKKQC-UHFFFAOYSA-N Selumetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1Cl CYOHGALHFOKKQC-UHFFFAOYSA-N 0.000 description 3
- MNWBNISUBARLIT-UHFFFAOYSA-N Sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 3
- LXMSZDCAJNLERA-ZHYRCANASA-N Spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 3
- 206010041823 Squamous cell carcinoma Diseases 0.000 description 3
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 3
- 229960003604 Testosterone Drugs 0.000 description 3
- 229960005454 Thioguanine Drugs 0.000 description 3
- UCFGDBYHRUNTLO-QHCPKHFHSA-N Topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 3
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N Trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 3
- 229960001727 Tretinoin Drugs 0.000 description 3
- 102000009524 Vascular Endothelial Growth Factor A Human genes 0.000 description 3
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 3
- YCOYDOIWSSHVCK-UHFFFAOYSA-N Vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 3
- 229960004528 Vincristine Drugs 0.000 description 3
- WAEXFXRVDQXREF-UHFFFAOYSA-N Vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 3
- 208000008383 Wilms Tumor Diseases 0.000 description 3
- 101700069422 ZHX2 Proteins 0.000 description 3
- 230000002378 acidificating Effects 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000001154 acute Effects 0.000 description 3
- 230000001058 adult Effects 0.000 description 3
- 201000006966 adult T-cell leukemia Diseases 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 230000000172 allergic Effects 0.000 description 3
- 229960000473 altretamine Drugs 0.000 description 3
- 238000007112 amidation reaction Methods 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 108010080146 androgen receptors Proteins 0.000 description 3
- 230000000118 anti-eoplastic Effects 0.000 description 3
- 230000000845 anti-microbial Effects 0.000 description 3
- 230000001640 apoptogenic Effects 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 150000003857 carboxamides Chemical class 0.000 description 3
- 229960005243 carmustine Drugs 0.000 description 3
- 201000010881 cervical cancer Diseases 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 229960001265 ciclosporin Drugs 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 3
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 230000002255 enzymatic Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 229960002074 flutamide Drugs 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 210000004475 gamma-delta T lymphocyte Anatomy 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 229960005277 gemcitabine Drugs 0.000 description 3
- 235000006539 genistein Nutrition 0.000 description 3
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 description 3
- 210000004602 germ cell Anatomy 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 231100000283 hepatitis Toxicity 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 230000002757 inflammatory Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- 101710030209 lin-45 Proteins 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 229960002247 lomustine Drugs 0.000 description 3
- 201000011649 lymphoblastic lymphoma Diseases 0.000 description 3
- 230000000527 lymphocytic Effects 0.000 description 3
- 201000007919 lymphoplasmacytic lymphoma Diseases 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 3
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 3
- 229960001924 melphalan Drugs 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 3
- 150000002739 metals Chemical class 0.000 description 3
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 3
- 229940113083 morpholine Drugs 0.000 description 3
- 201000007224 myeloproliferative neoplasm Diseases 0.000 description 3
- 201000008026 nephroblastoma Diseases 0.000 description 3
- ZNHPZUKZSNBOSQ-BQYQJAHWSA-N neratinib Chemical compound C=12C=C(NC\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZNHPZUKZSNBOSQ-BQYQJAHWSA-N 0.000 description 3
- 229950008835 neratinib Drugs 0.000 description 3
- 201000004931 neurofibromatosis Diseases 0.000 description 3
- 150000002825 nitriles Chemical group 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 201000010133 oligodendroglioma Diseases 0.000 description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 3
- 230000002611 ovarian Effects 0.000 description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 3
- 229960000639 pazopanib Drugs 0.000 description 3
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 3
- 108010026276 pembrolizumab Proteins 0.000 description 3
- 229960002621 pembrolizumab Drugs 0.000 description 3
- 229960005079 pemetrexed Drugs 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 229960005330 pimecrolimus Drugs 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229960004618 prednisone Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 201000004681 psoriasis Diseases 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 150000003230 pyrimidines Chemical class 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 230000002285 radioactive Effects 0.000 description 3
- 201000001275 rectum cancer Diseases 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 229960001302 ridaforolimus Drugs 0.000 description 3
- 229960004641 rituximab Drugs 0.000 description 3
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 201000000849 skin cancer Diseases 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 229960002256 spironolactone Drugs 0.000 description 3
- 230000003393 splenic Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 201000011549 stomach cancer Diseases 0.000 description 3
- 229920000638 styrene acrylonitrile Polymers 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 229960001796 sunitinib Drugs 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 229960000303 topotecan Drugs 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 229960004066 trametinib Drugs 0.000 description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 3
- 210000004881 tumor cells Anatomy 0.000 description 3
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 3
- 229940121358 tyrosine kinase inhibitors Drugs 0.000 description 3
- 201000006704 ulcerative colitis Diseases 0.000 description 3
- WVTKBKWTSCPRNU-KYJUHHDHSA-N (+)-Tetrandrine Chemical compound C([C@H]1C=2C=C(C(=CC=2CCN1C)OC)O1)C(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2C[C@@H]2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-KYJUHHDHSA-N 0.000 description 2
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 2
- CFCUWKMKBJTWLW-BGLFSJPPSA-N (2S,3S)-2-[(2S,4R,5R,6R)-4-[(2S,4R,5R,6R)-4-[(2S,4S,5R,6R)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-3-[(1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-6-[(2S,4R,5S,6R)-4-[(2S,4R,5S,6R)-4,5-dih Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BGLFSJPPSA-N 0.000 description 2
- WUWDLXZGHZSWQZ-WQLSENKSSA-N (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-1H-indol-2-one Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- HBWGDGHGYGHWKD-UHFFFAOYSA-N 1-methyl-4-pyridin-3-ylpiperazine Chemical compound C1CN(C)CCN1C1=CC=CN=C1 HBWGDGHGYGHWKD-UHFFFAOYSA-N 0.000 description 2
- YABJJWZLRMPFSI-UHFFFAOYSA-N 1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC=C(C(F)(F)F)C=C1 YABJJWZLRMPFSI-UHFFFAOYSA-N 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-methylpiperazine Chemical class CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- CGBJSGAELGCMKE-UHFFFAOYSA-N 2,4-difluoro-N-[2-methoxy-5-(4-pyridazin-4-ylquinolin-6-yl)pyridin-3-yl]benzenesulfonamide Chemical compound COC1=NC=C(C=2C=C3C(C=4C=NN=CC=4)=CC=NC3=CC=2)C=C1NS(=O)(=O)C1=CC=C(F)C=C1F CGBJSGAELGCMKE-UHFFFAOYSA-N 0.000 description 2
- JICOGKJOQXTAIP-UHFFFAOYSA-N 2-(4-hydroxyphenyl)-3-methyl-1-[[4-(2-piperidin-1-ylethoxy)phenyl]methyl]indol-5-ol Chemical compound C=1C=C(OCCN2CCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1 JICOGKJOQXTAIP-UHFFFAOYSA-N 0.000 description 2
- CQOQDQWUFQDJMK-SSTWWWIQSA-N 2-Methoxyestradiol Chemical compound C([C@@H]12)C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CCC1=C2C=C(OC)C(O)=C1 CQOQDQWUFQDJMK-SSTWWWIQSA-N 0.000 description 2
- PZBCKZWLPGJMAO-UHFFFAOYSA-N 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide Chemical compound C1=CC=2C3=NCCN3C(NC(=O)C=3C=NC(N)=NC=3)=NC=2C(OC)=C1OCCCN1CCOCC1 PZBCKZWLPGJMAO-UHFFFAOYSA-N 0.000 description 2
- BEUQXVWXFDOSAQ-UHFFFAOYSA-N 2-methyl-2-[4-[2-(5-methyl-2-propan-2-yl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]propanamide Chemical compound CC(C)N1N=C(C)N=C1C1=CN(CCOC=2C3=CC=C(C=2)C2=CN(N=C2)C(C)(C)C(N)=O)C3=N1 BEUQXVWXFDOSAQ-UHFFFAOYSA-N 0.000 description 2
- YXOLAZRVSSWPPT-UHFFFAOYSA-N 3,5,7,2',4'-Pentahydroxyflavonol Chemical compound OC1=CC(O)=CC=C1C1=C(O)C(=O)C2=C(O)C=C(O)C=C2O1 YXOLAZRVSSWPPT-UHFFFAOYSA-N 0.000 description 2
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- KGPGFQWBCSZGEL-ZDUSSCGKSA-N 4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol Chemical compound C=12N(CC)C(C=3C(=NON=3)N)=NC2=C(C#CC(C)(C)O)N=CC=1OC[C@H]1CCCNC1 KGPGFQWBCSZGEL-ZDUSSCGKSA-N 0.000 description 2
- VVLHQJDAUIPZFH-UHFFFAOYSA-N 4-[4-[[5-fluoro-4-[3-(prop-2-enoylamino)anilino]pyrimidin-2-yl]amino]phenoxy]-N-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC=3N=C(NC=4C=C(NC(=O)C=C)C=CC=4)C(F)=CN=3)=CC=2)=C1 VVLHQJDAUIPZFH-UHFFFAOYSA-N 0.000 description 2
- UXXQOJXBIDBUAC-UHFFFAOYSA-N 4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-yl]-N-(4-propan-2-yloxyphenyl)piperazine-1-carboxamide Chemical compound COC1=CC2=C(N3CCN(CC3)C(=O)NC=3C=CC(OC(C)C)=CC=3)N=CN=C2C=C1OCCCN1CCCCC1 UXXQOJXBIDBUAC-UHFFFAOYSA-N 0.000 description 2
- 101700007241 APOC4 Proteins 0.000 description 2
- 101710034857 ATIC Proteins 0.000 description 2
- 229950001573 Abemaciclib Drugs 0.000 description 2
- 229940022663 Acetate Drugs 0.000 description 2
- 206010001019 Acute promyelocytic leukaemia Diseases 0.000 description 2
- 108010026410 Ado-Trastuzumab Emtansine Proteins 0.000 description 2
- 108010090838 Alemtuzumab Proteins 0.000 description 2
- JKOQGQFVAUAYPM-UHFFFAOYSA-N Amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 description 2
- 229960001097 Amifostine Drugs 0.000 description 2
- 229960003437 Aminoglutethimide Drugs 0.000 description 2
- ROBVIMPUHSLWNV-UHFFFAOYSA-N Aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 2
- 206010061424 Anal cancer Diseases 0.000 description 2
- 208000002399 Aphthous Stomatitis Diseases 0.000 description 2
- KZNIFHPLKGYRTM-UHFFFAOYSA-N Apigenin Chemical compound C1=CC(O)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C=C2O1 KZNIFHPLKGYRTM-UHFFFAOYSA-N 0.000 description 2
- 206010003399 Arthropod bite Diseases 0.000 description 2
- 206010073480 B-cell prolymphocytic leukaemia Diseases 0.000 description 2
- 206010003908 B-cell small lymphocytic lymphoma Diseases 0.000 description 2
- JOGKUKXHTYWRGZ-UHFFFAOYSA-N BEZ235 Chemical compound O=C1N(C)C2=CN=C3C=CC(C=4C=C5C=CC=CC5=NC=4)=CC3=C2N1C1=CC=C(C(C)(C)C#N)C=C1 JOGKUKXHTYWRGZ-UHFFFAOYSA-N 0.000 description 2
- YUXMAKUNSXIEKN-BTJKTKAUSA-N BGT226 Chemical compound OC(=O)\C=C/C(O)=O.C1=NC(OC)=CC=C1C1=CC=C(N=CC2=C3N(C=4C=C(C(N5CCNCC5)=CC=4)C(F)(F)F)C(=O)N2C)C3=C1 YUXMAKUNSXIEKN-BTJKTKAUSA-N 0.000 description 2
- 229960000190 Bacillus Calmette–Guérin vaccine Drugs 0.000 description 2
- UCJGJABZCDBEDK-UHFFFAOYSA-N Bazedoxifene Chemical compound C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1 UCJGJABZCDBEDK-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 108010071919 Bispecific Antibodies Proteins 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 229960001561 Bleomycin Drugs 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- 229940083476 Bosulif Drugs 0.000 description 2
- 101710005912 CDH2 Proteins 0.000 description 2
- 102100019396 CDK2 Human genes 0.000 description 2
- 102100005310 CTLA4 Human genes 0.000 description 2
- 101700054183 CTLA4 Proteins 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L Calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N Camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 2
- 229960004117 Capecitabine Drugs 0.000 description 2
- 229960004562 Carboplatin Drugs 0.000 description 2
- 206010007275 Carcinoid tumour Diseases 0.000 description 2
- 208000010027 Carcinoma, Intraductal, Noninfiltrating Diseases 0.000 description 2
- 208000005024 Castleman Disease Diseases 0.000 description 2
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- 229960004630 Chlorambucil Drugs 0.000 description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N Chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 2
- QMBJSIBWORFWQT-DFXBJWIESA-N Chlormadinone acetate Chemical compound C1=C(Cl)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 QMBJSIBWORFWQT-DFXBJWIESA-N 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N Chlormethine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 229950009003 Cilengitide Drugs 0.000 description 2
- 229940001468 Citrate Drugs 0.000 description 2
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 2
- 206010010741 Conjunctivitis Diseases 0.000 description 2
- 208000009798 Craniopharyngioma Diseases 0.000 description 2
- 208000004921 Cutaneous Lupus Erythematosus Diseases 0.000 description 2
- ATDGTVJJHBUTRL-UHFFFAOYSA-N Cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 2
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 2
- 229960004397 Cyclophosphamide Drugs 0.000 description 2
- 229960000978 Cyproterone Acetate Drugs 0.000 description 2
- UWFYSQMTEOIJJG-FDTZYFLXSA-N Cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 description 2
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 2
- 108009000097 DNA Replication Proteins 0.000 description 2
- 230000004543 DNA replication Effects 0.000 description 2
- 229960003957 Dexamethasone Drugs 0.000 description 2
- 229960000605 Dexrazoxane Drugs 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N Docetaxel Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- 229950005778 Dovitinib Drugs 0.000 description 2
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 2
- 229950004203 Droloxifene Drugs 0.000 description 2
- CYQFCXCEBYINGO-DLBZAZTESA-N Dronabinol Natural products C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@H]21 CYQFCXCEBYINGO-DLBZAZTESA-N 0.000 description 2
- 206010013687 Drug eruption Diseases 0.000 description 2
- 102100010782 EGFR Human genes 0.000 description 2
- 101700039191 EGFR Proteins 0.000 description 2
- 229940121647 EGFR inhibitors Drugs 0.000 description 2
- 229950002189 Enzastaurin Drugs 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 206010014950 Eosinophilia Diseases 0.000 description 2
- 229940082789 Erbitux Drugs 0.000 description 2
- 210000003238 Esophagus Anatomy 0.000 description 2
- 208000002047 Essential Thrombocythemia Diseases 0.000 description 2
- 229960005309 Estradiol Drugs 0.000 description 2
- 208000006168 Ewing Sarcoma Diseases 0.000 description 2
- 102100004573 FLT3 Human genes 0.000 description 2
- 101710009074 FLT3 Proteins 0.000 description 2
- XHEFDIBZLJXQHF-UHFFFAOYSA-N Fisetin Chemical compound C=1C(O)=CC=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 XHEFDIBZLJXQHF-UHFFFAOYSA-N 0.000 description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N Floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 2
- 229960000961 Floxuridine Drugs 0.000 description 2
- 206010017533 Fungal infection Diseases 0.000 description 2
- 229940080856 Gleevec Drugs 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 229960003690 Goserelin Acetate Drugs 0.000 description 2
- 101710004393 HAVCR2 Proteins 0.000 description 2
- 102100016384 HAVCR2 Human genes 0.000 description 2
- 229910004039 HBF4 Inorganic materials 0.000 description 2
- 208000001258 Hemangiosarcoma Diseases 0.000 description 2
- 206010073071 Hepatocellular carcinoma Diseases 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 102100005044 IL11 Human genes 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
- 229960000908 Idarubicin Drugs 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin hydrochloride Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- 229960003445 Idelalisib Drugs 0.000 description 2
- 229960001101 Ifosfamide Drugs 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N Ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- 210000000987 Immune System Anatomy 0.000 description 2
- 229940102223 Injectable Solution Drugs 0.000 description 2
- 206010073094 Intraductal proliferative breast lesion Diseases 0.000 description 2
- 108010089187 Ipilimumab Proteins 0.000 description 2
- 229940084651 Iressa Drugs 0.000 description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N Irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
- 102100019518 JAK3 Human genes 0.000 description 2
- 101700007593 JAK3 Proteins 0.000 description 2
- 206010023332 Keratitis Diseases 0.000 description 2
- 206010023347 Keratoacanthoma Diseases 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 2
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 2
- 206010023825 Laryngeal cancer Diseases 0.000 description 2
- GXESHMAMLJKROZ-IAPPQJPRSA-N Lasofoxifene Chemical compound C1([C@@H]2[C@@H](C3=CC=C(C=C3CC2)O)C=2C=CC(OCCN3CCCC3)=CC=2)=CC=CC=C1 GXESHMAMLJKROZ-IAPPQJPRSA-N 0.000 description 2
- VHOGYURTWQBHIL-UHFFFAOYSA-N Leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 2
- GOTYRUGSSMKFNF-UHFFFAOYSA-N Lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 208000001152 Leukemia, Prolymphocytic, B-Cell Diseases 0.000 description 2
- 208000005749 Leukemia, Promyelocytic, Acute Diseases 0.000 description 2
- 108010000817 Leuprolide Proteins 0.000 description 2
- 229940089022 Leuprolide Acetate Drugs 0.000 description 2
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levotetramisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 2
- IQPNAANSBPBGFQ-UHFFFAOYSA-N Luteolin Chemical compound C=1C(O)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(O)C(O)=C1 IQPNAANSBPBGFQ-UHFFFAOYSA-N 0.000 description 2
- 208000009285 Lymphoma, Large B-Cell, Diffuse Diseases 0.000 description 2
- 208000006116 Lymphomatoid Granulomatosis Diseases 0.000 description 2
- 102100000165 MS4A1 Human genes 0.000 description 2
- 101710010909 MS4A1 Proteins 0.000 description 2
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 2
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 229940091250 Magnesium supplements Drugs 0.000 description 2
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 2
- 208000003393 Mammary Paget's Disease Diseases 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 229960004961 Mechlorethamine Drugs 0.000 description 2
- 208000000172 Medulloblastoma Diseases 0.000 description 2
- KBOPZPXVLCULAV-UHFFFAOYSA-N Mesalazine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 2
- 229960004635 Mesna Drugs 0.000 description 2
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 2
- 206010027406 Mesothelioma Diseases 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- VHRSUDSXCMQTMA-PJHHCJLFSA-N Methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 2
- 229960001156 Mitoxantrone Drugs 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N Mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- FOFDIMHVKGYHRU-UHFFFAOYSA-N N-(1,3-benzodioxol-5-ylmethyl)-4-([1]benzofuro[3,2-d]pyrimidin-4-yl)piperazine-1-carbothioamide 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
- DUYJMQONPNNFPI-UHFFFAOYSA-N N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide Chemical compound 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 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
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 2
- 108010035649 Natalizumab Proteins 0.000 description 2
- XWXYUMMDTVBTOU-UHFFFAOYSA-N Nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 2
- 206010029461 Nodal marginal zone B-cell lymphomas Diseases 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 229940049964 Oleate Drugs 0.000 description 2
- 229950000778 Olmutinib Drugs 0.000 description 2
- 229960005343 Ondansetron Drugs 0.000 description 2
- FELGMEQIXOGIFQ-UHFFFAOYSA-N Ondansetron Chemical compound CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-UHFFFAOYSA-N 0.000 description 2
- 229940098444 Opdivo Drugs 0.000 description 2
- 229940054534 Ophthalmic Solution Drugs 0.000 description 2
- 206010031096 Oropharyngeal cancer Diseases 0.000 description 2
- 208000010191 Osteitis Deformans Diseases 0.000 description 2
- WRUUGTRCQOWXEG-UHFFFAOYSA-N Pamidronic acid Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 2
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 2
- 229960001373 Pegfilgrastim Drugs 0.000 description 2
- 206010034299 Penile cancer Diseases 0.000 description 2
- 229950010632 Perifosine Drugs 0.000 description 2
- 206010034590 Peripheral nerve sheath tumour malignant Diseases 0.000 description 2
- CTRLRINCMYICJO-UHFFFAOYSA-N Phenyl azide Chemical compound [N-]=[N+]=NC1=CC=CC=C1 CTRLRINCMYICJO-UHFFFAOYSA-N 0.000 description 2
- 102000003993 Phosphatidylinositol 3-Kinases Human genes 0.000 description 2
- 108090000430 Phosphatidylinositol 3-Kinases Proteins 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229950010773 Pidilizumab Drugs 0.000 description 2
- 229940023488 Pill Drugs 0.000 description 2
- 229950002592 Pimasertib Drugs 0.000 description 2
- 208000007525 Plasmablastic Lymphoma Diseases 0.000 description 2
- 229960003171 Plicamycin Drugs 0.000 description 2
- 229960003975 Potassium Drugs 0.000 description 2
- OKBMCNHOEMXPTM-UHFFFAOYSA-M Potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 2
- 206010065857 Primary effusion lymphoma Diseases 0.000 description 2
- 206010057846 Primitive neuroectodermal tumour Diseases 0.000 description 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N Procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 2
- CPTBDICYNRMXFX-UHFFFAOYSA-N Procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 2
- 206010036774 Proctitis Diseases 0.000 description 2
- CVWXJKQAOSCOAB-UHFFFAOYSA-N Quizartinib Chemical compound O1C(C(C)(C)C)=CC(NC(=O)NC=2C=CC(=CC=2)C=2N=C3N(C4=CC=C(OCCN5CCOCC5)C=C4S3)C=2)=N1 CVWXJKQAOSCOAB-UHFFFAOYSA-N 0.000 description 2
- 229950008933 Refametinib Drugs 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 206010061934 Salivary gland cancer Diseases 0.000 description 2
- 206010039710 Scleroderma Diseases 0.000 description 2
- 210000000952 Spleen Anatomy 0.000 description 2
- 108010039445 Stem Cell Factor Proteins 0.000 description 2
- 229960001052 Streptozocin Drugs 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N Streptozotocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 208000010502 Subcutaneous panniculitis-like T-cell lymphoma Diseases 0.000 description 2
- 206010042863 Synovial sarcoma Diseases 0.000 description 2
- 201000008717 T-cell large granular lymphocyte leukemia Diseases 0.000 description 2
- 108060008443 TPPP Proteins 0.000 description 2
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 2
- 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 2
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 2
- 229940069905 Tasigna Drugs 0.000 description 2
- 210000001138 Tears Anatomy 0.000 description 2
- 229960005353 Testolactone Drugs 0.000 description 2
- 229940033529 Tetrahydrocannabinol Drugs 0.000 description 2
- 229960003433 Thalidomide Drugs 0.000 description 2
- UEJJHQNACJXSKW-UHFFFAOYSA-N Thalidomide Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N ThioTEPA Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 2
- 229960001196 Thiotepa Drugs 0.000 description 2
- 206010043515 Throat cancer Diseases 0.000 description 2
- XFCLJVABOIYOMF-QPLCGJKRSA-N Toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 2
- 231100000765 Toxin Toxicity 0.000 description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- 206010046431 Urethral cancer Diseases 0.000 description 2
- 210000003932 Urinary Bladder Anatomy 0.000 description 2
- 102100015314 VSIR Human genes 0.000 description 2
- 101710036075 VSIR Proteins 0.000 description 2
- 206010046885 Vaginal cancer Diseases 0.000 description 2
- 206010046914 Vaginal infection Diseases 0.000 description 2
- 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 2
- 229950000578 Vatalanib Drugs 0.000 description 2
- 206010047461 Viral infection Diseases 0.000 description 2
- 208000001756 Virus Disease Diseases 0.000 description 2
- 229960000237 Vorinostat Drugs 0.000 description 2
- 206010047741 Vulval cancer Diseases 0.000 description 2
- 206010047802 Waldenstrom's macroglobulinaemias Diseases 0.000 description 2
- QDLHCMPXEPAAMD-QAIWCSMKSA-N Wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 2
- 241000209149 Zea Species 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- CGTADGCBEXYWNE-BJFMSCRISA-N Zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](C(C)=CC=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-BJFMSCRISA-N 0.000 description 2
- 229950009819 Zotarolimus Drugs 0.000 description 2
- AVFUHBJCUUTGCD-UHFFFAOYSA-M [Br-].[Mg+]C Chemical compound [Br-].[Mg+]C AVFUHBJCUUTGCD-UHFFFAOYSA-M 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IKDXDQDKCZPQSZ-JHYYTBFNSA-N acetic acid;(2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopro Chemical compound CC(O)=O.C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 IKDXDQDKCZPQSZ-JHYYTBFNSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229940089792 ado-trastuzumab emtansine Drugs 0.000 description 2
- 201000005188 adrenal gland cancer Diseases 0.000 description 2
- 229960000548 alemtuzumab Drugs 0.000 description 2
- 229960001445 alitretinoin Drugs 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000007854 aminals Chemical class 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 201000003076 angiosarcoma Diseases 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 230000002280 anti-androgenic Effects 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 201000011165 anus cancer Diseases 0.000 description 2
- 239000003886 aromatase inhibitor Substances 0.000 description 2
- 238000007080 aromatic substitution reaction Methods 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- DVQHYTBCTGYNNN-UHFFFAOYSA-N azane;cyclobutane-1,1-dicarboxylic acid;platinum Chemical compound N.N.[Pt].OC(=O)C1(C(O)=O)CCC1 DVQHYTBCTGYNNN-UHFFFAOYSA-N 0.000 description 2
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 2
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 description 2
- 150000007514 bases Chemical class 0.000 description 2
- 229960000817 bazedoxifene Drugs 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229960002938 bexarotene Drugs 0.000 description 2
- LKJPYSCBVHEWIU-KRWDZBQOSA-N bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 2
- 229960000997 bicalutamide Drugs 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- 210000004271 bone marrow stromal cells Anatomy 0.000 description 2
- 201000005216 brain cancer Diseases 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 229960002092 busulfan Drugs 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N cd3od Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000022534 cell killing Effects 0.000 description 2
- 230000011748 cell maturation Effects 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 108091006028 chimera Proteins 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229960002436 cladribine Drugs 0.000 description 2
- ZNEWHQLOPFWXOF-UHFFFAOYSA-N coenzyme M Chemical compound OS(=O)(=O)CCS ZNEWHQLOPFWXOF-UHFFFAOYSA-N 0.000 description 2
- 201000011231 colorectal cancer Diseases 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- 235000005824 corn Nutrition 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 230000001808 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- 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 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 201000004624 dermatitis Diseases 0.000 description 2
- DHZYXWMZLAKTQV-UHFFFAOYSA-N diazepin-3-one Chemical class O=C1C=CC=CN=N1 DHZYXWMZLAKTQV-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 2
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 2
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 2
- 125000000532 dioxanyl group Chemical group 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- CNXMDTWQWLGCPE-UHFFFAOYSA-N ditert-butyl-(2-phenylphenyl)phosphane Chemical compound CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1C1=CC=CC=C1 CNXMDTWQWLGCPE-UHFFFAOYSA-N 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- 229960004242 dronabinol Drugs 0.000 description 2
- 201000007273 ductal carcinoma in situ Diseases 0.000 description 2
- 231100001003 eczema Toxicity 0.000 description 2
- 210000002919 epithelial cells Anatomy 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N ethoxyethane;trifluoroborane Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 201000006569 extramedullary plasmacytoma Diseases 0.000 description 2
- 150000002194 fatty esters Chemical class 0.000 description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 201000003928 fungal infectious disease Diseases 0.000 description 2
- 201000008052 gamma heavy chain disease Diseases 0.000 description 2
- 230000002496 gastric Effects 0.000 description 2
- 201000003741 gastrointestinal carcinoma Diseases 0.000 description 2
- 201000010915 glioblastoma multiforme Diseases 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000002489 hematologic Effects 0.000 description 2
- 201000005787 hematologic cancer Diseases 0.000 description 2
- 230000002440 hepatic Effects 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 2
- 230000002209 hydrophobic Effects 0.000 description 2
- 229960001330 hydroxycarbamide Drugs 0.000 description 2
- VSNHCAURESNICA-UHFFFAOYSA-N hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 2
- 229940027318 hydroxyurea Drugs 0.000 description 2
- 229960001507 ibrutinib Drugs 0.000 description 2
- 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 2
- IFSDAJWBUCMOAH-HNNXBMFYSA-N idelalisib Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 IFSDAJWBUCMOAH-HNNXBMFYSA-N 0.000 description 2
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 2
- 229940121650 immune-checkpoint protein inhibitors Drugs 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 230000001976 improved Effects 0.000 description 2
- 230000004968 inflammatory condition Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 229960005386 ipilimumab Drugs 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- 201000010666 keratoconjunctivitis Diseases 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- 229960002367 lasofoxifene Drugs 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229960000681 leflunomide Drugs 0.000 description 2
- 229960004942 lenalidomide Drugs 0.000 description 2
- 229960001614 levamisole Drugs 0.000 description 2
- 239000006194 liquid suspension Substances 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 201000009020 malignant peripheral nerve sheath tumor Diseases 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 description 2
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 2
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 229960004584 methylprednisolone Drugs 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 101700008033 myo2 Proteins 0.000 description 2
- IKMDFBPHZNJCSN-UHFFFAOYSA-N myricetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC(O)=C(O)C(O)=C1 IKMDFBPHZNJCSN-UHFFFAOYSA-N 0.000 description 2
- 229960005027 natalizumab Drugs 0.000 description 2
- 238000002663 nebulization Methods 0.000 description 2
- 201000011519 neuroendocrine tumor Diseases 0.000 description 2
- 201000004404 neurofibroma Diseases 0.000 description 2
- 229960002653 nilutamide Drugs 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 125000006501 nitrophenyl group Chemical group 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-N nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 201000002575 ocular melanoma Diseases 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 2
- 239000002997 ophthalmic solution Substances 0.000 description 2
- 201000002740 oral squamous cell carcinoma Diseases 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 201000006958 oropharynx cancer Diseases 0.000 description 2
- 229960003278 osimertinib Drugs 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-L oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 2
- 229960001756 oxaliplatin Drugs 0.000 description 2
- 201000010198 papillary carcinoma Diseases 0.000 description 2
- 201000005170 papillary thyroid carcinoma Diseases 0.000 description 2
- 230000001575 pathological Effects 0.000 description 2
- 108010044644 pegfilgrastim Proteins 0.000 description 2
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 2
- 108010042024 pertuzumab Proteins 0.000 description 2
- 229960002087 pertuzumab Drugs 0.000 description 2
- 230000000275 pharmacokinetic Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002935 phosphatidylinositol 3 kinase inhibitor Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Chemical group 0.000 description 2
- LHNIIDJUOCFXAP-UHFFFAOYSA-N pictrelisib Chemical compound C1CN(S(=O)(=O)C)CCN1CC1=CC2=NC(C=3C=4C=NNC=4C=CC=3)=NC(N3CCOCC3)=C2S1 LHNIIDJUOCFXAP-UHFFFAOYSA-N 0.000 description 2
- 108010051812 pidilizumab Proteins 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000000861 pro-apoptotic Effects 0.000 description 2
- 229960004919 procaine Drugs 0.000 description 2
- 229960000624 procarbazine Drugs 0.000 description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
- UDJFFSGCRRMVFH-UHFFFAOYSA-N pyrido[2,3-d]pyrimidine Chemical compound N1=CN=CC2=CC=CN=C21 UDJFFSGCRRMVFH-UHFFFAOYSA-N 0.000 description 2
- QDXGKRWDQCEABB-UHFFFAOYSA-N pyrimidine-5-carboxamide Chemical compound NC(=O)C1=CN=CN=C1 QDXGKRWDQCEABB-UHFFFAOYSA-N 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000001422 pyrrolinyl group Chemical group 0.000 description 2
- 150000004944 pyrrolopyrimidines Chemical class 0.000 description 2
- 238000007348 radical reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229960004836 regorafenib Drugs 0.000 description 2
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 2
- 230000000268 renotropic Effects 0.000 description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 2
- 229960003452 romidepsin Drugs 0.000 description 2
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 2
- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 description 2
- 229960002530 sargramostim Drugs 0.000 description 2
- 108010038379 sargramostim Proteins 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 238000002603 single-photon emission computed tomography Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 229960003339 sodium phosphate Drugs 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 201000006576 solitary osseous plasmacytoma Diseases 0.000 description 2
- 201000011096 spinal cancer Diseases 0.000 description 2
- 201000000445 splenic manifestation of leukemia Diseases 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 2
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 230000001954 sterilising Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 229940086735 succinate Drugs 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000011593 sulfur Chemical group 0.000 description 2
- 230000002195 synergetic Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- FHOVHCSODHLHQP-UHFFFAOYSA-N tert-butyl-(cyclohexen-1-ylmethoxy)-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCC1=CCCCC1 FHOVHCSODHLHQP-UHFFFAOYSA-N 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 2
- ODGCEQLVLXJUCC-UHFFFAOYSA-O tetrafluoroboric acid Chemical compound [H+].F[B-](F)(F)F ODGCEQLVLXJUCC-UHFFFAOYSA-O 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- 125000001984 thiazolidinyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 230000002992 thymic Effects 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 229960005267 tositumomab Drugs 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 108020003112 toxins Proteins 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 239000011778 trisodium citrate Substances 0.000 description 2
- 235000019263 trisodium citrate Nutrition 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 201000008100 vaginitis Diseases 0.000 description 2
- 229960000241 vandetanib Drugs 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 229960003862 vemurafenib Drugs 0.000 description 2
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- METQSPRSQINEEU-HXCATZOESA-N (1R,2R,4R,10R,11S,14S,15S,16S,18S,19S)-10,14-dimethylspiro[hexacyclo[9.8.0.0^{2,4}.0^{5,10}.0^{14,19}.0^{16,18}]nonadecane-15,2'-oxolan]-5-ene-5',7-dione Chemical compound C([C@]12[C@H]3C[C@H]3[C@H]3[C@H]4[C@@H]([C@]5(CCC(=O)C=C5[C@@H]5C[C@@H]54)C)CC[C@@]31C)CC(=O)O2 METQSPRSQINEEU-HXCATZOESA-N 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N (1R,3S,5Z)-5-{2-[(1R,3aS,4E,7aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-octahydro-1H-inden-4-ylidene]ethylidene}-4-methylidenecyclohexane-1,3-diol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- YCNCRLKXSLARFT-LLVKDONJSA-N (2R)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-3-[(2,2,2-trifluoroacetyl)amino]propanamide Chemical compound FC(F)(F)C(=O)NC[C@](O)(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 YCNCRLKXSLARFT-LLVKDONJSA-N 0.000 description 1
- QNDVLZJODHBUFM-FCXWGWLASA-N (2R)-3-[(2S,6R,8S,11R)-2-[(E,2R)-4-[(2S,2'S,4R,4aS,6R,8aR)-4-hydroxy-2-[(1S,3S)-1-hydroxy-3-[(2S,3R,6S)-3-methyl-1,7-dioxaspiro[5.5]undecan-2-yl]butyl]-3-methylidenespiro[4a,7,8,8a-tetrahydro-4H-pyrano[3,2-b]pyran-6,5'-oxolane]-2'-yl]but-3-en-2-yl]-11-hyd Chemical compound C([C@H](O1)[C@H](C)/C=C/[C@@H]2CC[C@@]3(CC[C@H]4O[C@@H](C([C@@H](O)[C@@H]4O3)=C)[C@@H](O)C[C@H](C)[C@@H]3[C@@H](CC[C@@]4(OCCCC4)O3)C)O2)C(C)=C[C@]21O[C@H](C[C@@](C)(O)C(O)=O)CC[C@H]2O QNDVLZJODHBUFM-FCXWGWLASA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- STUWGJZDJHPWGZ-LBPRGKRZSA-N (2S)-1-N-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-thiazol-2-yl]pyrrolidine-1,2-dicarboxamide Chemical compound S1C(C=2C=C(N=CC=2)C(C)(C)C(F)(F)F)=C(C)N=C1NC(=O)N1CCC[C@H]1C(N)=O STUWGJZDJHPWGZ-LBPRGKRZSA-N 0.000 description 1
- GRZXWCHAXNAUHY-NSISKUIASA-N (2S)-2-(4-chlorophenyl)-1-[4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]piperazin-1-yl]-3-(propan-2-ylamino)propan-1-one Chemical compound C1([C@H](C(=O)N2CCN(CC2)C=2C=3[C@H](C)C[C@@H](O)C=3N=CN=2)CNC(C)C)=CC=C(Cl)C=C1 GRZXWCHAXNAUHY-NSISKUIASA-N 0.000 description 1
- ZBVJFYPGLGEMIN-OYLNGHKZSA-N (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[(2-amino-2-oxoethyl)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-( Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1.C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 ZBVJFYPGLGEMIN-OYLNGHKZSA-N 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hy Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- ZVAGBRFUYHSUHA-LZOXOEDVSA-N (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole;methanesulfonic acid Chemical compound CS(O)(=O)=O.COC1=C\C(=C/2N=C3C=CC=CC3=C\2)N\C1=C/C=1NC(C)=CC=1C ZVAGBRFUYHSUHA-LZOXOEDVSA-N 0.000 description 1
- VJFDVDXXJRSPLZ-VIFPVBQESA-L (3S)-3-(1-carboxylatoethenoxy)cyclohepta-1,6-diene-1-carboxylate Chemical group [O-]C(=O)C(=C)O[C@H]1CCC=CC(C([O-])=O)=C1 VJFDVDXXJRSPLZ-VIFPVBQESA-L 0.000 description 1
- HOMJAAIVTDVQJA-IZHYLOQSSA-N (3Z)-3-[[3-[(dimethylamino)methyl]anilino]-phenylmethylidene]-N,N-dimethyl-2-oxo-1H-indole-6-carboxamide Chemical compound CN(C)CC1=CC=CC(N\C(=C/2C3=CC=C(C=C3NC\2=O)C(=O)N(C)C)C=2C=CC=CC=2)=C1 HOMJAAIVTDVQJA-IZHYLOQSSA-N 0.000 description 1
- BQNHHYZMVCQLJG-VHXPQNKSSA-N (3Z)-3-[[3-[(dimethylamino)methyl]anilino]-phenylmethylidene]-N-methyl-2-oxo-1H-indole-6-carboxamide Chemical compound O=C1NC2=CC(C(=O)NC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC1=CC=CC(CN(C)C)=C1 BQNHHYZMVCQLJG-VHXPQNKSSA-N 0.000 description 1
- DKSZLDSPXIWGFO-BLOJGBSASA-N (4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 description 1
- DEQANNDTNATYII-MEUDYGGUSA-N (4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-19-[[(2R)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-N-(1,3-dihydroxybutan-2-yl)-7-[(1R)-1-hydroxyethyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)NC(CO)C(O)C)C1=CC=CC=C1 DEQANNDTNATYII-MEUDYGGUSA-N 0.000 description 1
- DEQANNDTNATYII-OULOTJBUSA-N (4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-19-[[(2R)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-N-[(2R,3R)-1,3-dihydroxybutan-2-yl]-7-[(1R)-1-hydroxyethyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- UHIWBQIWXWWDKT-MRVPVSSYSA-N (4S)-4-hydroxy-2-(3-methoxypropyl)-1,1-dioxo-3,4-dihydrothieno[3,2-e]thiazine-6-sulfonamide Chemical compound O=S1(=O)N(CCCOC)C[C@@H](O)C2=C1SC(S(N)(=O)=O)=C2 UHIWBQIWXWWDKT-MRVPVSSYSA-N 0.000 description 1
- NBRQRXRBIHVLGI-OWXODZSWSA-N (4aS,5aR,12aR)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide Chemical compound C1C2=CC=CC(O)=C2C(O)=C(C2=O)[C@@H]1C[C@@H]1[C@@]2(O)C(O)=C(C(=O)N)C(=O)C1 NBRQRXRBIHVLGI-OWXODZSWSA-N 0.000 description 1
- UFBTYTGRUBUUIL-KPKJPENVSA-N (5E)-5-[[5-(4-fluorophenyl)furan-2-yl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C1=CC(F)=CC=C1C(O1)=CC=C1\C=C\1C(=O)NC(=O)S/1 UFBTYTGRUBUUIL-KPKJPENVSA-N 0.000 description 1
- QDITZBLZQQZVEE-YBEGLDIGSA-N (5Z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylidene]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)\C1=C\C1=CC=C(N=CC=C2C=3C=CN=CC=3)C2=C1 QDITZBLZQQZVEE-YBEGLDIGSA-N 0.000 description 1
- 125000006706 (C3-C6) carbocyclyl group Chemical group 0.000 description 1
- BWDQBBCUWLSASG-MDZDMXLPSA-N (E)-N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]prop-2-enamide Chemical compound C=1NC2=CC=CC=C2C=1CCN(CCO)CC1=CC=C(\C=C\C(=O)NO)C=C1 BWDQBBCUWLSASG-MDZDMXLPSA-N 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-Dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- QDVBKXJMLILLLB-UHFFFAOYSA-N 1,4'-bipiperidine Chemical compound C1CCCCN1C1CCNCC1 QDVBKXJMLILLLB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KOKTUHPFPWFELE-HCWSKCQFSA-N 1-[(2S,3R,4S,5R)-2-fluoro-3,4-dihydroxy-5-methyloxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@@]1(F)N1C(=O)NC(=O)C=C1 KOKTUHPFPWFELE-HCWSKCQFSA-N 0.000 description 1
- ZAXFYGBKZSQBIV-UHFFFAOYSA-N 1-[4-(3-ethyl-7-morpholin-4-yltriazolo[4,5-d]pyrimidin-5-yl)phenyl]-3-[4-(4-methylpiperazine-1-carbonyl)phenyl]urea Chemical compound N1=C2N(CC)N=NC2=C(N2CCOCC2)N=C1C(C=C1)=CC=C1NC(=O)NC(C=C1)=CC=C1C(=O)N1CCN(C)CC1 ZAXFYGBKZSQBIV-UHFFFAOYSA-N 0.000 description 1
- DWZAEMINVBZMHQ-UHFFFAOYSA-N 1-[4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl]-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea Chemical compound C1CC(N(C)C)CCN1C(=O)C(C=C1)=CC=C1NC(=O)NC1=CC=C(C=2N=C(N=C(N=2)N2CCOCC2)N2CCOCC2)C=C1 DWZAEMINVBZMHQ-UHFFFAOYSA-N 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- ZQQSYPZAPHRXRY-UHFFFAOYSA-N 1-hydroxyazetidine Chemical compound ON1CCC1 ZQQSYPZAPHRXRY-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- WHKWMTXTYKVFLK-UHFFFAOYSA-N 1-propan-2-ylpiperazine Chemical compound CC(C)N1CCNCC1 WHKWMTXTYKVFLK-UHFFFAOYSA-N 0.000 description 1
- HBALWXLTPDKZCF-UHFFFAOYSA-N 1-thiophen-3-yl-3,4-dihydroisoquinoline Chemical compound N=1CCC2=CC=CC=C2C=1C=1C=CSC=1 HBALWXLTPDKZCF-UHFFFAOYSA-N 0.000 description 1
- DOMWKUIIPQCAJU-LJHIYBGHSA-N 17-Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 description 1
- MHHOMHMNIRXARC-UHFFFAOYSA-N 1H-pyrido[2,3-d]pyrimidin-2-one Chemical compound C1=CN=C2NC(=O)N=CC2=C1 MHHOMHMNIRXARC-UHFFFAOYSA-N 0.000 description 1
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1H-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 description 1
- QMVPQBFHUJZJCS-NTKFZFFISA-N 1V8X590XDP Chemical compound O=C1N(NC(CO)CO)C(=O)C(C2=C3[CH]C=C(O)C=C3NC2=C23)=C1C2=C1C=CC(O)=C[C]1N3[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O QMVPQBFHUJZJCS-NTKFZFFISA-N 0.000 description 1
- HNRMPXKDFBEGFZ-UHFFFAOYSA-N 2,2-Dimethylbutane Chemical compound CCC(C)(C)C HNRMPXKDFBEGFZ-UHFFFAOYSA-N 0.000 description 1
- ROZCIVXTLACYNY-UHFFFAOYSA-N 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide Chemical compound C1=C(F)C(OC)=CC=C1NS(=O)(=O)C1=C(F)C(F)=C(F)C(F)=C1F ROZCIVXTLACYNY-UHFFFAOYSA-N 0.000 description 1
- RAYNZUHYMMLQQA-ZEQRLZLVSA-N 2,3,5-trihydroxy-7-methyl-N-[(2R)-2-phenylpropyl]-6-[1,6,7-trihydroxy-3-methyl-5-[[(2R)-2-phenylpropyl]carbamoyl]naphthalen-2-yl]naphthalene-1-carboxamide Chemical compound C1([C@@H](C)CNC(=O)C=2C3=CC(C)=C(C(=C3C=C(O)C=2O)O)C=2C(O)=C3C=C(O)C(O)=C(C3=CC=2C)C(=O)NC[C@H](C)C=2C=CC=CC=2)=CC=CC=C1 RAYNZUHYMMLQQA-ZEQRLZLVSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-Dimethylbutane Chemical compound CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- INUSQTPGSHFGHM-UHFFFAOYSA-N 2,4-dichloro-5-nitropyrimidine Chemical compound [O-][N+](=O)C1=CN=C(Cl)N=C1Cl INUSQTPGSHFGHM-UHFFFAOYSA-N 0.000 description 1
- QFWCYNPOPKQOKV-UHFFFAOYSA-N 2-(2-amino-3-methoxyphenyl)chromen-4-one Chemical compound COC1=CC=CC(C=2OC3=CC=CC=C3C(=O)C=2)=C1N QFWCYNPOPKQOKV-UHFFFAOYSA-N 0.000 description 1
- XKZQKPRCPNGNFR-UHFFFAOYSA-N 2-(3-hydroxyphenyl)phenol Chemical compound OC1=CC=CC(C=2C(=CC=CC=2)O)=C1 XKZQKPRCPNGNFR-UHFFFAOYSA-N 0.000 description 1
- NFIXBCVWIPOYCD-UHFFFAOYSA-N 2-(4-benzylphenoxy)-N,N-diethylethanamine Chemical compound C1=CC(OCCN(CC)CC)=CC=C1CC1=CC=CC=C1 NFIXBCVWIPOYCD-UHFFFAOYSA-N 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N 2-(morpholin-4-yl)ethyl (4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- MGGBYMDAPCCKCT-UHFFFAOYSA-N 2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)-1,3,5-triazine-2,4-diamine 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
- KQDBVHKNIYROHU-UHFFFAOYSA-N 2-[(4-aminopyrazolo[3,4-d]pyrimidin-1-yl)methyl]-5-methyl-3-(2-methylphenyl)quinazolin-4-one Chemical compound CC1=CC=CC=C1N1C(=O)C2=C(C)C=CC=C2N=C1CN1C2=NC=NC(N)=C2C=N1 KQDBVHKNIYROHU-UHFFFAOYSA-N 0.000 description 1
- ZMELOYOKMZBMRB-DLBZAZTESA-N 2-[6-chloro-5-[(2R,5S)-4-[(4-fluorophenyl)methyl]-2,5-dimethylpiperazine-1-carbonyl]-1-methylindol-3-yl]-N,N-dimethyl-2-oxoacetamide Chemical compound C([C@@H](C)N(C[C@@H]1C)C(=O)C=2C(=CC=3N(C)C=C(C=3C=2)C(=O)C(=O)N(C)C)Cl)N1CC1=CC=C(F)C=C1 ZMELOYOKMZBMRB-DLBZAZTESA-N 0.000 description 1
- IRTDIKMSKMREGO-OAHLLOKOSA-N 2-[[(1R)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoic acid Chemical compound N([C@H](C)C=1C=2N(C(C=C(N=2)N2CCOCC2)=O)C=C(C)C=1)C1=CC=CC=C1C(O)=O IRTDIKMSKMREGO-OAHLLOKOSA-N 0.000 description 1
- TXGKRVFSSHPBAJ-JKSUJKDBSA-N 2-[[(1R,2S)-2-aminocyclohexyl]amino]-4-[3-(triazol-2-yl)anilino]pyrimidine-5-carboxamide Chemical compound N[C@H]1CCCC[C@H]1NC1=NC=C(C(N)=O)C(NC=2C=C(C=CC=2)N2N=CC=N2)=N1 TXGKRVFSSHPBAJ-JKSUJKDBSA-N 0.000 description 1
- FZDFGHZZPBUTGP-UHFFFAOYSA-N 2-[[2-[bis(carboxymethyl)amino]-3-(4-isothiocyanatophenyl)propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)C(C)CN(CC(O)=O)CC(N(CC(O)=O)CC(O)=O)CC1=CC=C(N=C=S)C=C1 FZDFGHZZPBUTGP-UHFFFAOYSA-N 0.000 description 1
- WFSLJOPRIJSOJR-UHFFFAOYSA-N 2-[[4-amino-3-(3-hydroxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-5-methyl-3-(2-methylphenyl)quinazolin-4-one Chemical compound CC1=CC=CC=C1N1C(=O)C2=C(C)C=CC=C2N=C1CN1C2=NC=NC(N)=C2C(C=2C=C(O)C=CC=2)=N1 WFSLJOPRIJSOJR-UHFFFAOYSA-N 0.000 description 1
- QINPEPAQOBZPOF-UHFFFAOYSA-N 2-amino-N-[3-[[3-(2-chloro-5-methoxyanilino)quinoxalin-2-yl]sulfamoyl]phenyl]-2-methylpropanamide Chemical compound COC1=CC=C(Cl)C(NC=2C(=NC3=CC=CC=C3N=2)NS(=O)(=O)C=2C=C(NC(=O)C(C)(C)N)C=CC=2)=C1 QINPEPAQOBZPOF-UHFFFAOYSA-N 0.000 description 1
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 1
- INYSELGLAAADNH-UHFFFAOYSA-N 2-bromo-1,5,6,7-tetrahydropyrrolo[2,3-c]azepine-4,8-dione Chemical compound O=C1NCCC(=O)C2=C1NC(Br)=C2 INYSELGLAAADNH-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- IKCLCGXPQILATA-UHFFFAOYSA-M 2-chlorobenzoate Chemical compound [O-]C(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-M 0.000 description 1
- DZBKIOJXVOECRA-UHFFFAOYSA-N 2-chloropyrimidin-5-amine Chemical compound NC1=CN=C(Cl)N=C1 DZBKIOJXVOECRA-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- LLVZBTWPGQVVLW-SNAWJCMRSA-N 2-methoxy-N-[(E)-3-[4-[3-methyl-4-(6-methylpyridin-3-yl)oxyanilino]quinazolin-6-yl]prop-2-enyl]acetamide 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
- XTKLTGBKIDQGQL-UHFFFAOYSA-N 2-methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-morpholin-4-ylbenzimidazole-4-carboxylic acid Chemical compound CC1=NC2=C(C(O)=O)C=C(N3CCOCC3)C=C2N1CC1=CC=CC(C(F)(F)F)=C1C XTKLTGBKIDQGQL-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- NKBWMBRPILTCRD-UHFFFAOYSA-M 2-methylheptanoate Chemical compound CCCCCC(C)C([O-])=O NKBWMBRPILTCRD-UHFFFAOYSA-M 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- XSBLMLFNMRLZDG-UHFFFAOYSA-N 2-nitro-5-(4-piperidin-1-ylpiperidin-1-yl)pyridine Chemical compound C1=NC([N+](=O)[O-])=CC=C1N1CCC(N2CCCCC2)CC1 XSBLMLFNMRLZDG-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- FVYXIJYOAGAUQK-UHFFFAOYSA-N 3,5'-diallyl-4,2'-dihydroxybiphenyl Chemical compound C1=C(CC=C)C(O)=CC=C1C1=CC(CC=C)=CC=C1O FVYXIJYOAGAUQK-UHFFFAOYSA-N 0.000 description 1
- YWOWJQMFMXHLQD-UHFFFAOYSA-N 3-(trifluoromethyl)pyridin-2-amine Chemical compound NC1=NC=CC=C1C(F)(F)F YWOWJQMFMXHLQD-UHFFFAOYSA-N 0.000 description 1
- PFEOZHBOMNWTJB-UHFFFAOYSA-N 3-Methylpentane Chemical compound CCC(C)CC PFEOZHBOMNWTJB-UHFFFAOYSA-N 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N 3-Pentanone Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- FLBNLJLONKAPLR-DQSJHHFOSA-N 3-[(3Z)-3-[[4-[(dimethylamino)methyl]anilino]-phenylmethylidene]-2-oxo-1H-indol-6-yl]-N-ethylprop-2-ynamide Chemical compound O=C1NC2=CC(C#CC(=O)NCC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC1=CC=C(CN(C)C)C=C1 FLBNLJLONKAPLR-DQSJHHFOSA-N 0.000 description 1
- TYEXNVNUZXJNBN-YYADALCUSA-N 3-[(5E)-5-[[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]hydrazinylidene]-6-oxocyclohexa-1,3-dien-1-yl]benzoic acid Chemical compound O=C1C(N\N=C/2C(C(=CC=C\2)C=2C=C(C=CC=2)C(O)=O)=O)=C(C)NN1C1=CC=C(C)C(C)=C1 TYEXNVNUZXJNBN-YYADALCUSA-N 0.000 description 1
- NHFDRBXTEDBWCZ-ZROIWOOFSA-N 3-[2,4-dimethyl-5-[(Z)-(2-oxo-1H-indol-3-ylidene)methyl]-1H-pyrrol-3-yl]propanoic acid Chemical compound OC(=O)CCC1=C(C)NC(\C=C/2C3=CC=CC=C3NC\2=O)=C1C NHFDRBXTEDBWCZ-ZROIWOOFSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- JDQNYWYMNFRKNQ-UHFFFAOYSA-N 3-ethyl-4-methylpyridine Chemical compound CCC1=CN=CC=C1C JDQNYWYMNFRKNQ-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- FSASIHFSFGAIJM-UHFFFAOYSA-N 3-methyladenine Chemical compound CN1C=NC(N)=C2N=CN=C12 FSASIHFSFGAIJM-UHFFFAOYSA-N 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- BGLPECHZZQDNCD-UHFFFAOYSA-N 4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide Chemical compound C1CN(S(=O)(=O)CC)CCN1C(C=C1)=CC=C1NC1=NC=C(C(N)=O)C(NC2CC2)=N1 BGLPECHZZQDNCD-UHFFFAOYSA-N 0.000 description 1
- JVYNJRBSXBYXQB-UHFFFAOYSA-N 4-[3-(4-carboxyphenoxy)propoxy]benzoic acid;decanedioic acid Chemical compound OC(=O)CCCCCCCCC(O)=O.C1=CC(C(=O)O)=CC=C1OCCCOC1=CC=C(C(O)=O)C=C1 JVYNJRBSXBYXQB-UHFFFAOYSA-N 0.000 description 1
- HGVNLRPZOWWDKD-UHFFFAOYSA-N 4-[4-[2-(difluoromethyl)benzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl]morpholine Chemical compound FC(F)C1=NC2=CC=CC=C2N1C(N=1)=NC(N2CCOCC2)=NC=1N1CCOCC1 HGVNLRPZOWWDKD-UHFFFAOYSA-N 0.000 description 1
- XRYJULCDUUATMC-CYBMUJFWSA-N 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C1=CC=C(O)C=C1 XRYJULCDUUATMC-CYBMUJFWSA-N 0.000 description 1
- LQBVNQSMGBZMKD-UHFFFAOYSA-N 4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide Chemical compound C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 description 1
- HPLNQCPCUACXLM-PGUFJCEWSA-N 4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide Chemical compound C([C@@H](CCN(C)C)NC=1C(=CC(=CC=1)S(=O)(=O)NC(=O)C=1C=CC(=CC=1)N1CCN(CC=2C(=CC=CC=2)C=2C=CC(Cl)=CC=2)CC1)[N+]([O-])=O)SC1=CC=CC=C1 HPLNQCPCUACXLM-PGUFJCEWSA-N 0.000 description 1
- HHFBDROWDBDFBR-UHFFFAOYSA-N 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NC1=NC=C(CN=C(C=2C3=CC=C(Cl)C=2)C=2C(=CC=CC=2F)F)C3=N1 HHFBDROWDBDFBR-UHFFFAOYSA-N 0.000 description 1
- JDUBGYFRJFOXQC-KRWDZBQOSA-N 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide Chemical compound C1([C@H](CCO)NC(=O)C2(CCN(CC2)C=2C=3C=CNC=3N=CN=2)N)=CC=C(Cl)C=C1 JDUBGYFRJFOXQC-KRWDZBQOSA-N 0.000 description 1
- ZCCPLJOKGAACRT-UHFFFAOYSA-N 4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide Chemical compound CC1=CC=C(C(=O)NC=2C=C(C=CC=2)C(F)(F)F)C=C1NC(C=1C=NN(C)C=1N=1)=NC=1C1=CC=CN=C1 ZCCPLJOKGAACRT-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- JIFCFQDXHMUPGP-UHFFFAOYSA-N 4-tert-butyl-N-[2-methyl-3-[4-methyl-6-[4-(morpholine-4-carbonyl)anilino]-5-oxopyrazin-2-yl]phenyl]benzamide Chemical compound C1=CC=C(C=2N=C(NC=3C=CC(=CC=3)C(=O)N3CCOCC3)C(=O)N(C)C=2)C(C)=C1NC(=O)C1=CC=C(C(C)(C)C)C=C1 JIFCFQDXHMUPGP-UHFFFAOYSA-N 0.000 description 1
- XISPDFMAOWZEQG-UHFFFAOYSA-N 4H-1,4-oxazin-3-one Chemical compound O=C1COC=CN1 XISPDFMAOWZEQG-UHFFFAOYSA-N 0.000 description 1
- RXRZPHQBTHQXSV-UHFFFAOYSA-N 5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide Chemical compound CC(C)(C)NS(=O)(=O)C1=CN=CC(C2=CN3N=C(N)N=C3C(F)=C2)=C1 RXRZPHQBTHQXSV-UHFFFAOYSA-N 0.000 description 1
- RFWVETIZUQEJEF-UHFFFAOYSA-N 5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide Chemical compound OCCONC(=O)C=1C=CC2=CN=CN2C=1NC1=CC=C(I)C=C1F RFWVETIZUQEJEF-UHFFFAOYSA-N 0.000 description 1
- HJSSTXGDOIYXFL-DTORHVGOSA-N 5-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridin-2-amine Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(N)N=C1 HJSSTXGDOIYXFL-DTORHVGOSA-N 0.000 description 1
- UXPVYPKUBZTKIP-DTORHVGOSA-N 5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyridin-2-amine Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=CC=C(N)N=C1 UXPVYPKUBZTKIP-DTORHVGOSA-N 0.000 description 1
- GLEGVQXZOJSYSA-UHFFFAOYSA-N 5-[4-(2-methylpropyl)piperazin-1-yl]pyridin-2-amine Chemical compound C1CN(CC(C)C)CCN1C1=CC=C(N)N=C1 GLEGVQXZOJSYSA-UHFFFAOYSA-N 0.000 description 1
- YJISHJVIRFPGGN-UHFFFAOYSA-N 5-[5-[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxy-6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 YJISHJVIRFPGGN-UHFFFAOYSA-N 0.000 description 1
- ZHJGWYRLJUCMRT-QGZVFWFLSA-N 5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide Chemical compound O([C@H](C)C=1C(=CC=CC=1)C(F)(F)F)C(=C(S1)C(N)=O)C=C1N(C1=C2)C=NC1=CC=C2CN1CCN(C)CC1 ZHJGWYRLJUCMRT-QGZVFWFLSA-N 0.000 description 1
- ATXXLNCPVSUCNK-UHFFFAOYSA-N 5-bromo-2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Br)C=N1 ATXXLNCPVSUCNK-UHFFFAOYSA-N 0.000 description 1
- XXSSGBYXSKOLAM-UHFFFAOYSA-N 5-bromo-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide Chemical compound OCC(O)CONC(=O)C1=CC(Br)=C(F)C(F)=C1NC1=CC=C(I)C=C1F XXSSGBYXSKOLAM-UHFFFAOYSA-N 0.000 description 1
- VERWOWGGCGHDQE-UHFFFAOYSA-N 5-chloro-2-N-(5-methyl-4-piperidin-4-yl-2-propan-2-yloxyphenyl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine 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 1
- QQWUGDVOUVUTOY-UHFFFAOYSA-N 5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine Chemical compound COC1=CC(N2CCC(CC2)N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1S(=O)(=O)C(C)C QQWUGDVOUVUTOY-UHFFFAOYSA-N 0.000 description 1
- XSMSNFMDVXXHGJ-UHFFFAOYSA-N 6-(1H-indazol-6-yl)-N-(4-morpholin-4-ylphenyl)imidazo[1,2-a]pyrazin-8-amine Chemical compound C1COCCN1C(C=C1)=CC=C1NC1=NC(C=2C=C3NN=CC3=CC=2)=CN2C1=NC=C2 XSMSNFMDVXXHGJ-UHFFFAOYSA-N 0.000 description 1
- ACWZRVQXLIRSDF-UHFFFAOYSA-N 6-(4-bromo-2-fluoroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1F ACWZRVQXLIRSDF-UHFFFAOYSA-N 0.000 description 1
- BLQYVHBZHAISJM-CMDGGOBGSA-N 6-(4-methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine Chemical compound C1CN(C)CCN1C1=CC(NC=2NN=C(C)C=2)=NC(\C=C\C=2C=CC=CC=2)=N1 BLQYVHBZHAISJM-CMDGGOBGSA-N 0.000 description 1
- PHEZJEYUWHETKO-UHFFFAOYSA-N 6-Fluoro-2-(2'-Fluoro-1,1'-Biphenyl-4-Yl)-3-Methylquinoline-4-Carboxylic Acid Chemical compound N1=C2C=CC(F)=CC2=C(C(O)=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PHEZJEYUWHETKO-UHFFFAOYSA-N 0.000 description 1
- ILYBMUDLGFMEMU-UHFFFAOYSA-N 7-$l^{1}-oxidanyl-2,3,4,5,6,7-hexaoxoheptan-1-olate Chemical compound [O]C(=O)C(=O)C(=O)C(=O)C(=O)C(=O)C[O-] ILYBMUDLGFMEMU-UHFFFAOYSA-N 0.000 description 1
- PSGRLCOSIXJUAL-ZPQKBBRKSA-N 71YF100S3H Chemical compound CS(O)(=O)=O.C1=CC=C2C(C(OC3C[C@@H]4CC5C[C@@H](N4CC5=O)C3)=O)=CNC2=C1 PSGRLCOSIXJUAL-ZPQKBBRKSA-N 0.000 description 1
- YEAHTLOYHVWAKW-UHFFFAOYSA-N 8-(1-hydroxyethyl)-2-methoxy-3-[(4-methoxyphenyl)methoxy]benzo[c]chromen-6-one Chemical compound C1=CC(OC)=CC=C1COC(C(=C1)OC)=CC2=C1C1=CC=C(C(C)O)C=C1C(=O)O2 YEAHTLOYHVWAKW-UHFFFAOYSA-N 0.000 description 1
- LMJFJIDLEAWOQJ-CQSZACIVSA-N 8-[(1R)-1-(3,5-difluoroanilino)ethyl]-N,N-dimethyl-2-morpholin-4-yl-4-oxochromene-6-carboxamide Chemical compound N([C@H](C)C=1C2=C(C(C=C(O2)N2CCOCC2)=O)C=C(C=1)C(=O)N(C)C)C1=CC(F)=CC(F)=C1 LMJFJIDLEAWOQJ-CQSZACIVSA-N 0.000 description 1
- SJVQHLPISAIATJ-ZDUSSCGKSA-N 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]isoquinolin-1-one Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=CC2=CC=CC(Cl)=C2C(=O)N1C1=CC=CC=C1 SJVQHLPISAIATJ-ZDUSSCGKSA-N 0.000 description 1
- WDHAAJIGSXNPFO-UHFFFAOYSA-N 8H-pyrido[2,3-d]pyrimidin-7-one Chemical compound N1=CN=C2NC(=O)C=CC2=C1 WDHAAJIGSXNPFO-UHFFFAOYSA-N 0.000 description 1
- KDGFLJKFZUIJMX-UHFFFAOYSA-N 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-ylpiperidin-1-yl)-11-oxo-5H-benzo[b]carbazole-3-carbonitrile 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 1
- 208000002008 AIDS-Related Lymphoma Diseases 0.000 description 1
- 229940100198 ALKYLATING AGENTS Drugs 0.000 description 1
- VJZITPJGSQKZMX-XDPRQOKASA-N AMRUBICIN Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C(O)=C21)(N)C(=O)C)[C@H]1C[C@H](O)[C@H](O)CO1 VJZITPJGSQKZMX-XDPRQOKASA-N 0.000 description 1
- 229940030486 ANDROGENS Drugs 0.000 description 1
- 108060000400 ANGPTL8 Proteins 0.000 description 1
- 229940034982 ANTINEOPLASTIC AGENTS Drugs 0.000 description 1
- 229960003272 ASPARAGINASE Drugs 0.000 description 1
- 229940092117 ATGAM Drugs 0.000 description 1
- 230000035533 AUC Effects 0.000 description 1
- 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 1
- 108010061171 Abatacept Proteins 0.000 description 1
- 229940028652 Abraxane Drugs 0.000 description 1
- DUYNJNWVGIWJRI-LJAQVGFWSA-N Acolbifene Chemical compound C1=CC([C@H]2C(=C(C3=CC=C(O)C=C3O2)C)C=2C=CC(O)=CC=2)=CC=C1OCCN1CCCCC1 DUYNJNWVGIWJRI-LJAQVGFWSA-N 0.000 description 1
- 229950002421 Acolbifene Drugs 0.000 description 1
- 208000004064 Acoustic Neuroma Diseases 0.000 description 1
- 208000009621 Actinic Keratosis Diseases 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 108010007562 Adalimumab Proteins 0.000 description 1
- 201000004304 Addison's disease Diseases 0.000 description 1
- 206010001197 Adenocarcinoma of the cervix Diseases 0.000 description 1
- 208000007128 Adrenocortical Carcinoma Diseases 0.000 description 1
- 208000009746 Adult T-Cell Leukemia-Lymphoma Diseases 0.000 description 1
- TXUZVZSFRXZGTL-QPLCGJKRSA-N Afimoxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=C(O)C=C1 TXUZVZSFRXZGTL-QPLCGJKRSA-N 0.000 description 1
- 229940042992 Afinitor Drugs 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000282979 Alces alces Species 0.000 description 1
- 108010090726 Alefacept Proteins 0.000 description 1
- 229940110282 Alimta Drugs 0.000 description 1
- 240000000800 Allium ursinum Species 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N Allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 229960003235 Allopurinol Sodium Drugs 0.000 description 1
- 229960002692 Allylestrenol Drugs 0.000 description 1
- ATXHVCQZZJYMCF-XUDSTZEESA-N Allylestrenol Chemical compound C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)CC=C)[C@@H]4[C@@H]3CCC2=C1 ATXHVCQZZJYMCF-XUDSTZEESA-N 0.000 description 1
- 208000004631 Alopecia Areata Diseases 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N Alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229960001220 Amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N Amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229950009545 Amuvatinib Drugs 0.000 description 1
- 206010002023 Amyloidosis Diseases 0.000 description 1
- 206010002022 Amyloidosis Diseases 0.000 description 1
- OTBXOEAOVRKTNQ-UHFFFAOYSA-N Anagrelide Chemical compound N1=C2NC(=O)CN2CC2=C(Cl)C(Cl)=CC=C21 OTBXOEAOVRKTNQ-UHFFFAOYSA-N 0.000 description 1
- 206010002224 Anaplastic astrocytoma Diseases 0.000 description 1
- MWPLVEDNUUSJAV-UHFFFAOYSA-N Anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 1
- VGQOVCHZGQWAOI-HYUHUPJXSA-N Anthramycin Chemical compound N1[C@@H](O)[C@@H]2CC(\C=C\C(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-HYUHUPJXSA-N 0.000 description 1
- 229940046836 Anti-estrogens Drugs 0.000 description 1
- HJBWBFZLDZWPHF-UHFFFAOYSA-N Apalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C2(CCC2)C(=O)N(C=2C=C(C(C#N)=NC=2)C(F)(F)F)C1=S HJBWBFZLDZWPHF-UHFFFAOYSA-N 0.000 description 1
- 229950007511 Apalutamide Drugs 0.000 description 1
- 229940117893 Apigenin Drugs 0.000 description 1
- 241000256844 Apis mellifera Species 0.000 description 1
- 229950004111 Apitolisib Drugs 0.000 description 1
- UUSZLLQJYRSZIS-LXNNNBEUSA-N Aplidine Chemical compound CN([C@H](CC(C)C)C(=O)N[C@@H]1C(=O)N[C@@H]([C@H](CC(=O)O[C@H](C(=O)[C@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(OC)=CC=2)C(=O)O[C@@H]1C)C(C)C)O)[C@@H](C)CC)C(=O)[C@@H]1CCCN1C(=O)C(C)=O UUSZLLQJYRSZIS-LXNNNBEUSA-N 0.000 description 1
- ATALOFNDEOCMKK-OITMNORJSA-N Aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 1
- 229940059756 Arava Drugs 0.000 description 1
- 229940087620 Aromasin Drugs 0.000 description 1
- 229940046844 Aromatase inhibitors Drugs 0.000 description 1
- 229940091658 Arsenic Drugs 0.000 description 1
- 206010003267 Arthritis reactive Diseases 0.000 description 1
- MCGDSOGUHLTADD-UHFFFAOYSA-N Arzoxifene Chemical compound C1=CC(OC)=CC=C1C1=C(OC=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 MCGDSOGUHLTADD-UHFFFAOYSA-N 0.000 description 1
- 229950005529 Arzoxifene Drugs 0.000 description 1
- 229940072224 Asacol Drugs 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 229950009925 Atacicept Drugs 0.000 description 1
- 229950003462 Atiprimod Drugs 0.000 description 1
- SERHTTSLBVGRBY-UHFFFAOYSA-N Atiprimod Chemical compound C1CC(CCC)(CCC)CCC11CN(CCCN(CC)CC)CC1 SERHTTSLBVGRBY-UHFFFAOYSA-N 0.000 description 1
- MOTJMGVDPWRKOC-QPVYNBJUSA-N Atrasentan Chemical compound C1([C@H]2[C@@H]([C@H](CN2CC(=O)N(CCCC)CCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1 MOTJMGVDPWRKOC-QPVYNBJUSA-N 0.000 description 1
- 108090000206 Autoantibodies Proteins 0.000 description 1
- 102000003852 Autoantibodies Human genes 0.000 description 1
- 229940120638 Avastin Drugs 0.000 description 1
- 244000075850 Avena orientalis Species 0.000 description 1
- 235000007319 Avena orientalis Nutrition 0.000 description 1
- 235000007558 Avena sp Nutrition 0.000 description 1
- 229960002756 Azacitidine Drugs 0.000 description 1
- 229960002170 Azathioprine Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N Azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N BINAP Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 101700078037 BIND Proteins 0.000 description 1
- CWHUFRVAEUJCEF-UHFFFAOYSA-N BKM120 Chemical compound C1=NC(N)=CC(C(F)(F)F)=C1C1=CC(N2CCOCC2)=NC(N2CCOCC2)=N1 CWHUFRVAEUJCEF-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010060945 Bacterial infection Diseases 0.000 description 1
- 231100000699 Bacterial toxin Toxicity 0.000 description 1
- 108010067213 Basiliximab Proteins 0.000 description 1
- 208000003373 Basosquamous Carcinoma Diseases 0.000 description 1
- 229950001429 Batabulin Drugs 0.000 description 1
- 241001237885 Beet virus Q Species 0.000 description 1
- FEJKLNWAOXSSNR-UHFFFAOYSA-N Benorilate Chemical compound C1=CC(NC(=O)C)=CC=C1OC(=O)C1=CC=CC=C1OC(C)=O FEJKLNWAOXSSNR-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N Benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N Benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N Benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229950003054 Binimetinib Drugs 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- 206010061590 Blood disease Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 206010006007 Bone sarcoma Diseases 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N Bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 241001416153 Bos grunniens Species 0.000 description 1
- 206010006143 Brain stem glioma Diseases 0.000 description 1
- 229950010231 Brequinar Drugs 0.000 description 1
- 208000003362 Bronchogenic Carcinoma Diseases 0.000 description 1
- 229950003628 Buparlisib Drugs 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- 229960005084 CALCITRIOL Drugs 0.000 description 1
- 125000006416 CBr Chemical group BrC* 0.000 description 1
- 101700076962 CCNH Proteins 0.000 description 1
- 102100012044 CCNH Human genes 0.000 description 1
- 102100014481 CDH2 Human genes 0.000 description 1
- 102100006116 CDK7 Human genes 0.000 description 1
- 101700007872 CDK7 Proteins 0.000 description 1
- XDLYKKIQACFMJG-WKILWMFISA-N CHEMBL1234354 Chemical compound C1=NC(OC)=CC=C1C(C1=O)=CC2=C(C)N=C(N)N=C2N1[C@@H]1CC[C@@H](OCCO)CC1 XDLYKKIQACFMJG-WKILWMFISA-N 0.000 description 1
- 101710025159 CMPK1 Proteins 0.000 description 1
- WQCHQVJEKGJLRA-UHFFFAOYSA-N CN1C(CNCC1)C=1C=NC(=CC=1)[N+](=O)[O-] Chemical compound CN1C(CNCC1)C=1C=NC(=CC=1)[N+](=O)[O-] WQCHQVJEKGJLRA-UHFFFAOYSA-N 0.000 description 1
- 102100016705 COL18A1 Human genes 0.000 description 1
- 239000012275 CTLA-4 inhibitor Substances 0.000 description 1
- 229940121652 CTLA-4 inhibitors Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N C[N+](C)(C)CCO Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- ONIQOQHATWINJY-UHFFFAOYSA-N Cabozantinib Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 ONIQOQHATWINJY-UHFFFAOYSA-N 0.000 description 1
- 229960003563 Calcium Carbonate Drugs 0.000 description 1
- HXCHCVDVKSCDHU-LULTVBGHSA-N Calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 1
- 239000005461 Canertinib Substances 0.000 description 1
- 229950002826 Canertinib Drugs 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
- UJVLDDZCTMKXJK-WNHSNXHDSA-N Canrenone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CCC(=O)C=C3C=C2)C)CC[C@@]11C)C[C@@]11CCC(=O)O1 UJVLDDZCTMKXJK-WNHSNXHDSA-N 0.000 description 1
- 229940056434 Caprelsa Drugs 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- BLMPQMFVWMYDKT-NZTKNTHTSA-N Carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 description 1
- XGGTZCKQRWXCHW-WMTVXVAQSA-N Casopitant Chemical compound C1([C@H]2C[C@H](CCN2C(=O)N(C)[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)N2CCN(CC2)C(C)=O)=CC=C(F)C=C1C XGGTZCKQRWXCHW-WMTVXVAQSA-N 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N Celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 210000000170 Cell Membrane Anatomy 0.000 description 1
- 229940107810 Cellcept Drugs 0.000 description 1
- 229950006295 Cerdulatinib Drugs 0.000 description 1
- 210000003679 Cervix Uteri Anatomy 0.000 description 1
- 229960001616 Chlormadinone Acetate Drugs 0.000 description 1
- 229960002559 Chlorotrianisene Drugs 0.000 description 1
- BFPSDSIWYFKGBC-UHFFFAOYSA-N Chlorotrianisene Chemical compound C1=CC(OC)=CC=C1C(Cl)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 BFPSDSIWYFKGBC-UHFFFAOYSA-N 0.000 description 1
- 229940107161 Cholesterol Drugs 0.000 description 1
- 229960001231 Choline Drugs 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 210000000349 Chromosomes Anatomy 0.000 description 1
- 206010063209 Chronic allograft nephropathy Diseases 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N Cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- 229960001380 Cimetidine Drugs 0.000 description 1
- 229960002286 Clodronic Acid Drugs 0.000 description 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N Clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N Clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- 229960003608 Clomifene Drugs 0.000 description 1
- 229940107775 Clomiphene Drugs 0.000 description 1
- 230000037242 Cmax Effects 0.000 description 1
- 229960004415 Codeine Phosphate Drugs 0.000 description 1
- 206010009839 Coeliac disease Diseases 0.000 description 1
- IAKHMKGGTNLKSZ-INIZCTEOSA-N Colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 210000001072 Colon Anatomy 0.000 description 1
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 1
- 208000010247 Contact Dermatitis Diseases 0.000 description 1
- 229950002550 Copanlisib Drugs 0.000 description 1
- JYGXADMDTFJGBT-VWUMJDOOSA-N Cortisol Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N Crizotinib Chemical compound 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 1
- 102000016736 Cyclins Human genes 0.000 description 1
- 108050006400 Cyclins Proteins 0.000 description 1
- GVOUFPWUYJWQSK-UHFFFAOYSA-N Cyclofenil Chemical compound C1=CC(OC(=O)C)=CC=C1C(C=1C=CC(OC(C)=O)=CC=1)=C1CCCCC1 GVOUFPWUYJWQSK-UHFFFAOYSA-N 0.000 description 1
- 229960002944 Cyclofenil Drugs 0.000 description 1
- 229940119017 Cyclosporine Drugs 0.000 description 1
- DUSHUSLJJMDGTE-ZJPMUUANSA-N Cyproterone Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DUSHUSLJJMDGTE-ZJPMUUANSA-N 0.000 description 1
- 206010011732 Cyst Diseases 0.000 description 1
- 208000002445 Cystadenocarcinoma Diseases 0.000 description 1
- 231100000602 Cytoskeletal drug Toxicity 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 230000000970 DNA cross-linking Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-M DODECANESULFONATE ION Chemical compound CCCCCCCCCCCCS([O-])(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-M 0.000 description 1
- BFSMGDJOXZAERB-UHFFFAOYSA-N Dabrafenib Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 BFSMGDJOXZAERB-UHFFFAOYSA-N 0.000 description 1
- LHAPIGUPZIFFMA-XOGXUEEYSA-N Dacetuzumab Chemical compound O.Cl.O([C@@H]1[C@](C2=3)([C@]4(CC=5C6=CC=CC=C6NC=51)O)CC1)C=3C(O)=CC=C2CC4N1CC1CC1 LHAPIGUPZIFFMA-XOGXUEEYSA-N 0.000 description 1
- 229950007409 Dacetuzumab Drugs 0.000 description 1
- 108010084740 Daclizumab Proteins 0.000 description 1
- 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 1
- 229950002205 Dacomitinib Drugs 0.000 description 1
- 108010019673 Darbepoetin alfa Proteins 0.000 description 1
- 229940026692 Decadron Drugs 0.000 description 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N Decitabine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- CGBCCZZJVKUAMX-DFXBJWIESA-N Delmadinone acetate Chemical compound C1=C(Cl)C2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 CGBCCZZJVKUAMX-DFXBJWIESA-N 0.000 description 1
- SWJBYJJNDIXFSA-KUHUBIRLSA-N Demethoxyviridin Chemical compound O=C1C2=C3CCC(=O)C3=CC=C2[C@]2(C)C3=C1OC=C3C(=O)C[C@H]2O SWJBYJJNDIXFSA-KUHUBIRLSA-N 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N Depacane Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 229960004833 Dexamethasone phosphate Drugs 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Substances CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathy Diseases 0.000 description 1
- 206010061835 Diabetic nephropathy Diseases 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K Dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Didronel Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N Diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N Diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N Disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- CGHRJBLSXVCYQF-YXSUXZIUSA-N Dolasetron Chemical compound C1=CC=C[C]2C(C(O[C@@H]3C[C@@H]4C[C@@H]5C[C@@H](N4CC5=O)C3)=O)=CN=C21 CGHRJBLSXVCYQF-YXSUXZIUSA-N 0.000 description 1
- RMEDXOLNCUSCGS-UHFFFAOYSA-N Droperidol Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CC=C(N2C(NC3=CC=CC=C32)=O)CC1 RMEDXOLNCUSCGS-UHFFFAOYSA-N 0.000 description 1
- 229960000394 Droperidol Drugs 0.000 description 1
- 208000006402 Ductal Carcinoma Diseases 0.000 description 1
- 229950000317 Dulanermin Drugs 0.000 description 1
- 229950009791 Durvalumab Drugs 0.000 description 1
- 229950004949 Duvelisib Drugs 0.000 description 1
- JGMOKGBVKVMRFX-HQZYFCCVSA-N Dydrogesterone Chemical compound C1=CC2=CC(=O)CC[C@@]2(C)[C@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 JGMOKGBVKVMRFX-HQZYFCCVSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N EPIRUBICIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- 229960001904 EPIRUBICIN Drugs 0.000 description 1
- 229950001287 Edotecarin Drugs 0.000 description 1
- 229940020485 Elidel Drugs 0.000 description 1
- 229940120655 Eloxatin Drugs 0.000 description 1
- 229940073038 Elspar Drugs 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- AUVVAXYIELKVAI-CKBKHPSWSA-N Emetine Chemical compound N1CCC2=CC(OC)=C(OC)C=C2[C@H]1C[C@H]1C[C@H]2C3=CC(OC)=C(OC)C=C3CCN2C[C@@H]1CC AUVVAXYIELKVAI-CKBKHPSWSA-N 0.000 description 1
- 229950001969 Encorafenib Drugs 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- 229950002798 Enlimomab Drugs 0.000 description 1
- 229950004136 Entospletinib Drugs 0.000 description 1
- 229950000521 Entrectinib Drugs 0.000 description 1
- WXCXUHSOUPDCQV-UHFFFAOYSA-N Enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 description 1
- 229940088598 Enzyme Drugs 0.000 description 1
- 210000003979 Eosinophils Anatomy 0.000 description 1
- 229950002109 Epoetin delta Drugs 0.000 description 1
- 229950008767 Epoetin omega Drugs 0.000 description 1
- 229950005185 Epoetin zeta Drugs 0.000 description 1
- 206010015108 Epstein-Barr virus infection Diseases 0.000 description 1
- 229940109526 Ery Drugs 0.000 description 1
- 206010015281 Erythroleukaemia Diseases 0.000 description 1
- 240000006890 Erythroxylum coca Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 229960001842 Estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N Estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- PROQIPRRNZUXQM-ZXXIGWHRSA-N Estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 description 1
- 229960001348 Estriol Drugs 0.000 description 1
- 229940011871 Estrogens Drugs 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- 229950009569 Etaracizumab Drugs 0.000 description 1
- ZMMJGEGLRURXTF-UHFFFAOYSA-N Ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N Ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940009626 Etidronate Drugs 0.000 description 1
- XFBVBWWRPKNWHW-UHFFFAOYSA-N Etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 1
- 229960005293 Etodolac Drugs 0.000 description 1
- 101710038729 F2R Proteins 0.000 description 1
- 229950011548 FADROZOLE Drugs 0.000 description 1
- CLPFFLWZZBQMAO-UHFFFAOYSA-N Fadrozole Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 1
- 229940087861 Faslodex Drugs 0.000 description 1
- ZPAKPRAICRBAOD-UHFFFAOYSA-N Fenbufen Chemical compound C1=CC(C(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 ZPAKPRAICRBAOD-UHFFFAOYSA-N 0.000 description 1
- 229950008085 Figitumumab Drugs 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N Finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N Fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- AAXVEMMRQDVLJB-BULBTXNYSA-N Fludrocortisone Chemical compound O=C1CC[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 AAXVEMMRQDVLJB-BULBTXNYSA-N 0.000 description 1
- 229960002011 Fludrocortisone Drugs 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N Fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- 229960001751 Fluoxymesterone Drugs 0.000 description 1
- 102000016621 Focal Adhesion Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108010067715 Focal Adhesion Protein-Tyrosine Kinases Proteins 0.000 description 1
- OSVMTWJCGUFAOD-KZQROQTASA-N Formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
- 229950005309 Fostamatinib Drugs 0.000 description 1
- GKDRMWXFWHEQQT-UHFFFAOYSA-N Fostamatinib Chemical compound COC1=C(OC)C(OC)=CC(NC=2N=C(NC=3N=C4N(COP(O)(O)=O)C(=O)C(C)(C)OC4=CC=3)C(F)=CN=2)=C1 GKDRMWXFWHEQQT-UHFFFAOYSA-N 0.000 description 1
- 230000035520 G1 Phase Effects 0.000 description 1
- 230000010190 G1 phase Effects 0.000 description 1
- DEZZLWQELQORIU-RELWKKBWSA-N GDC-0879 Chemical compound N=1N(CCO)C=C(C=2C=C3CCC(/C3=CC=2)=N\O)C=1C1=CC=NC=C1 DEZZLWQELQORIU-RELWKKBWSA-N 0.000 description 1
- 210000000232 Gallbladder Anatomy 0.000 description 1
- 229950004792 Gavilimomab Drugs 0.000 description 1
- 229950008209 Gedatolisib Drugs 0.000 description 1
- 108010091266 Gemtuzumab Proteins 0.000 description 1
- UIVFUQKYVFCEKJ-OPTOVBNMSA-N Gimatecan Chemical compound C1=CC=C2C(\C=N\OC(C)(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UIVFUQKYVFCEKJ-OPTOVBNMSA-N 0.000 description 1
- 229950009073 Gimatecan Drugs 0.000 description 1
- 210000004907 Glands Anatomy 0.000 description 1
- 208000005017 Glioblastoma Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 229940065521 Glucocorticoid inhalants for obstructive airway disease Drugs 0.000 description 1
- 229960002989 Glutamic Acid Drugs 0.000 description 1
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N Glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 1
- 229940015043 Glyoxal Drugs 0.000 description 1
- 229960002913 Goserelin Drugs 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- IUAYMJGZBVDSGL-UHFFFAOYSA-N Gramicidin Chemical compound N1C(=O)C(CC(C)C)NC(=O)C(CCCN)NC(=O)C(C(C)C)NC(=O)C2CCCN2C(=O)C(CC=2C=CC=CC=2)NC(=O)C(CC(C)C)NC(=O)C(CCCN)NC(=O)C(C(C)C)NC(=O)C2CCCN2C(=O)C1CC1=CC=CC=C1 IUAYMJGZBVDSGL-UHFFFAOYSA-N 0.000 description 1
- 229960003727 Granisetron Drugs 0.000 description 1
- MFWNKCLOYSRHCJ-BTTYYORXSA-N Granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 description 1
- 208000003807 Graves Disease Diseases 0.000 description 1
- 201000004779 Graves' disease Diseases 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 201000000439 HCL-V Diseases 0.000 description 1
- 102100000579 HGF Human genes 0.000 description 1
- LNEPOXFFQSENCJ-UHFFFAOYSA-N Haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 1
- 208000002125 Hemangioendothelioma Diseases 0.000 description 1
- 206010019759 Hepatitis chronic persistent Diseases 0.000 description 1
- 206010066957 Hepatosplenic T-cell lymphoma Diseases 0.000 description 1
- 229940022353 Herceptin Drugs 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 206010020118 Histiocytosis Diseases 0.000 description 1
- 206010020244 Hodgkin's disease nodular sclerosis Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000006572 Human Influenza Diseases 0.000 description 1
- 241001502974 Human gammaherpesvirus 8 Species 0.000 description 1
- 229940048921 Humira Drugs 0.000 description 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N Hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 1
- 208000009576 Hypercholesterolemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021042 Hypopharyngeal cancer Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 229940061301 Ibrance Drugs 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- JJKOTMDDZAJTGQ-DQSJHHFOSA-N Idoxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN2CCCC2)=CC=1)/C1=CC=C(I)C=C1 JJKOTMDDZAJTGQ-DQSJHHFOSA-N 0.000 description 1
- 229950002248 Idoxifene Drugs 0.000 description 1
- 229960004716 Idoxuridine Drugs 0.000 description 1
- 229960003685 Imatinib mesylate Drugs 0.000 description 1
- 108010027440 Immunoconjugates Proteins 0.000 description 1
- 102000018748 Immunoconjugates Human genes 0.000 description 1
- 102000018358 Immunoglobulins Human genes 0.000 description 1
- 108060003951 Immunoglobulins Proteins 0.000 description 1
- 208000007866 Immunoproliferative Small Intestinal Disease Diseases 0.000 description 1
- 231100000608 Immunotoxin Toxicity 0.000 description 1
- 108010004484 Immunotoxins Proteins 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Incidol Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N Indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
- QADPYRIHXKWUSV-UHFFFAOYSA-N Infigratinib 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 1
- 208000005726 Inflammatory Breast Neoplasms Diseases 0.000 description 1
- 108010053490 Infliximab Proteins 0.000 description 1
- 206010022000 Influenza Diseases 0.000 description 1
- 229960003521 Interferon Alfa-2a Drugs 0.000 description 1
- 229960003507 Interferon Alfa-2b Drugs 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 229940074383 Interleukin-11 Drugs 0.000 description 1
- 108090000177 Interleukin-11 Proteins 0.000 description 1
- 229940117681 Interleukin-12 Drugs 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 229940076264 Interleukin-3 Drugs 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 102000004890 Interleukin-8 Human genes 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 241001058354 Inti Species 0.000 description 1
- 206010070999 Intraductal papillary mucinous neoplasm Diseases 0.000 description 1
- 206010061252 Intraocular melanoma Diseases 0.000 description 1
- 206010022970 Iron deficiency Diseases 0.000 description 1
- 206010022971 Iron deficiency Diseases 0.000 description 1
- 208000006617 Islet Cell Carcinoma Diseases 0.000 description 1
- WFKAJVHLWXSISD-UHFFFAOYSA-N Isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 1
- VFQXVTODMYMSMJ-UHFFFAOYSA-N Isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 description 1
- 229940011083 Istodax Drugs 0.000 description 1
- 210000001847 Jaw Anatomy 0.000 description 1
- 206010023256 Juvenile melanoma benign Diseases 0.000 description 1
- 102100013180 KDR Human genes 0.000 description 1
- XMAYWYJOQHXEEK-OZXSUGGESA-N Ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- 229940022039 Keytruda Drugs 0.000 description 1
- 210000003734 Kidney Anatomy 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 1
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 1
- 239000002137 L01XE24 - Ponatinib Substances 0.000 description 1
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 description 1
- 102100005720 LEFTY2 Human genes 0.000 description 1
- 101710017548 LEFTY2 Proteins 0.000 description 1
- CMJCXYNUCSMDBY-ZDUSSCGKSA-N LGX818 Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 CMJCXYNUCSMDBY-ZDUSSCGKSA-N 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N Lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 206010023791 Large granular lymphocytosis Diseases 0.000 description 1
- 229940067606 Lecithin Drugs 0.000 description 1
- 229960002293 Leucovorin Calcium Drugs 0.000 description 1
- 206010024305 Leukaemia monocytic Diseases 0.000 description 1
- 208000009503 Leukemia, Erythroblastic, Acute Diseases 0.000 description 1
- 208000000015 Leukemia, Neutrophilic, Chronic Diseases 0.000 description 1
- 208000000748 Leukemia, Prolymphocytic, T-Cell Diseases 0.000 description 1
- 229940087875 Leukine Drugs 0.000 description 1
- 229940008250 Leuprolide Drugs 0.000 description 1
- 229950002884 Lexatumumab Drugs 0.000 description 1
- 210000000088 Lip Anatomy 0.000 description 1
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N Lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 208000000265 Lobular Carcinoma Diseases 0.000 description 1
- DIWRORZWFLOCLC-UHFFFAOYSA-N Lorazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-UHFFFAOYSA-N 0.000 description 1
- 229950004563 Lucatumumab Drugs 0.000 description 1
- 206010025135 Lupus erythematosus Diseases 0.000 description 1
- 206010025224 Lymphangiosarcomas Diseases 0.000 description 1
- 206010025312 Lymphoma AIDS related Diseases 0.000 description 1
- 208000006557 Lymphoma, B-Cell, Marginal Zone Diseases 0.000 description 1
- 208000005194 Lymphoma, Large-Cell, Immunoblastic Diseases 0.000 description 1
- 230000035779 M Phase Effects 0.000 description 1
- 230000027311 M phase Effects 0.000 description 1
- 101700079340 MID1 Proteins 0.000 description 1
- 102100009854 MID1 Human genes 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L Magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 229950001869 Mapatumumab Drugs 0.000 description 1
- OCSMOTCMPXTDND-OUAUKWLOSA-N Marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 229950008959 Marimastat Drugs 0.000 description 1
- 229940034322 Marqibo Drugs 0.000 description 1
- 208000008585 Mastocytosis Diseases 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 210000003593 Megakaryocytes Anatomy 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N Meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 210000003584 Mesangial Cells Anatomy 0.000 description 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 1
- 206010061289 Metastatic neoplasm Diseases 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N Methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N Methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N Metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 102000028664 Microtubules Human genes 0.000 description 1
- 108091022031 Microtubules Proteins 0.000 description 1
- 210000004688 Microtubules Anatomy 0.000 description 1
- DDLIGBOFAVUZHB-UHFFFAOYSA-N Midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 1
- 229960003793 Midazolam Drugs 0.000 description 1
- PQLXHQMOHUQAKB-UHFFFAOYSA-N Miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 description 1
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 1
- 229960004857 Mitomycin Drugs 0.000 description 1
- 208000010190 Monoclonal Gammopathy of Undetermined Significance Diseases 0.000 description 1
- ZTFBIUXIQYRUNT-MDWZMJQESA-N Mubritinib Chemical compound C1=CC(C(F)(F)F)=CC=C1\C=C\C1=NC(COC=2C=CC(CCCCN3N=NC=C3)=CC=2)=CO1 ZTFBIUXIQYRUNT-MDWZMJQESA-N 0.000 description 1
- 210000003097 Mucus Anatomy 0.000 description 1
- 208000006876 Multiple Endocrine Neoplasia Type 2b Diseases 0.000 description 1
- 108090000393 Muromonab-CD3 Proteins 0.000 description 1
- 241001467552 Mycobacterium bovis BCG Species 0.000 description 1
- 229960000951 Mycophenolic Acid Drugs 0.000 description 1
- 206010028549 Myeloid leukaemia Diseases 0.000 description 1
- 210000000329 Myocytes, Smooth Muscle Anatomy 0.000 description 1
- 208000005927 Myosarcoma Diseases 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- 208000001611 Myxosarcoma Diseases 0.000 description 1
- DPCXEUSDRQOOGZ-QLYXXIJNSA-N N,N-dimethyl-2-[4-[(4Z)-4-(1-nitroso-2,3-dihydroinden-5-ylidene)-5-(1H-pyridin-4-ylidene)-1H-imidazol-2-yl]phenoxy]ethanamine Chemical compound C1=CC(OCCN(C)C)=CC=C1C(NC1=C2C=CNC=C2)=N\C1=C\1C=C2CCC(N=O)=C2C=C/1 DPCXEUSDRQOOGZ-QLYXXIJNSA-N 0.000 description 1
- KHWYSUBVXWWBRB-UHFFFAOYSA-N N,α-Diethylphenylethylamine Chemical compound CCNC(CC)CC1=CC=CC=C1 KHWYSUBVXWWBRB-UHFFFAOYSA-N 0.000 description 1
- ZJAVHOMVDCMAMF-UHFFFAOYSA-N N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyridine-3-carboxamide Chemical compound N=1C2=C(OC)C(OC)=CC=C2C2=NCCN2C=1NC(=O)C1=CC=CN=C1 ZJAVHOMVDCMAMF-UHFFFAOYSA-N 0.000 description 1
- KWRYMZHCQIOOEB-LBPRGKRZSA-N N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H-purin-6-amine Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=CC2=CC=C(F)C=C2N=C1C1=CC=CC=N1 KWRYMZHCQIOOEB-LBPRGKRZSA-N 0.000 description 1
- IDINUJSAMVOPCM-UHFFFAOYSA-N N-[2-[4-(3-aminopropylamino)butylamino]-1-hydroxy-2-oxoethyl]-7-(diaminomethylideneamino)heptanamide Chemical compound NCCCNCCCCNC(=O)C(O)NC(=O)CCCCCCN=C(N)N IDINUJSAMVOPCM-UHFFFAOYSA-N 0.000 description 1
- KIISCIGBPUVZBF-UHFFFAOYSA-N N-[3-[5-chloro-2-[4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]sulfanylphenyl]prop-2-enamide Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC=C(Cl)C(SC=2C=C(NC(=O)C=C)C=CC=2)=N1 KIISCIGBPUVZBF-UHFFFAOYSA-N 0.000 description 1
- CDOOFZZILLRUQH-GDLZYMKVSA-N N-[3-[6-[4-[(2R)-1,4-dimethyl-3-oxopiperazin-2-yl]anilino]-4-methyl-5-oxopyrazin-2-yl]-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide Chemical compound CN1CCN(C)C(=O)[C@H]1C(C=C1)=CC=C1NC1=NC(C=2C(=C(NC(=O)C=3SC=4CCCCC=4C=3)C=CC=2)C)=CN(C)C1=O CDOOFZZILLRUQH-GDLZYMKVSA-N 0.000 description 1
- 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 1
- BFSRTTWIPACGMI-UHFFFAOYSA-N N-[3-[[2-[4-[[1-(2-fluoroethyl)azetidin-3-yl]amino]-2-methoxyanilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide Chemical compound C=1C=C(NC=2N=C(NC=3C=C(NC(=O)C=C)C=CC=3)C(=CN=2)C(F)(F)F)C(OC)=CC=1NC1CN(CCF)C1 BFSRTTWIPACGMI-UHFFFAOYSA-N 0.000 description 1
- KXBDTLQSDKGAEB-UHFFFAOYSA-N N-[3-[[5-fluoro-2-[4-(2-methoxyethoxy)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide Chemical compound C1=CC(OCCOC)=CC=C1NC1=NC=C(F)C(NC=2C=C(NC(=O)C=C)C=CC=2)=N1 KXBDTLQSDKGAEB-UHFFFAOYSA-N 0.000 description 1
- GCYIGMXOIWJGBU-UHFFFAOYSA-N N-[4-(4-aminopiperidin-1-yl)-2-methoxyphenyl]-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine Chemical compound C=1C=C(NC=2N=C(C(Cl)=CN=2)C=2C3=CC=CC=C3NC=2)C(OC)=CC=1N1CCC(N)CC1 GCYIGMXOIWJGBU-UHFFFAOYSA-N 0.000 description 1
- 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 1
- JFVNFXCESCXMBC-UHFFFAOYSA-N N-[5-[4-chloro-3-(2-hydroxyethylsulfamoyl)phenyl]-4-methyl-1,3-thiazol-2-yl]acetamide Chemical compound S1C(=N/C(=O)C)\NC(C)=C1C1=CC=C(Cl)C(S(=O)(=O)NCCO)=C1 JFVNFXCESCXMBC-UHFFFAOYSA-N 0.000 description 1
- OJFKUJDRGJSAQB-UHFFFAOYSA-N N-[7-cyano-6-[4-fluoro-3-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]phenoxy]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide Chemical compound C1=C(NC(=O)CC=2C=C(C=CC=2)C(F)(F)F)C(F)=CC=C1OC(C(=C1S2)C#N)=CC=C1N=C2NC(=O)C1CC1 OJFKUJDRGJSAQB-UHFFFAOYSA-N 0.000 description 1
- JOWXJLIFIIOYMS-UHFFFAOYSA-N N-hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl-methylamino]pyrimidine-5-carboxamide Chemical compound C1=NC(OC)=CC=C1C1=NC(N2CCOCC2)=C(SC(CN(C)C=2N=CC(=CN=2)C(=O)NO)=C2)C2=N1 JOWXJLIFIIOYMS-UHFFFAOYSA-N 0.000 description 1
- AAFYOVPTFNNVDN-UHFFFAOYSA-N N-methyl-N-phenacylnitrous amide Chemical compound O=NN(C)CC(=O)C1=CC=CC=C1 AAFYOVPTFNNVDN-UHFFFAOYSA-N 0.000 description 1
- SQDFHQJTAWCFIB-UHFFFAOYSA-N N-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 1
- YZDJQTHVDDOVHR-UHFFFAOYSA-N N-{3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl}propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(Cl)=CN=C3NC=2)=C1F YZDJQTHVDDOVHR-UHFFFAOYSA-N 0.000 description 1
- 101710007214 NAE1 Proteins 0.000 description 1
- 102100014664 NAE1 Human genes 0.000 description 1
- 229940090008 Naprosyn Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N Naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 206010028729 Nasal cavity cancer Diseases 0.000 description 1
- 206010028767 Nasal sinus cancer Diseases 0.000 description 1
- 210000000581 Natural Killer T-Cells Anatomy 0.000 description 1
- 206010028811 Natural killer-cell leukaemia Diseases 0.000 description 1
- 229950004847 Navitoclax Drugs 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
- 229950000908 Nazartinib Drugs 0.000 description 1
- 210000003739 Neck Anatomy 0.000 description 1
- 229960005230 Nelfinavir Mesylate Drugs 0.000 description 1
- 229940063121 Neoral Drugs 0.000 description 1
- 229960005163 Netupitant Drugs 0.000 description 1
- 229940071846 Neulasta Drugs 0.000 description 1
- 208000007538 Neurilemmoma Diseases 0.000 description 1
- 208000010336 Neuroectodermal Tumors, Primitive, Peripheral Diseases 0.000 description 1
- 210000000440 Neutrophils Anatomy 0.000 description 1
- 229940080607 Nexavar Drugs 0.000 description 1
- HYWYRSMBCFDLJT-UHFFFAOYSA-N Nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 description 1
- XHWRWCSCBDLOLM-UHFFFAOYSA-N Nolatrexed Chemical compound CC1=CC=C2NC(N)=NC(=O)C2=C1SC1=CC=NC=C1 XHWRWCSCBDLOLM-UHFFFAOYSA-N 0.000 description 1
- 229950000891 Nolatrexed Drugs 0.000 description 1
- IIVBFTNIGYRNQY-YQLZSBIMSA-N Nomegestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 IIVBFTNIGYRNQY-YQLZSBIMSA-N 0.000 description 1
- IMONTRJLAWHYGT-ZCPXKWAGSA-N Norethindrone Acetate Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@](C#C)(OC(=O)C)[C@@]1(C)CC2 IMONTRJLAWHYGT-ZCPXKWAGSA-N 0.000 description 1
- 102000007399 Nuclear hormone receptors Human genes 0.000 description 1
- 108020005497 Nuclear hormone receptors Proteins 0.000 description 1
- KRWMERLEINMZFT-UHFFFAOYSA-N O(6)-benzylguanine; Chemical compound C=12NC=NC2=NC(N)=NC=1OCC1=CC=CC=C1 KRWMERLEINMZFT-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 229950006584 Obatoclax Drugs 0.000 description 1
- 229950005751 Ocrelizumab Drugs 0.000 description 1
- 229960002700 Octreotide Drugs 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 229960001494 Octreotide Acetate Drugs 0.000 description 1
- 206010070577 Oestrogen receptor positive breast cancer Diseases 0.000 description 1
- 206010067572 Oestrogenic effect Diseases 0.000 description 1
- 229950008089 Omipalisib Drugs 0.000 description 1
- 229940099216 Oncaspar Drugs 0.000 description 1
- 229950007283 Oregovomab Drugs 0.000 description 1
- XZEUAXYWNKYKPL-URLMMPGGSA-N Ormeloxifene Chemical compound C1([C@@H]2[C@H](C3=CC=C(C=C3OC2(C)C)OC)C=2C=CC(OCCN3CCCC3)=CC=2)=CC=CC=C1 XZEUAXYWNKYKPL-URLMMPGGSA-N 0.000 description 1
- 229960003552 Other antineoplastic agents in ATC Drugs 0.000 description 1
- 206010061328 Ovarian epithelial cancer Diseases 0.000 description 1
- 210000001672 Ovary Anatomy 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 101700036247 PARP1 Proteins 0.000 description 1
- 102100014579 PARP1 Human genes 0.000 description 1
- 101700053624 PARP2 Proteins 0.000 description 1
- 239000012270 PD-1 inhibitor Substances 0.000 description 1
- 229940121655 PD-1 inhibitors Drugs 0.000 description 1
- 239000012272 PD-L2 inhibitor Substances 0.000 description 1
- 229940121654 PD-L2 inhibitors Drugs 0.000 description 1
- 229950004941 PICTILISIB Drugs 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 229940098901 POLIFEPROSAN 20 Drugs 0.000 description 1
- 101700027237 PROA Proteins 0.000 description 1
- 206010033369 Paget's disease of the vulva Diseases 0.000 description 1
- 229940088130 Pamidronate Disodium Drugs 0.000 description 1
- 210000000496 Pancreas Anatomy 0.000 description 1
- 229940096763 Panretin Drugs 0.000 description 1
- SHGAZHPCJJPHSC-UHFFFAOYSA-N Panrexin Chemical compound OC(=O)C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-UHFFFAOYSA-N 0.000 description 1
- 208000004019 Papillary Adenocarcinoma Diseases 0.000 description 1
- 210000003899 Penis Anatomy 0.000 description 1
- 229940072223 Pentasa Drugs 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 210000000578 Peripheral Nerves Anatomy 0.000 description 1
- 206010034695 Pernicious anaemia Diseases 0.000 description 1
- 206010034800 Phaeochromocytoma Diseases 0.000 description 1
- 206010034811 Pharyngeal cancer Diseases 0.000 description 1
- 240000005158 Phaseolus vulgaris Species 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- DHHVAGZRUROJKS-UHFFFAOYSA-N Phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 1
- 210000004214 Philadelphia Chromosome Anatomy 0.000 description 1
- 102000029987 Phosphatidylethanolamine-binding protein Human genes 0.000 description 1
- 108091000043 Phosphatidylethanolamine-binding protein Proteins 0.000 description 1
- IIMIOEBMYPRQGU-UHFFFAOYSA-L Picoplatin Chemical compound N.[Cl-].[Cl-].[Pt+2].CC1=CC=CC=N1 IIMIOEBMYPRQGU-UHFFFAOYSA-L 0.000 description 1
- 229950005769 Pilaralisib Drugs 0.000 description 1
- QCHFTSOMWOSFHM-WPRPVWTQSA-N Pilopine HS Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- 206010050487 Pinealoblastoma Diseases 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 229950007124 Pipendoxifene Drugs 0.000 description 1
- 231100000742 Plant toxin Toxicity 0.000 description 1
- CLSUSRZJUQMOHH-UHFFFAOYSA-L Platinum(II) chloride Chemical compound Cl[Pt]Cl CLSUSRZJUQMOHH-UHFFFAOYSA-L 0.000 description 1
- 229950008499 Plitidepsin Drugs 0.000 description 1
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 1
- PHXJVRSECIGDHY-UHFFFAOYSA-N Ponatinib Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 PHXJVRSECIGDHY-UHFFFAOYSA-N 0.000 description 1
- 206010051358 Post transplant lymphoproliferative disease Diseases 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N Potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- OGSBUKJUDHAQEA-WMCAAGNKSA-N Pralatrexate Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CC(CC#C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OGSBUKJUDHAQEA-WMCAAGNKSA-N 0.000 description 1
- 206010056486 Pre-existing disease Diseases 0.000 description 1
- 208000008691 Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 206010036543 Precursor T-lymphoblastic lymphoma/leukaemia Diseases 0.000 description 1
- 101710010913 Pret-070 Proteins 0.000 description 1
- 208000000814 Primary Cutaneous Anaplastic Large Cell Lymphoma Diseases 0.000 description 1
- 208000003991 Primitive Neuroectodermal Tumors Diseases 0.000 description 1
- WIKYUJGCLQQFNW-UHFFFAOYSA-N Prochlorperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 WIKYUJGCLQQFNW-UHFFFAOYSA-N 0.000 description 1
- 229940029359 Procrit Drugs 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N Propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 210000002307 Prostate Anatomy 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010037127 Pseudolymphoma Diseases 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J Pyrophosphate Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 1
- 229960001285 Quercetin Drugs 0.000 description 1
- 229950001626 Quizartinib Drugs 0.000 description 1
- 102100009869 RBM14 Human genes 0.000 description 1
- 101710016478 RNASEH2A Proteins 0.000 description 1
- AECPBJMOGBFQDN-YMYQVXQQSA-N Radicicol Chemical compound C1CCCC(=O)C[C@H]2[C@H](Cl)C(=O)CC(=O)[C@H]2C(=O)O[C@H](C)C[C@H]2O[C@@H]21 AECPBJMOGBFQDN-YMYQVXQQSA-N 0.000 description 1
- 229940099538 Rapamune Drugs 0.000 description 1
- 208000002574 Reactive Arthritis Diseases 0.000 description 1
- 229940116176 Remicade Drugs 0.000 description 1
- 206010038428 Renal disease Diseases 0.000 description 1
- 206010038932 Retinopathy Diseases 0.000 description 1
- 229950003238 Rilotumumab Drugs 0.000 description 1
- 229950009855 Rociletinib Drugs 0.000 description 1
- XMVJITFPVVRMHC-UHFFFAOYSA-N Roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 1
- 229940030484 SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM ESTROGENS Drugs 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N Saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- IRHXGOXEBNJUSN-YOXDLBRISA-N Saquinavir mesylate Chemical compound CS(O)(=O)=O.C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 IRHXGOXEBNJUSN-YOXDLBRISA-N 0.000 description 1
- 208000006938 Schwannomatosis Diseases 0.000 description 1
- 210000004706 Scrotum Anatomy 0.000 description 1
- 210000001732 Sebaceous Glands Anatomy 0.000 description 1
- BTIHMVBBUGXLCJ-OAHLLOKOSA-N Seliciclib Chemical compound C=12N=CN(C(C)C)C2=NC(N[C@@H](CO)CC)=NC=1NCC1=CC=CC=C1 BTIHMVBBUGXLCJ-OAHLLOKOSA-N 0.000 description 1
- 229950000055 Seliciclib Drugs 0.000 description 1
- 229950010746 Selumetinib Drugs 0.000 description 1
- 206010040070 Septic shock Diseases 0.000 description 1
- 230000037165 Serum Concentration Effects 0.000 description 1
- 208000002669 Sex Cord-Gonadal Stromal Tumors Diseases 0.000 description 1
- 208000009359 Sezary Syndrome Diseases 0.000 description 1
- 201000006984 Sezary's disease Diseases 0.000 description 1
- 229940115586 Simulect Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N Simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 229950003804 Siplizumab Drugs 0.000 description 1
- 208000006641 Skin Disease Diseases 0.000 description 1
- 210000004927 Skin cells Anatomy 0.000 description 1
- 206010054184 Small intestine carcinoma Diseases 0.000 description 1
- 229960004249 Sodium Acetate Drugs 0.000 description 1
- 229940005550 Sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M Sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- UPMFZISCCZSDND-JJKGCWMISA-M Sodium gluconate Chemical compound [Na+].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O UPMFZISCCZSDND-JJKGCWMISA-M 0.000 description 1
- 229940005574 Sodium gluconate Drugs 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M Sodium stearate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 240000001016 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 229950007865 Sonolisib Drugs 0.000 description 1
- BQAZCCVUZDIZDC-UHFFFAOYSA-N Sorafenib N-oxide Chemical compound C1=[N+]([O-])C(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 BQAZCCVUZDIZDC-UHFFFAOYSA-N 0.000 description 1
- UIRKNQLZZXALBI-MSVGPLKSSA-N Squalamine Chemical compound C([C@@H]1C[C@H]2O)[C@@H](NCCCNCCCCN)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CC[C@H](C(C)C)OS(O)(=O)=O)[C@@]2(C)CC1 UIRKNQLZZXALBI-MSVGPLKSSA-N 0.000 description 1
- 229950001248 Squalamine Drugs 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N Staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 229940090374 Stivarga Drugs 0.000 description 1
- 229940006509 Strontium-89 Drugs 0.000 description 1
- 229940034785 Sutent Drugs 0.000 description 1
- 229940037128 Systemic Glucocorticoids Drugs 0.000 description 1
- 208000000389 T-Cell Leukemia Diseases 0.000 description 1
- 206010042985 T-cell prolymphocytic leukaemia Diseases 0.000 description 1
- 238000009171 T-cell vaccination Methods 0.000 description 1
- 101710040065 THPO Proteins 0.000 description 1
- 102100016214 THPO Human genes 0.000 description 1
- 101710040533 TNFRSF8 Proteins 0.000 description 1
- 102100009538 TNFRSF8 Human genes 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 229960001967 Tacrolimus Drugs 0.000 description 1
- 229940092753 Tagrisso Drugs 0.000 description 1
- 229950008389 Talmapimod Drugs 0.000 description 1
- 239000005463 Tandutinib Substances 0.000 description 1
- 229950009893 Tandutinib Drugs 0.000 description 1
- 229950007866 Tanespimycin Drugs 0.000 description 1
- 229940120982 Tarceva Drugs 0.000 description 1
- 229950001269 Taselisib Drugs 0.000 description 1
- 229940066453 Tecentriq Drugs 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temodal Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 208000001608 Teratocarcinoma Diseases 0.000 description 1
- 229950003046 Tesevatinib Drugs 0.000 description 1
- 229950007967 Tesmilifene Drugs 0.000 description 1
- 206010062123 Testicular embryonal carcinoma Diseases 0.000 description 1
- GKCBAIGFKIBETG-UHFFFAOYSA-N Tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 1
- 229960002372 Tetracaine Drugs 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N Tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 229920002807 Thiomer Polymers 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N Thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 108010041111 Thrombopoietin Proteins 0.000 description 1
- 102000036902 Thrombopoietin Human genes 0.000 description 1
- 208000006303 Thrombotic Microangiopathy Diseases 0.000 description 1
- 206010043645 Thrombotic microangiopathy Diseases 0.000 description 1
- 229940107955 Thymoglobulin Drugs 0.000 description 1
- 208000008732 Thymoma Diseases 0.000 description 1
- UCEQXRCJXIVODC-PMACEKPBSA-N Tivantinib 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
- SPMVMDHWKHCIDT-UHFFFAOYSA-N Tivozanib Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC=1C=C(C)ON=1 SPMVMDHWKHCIDT-UHFFFAOYSA-N 0.000 description 1
- 230000035852 Tmax Effects 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 206010044002 Tonsil cancer Diseases 0.000 description 1
- 229950010529 Topilutamide Drugs 0.000 description 1
- 229960004167 Toremifene Citrate Drugs 0.000 description 1
- 229940116362 Tragacanth Drugs 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 229950007217 Tremelimumab Drugs 0.000 description 1
- 229950007229 Tresperimus Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- RTKIYFITIVXBLE-QEQCGCAPSA-N Trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 1
- 229950003873 Triciribine Drugs 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N Trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N Trimethylsilyl chloride Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 1
- HWKQNAWCHQMZHK-UHFFFAOYSA-N Trolnitrate Chemical compound [O-][N+](=O)OCCN(CCO[N+]([O-])=O)CCO[N+]([O-])=O HWKQNAWCHQMZHK-UHFFFAOYSA-N 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 229940094060 Tykerb Drugs 0.000 description 1
- 240000000913 Typha elephantina Species 0.000 description 1
- 235000018747 Typha elephantina Nutrition 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N U-18,496 Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N Uramustine Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- 206010046392 Ureteric cancer Diseases 0.000 description 1
- 210000004291 Uterus Anatomy 0.000 description 1
- 108091007928 VEGF receptors Proteins 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N Valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 229940058865 Vectibix Drugs 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 229960003048 Vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229960002110 Vincristine Sulfate Drugs 0.000 description 1
- 229960004355 Vindesine Drugs 0.000 description 1
- 229960002166 Vinorelbine tartrate Drugs 0.000 description 1
- GBABOYUKABKIAF-IWWDSPBFSA-N VinorelbineTartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IWWDSPBFSA-N 0.000 description 1
- 241000625014 Vir Species 0.000 description 1
- 229950001212 Volociximab Drugs 0.000 description 1
- 229940069559 Votrient Drugs 0.000 description 1
- 208000000260 Warts Diseases 0.000 description 1
- 208000006110 Wiskott-Aldrich Syndrome Diseases 0.000 description 1
- 102000001392 Wiskott-Aldrich Syndrome Protein Human genes 0.000 description 1
- 108010093528 Wiskott-Aldrich Syndrome Protein Proteins 0.000 description 1
- HJSSPYJVWLTYHG-UHFFFAOYSA-N XL765 Chemical compound COC1=CC(OC)=CC(NC=2C(=NC3=CC=CC=C3N=2)NS(=O)(=O)C=2C=CC(NC(=O)C=3C=C(OC)C(C)=CC=3)=CC=2)=C1 HJSSPYJVWLTYHG-UHFFFAOYSA-N 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Xylocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 229940055760 Yervoy Drugs 0.000 description 1
- 229940036061 Zaltrap Drugs 0.000 description 1
- 229950009002 Zanolimumab Drugs 0.000 description 1
- 229940034727 Zelboraf Drugs 0.000 description 1
- 229940061261 Zolinza Drugs 0.000 description 1
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 description 1
- NOECSYBNZHIVHW-LKADTRSGSA-N [(2R,3aS,3bS,5aS,6R,8aS,8bR,10aS)-2,6-diethynyl-3a,5a-dimethyl-2-propanoyloxy-1,3,3b,4,5,7,8,8a,8b,9,10,10a-dodecahydroindeno[5,4-e]inden-6-yl] propanoate Chemical compound C([C@]1(C)[C@](OC(=O)CC)(C#C)CC[C@H]1[C@@H]1CC2)C[C@@H]1[C@]1(C)[C@@H]2C[C@@](C#C)(OC(=O)CC)C1 NOECSYBNZHIVHW-LKADTRSGSA-N 0.000 description 1
- QTQAWLPCGQOSGP-DVKIRIBLSA-N [(3R,5R,6S,7R,8E,10R,11R,12E,14E)-6-hydroxy-5,11,21-trimethoxy-3,7,9,15-tetramethyl-16,20,22-trioxo-17-azabicyclo[16.3.1]docosa-1(21),8,12,14,18-pentaen-10-yl] carbamate 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(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-DVKIRIBLSA-N 0.000 description 1
- QIUASFSNWYMDFS-NILGECQDSA-N [(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5-h]isochromen-10-yl] acetate Chemical compound CC(=O)O[C@@H]1C[C@]2(C)C(=O)CC[C@H]2C2=C1[C@@]1(C)[C@@H](COC)OC(=O)\C(=C\N(CC=C)CC=C)C1=C(O)C2=O QIUASFSNWYMDFS-NILGECQDSA-N 0.000 description 1
- LVBMFPUTQOHXQE-UHFFFAOYSA-N [2-[6-(diaminomethylideneamino)hexylamino]-2-oxoethyl] N-[4-(3-aminopropylamino)butyl]carbamate Chemical compound NCCCNCCCCNC(=O)OCC(=O)NCCCCCCN=C(N)N LVBMFPUTQOHXQE-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229960003697 abatacept Drugs 0.000 description 1
- UVIQSJCZCSLXRZ-UBUQANBQSA-N abiraterone acetate Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](CC4=CC[C@H]31)OC(=O)C)C=C2C1=CC=CN=C1 UVIQSJCZCSLXRZ-UBUQANBQSA-N 0.000 description 1
- 229960004103 abiraterone acetate Drugs 0.000 description 1
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 230000011759 adipose tissue development Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 229960002833 aflibercept Drugs 0.000 description 1
- 108010081667 aflibercept Proteins 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N aldehydo-D-arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- 229960001611 alectinib Drugs 0.000 description 1
- 229960002459 alefacept Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 201000005794 allergic hypersensitivity disease Diseases 0.000 description 1
- 201000004384 alopecia Diseases 0.000 description 1
- 229950010482 alpelisib Drugs 0.000 description 1
- 201000008063 alpha chain disease Diseases 0.000 description 1
- 229960004538 alprazolam Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229960002550 amrubicin Drugs 0.000 description 1
- 229960001694 anagrelide Drugs 0.000 description 1
- 230000002491 angiogenic Effects 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000002424 anti-apoptotic Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agents Drugs 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 230000001494 anti-thymocyte Effects 0.000 description 1
- 230000000259 anti-tumor Effects 0.000 description 1
- 239000000611 antibody drug conjugate Substances 0.000 description 1
- 108091008116 antibody drug conjugates Proteins 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 235000008714 apigenin Nutrition 0.000 description 1
- 229960001372 aprepitant Drugs 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- 101700004528 arp Proteins 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- 125000005418 aryl aryl group Chemical group 0.000 description 1
- 125000004350 aryl cycloalkyl group Chemical group 0.000 description 1
- ZDQSOHOQTUFQEM-XZQJPUKSSA-N ascomycin Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)CC(C)=C[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](O)[C@H](OC)C1 ZDQSOHOQTUFQEM-XZQJPUKSSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 108010072668 atezolizumab Proteins 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- 230000003143 atherosclerotic Effects 0.000 description 1
- 229950010993 atrasentan Drugs 0.000 description 1
- 239000003719 aurora kinase inhibitor Substances 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 201000009596 autoimmune hypersensitivity disease Diseases 0.000 description 1
- 229960003005 axitinib Drugs 0.000 description 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 239000000688 bacterial toxin Substances 0.000 description 1
- 229960004669 basiliximab Drugs 0.000 description 1
- 229960005347 belatacept Drugs 0.000 description 1
- 229960003094 belinostat Drugs 0.000 description 1
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 description 1
- 229960004277 benorilate Drugs 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- AKUJBENLRBOFTD-QZIXMDIESA-N betamethasone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(C)=O)(O)[C@@]1(C)C[C@@H]2O AKUJBENLRBOFTD-QZIXMDIESA-N 0.000 description 1
- 229960004648 betamethasone acetate Drugs 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 239000006177 biological buffer Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 201000002393 blood protein disease Diseases 0.000 description 1
- 201000006491 bone marrow cancer Diseases 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 229910052796 boron Chemical group 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 201000000135 breast papillary carcinoma Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- RGVBVVVFSXWUIM-UHFFFAOYSA-M bromo(dimethyl)sulfanium;bromide Chemical compound [Br-].C[S+](C)Br RGVBVVVFSXWUIM-UHFFFAOYSA-M 0.000 description 1
- 201000005200 bronchus cancer Diseases 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 229960001292 cabozantinib Drugs 0.000 description 1
- 235000020964 calcitriol Nutrition 0.000 description 1
- 239000011612 calcitriol Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 1
- 235000008207 calcium folinate Nutrition 0.000 description 1
- 239000011687 calcium folinate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 229960005057 canrenone Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 201000000274 carcinosarcoma Diseases 0.000 description 1
- 229960002438 carfilzomib Drugs 0.000 description 1
- 108010021331 carfilzomib Proteins 0.000 description 1
- 229960003778 casopitant Drugs 0.000 description 1
- 230000003197 catalytic Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 230000002490 cerebral Effects 0.000 description 1
- 229960001602 ceritinib Drugs 0.000 description 1
- 201000006662 cervical adenocarcinoma Diseases 0.000 description 1
- SBNPWPIBESPSIF-MHWMIDJBSA-N cetrorelix Chemical compound C([C@@H](C(=O)N[C@H](CCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 SBNPWPIBESPSIF-MHWMIDJBSA-N 0.000 description 1
- 229960003230 cetrorelix Drugs 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 201000009047 chordoma Diseases 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 201000010903 chronic neutrophilic leukemia Diseases 0.000 description 1
- 231100000160 chronic toxicity Toxicity 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 235000008957 cocaer Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229960005188 collagen Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 230000001010 compromised Effects 0.000 description 1
- 230000002153 concerted Effects 0.000 description 1
- 239000000562 conjugate Substances 0.000 description 1
- 229940035811 conjugated estrogens Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 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
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([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
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 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
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- PMATZTZNYRCHOR-UHFFFAOYSA-N cyclosporine A Chemical compound CCC1NC(=O)C(C(O)C(C)CC=CC)N(C)C(=O)C(C(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(C)NC(=O)C(C)NC(=O)C(CC(C)C)N(C)C(=O)C(C(C)C)NC(=O)C(CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-UHFFFAOYSA-N 0.000 description 1
- 229960003843 cyproterone Drugs 0.000 description 1
- GBOGMAARMMDZGR-TYHYBEHESA-N cytochalasin B Chemical compound C([C@H]1[C@@H]2[C@@H](C([C@@H](O)[C@@H]3/C=C/C[C@H](C)CCC[C@@H](O)/C=C/C(=O)O[C@@]23C(=O)N1)=C)C)C1=CC=CC=C1 GBOGMAARMMDZGR-TYHYBEHESA-N 0.000 description 1
- 230000001086 cytosolic Effects 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 229960002465 dabrafenib Drugs 0.000 description 1
- 108010049391 dacetuzumab Proteins 0.000 description 1
- 229960002806 daclizumab Drugs 0.000 description 1
- 229950006418 dactolisib Drugs 0.000 description 1
- 230000002354 daily Effects 0.000 description 1
- 229960005029 darbepoetin alfa Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229950006075 delmadinone acetate Drugs 0.000 description 1
- 229960002923 denileukin diftitox Drugs 0.000 description 1
- 108010017271 denileukin diftitox Proteins 0.000 description 1
- 231100000080 dermatitis contact Toxicity 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001627 detrimental Effects 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 150000004985 diamines Chemical group 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 125000006003 dichloroethyl group Chemical group 0.000 description 1
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- 125000006001 difluoroethyl group Chemical group 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000004598 dihydrobenzofuryl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 125000004582 dihydrobenzothienyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 125000005056 dihydrothiazolyl group Chemical group S1C(NC=C1)* 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 201000008325 diseases of cellular proliferation Diseases 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- HSYBQXDGYCYSGA-UHFFFAOYSA-L disodium;[6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxopyrido[3,2-b][1,4]oxazin-4-yl]methyl phosphate Chemical class [Na+].[Na+].COC1=C(OC)C(OC)=CC(NC=2N=C(NC=3N=C4N(COP([O-])([O-])=O)C(=O)C(C)(C)OC4=CC=3)C(F)=CN=2)=C1 HSYBQXDGYCYSGA-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002612 dispersion media Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 108060003523 dnaK Proteins 0.000 description 1
- 229960003413 dolasetron Drugs 0.000 description 1
- 229960003218 dolasetron mesylate Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229960004845 drospirenone Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 108010016436 durvalumab Proteins 0.000 description 1
- 229960004913 dydrogesterone Drugs 0.000 description 1
- 108010010371 efalizumab Proteins 0.000 description 1
- 229960000284 efalizumab Drugs 0.000 description 1
- 229960001069 eltrombopag Drugs 0.000 description 1
- 201000011025 embryonal testis carcinoma Diseases 0.000 description 1
- 229960002694 emetine Drugs 0.000 description 1
- AUVVAXYIELKVAI-UWBTVBNJSA-N emetine Natural products N1CCC2=CC(OC)=C(OC)C=C2[C@H]1C[C@H]1C[C@H]2C3=CC(OC)=C(OC)C=C3CCN2C[C@H]1CC AUVVAXYIELKVAI-UWBTVBNJSA-N 0.000 description 1
- 230000001804 emulsifying Effects 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 229940046080 endocrine therapy drugs Estrogens Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 108010075876 enlimomab Proteins 0.000 description 1
- 229960004671 enzalutamide Drugs 0.000 description 1
- 201000005231 epithelioid sarcoma Diseases 0.000 description 1
- 108010067416 epoetin delta Proteins 0.000 description 1
- 108010090921 epoetin omega Proteins 0.000 description 1
- 108010030868 epoetin zeta Proteins 0.000 description 1
- 239000002834 estrogen receptor modulator Substances 0.000 description 1
- 201000007280 estrogen-receptor negative breast cancer Diseases 0.000 description 1
- 201000007281 estrogen-receptor positive breast cancer Diseases 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- 108010059577 etaracizumab Proteins 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N ethyl amine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 231100000573 exposure to toxins Toxicity 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 201000008819 extrahepatic bile duct carcinoma Diseases 0.000 description 1
- 201000001342 fallopian tube cancer Diseases 0.000 description 1
- 229960001395 fenbufen Drugs 0.000 description 1
- 201000001169 fibrillary astrocytoma Diseases 0.000 description 1
- 201000008808 fibrosarcoma Diseases 0.000 description 1
- 108010025050 figitumumab Proteins 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 235000011990 fisetin Nutrition 0.000 description 1
- 101700053117 fixN Proteins 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- 229960005304 fludarabine phosphate Drugs 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229960004421 formestane Drugs 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 201000004066 ganglioglioma Diseases 0.000 description 1
- 201000008361 ganglioneuroma Diseases 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 229950005277 gossypol Drugs 0.000 description 1
- 229930000755 gossypol Natural products 0.000 description 1
- 201000011626 grade III astrocytoma Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 201000010238 heart disease Diseases 0.000 description 1
- 239000003481 heat shock protein 90 inhibitor Substances 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 201000002138 hematopoietic system disease Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- 150000004688 heptahydrates Chemical class 0.000 description 1
- 125000005241 heteroarylamino group Chemical group 0.000 description 1
- 125000005349 heteroarylcycloalkyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 201000008298 histiocytosis Diseases 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- HHXHVIJIIXKSOE-QILQGKCVSA-N histrelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC(N=C1)=CN1CC1=CC=CC=C1 HHXHVIJIIXKSOE-QILQGKCVSA-N 0.000 description 1
- 229960002193 histrelin Drugs 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 description 1
- 229960000930 hydroxyzine Drugs 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 201000009939 hypertensive encephalopathy Diseases 0.000 description 1
- 201000006866 hypopharynx cancer Diseases 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229950007440 icotinib Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 239000002596 immunotoxin Substances 0.000 description 1
- 230000002637 immunotoxin Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 201000008255 invasive lobular carcinoma Diseases 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 201000004614 iritis Diseases 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000001678 irradiating Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-M isethionate Chemical class OCCS([O-])(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-M 0.000 description 1
- 201000002529 islet cell tumor Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-M isobutyrate Chemical compound CC(C)C([O-])=O KQNPFQTWMSNSAP-UHFFFAOYSA-M 0.000 description 1
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000010977 jade Substances 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M laurate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 230000003902 lesions Effects 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 108010046731 lexatumumab Proteins 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 238000006138 lithiation reaction Methods 0.000 description 1
- 229960001078 lithium Drugs 0.000 description 1
- 238000011068 load Methods 0.000 description 1
- 201000011059 lobular neoplasia Diseases 0.000 description 1
- 229960004391 lorazepam Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- FBQPGGIHOFZRGH-UHFFFAOYSA-N lucanthone Chemical compound S1C2=CC=CC=C2C(=O)C2=C1C(C)=CC=C2NCCN(CC)CC FBQPGGIHOFZRGH-UHFFFAOYSA-N 0.000 description 1
- 229950005239 lucanthone Drugs 0.000 description 1
- 108010020744 lucatumumab Proteins 0.000 description 1
- 201000005244 lung non-small cell carcinoma Diseases 0.000 description 1
- 235000009498 luteolin Nutrition 0.000 description 1
- 201000010453 lymph node cancer Diseases 0.000 description 1
- 201000000564 macroglobulinemia Diseases 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 239000011776 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 201000003175 male breast cancer Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 108010021856 mapatumumab Proteins 0.000 description 1
- 210000003826 marginal zone B cell Anatomy 0.000 description 1
- 208000009018 medullary Thyroid cancer Diseases 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- JBVNBBXAMBZTMQ-CEGNMAFCSA-N megestrol Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 JBVNBBXAMBZTMQ-CEGNMAFCSA-N 0.000 description 1
- 201000003776 meninges sarcoma Diseases 0.000 description 1
- 201000009574 mesenchymal chondrosarcoma Diseases 0.000 description 1
- 230000002503 metabolic Effects 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- 230000001394 metastastic Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- QJXSSECYGUFRQL-UHFFFAOYSA-N methyl 2-(chloromethoxy)acetate Chemical compound COC(=O)COCCl QJXSSECYGUFRQL-UHFFFAOYSA-N 0.000 description 1
- ZXUQEPZWVQIOJE-UHFFFAOYSA-N methyl 2-chloro-2-oxoacetate Chemical compound COC(=O)C(Cl)=O ZXUQEPZWVQIOJE-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 229960003775 miltefosine Drugs 0.000 description 1
- 230000000116 mitigating Effects 0.000 description 1
- 229960005485 mitobronitol Drugs 0.000 description 1
- 230000000394 mitotic Effects 0.000 description 1
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 1
- 201000004058 mixed glioma Diseases 0.000 description 1
- 108010032806 molgramostim Proteins 0.000 description 1
- 229960003063 molgramostim Drugs 0.000 description 1
- 108010045030 monoclonal antibodies Proteins 0.000 description 1
- 102000005614 monoclonal antibodies Human genes 0.000 description 1
- 201000006894 monocytic leukemia Diseases 0.000 description 1
- 201000002335 monodermal teratoma Diseases 0.000 description 1
- 235000007708 morin Nutrition 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 201000008050 mu chain disease Diseases 0.000 description 1
- 201000010879 mucinous adenocarcinoma Diseases 0.000 description 1
- 230000004690 mucosal barrier Effects 0.000 description 1
- 201000003731 mucosal melanoma Diseases 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 101700054071 myo1 Proteins 0.000 description 1
- 235000007743 myricetin Nutrition 0.000 description 1
- 229940116852 myricetin Drugs 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000005487 naphthalate group Chemical group 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- 108010033813 necitumumab Proteins 0.000 description 1
- 229960000513 necitumumab Drugs 0.000 description 1
- NQHXCOAXSHGTIA-SKXNDZRYSA-N nelfinavir mesylate Chemical compound CS(O)(=O)=O.CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 NQHXCOAXSHGTIA-SKXNDZRYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000009925 nephrosclerosis Diseases 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- WAXQNWCZJDTGBU-UHFFFAOYSA-N netupitant Chemical compound C=1N=C(N2CCN(C)CC2)C=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 WAXQNWCZJDTGBU-UHFFFAOYSA-N 0.000 description 1
- 201000009494 neurilemmomatosis Diseases 0.000 description 1
- 230000000955 neuroendocrine Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229960004190 nomegestrol acetate Drugs 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 229960001652 norethindrone acetate Drugs 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 108010045555 obinutuzumab Proteins 0.000 description 1
- 229960003347 obinutuzumab Drugs 0.000 description 1
- 108010030900 ocrelizumab Proteins 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 201000008106 ocular cancer Diseases 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 108010046821 oprelvekin Proteins 0.000 description 1
- 229960001840 oprelvekin Drugs 0.000 description 1
- 201000005443 oral cavity cancer Diseases 0.000 description 1
- 108010060422 oregovomab Proteins 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
- 229960003327 ormeloxifene Drugs 0.000 description 1
- 201000011029 ovarian embryonal carcinoma Diseases 0.000 description 1
- 201000006588 ovary adenocarcinoma Diseases 0.000 description 1
- 235000020825 overweight Nutrition 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- 229960003978 pamidronic acid Drugs 0.000 description 1
- 229960005184 panobinostat Drugs 0.000 description 1
- FPOHNWQLNRZRFC-ZHACJKMWSA-N panobinostat Chemical compound CC=1NC2=CC=CC=C2C=1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FPOHNWQLNRZRFC-ZHACJKMWSA-N 0.000 description 1
- 201000007052 paranasal sinus cancer Diseases 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 201000009612 pediatric lymphoma Diseases 0.000 description 1
- 229960001744 pegaspargase Drugs 0.000 description 1
- 108010001564 pegaspargase Proteins 0.000 description 1
- 108010092853 peginterferon alfa-2a Proteins 0.000 description 1
- 201000011152 pemphigus Diseases 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 201000001245 periodontitis Diseases 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 230000003285 pharmacodynamic Effects 0.000 description 1
- 201000008006 pharynx cancer Diseases 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
- WLJVXDMOQOGPHL-UHFFFAOYSA-M phenylacetate Chemical compound [O-]C(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-M 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L phosphate Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- 201000007286 pilocytic astrocytoma Diseases 0.000 description 1
- 201000004123 pineal gland cancer Diseases 0.000 description 1
- 201000003113 pineoblastoma Diseases 0.000 description 1
- 201000002511 pituitary cancer Diseases 0.000 description 1
- 239000003123 plant toxin Substances 0.000 description 1
- 108010049948 plitidepsin Proteins 0.000 description 1
- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 1
- 229920001888 polyacrylic acid Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000447 polyanionic polymer Polymers 0.000 description 1
- 229960001131 ponatinib Drugs 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 229960000214 pralatrexate Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 201000006037 primary mediastinal B-cell lymphoma Diseases 0.000 description 1
- 229960003111 prochlorperazine Drugs 0.000 description 1
- 201000007283 progesterone-receptor positive breast cancer Diseases 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- DROIHSMGGKKIJT-UHFFFAOYSA-N propane-1-sulfonamide Chemical compound CCCS(N)(=O)=O DROIHSMGGKKIJT-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L propanedioate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 201000005825 prostate adenocarcinoma Diseases 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 229940121649 protein inhibitors Drugs 0.000 description 1
- 239000003197 protein kinase b inhibitor Substances 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000002685 pulmonary Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical group CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 1
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 1
- FUXJMHXHGDAHPD-UHFFFAOYSA-N pyrimidine-2-carboxamide Chemical compound NC(=O)C1=NC=CC=N1 FUXJMHXHGDAHPD-UHFFFAOYSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 235000005875 quercetin Nutrition 0.000 description 1
- 229930002344 quercetin Natural products 0.000 description 1
- 230000001950 radioprotection Effects 0.000 description 1
- 230000003439 radiotherapeutic Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 108010026911 ramucirumab Proteins 0.000 description 1
- 229960002633 ramucirumab Drugs 0.000 description 1
- 229960000460 razoxane Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 201000007444 renal pelvis carcinoma Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000241 respiratory Effects 0.000 description 1
- 200000000008 restenosis Diseases 0.000 description 1
- 239000011604 retinal Substances 0.000 description 1
- 201000000582 retinoblastoma Diseases 0.000 description 1
- 108010011457 rilotumumab Proteins 0.000 description 1
- 108010091666 romidepsin Proteins 0.000 description 1
- 108010017584 romiplostim Proteins 0.000 description 1
- 229960004262 romiplostim Drugs 0.000 description 1
- 229960000215 ruxolitinib Drugs 0.000 description 1
- 229960003542 saquinavir mesylate Drugs 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000000849 selective androgen receptor modulator Substances 0.000 description 1
- 201000010208 seminoma Diseases 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 231100000197 serious side effect Toxicity 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Chemical group 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- 108010073705 siplizumab Proteins 0.000 description 1
- 201000003708 skin melanoma Diseases 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 239000000176 sodium gluconate Substances 0.000 description 1
- 235000012207 sodium gluconate Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- DCQXTYAFFMSNNH-UHFFFAOYSA-M sodium;2-[bis(2-hydroxyethyl)amino]ethanol;acetate Chemical compound [Na+].CC([O-])=O.OCCN(CCO)CCO DCQXTYAFFMSNNH-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 229960000487 sorafenib tosylate Drugs 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- CIOAGBVUUVVLOB-OUBTZVSYSA-N strontium-89 Chemical compound [89Sr] CIOAGBVUUVVLOB-OUBTZVSYSA-N 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 201000010965 sweat gland carcinoma Diseases 0.000 description 1
- 230000002522 swelling Effects 0.000 description 1
- 201000008736 systemic mastocytosis Diseases 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tBuOOH Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical compound C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 1
- 201000009365 thymic carcinoma Diseases 0.000 description 1
- 108010056900 thymoglobulin Proteins 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 108010078548 tocilizumab Proteins 0.000 description 1
- 229960003989 tocilizumab Drugs 0.000 description 1
- 229960001350 tofacitinib Drugs 0.000 description 1
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 201000006134 tongue cancer Diseases 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 239000003860 topical agent Substances 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 description 1
- 229960000977 trabectedin Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 108010072993 tremelimumab Proteins 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- HOGVTUZUJGHKPL-HTVVRFAVSA-N triciribine Chemical compound C=12C3=NC=NC=1N(C)N=C(N)C2=CN3[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O HOGVTUZUJGHKPL-HTVVRFAVSA-N 0.000 description 1
- 229960000294 triptorelin pamoate Drugs 0.000 description 1
- 239000003656 tris buffered saline Substances 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960003688 tropisetron Drugs 0.000 description 1
- ZNRGQMMCGHDTEI-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CNC2=C1 ZNRGQMMCGHDTEI-ITGUQSILSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 201000007423 tubular adenocarcinoma Diseases 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical compound CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000000982 vasogenic Effects 0.000 description 1
- 229960001183 venetoclax Drugs 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- HHJUWIANJFBDHT-KOTLKJBCSA-N vindesine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 HHJUWIANJFBDHT-KOTLKJBCSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 108010031272 volociximab Proteins 0.000 description 1
- 229950001576 voxtalisib Drugs 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 108010052251 zanolimumab Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229960002760 ziv-aflibercept Drugs 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N α-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
Abstract
This invention is in the area of pyrimidine-based compounds for the treatment of disorders involving abnormal cellular proliferation, including but not limited to tumors and cancers.
Description
PYRIMIDINE-BASED ANTIPROLIFERATIVE AGENTS
CROSS-REFERENCE TO RELATED ATIONS
This application claims the benefit of US. Provisional Application 62/357,630 which
was filed on July 1, 2016. The entirety of this application is hereby incorporated by reference
herein for all purposes.
FIELD OF THE INVENTION
This invention is in the area of pyrimidine-based compounds for the ent of
disorders involving abnormal cellular proliferation, ing but not limited to tumors and
cancers.
BACKGROUND
In normal , cellular proliferation is generally restricted to cells that are required
to replenish the tissue. Once cells have ally differentiated, they have a specialized
function and no longer divide. Most tissues are made up of non-dividing cells. Thus normal
cell proliferation is tightly controlled to ensure that only the necessary cells divide. There is
also a l balance between cell division and mmed cell death (apoptosis).
Cell division, sometimes referred to as the cell cycle, has four phases: G1 phase
(synthesis of various enzymes required for DNA replication), S phase (DNA replication
producing two identical sets of chromosomes), G2 (significant protein synthesis, including
production of microtubules) and M phase (nuclear division, cytoplasmic division and formation
ofnew cell membrane). Cell division also includes a complex system of cell signaling networks
that allow cells to ret information from us extracellular signals, including through
receptor proteins, inflammatory factors and pro-apoptotic and anti-apoptotic signals.
Dysfunctional signals include those from genetic mutation, infection, exposure to
environmental factors including toxins, system stress, autoimmune disorders, and
ation.
A range of disorders can occur when the process of cell proliferation becomes
dysfunctional, including benign growths, neoplasms, tumorigenesis, cancerogenesis,
mune disorders, inflammatory disorders graft-versus-host rejection, and fibrotic
disorders.
A number of spectrum anti-neoplastic agents have been developed. Cytoskeletal
drugs like axel target tubulin to arrest mitotic cell division and are used to treat a variety
of cancers including ovarian, breast, lung, pancreatic, and ular tumors (See e.g., Jordan,
, Nature Reviews Cancer (2004) 4: 253-265). Organometallic—based drugs such as
cisplatin have been used to treat lymphomas, sarcomas, germ cell tumors, and some carcinomas
including bladder, small cell lung cancer, and ovarian cancer. Cisplatin has the ability to bind
nitrogenous bases and cause extensive DNA cross-linking that ultimately leads to apoptosis
(See e.g., Siddick, Oncogene (2003) 22: 7265—7279). Intercalating and ting agents have
also been extensive use in the clinic for the ent ofvarious neoplasms, however, the global
toxicity associated with these drugs presents a critical concern for patients requiring erm
therapy.
Palbociclib (PD-033299, e) is sold by Pfizer for the ent of estrogen-
positive, HER2—negative breast cancer in combination with letrozole. The compound inhibits
CDK4 and CDK6. The structure of palbociclib is:
K/NH
Abemaciclib (LY2835219) is a CDK 4/6 inhibitor currently in human clinical trials for
the treatment of various types of cancers. It is in a phase III trial for stage IV non-small cell
lung carcinoma; in combination with Fulvestrant for women with breast cancer; and with either
anastrozole or letrozole for first line treatment of breast cancer. The ure of abemaciclib
\( N/LQ‘N
*‘QNAY‘ ti.
Ribociclib (Lee011; Kisqali), is a CDK 4/6 inhibitor approved for use in combination
with an aromatase inhibitor to treat some metastatic breast cancers, and is in clinical trials for
the treatment of certain other tumors. The structure of ribociclib is:
H 9
(“MAJ EJJ//N\ N\ N O
N ______
HNJ "
Various other pyrimidine-based agents have been developed for the treatment of
hyperproliferative diseases. US. Patent Nos. 8,822,683; 197; 8,598,186; 8,691,830;
8,829,102; 8,822,683; 9,102,682; 9,499,564; 9,481,591; and 9,260,442, filed by s and
Strum and assigned to G1 Therapeutics be a class of eroaryl)-pyrrolo[3,2-
d]pyrimidinamine cyclin dependent kinase inhibitors including those of the formula (with
variables as defined therein):
R? i
\ {ally
I /
b fig/N“ N\ N
R Z.‘ \R
R2 R8
Xi], {Rn
\ y
/~I)i( N \ / 0
XX ,1 iA /\
X 7‘5
R6 N N
H \7/N\"
R2 138::
x, Rlyi >
Y 2X KM Pal; \ \ ’
NAN/ N\
Rb‘ H N
\R
WC 2013/148748 (U.S.S.N. 61/617,657) titled “Lactam Kinase tors”, WO
2013/163239 (U.S.S.N. 61/638,491) titled “Synthesis of Lactams” and filed
by Tavares and also assigned to G1 eutics describes the synthesis of N—(heteroaryl)—
pyrrolo[3,2-d]pyrimidinamines and their use as lactam kinase inhibitors.
Other publications include the following. WC 2014/144326 filed by Strum et al. and
assigned to G1 Therapeutics describes compounds and methods for protection of normal cells
during chemotherapy using pyrimidine-based CDK4/6 inhibitors. WC 2014/144596 filed by
Strum et al. and ed to G1 Therapeutics bes compounds and methods for protection
of hematopoietic stem and progenitor cells t ionizing radiation using pyrimidine-based
CDK4/6 inhibitors. W0 2014/144847 filed by Strum et al. and assigned to G1 Therapeutics
describes HSPC-sparing treatments of abnormal cellular proliferation using pyrimidine-based
CDK4/6 inhibitors. W0 2014/144740 filed by Strum et al. and assigned to G1 Therapeutics
bes highly active eoplastic and anti-proliferative pyrimidine-based CDK 4/6
inhibitors. W0 61285 filed by Strum et al. and assigned to G1 Therapeutics describes
tricyclic pyrimidine-based CDK inhibitors for use in radioprotection. W0 2015/161287 filed
by Strum et a1. and assigned to G1 Therapeutics describes analogous tricyclic pyrimidine-based
CDK inhibitors for the protection of cells during chemotherapy. W0 2015/161283 filed by
Strum et a1. and assigned to G1 Therapeutics bes analogous tricyclic pyrimidine-based
CDK inhibitors for use in HSPC-sparing treatments of RB-positive abnormal ar
proliferation. W0 2015/161288 filed by Strum et al. and assigned to G1 Therapeutics describes
analogous tricyclic pyrimidine—based CDK inhibitors for use as anti-neoplastic and anti—
proliferative agents. W0 2016/040858 filed by Strum et al. and assigned to G1 Therapeutics
describes the use of ations of pyrimidine-based CDK4/6 inhibitors with other anti—
neoplastic agents. W0 2016/040848 filed by Strum et al. and assigned to G1 Therapeutics
describes compounds and methods for treating certain Rb-negative cancers with CDK4/6
inhibitors and topoisomerase inhibitors.
W0 03/062236 fies a series of 2-(pyridinylamino-pyrido[2,3]pyrimidin
ones for the treatment of Rb ve cancers that show selectivity for CDK4/6, including 6-
acetylcyclopentyl-5 -methyl(5 -piperazinyl-pyridinylammino)-8H-pyrido-[2,3-d]-
pyrimidinone (PD0332991), which was given fast-track approval by the FDA and is
tly sold as Ibrance (Palbociclib) by Pfizer for the treatment of metastatic breast cancer.
VanderWel et al. be an iodine-containing pyrido[2,3-d]pyrimidineone (CKIA)
as a potent and selective CDK4 inhibitor (see VanderWel et al., J. Med. Chem. 48 (2005) 2371—
2387)
W0 2010/020675 filed by Novartis AG describes pyrrolopyrimidine compounds as
CDK inhibitors. W0 2011/101409 also filed by is describes pyrrolopyrimidines with
CDK 4/6 inhibitory activity.
Johnson et al. ed that pharmacological inhibition of CDK4/6 using the CDK4/6
inhibitors 6-acetylcyclopentylmethyl(5-piperazin—1-yl-pyridinylammino)-8H-
pyrido-[2,3-d]-pyrimidinone (PD0332991) and 2-bromo-12,13-dihydro-5H-indolo[2,3-
a]pyrrolo[3,4]carbazole—5,6-dione ) exhibited IR protective characteristics in CDK4/6-
dependent cell lines. (Johnson et al. Mitigation of hematological radiation toxicity in mice
through pharmacological quiescence induced by CDK4/6 inhibition. J Clin. Invest. 2010;
120(7): 2528-2536).
There remains a need for onal compounds to treat disorders associated with
abnormal cellular proliferation, including a tumor or cancer.
SUMMARY
Compounds are presented that have advantageous antiproliferative activity, including
anticancer and antitumor activity. Based on this discovery, nds and methods are
presented for the treatment of a patient with a proliferative disorder including a tumor or cancer
that includes stering an ive amount of one or a combination of the compounds
described herein to a patient in need thereof, optionally in a pharmaceutically acceptable
carrier. In certain embodiments the antiproliferative disorder is selected from a benign ,
neoplasm, tumor, cancer, autoimmune disorder, inflammatory disorder, graft-versus-host
rejection and a c disorder. In a typical embodiment the patient is a human.
The invention includes an active compound of Formula I, Formula II, Formula 111
Formula IV, Formula V, Formula VI, Formula VII, a VIII, Formula IX, Formula X,
Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula
XVII, Formula XVIII, a XIX, Formula XX, Formula XXI, Formula XXII, or Formula
XXIII or a pharmaceutically acceptable salt or composition thereof. In one embodiment, an
active compound or its salt, composition, or prodrug thereof is used to treat a medical disorder
involving abnormal cellular eration.
The invention includes an antiproliferative (including antineoplastic) compound of
aI, Formula II, Formula III Formula IV, Formula V, Formula VI, Formula VII, a
VIII, Formula IX, Formula X, Formula XI, a XII, Formula XIII, Formula XIV, Formula
XV, Formula XVI, Formula XVII, Formula XVIII, or Formula XIX:
WO 05860
(XVIII), or
or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, prodrug, and/or a
pharmaceutically acceptable composition thereof;
X is NH, NR9, S, or O;
yis 0,1,2, 3 or4,
m is 0, 1, or 2;
n is 0, 1, or 2,
Z is independently CH, CR9, or N,
Q is CH2 or CO;
R is hydrogen, C1-C6alkyl, -(Co—C2alkyl)(C3-Cscarbocyclyl), -(Co-C2alkyl)(C3-
Csheterocyclyl),-(Co-C2alkyl)(aryl), -(C0—C2alkyl)(heteroaryl), —COOalkyl, -COOarylalkyl, or
—COOH;
each R1 is independently alkyl, aryl, cycloalkyl or haloalkyl, wherein each of said alkyl,
cycloalkyl and haloalkyl groups optionally includes heteroatoms O, N, or S in place of a carbon
in the chain and two Rl’s on adjacent ring atoms or on the same ring atom together with the
ring atom(s) to which they are attached optionally form a 3membered cycle or two Rl’s on
adjacent ring atoms together with the ring atom(s) to which they are attached ally form
a 6-membered aryl ring;
or R1 is hydrogen,
R2 is —(alkylene)m—heterocyclo, —(alkylene)m—heteroaryl, —(alkylene)m—NR3R4,
—(alkylene)m—C(O)—NR3R4, —(alkylene)m—C(O)—O-alkyl, —(alkylene)m—O—R5,
1ene)m—S(O)n—R5, or —(alky1ene)m—S(O)n—NR3R4 any of which may be optionally
independently substituted with one or more RX groups as d by e, and wherein two
Rx groups bound to the same or adjacent atom may optionally combine to form a ring;
R3 and R4 at each occurrence are independently selected from:
(i) hydrogen or
(ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, lkylalkyl,
heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally
independently substituted with one or more Rx groups as allowed by valance,
and n two RX groups bound to the same or adjacent atom may optionally
combine to form a ring; or R3 and R4 together with the nitrogen atom to which
they are ed may combine to form a heterocyclo ring optionally
independently substituted with one or more RX groups as allowed by valance,
and wherein two RX groups bound to the same or adjacent atom may optionally
combine to form a ring;
R5 is independently selected at each occurrence from:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,
cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally
independently tuted with one or more RX groups as allowed by valance;
Rx at each occurrence is independently selected from halo, cyano, nitro, oxo, alkyl,
kyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl,
lkylalkyl, heterocycloalkyl, -(alkylene)m-OR5, -(alkylene)m-O-alkylene-OR5, -
(alkylene)m-S(O)n—R5, —(alkylene)m-NR3R4, -(alkylene)m-CN, -(alkylene)m—C(O)—R5, -
(alkylene)m-C(S)—R5, -(alkylene)m-C(O)—OR5, -(alkylene)m-O—C(O)—R5,
-(a1ky1ene)m-C(S)—OR5, -(a1kylene)m-C(O)—(alky1ene)m-NR3R4, —(alkylene)m-C(S)—NR3R4,
-(alkylene)m-N(R3)—C(O)—NR3R4, -(alkylene)m-N(R3)—C(S)—NR3R4, lene)m-N(R3)—
C(O)—R5, -(alkylene)m-N(R3)—C(S)—R5, lene)m-O—C(O)—NR3R4, -(alkylene)m—O—C(S)—
NR3R4, -(alkylene)m—SOz—NR3R4, -(alkylene)m—N(R3)—SOz—RS, -(alkylene)m-N(R3)—SOz—
NR3R4, -(alkylene)m-N(R3)—C(O)—OR5) -(alkylene)m-N(R3)—C(S)—OR5, or -(alkylene)m-
N(R3)—SOz—R5, wherein: said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,
heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be
further independently substituted as described herein;
R6 is ed independently at each ce from: hydrogen, halogen, alkyl, alkenyl,
alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, cycloalkyl, arylalkyl,
or arylalkyl,
R8 a3
R8 R8 R8
R8 \ V
Y R \ l R8 /
R3 / I /
R7 is selected from: Y RS R8 R8
, , , ,
X2 X2 Y\ x2 x2
(:7 / \ 1/ x2 '-\
xix Y 47 N
X:\ 1 Y\ X
\ l X“ K I
/ M
Y X1 Y
WO 05860
/ N 35/ X {it/1 Y 1,? Xv / Flirxd
Y\’A>~<X\\J>ix‘/L~x Rik \ Aril / /
x N N Y X
g/Y\‘“‘><‘ /}\v Wfi RX" Y\X
X\‘\:\ I X;\ / X:\ i Y\\ / i
x3 yak/K Y x1 X3
de~ 4 x3 [\XZS
X X 4" R x/ \\
or R7 is selected from cycloalkyl, heterocycle, and alkyl, each of which lkyl,
cycle, and alkyl groups is optionally substituted with one or more substituents selected
from amino, -NHR14, -NR14R15, hydroxyl, OR”, R6, and R2,
R14 and R15 are independently selected from: hydrogen, alkyl, alkenyl, alkynyl,
—C(O)H, -C(O)alkyl, -C(S)alkyl, aryl, —S02alkyl, heteroaryl, arylalkyl, and heteroarylalkyl.
Y is NH, O, S, or NR9,
X1, X2, X3, and X4, are independently N or CR8, n at least one of X1, X2, X3,
and X4, is CR8;
R8 is selected independently at each instance from: R6 and R2, wherein one R8 is R2;
R9 is selected from: —C(O)H, -C(O)alkyl, -C(S)alkyl, alkyl, aryl, heteroaryl, arylalkyl,
and heteroarylalkyl;
R10 is ed from: hydrogen, —COOalkyl, -COOarylalkyl, —COOH, -OH, —C(O)H, -
C(O)alkyl, -C(S)alkyl, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; and
wherein for compounds of Formula VII y is 0, 1, or 2.
In an additional aspect the invention includes an active compound of Formula XX,
a XXI, Formula XXII, Formula XXIII, or Formula XXIV or a pharmaceutically
acceptable salt or composition thereof. The compounds of Formula XX, Formula XXI,
Formula XXII, a XXIII, and XXIV have the following structures:
t: (R) ”N7
’ My
(XX), R (XXI),
N.“ \ N \
N\ / N \IN N\ / N EWR
)xN xv: [LN \Iro
HNI (R )y mi (M),
R (XXII), R (XXIII), and
fl» \ JR
N N‘”R
I I” N
H‘J ’
.7 k‘ 3n“:
R" \(J
(R‘).
Y (XXIV),
wherein m, R, R1, R7, Q, and y are defined above.
In one embodiment the compound of Formula XX is:
/\ \4
N N”R F? \
/\\LN/ N
7L{ N‘\ / “““N /N”R
HN 0 )\N
X? {Rl‘i
R Hp‘l R"
\ R1
ly 01‘ R7
In an additional aspect the invention includes an active compound of Formula XXV:
N\ fitW’zx/O N”R
/\"‘-N,f—mN\,\J
“N {R1}
R“ V
(XXV),
wherein R, R1, R2, R6, and y are defined above;
R16 is selected from cycloalkyl, heterocycle, and alkyl, each of which lkyl,
heterocycle, and alkyl groups is optionally substituted with one or more tuents selected
from amino, , -NR14R15, hydroxyl, OR”, R6, and R2,
R14 and R15 are independently selected from: hydrogen, alkyl, l, alkynyl,
—C(O)H, -C(O)alkyl, -C(S)alkyl, aryl, —SOzalkyl, heteroaryl, arylalkyl, and heteroarylalkyl.
WO 05860
In an alternative embodiment the nd of the present invention is selected from
N/ \ N
/ \
In another alternative embodiment the compound of the present invention is selected
from
Q Q
C} C} 53
)m )W ,and f
In another alternative embodiment the compound of the present invention is selected
from
NH NH NH
, ,and
In an alternative embodiment the compound of the present invention is:
N/\N
>"—“N
HN ’J
In another alternative embodiment the compound of the present invention is:
These nds can be used to treat such condition in a host in need f, typically
a human.
In one embodiment, the active compound acts as an inhibitor of a cyclin-dependent
kinase (CDK), for example CDK4 and/or CDK6. In an aspect, the compound is a selective
2017/040093
inhibitor of CDK4 and/or CDK6. In another embodiment, the selectivity is for CDK4 and/or
CDK6 over CDK2. Based on this, in one ment, the method for the ent of a
disorder of abnormal cellular proliferation that is mediated by CDK4 and or CDK6 is provided
that includes the administration of an effective amount of a compound of the present invention
or a pharmaceutically acceptable salt f, optionally in a pharmaceutically acceptable
carrier, as described in more detail below.
In an alternative embodiment, a method for the treatment of a disorder of abnormal
cellular proliferation that is not mediated by CDK4 and or CDK6 is provided that includes the
administration of an ive amount of a compound of the present invention or a
pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier,
as described in more detail below.
In another embodiment, a method for the ent of a fibrotic disorder in a host is
provided that includes the administration of an effective amount of a compound of the present
invention or a pharmaceutically acceptable salt f, optionally in a pharmaceutically
acceptable carrier.
In another ment, a method for the treatment of rheumatoid arthritis or psoriasis
in a host is provided that includes the administration of an effective amount of a compound of
the present invention or a pharmaceutically acceptable salt thereof, optionally in a
pharmaceutically acceptable carrier.
In yet another embodiment, a method for the treatment of an mune disorder in a
host is provided that includes the administration of an effective amount of a compound of the
present invention or a pharmaceutically acceptable salt thereof, optionally in a
pharmaceutically acceptable carrier.
In a principal embodiment, a method for the treatment of a tumor or cancer in a host is
provided that includes the administration of an effective amount of a compound of the present
invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically
acceptable r. In an aspect of this embodiment, the cancer is an Rb-positive tumor or
cancer. In another aspect of this embodiment, the cancer is an ative tumor or cancer. In
certain aspects, the cancer is selected from breast cancer, prostate cancer (including androgen-
resistant prostate cancer), another cancer of the uctive system such as endometrial,
ovarian or testicular cancer, small cell lung carcinoma, glioblastoma and head and/or neck
In yet r embodiment, a method for the treatment of a disorder of abnormal
cellular proliferation in a host such as a human is provided that includes administering an
effective amount of a ation of one or more of the active compounds described herein in
combination or alternation with r active compound. In certain aspects of the invention,
the second compound is a chemotherapeutic agent. In another aspect of this embodiment, the
second active compound is an immune modulator, including but not limited to a checkpoint
inhibitor such as an anti—PDl, TLA, anti-LAG—3, anti-Tim, etc antibody, small molecule,
peptide, nucleotide or other inhibitor (including but not d to umab (Yervoy),
Pembrolizumab (Keytruda) and nivolumab (Opdivo).
In yet another embodiment, one of the active compounds described herein is
administered in an effective amount for the treatment of abnormal tissue of the female
reproductive system such as breast, ovarian, endometrial, or uterine cancer, in combination or
alternation with an effective amount of an estrogen tor including but not limited to a
SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader),
a complete estrogen receptor degrader, or another form of partial or complete estrogen
antagonist.
In another embodiment, one of the active compounds described herein is administered
in an effective amount for the treatment of abnormal tissue of the male reproductive system
such as prostate or testicular cancer, in combination or alternation with an effective amount of
an androgen (such as testosterone) inhibitor including but not limited to a selective androgen
receptor tor, a selective androgen receptor degrader, a complete androgen or
degrader, or another form of partial or complete androgen antagonist. In one embodiment, the
te or testicular cancer is androgen-resistant.
In one embodiment, the nds described herein inhibit Cyclin Dependent .
For example, a compound described in the present invention provides a dose-dependent Gl—
arresting effect on a subject’s CDK replication dependent healthy cells, for example HSPCs or
renal epithelial cells. The s provided for herein are sufficient to afford chemoprotection
to targeted CDK replication dependent healthy cells during chemotherapeutic agent exposure,
for e, during the time period that a DNA—damaging chemotherapeutic agent is e
of DNA-damaging effects on CDK replication dependent healthy cells in the subject.
In one embodiment, the use of the compounds or methods described herein is combined
with the use of hematopoietic growth factors including, but not limited to, granulocyte colony
stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF),
thrombopoietin, interleukin (IL)-12, steel , and opoietin (EPO), or their derivatives.
In one embodiment, the compound is administered prior to administration of the hematopoietic
WO 05860
growth factor. In one embodiment, the hematopoietic growth factor administration is timed so
that the compound’s effect on HSPCs has dissipated.
The present invention thus includes at least the ing features:
(a) a compound of the present invention as described herein, and pharmaceutically
acceptable salts and prodrugs thereof;
(b) a compound of the present invention as described herein, and pharmaceutically
acceptable salts and prodrugs thereof that are useful in the treatment of a disorder of al
ar eration, including a tumor or cancer,
(c) use of a compound of the present invention, or pharmaceutically able salts
and gs thereof in the manufacture of a ment for the treatment of a disorder of
abnormal cellular proliferation, such as a tumor or cancer,
((1) a method for manufacturing a medicament intended for the eutic use of
treating a er of abnormal cellular proliferation including a tumor or cancer, characterized
in that a compound of the present invention as described herein is used in the manufacture,
(e) a compound of the present ion as described herein, and pharmaceutically
acceptable salts and prodrugs f that are useful in the treatment of cancer, including any
of the cancers described herein;
(f) use of a compound of the present invention, and pharmaceutically acceptable salts
and prodrugs thereof in the manufacture of a medicament for the treatment of cancer, ing
any of the cancers described herein,
(g) a method for manufacturing a medicament intended for the therapeutic use of
treating cancer, including any ofthe cancers described herein, characterized in that a compound
of the present invention as described herein is used in the manufacture;
(h) a compound of the present invention as described herein, and pharmaceutically
acceptable salts and prodrugs thereof that are useful in the treatment of a tumor, including any
of the tumors described herein;
(i) use of a compound of the present invention, and pharmaceutically acceptable salts
and gs thereof in the manufacture of a medicament for the treatment of a tumor,
including any of the tumors described herein,
(1') a method for cturing a medicament intended for the therapeutic use of
treating a tumor, including any of the tumors described herein, characterized in that a
compound of the present invention as described herein is used in the manufacture,
WO 05860
(k) a compound of the present invention as described herein, and ceutically
able salts and prodrugs thereof that are useful in the treatment of a flbrotic disorder;
(1) use of a compound of the present ion, and pharmaceutically acceptable salts
and prodrugs thereof in the manufacture of a medicament for the treatment of a fibrotic
disorder;
(m) a method for manufacturing a medicament intended for the therapeutic use of
treating a fibrotic disorder, characterized in that a compound of the present invention as
described herein is used in the manufacture,
(n) a compound of the present invention as described herein, and pharmaceutically
acceptable salts and prodrugs thereof that are useful in the treatment of an autoimmune or
inflammatory disorder;
(0) use of a compound of the present invention, and ceutically acceptable salts
and prodrugs thereof in the manufacture of a medicament for the treatment of an autoimmune
or inflammatory disorder,
(p) a method for manufacturing a medicament intended for the therapeutic use of
treating an autoimmune or atory disorder, characterized in that a compound of the
present invention as described herein is used in the manufacture;
(q) a pharmaceutical formulation comprising an effective host—treating amount of the
compound of the present invention or a ceutically acceptable salt or prodrug thereof
together with a pharmaceutically acceptable carrier or diluent;
(r) a compound of the present invention as described herein as a mixture of enantiomers
or diastereomers (as nt), including as a racemate;
(s) a compound of the present invention as described herein in omerically or
diastereomerically (as relevant) enriched form, including as an isolated enantiomer or
disastereomer (i.e., greater than 85, 90, 95, 97 or 99% pure), and,
(t) a process for the preparation oftherapeutic products that contain an effective amount
of a nd of the present ion, as described herein.
(u) a compound of the present invention as described herein, and pharmaceutically
acceptable salts and prodrugs thereof that are useful in chemoprotection,
(V) use of a compound of the present invention, and pharmaceutically acceptable salts
and gs thereof in the manufacture of a medicament for chemoprotection; and
(w) a method for cturing a medicament intended for the eutic use of
chemoprotection, characterized in that a compound ofthe present invention as described herein
is used in the manufacture.
BRIEF DESCRIPTION OF FIGURES
is a bar graph showing the population of cells with a DNA content less than 2N,
cells in the GO-Gl phase, cells in the S phase, and cells in the G2-M phase as a way to measure
the relative amount of tic cells ing stration of control, Compound 30,
Compound 36, Compound 37, Compound 38, Compound 39, nd 40, and Compound
41. The Compound number and dose, measured in uM and nM) are shown on the x—axis and
the cell population, measured in percent, is shown on the y-axis.
is a bar graph showing the population of cells with a DNA content less than 2N,
cells in the GO-Gl phase, cells in the S phase, and cells in the G2-M phase as a way to measure
the relative amount of apoptotic cells following administration of control, Compound 31,
Compound 33, and Compound 34. The Compound number and dose, measured in uM and nM)
are shown on the X-axis and the cell population, measured in percent, is shown on the .
is Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV,
and Formula XXV.
is a bar graph showing the population of cells with a DNA content less than 2N,
cells in the GO-Gl phase, cells in the S phase, and cells in the G2-M phase as a way to e
the relative amount of apoptotic cells following administration of control and Compound 28.
The population of apoptotic cells after exposure to Compound 28 was greater than 70% at
* is <2000 .
every dose administered. The assay was done in a population of H568 cells.
The Compound number and dose, measured in uM and nM, are shown on the x-axis and the
cell population, measured in percent, is shown on the y-axis.
DETAILED DESCRIPTION
I. COMPOUNDS
In one embodiment, compounds of Formula 1, Formula II, Formula 111 Formula IV,
Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, a X, Formula XI,
Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII,
Formula XVIII, or Formula XIX are provided:
NiHfifz NiNN” \
Wis? {Rlly HNx
(I), R"
_ N
“’8‘“ ( R‘ )y W):N [JV/f:
R" (XIII) WW ,
N /m\N’(N”R NVN“N
)‘x‘N ”W
“N. (R )3, HI): My
R7 (XV), R7 (XVI),
(XVIII), and
r;2:;
R' HN>- ‘ly (XIX)
or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug, optionally in a
pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition
thereof; wherein the variables are as defined above in the Summary section.
In an alternative embodiment, a compound of Formula XX, Formula XXI, Formula
XXII, Formula XXIII or a XXIV is provided:
/ N HZ
HN\/\QJ<
7 {RE}, HN‘ l: R1)
\\I a“ \
N\«o i,I N lurk:
9%) N Q
HN‘ IE1)
y,(XXII) R7 y
) and
RM? N MR
\ /)_____ N i
Y (XXIV)
or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug, optionally in a
pharmaceutically acceptable r to form a ceutically able composition
thereof; wherein the variables are as defined above in the Summary section.
In another embodiment, a compound of Formula 1-], Formula II-I, Formula III-I,
Formula IV-l, Formula V-I, Formula VI-l, Formula VII-l, Formula , Formula IX-l,
Formula X-l, a XI-l, Formula XII-l Formula XIII-l Formula XIV-1, Formula XV-I,
, ,
Formula XVI-l, Formula XVII-l, Formula 1, Formula XIX-1, Formula XX-l Formula
XXI-l, Formula XXII-1, Formula XXIII-l, Formula XXIV-l, or Formula XXV-l is provided:
/\ \ Z:
N‘ NI [MIR
/ /_______ ‘N
”N / R R
R7 L ) R7’HN (R1)\
Y (VII-1), 3" (VIII-1),
-1), \_ y
R R7 (XIV-1),
R' 1), (XVIII-1),
2:2 NRMN’R
N NV ““KJ wQ
>294 HN
R7HN (R1) it? {R4}
y(XIX-1), ' 3’ (XX-1),
\ x \ \
Nx / N HZ Nx / N 1”
Hit/LN “if; HN’LN XV?
i i R!) i l: R
R7 y (XXI-1), )3,
R7 1),
so \ if
i / [\-
“~-. \ ‘N
N N”-R HN. ( }
)\N\ f N I \I m
WQ R \rj
“Ni? (My (‘52?)
R (XXIII-1), ‘1’ (XXIV-1), or
/:\ \
>‘N \wv
Hi‘l {R1}
R15 V (XXV-1),
or a pharmaceutically acceptable salt, N-oxide, isotopic denvative, or prodrug, optionally in a
pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition
thereof;
wherein:
2017/040093
X is NH, NR9, S, or O;
y is 0,1, 2, 3, or4;
m is 0, 1, or 2,
n is 0, 1, or 2;
Z is independently CH, CR9, or N,
Q is CH2 or CO;
R is hydrogen, Ci-Cealkyl, -(Co-C2alkyl)(C3-Cscarbocyclyl), -(Co-C2alkyl)(C3—
rocyclyl),-(Co-C2alkyl)(aryl), -(Co-C2alkyl)(heteroaryl), -COOalkyl, -COOarylalkyl, or
—COOH;
each R1 is independently alkyl, aryl, cycloalkyl or haloalkyl, n each of said alkyl,
cycloalkyl and haloalkyl groups optionally includes heteroatoms O, N, or S in place of a carbon
in the chain and two Rl’s on adjacent ring atoms or on the same ring atom together with the
ring atom(s) to which they are attached optionally form a 3—8—membered cycle or two Rl’s on
adjacent ring atoms together with the ring atom(s) to which they are attached optionally form
a 6-membered aryl ring;
or R1 is hydrogen;
R2 is —(alkylene)m—heterocyclo, —(alkylene)m—heteroaryl, —(alkylene)m—NR3R4,
—(alkylene)m—C(O)—NR3R4; —(alkylene)m—C(O)—O-alkyl; —(alkylene)m—O—R5,
—(alkylene)m—S(O)n—R5, or —(alkylene)m—S(O)n—NR3R4 any of which may be ally
independently substituted with one or more RX groups as allowed by valance, and wherein two
RX groups bound to the same or adjacent atom may optionally combine to form a ring;
R3 and R4 at each occurrence are independently:
(i) hydrogen or
(ii) alkyl, lkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkyl, arylalkyl, or heteroarylalkyl, or R3 and R4 together with the
nitrogen atom to which they are attached may e to form a heterocyclo
ring;
R5 is independently:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl, cycloalkyl, cyclo, aryl, heteroaryl,
cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl;
RX at each occurrence is independently selected from halo, cyano, nitro, oxo, alkyl,
haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl, heterocycloalkyl, lene)m-OR5, -(alkylene)m-O-a1kylene-OR5, —
WO 05860
(alkylene)m-S(O)n—R5, -(alkylene)m-NR3R4, -(alkylene)m-CN, -(alkylene)m-C(O)—R5, -
(alkylene)m-C(S)—R5, -(alkylene)m-C(O)—OR5, lene)m-O—C(O)—R5,
-(alkylene)m-C(S)—OR5, -(alkylene)m-C(O)-(alkylene)m-NR3R4, -(alkylene)m-C(S)—NR3R4,
-(a1kylene)m-N(R3)—C(O)—NR3R4, -(alkylene)m-N(R3)—C(S)—NR3R4, -(alky1ene)m-N(R3)—
C(O)—R5, -(alkylene)m-N(R3)—C(S)—R5, -(alkylene)m-O—C(O)—NR3R4, -(alkylene)m—O—C(S)—
NR3R4, -(alkylene)m—802—NR3R4, lene)m—N(R3)—802—R5, -(alkylene)m-N(R3)—SOz—
NR3R4, -(alkylene)m-N(R3)—C(O)—OR5) -(alkylene)m-N(R3)—C(S)—OR5, or -(alkylene)m—
N(R3)—SOz—R5;
R6 is selected independently at each instance from: hydrogen, halogen, alkyl, alkenyl,
alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, lkylalkyl, heterocycloalkyl, arylalkyl,
or heteroarylalkyl;
8 n
P‘3 R5 R
R8 \
8 :4]
Y R \ l Xl l
R3 / I / \
. Y
R7 is selected from: Y R8 Ra
, , , ,
X2 \A X2 xi”: x2
/ \ / X2 \
4:; Y 4:, N :1: N
Y x1 l x1 x1 i v
\ 1/ \\ r/ \ \ 4/
x Y X’
Y XF ._ Y
\ X2 X
X1 \ ""\ X‘
’6! Y ’0 / ‘3‘. X2 / \X1
/}L‘“Y 4/}\x3 /\\-:x3
l /X1\Y xf’ \
x?- “ I ‘
\,/ X\ Y\ / <Y\\><1\ <4/ X“
x3 v x“ x3 x3
or R7 is selected from cycloalkyl, heterocycle, and alkyl, each of which cycloalkyl,
heterocycle, and alkyl groups is optionally tuted with one or more substituents selected
from amino, -NHR14, -NR14R15, hydroxyl, OR”, R6, and R2;
WO 05860
R14 and R15 are independently selected from: hydrogen, alkyl, alkenyl, alkynyl,
—C(O)H, —C(O)alkyl, -C(S)alkyl, aryl, —SOzalkyl, heteroaryl, kyl, and arylalkyl;
R16 is ed from cycloalkyl, heterocycle, and alkyl, each of which cycloalkyl,
heterocycle, and alkyl groups is optionally substituted with one or more substituents selected
from amino, -NHR14, -NR14R15, yl, OR”, R6, and R2,
Y is NH, O, S, or NR9;
X1, X2, X3 and X4, are independently N or CR8, wherein at least one of X1, X2, X3,
and X4, is CR3;
R8 is selected independently at each instance from: R6 and R2, wherein one R8 is R2,
R9 is selected from: —C(O)H, -C(O)alkyl, -C(S)alkyl, alkyl, aryl, heteroaryl, arylalkyl,
and heteroarylalkyl,
R10 is selected from: hydrogen, -COOalkyl, -COOarylalkyl, —COOH, -OH, —C(O)H, -
C(O)a1ky1, -C(S)alky1, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; and
wherein for compounds of Formula VII y is 0, 1, or 2.
WO 05860
N/QQQQQXQ
QQQQQQ
Raf? {Q :2;)9/-~N
”Q, ,
m M” Q Q“ “Q/N-~.N
“ CQQQQ
< ~Q2WNQ
WO 05860
WO 05860
In another embodiment, a nd of Formula 1-2, Formula 11-2, Formula III-2,
Formula IV-2, a V-Z, Formula VI-Z, Formula VII-2, Formula VIII-2, Formula IX-2,
Formula X-2, Formula XI-2, Formula XII-2, Formula XIII-2, Formula XIV-2, Formula XV-Z,
Formula XVI-2, Formula XVII-2, Formula XVIII-2, a XIX-2, Formula XX-2 Formula
XXI-2, Formula XXII-2, Formula XXIII-2, or Formula XXIV—2 is provided:
(IV-2),
”KW n N "’
)L-N/ hi
HN fiR‘VQT/LéNAN :0
FL; Gym
(V-2), (v1-2),
FN \\ 27:2
N NH 29f
)L WN ##H rx/ \\ ' N
‘ G
HN >35“!
k7 R7HN
(VII-2), (VIII-2),
WAN/NM/‘\1\N
1 .H
R7 < HN
h" : (X_2)>
x 3a x
N O
(XI-2), (XII-2),
NWN N x
1 Q‘N ”/11“ N9
)\ N» / N
\N “N
“N HN
R7 \R7
(XIII-2), (XIV-2),
x N
N NH “N
)<-= NW0?”
9.: N
RT‘N N N
H ”“5
(XV-2), R (XVI-2),
(XVIII-2),
WO 05860
)erz/ N i
Q 32'!
"”17 c R?
(XXIII-2), 5’ (XXIV-2), or
[9'3
f2: ‘\
N W’R
\ / N J
(XXV-2);
or a pharmaceutically acceptable salt, N—oxide, isotopic derivative, or prodrug, optionally in a
pharmaceutically acceptable carrier to form a pharmaceutically acceptable composition
thereof; wherein R“, R7, Q, Z, R1, y, and X are as defined in Formula X-l and Formula XIX-
] above.
In some aspects, R6 is hydrogen.
In some aspects, Rx is not further substituted.
In some s, R2 is —(alkylene)m—heterocyclo, —(alkylene)m—heteroaryl,
—(alkylene)m—NR3R4, —(alkylene)m—C(O)—NR3R4; —(alkylene)m—O—R5,
—(alkylene)m—S(O)n—R5, or lene)m—S(0)11—NR3R4 any of which may be optionally
ndently substituted with one or more Rx groups as allowed by valance, and n two
RK groups bound to the same or adjacent atom may optionally combine to form a ring and
wherein m is 0 or 1 and n is 0, 1 or 2.
In some aspects, R2 is —(alkylene)m—heterocyclo, —(alkylene)m—NR3R4,
—(alkylene)m—C(O)—NR3R4, —(alkylene)m—C(O)—O-alkyl or —(alkylene)m—OR5 any of which
WO 05860
may be optionally independently substituted with one or more RX groups as allowed by valance,
and wherein two RX groups bound to the same or nt atom may optionally combine to
form a ring.
In some aspects, R2 is —(alkylene)m—heterocyclo, lene)m—NR3R4,
—(alkylene)m—C(O)—NR3R4, —(alkylene)m—C(O)—O-alkyl or —(alkylene)m—ORS without further
substitution.
In some aspects, m in R2 is 1. In a further aspect, the alkylene in R2 is methylene.
MR? (RX1 )1
In some aspects, R2 is wherein:
R” is a bond, alkylene, -(alkylene)m-O-(alkylene)m-, -(alkylene)m-C(O)—(alkylene)m—,
-(alkylene)m-S(O)2-(alkylene)m- and —(alkylene)m-NH-(alkylene)m- wherein each m is
independently 0 or 1,
P is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group;
each RX1 is independently -(alkylene)m-(C(0))m-(alkylene)m-(N(RN))m-(alkyl)m wherein
each m is independently 0 or 1 provided at least one m is 1, -(C(O))-O-alkyl,
—(alkylene)m-cycloalkyl wherein m is 0 or 1, -N(RN)-cycloalkyl, -C(O)—cycloalkyl,
lene)m-heterocyclyl wherein m is 0 or I, or -heterocyclyl, -C(O)—heterocyclyl,—
S(O)2-(alkylene)m wherein m is 1 or 2, wherein:
RN is H, C1 to C4 alkyl or C1 to C6 alkyl, and
wherein two RX1 can, together with the atoms to which they attach on P, which may be
the same atom, form a ring, and
tis 0, l or 2.
In some aspects, each R"1 is only optionally substituted by unsubstituted alkyl, halogen
or hydroxy.
In some aspects, RX1 is hydrogen or unsubstituted C1-C4 alkyl.
In some aspects, at least one RXI is -(alkylene)m-heterocyclyl wherein m is 0 or 1.
MRZ‘MN P* (in )t
Ir...
In some aspects, R2 is n P* is a 4- t0 8-
membered mono- or bicyclic saturated heterocyclyl group.
In some aspects, R2 is
_R2*_ N_RX1
In some aspects, R2 is \—/
—R2* (RX2)s
In some aspects, R2 is wherein:
R” is a bond, alkylene, -(alkylene)m-O—(alkylene)m-, -(alkylene)m-C(O)—(alkylene)m-,
-(alkylene)m-S(0)2-(alkylene)m- and -(alkylene)m-NH-(alkylene)m- wherein each m is
independently 0 or 1;
P is a 4- to ered mono- or bicyclic saturated heterocyclyl group;
P1 is a 4- to 6-membered monocyclic saturated heterocyclyl group;
each RX2 is independently hydrogen or alkyl, and
sis 0,10r2.
_R2*_N (RXZ)s
In some aspects, R2 is
In some s, P1 includes at least one nitrogen.
In some aspects, any alkylene in R2* in any previous aspect is not further substituted.
K,f5 K«K33
In some aspects, R2 is
, ,
V 52Wfl‘\
S“\ (N
N 5""me x"\N j
k, ”a“ H;
4“ ,Mu—J K
33K AK <5” 3 w i «3“
$3! Ni «2 \\N/Ufr(‘h 33 \Nr’x
KK,EL
\E\'3.x”Q]
K. LVKM
3 9
\ .w
33;. 5:» 3‘?\ V" H
Nx‘l ,-
NE‘ “W N 1
,x \N’fi
Kw” k ';
Jib»;« V’O ‘VM OH H
: é
v v
L “NAB\f ”NW
“”1k“!
’ \?V x Ki“, \“M’
\J‘ b§ I N'JW
i ‘K
I Va 1
7 \j 087
55: m
(S- \Nr
“NNN’N 7
L ER
S xv,“T/ N/fi ,
r’ W
N“? x3 K, N" x/N”I
53R x
L L am KW” NW” ”OB i
MAN,” ‘
x‘ R \{ \rmwxfk N{JV
9% H
9 ,
N \\3”\~
cm SNx x
kv' Km” “Now§ i 351“ , i“ 35:
N, w 3
H I L \Vf \ \N/W
xx" ‘xx’ is; K M" (N x
$31» x“\ ,x QR s x /\ ,3“
M N’A‘
«*NH K L a f
N .r"\ 4-"
’ f Nx’VVx ”Axfifi N" N
H ¥
D 3 7
53:\ M 3
s‘KNm ‘N. xx ,J’V'x
we» ‘3 “H (j N
s {
J k ,N- R3 :3: .N 33
[\v" 71/ x» Kx ,
N“ \{I
H {3 Q
S‘N V"
"\\ » N ‘ NY w
v\ F
Nmex’ E 33““ x” 55:" ,
,fi‘k a 3.; "(\Tflb
|\ ‘
. . £¥
,N \ 3334323
’v" L\ \M
858?: \v’, : {d V»:
fax. 551‘ .V. 5:.
N/W [J
N(x Sax“[\Lfl .5 x
N ”\T
K!” g \w’ \(‘SN {\vffixw‘lcca kv", “Sit“: ;
“"I‘N \vf" {:38 0 § g‘éfi
a :4
3;“ 3‘ v
N k
3 \NJ‘, ”N 3‘ \wx‘fl‘ ,«\NH 3‘\
9% w” qu‘N fo5
H i“ j g“ i? i 5
w O w
7 7
wfixx‘ “a”: N ,OH
I“ ”‘v ”‘6’”xv’ ‘OH
(xx ‘3“
. 3
”N\«x’m‘o’am; Kr’bj‘wf’“ : K/fi\x\x‘fi
(‘3‘. "“
(v S§:""~ a
S)\ ,m' N
«I \
N“xx 3‘\\ \f \
a,” x “r“*3 3 33‘».
\ rx ”-4”
¥\ N \
fl» x»
0‘5 W W NM W
0 :33»: NH:. F
w H
%“ N Y\:x:"’\ a
In some aspects, the compound has l Formula la:
Nm\ N’R
Rzfl )QN NW1
x2: N ( R )
X1 H y la
wherein R, R1, R2, X1, X2 and y are as previously defined.
In some aspects, the compound has general Formula lb:
N H y 1b
wherein R, R1, R2, and y are as previously defined.
In some aspects, the compound has general Formula Ic:
Rzm NWCYLE‘J’RN\/”
EN)?)‘EN Ic
wherein R and R2 are as previously defined.
In some aspects, the compound has l Formula Id:
R2f\ -------N
\ )i"N
\N 7/
X\ ‘X i H /’
wherein R, R2, X1 and X2 are as previously defined.
In some aspects, the compound has general Formula Ie:
\/"J Ie
wherein R, R2, X1 and X2 are as previously defined.
In some s, the compound has general a If:
n R, R2, X1, X2, and X3 are as previously defined.
In some aspects, the compound has general Formula 11a:
2017/040093
wherein R, R1, R2, X1, X2, and y are as previously defined.
In some aspects, the compound has l Formula 11b:
/N if
N?~.. r»; \ N»?
R2 \
' / \
\\ /‘N N““1- \
Lt: /\~N < R I}
N H 3’ 11b
wherein R, R1, R2, and y are as previously defined.
In some aspects, the compound has general Formula 110:
NWN m,
R2 \? liq/R
\< \
/\\*‘N “
\ \N
N H IIc
wherein R and R2, are as previously defined.
In some aspects, the compound has general Formula 11d:
/ N\
NWN N’R
R2m / \
X mx'l2., N
IId
wherein R, R2, X1 and X2 are as previously defined.
In some aspects, the compound has general Formula He:
NWN/ \ N”R
Rzfl FM
X2:X1 N
wherein R, R2, X1 and X2 are as previously defined.
In some aspects, the compound has general Formula IIf:
N/N\
NW NMR
szx3
,5/ >\ “N
\N {g
Hf
wherein R, R2, X1, X2, and X3 are as previously defined,
In some aspects, the compound has l Formula IIIa:
Rfl )‘QN {Ifilly,
Xzi‘x‘i E IIIa
wherein R, R1, R2, X1, X2, and y are as usly defined.
In some aspects, the compound has general Formula IIIb:
R2 //\\\\ ho
N)\N 1’ R1)
wherein R, R1, R2, X, and y are as usly defined.
In some aspects, the compound has general Formula IIIc:
Mm“yet X
R2/>:\km
fl 1110
n R, X, and R2 are as previously defined.
In some aspects, the compound has general a 111d:
/ /R
N \ / N
R2 / N.
X \X12‘ N
IIId
wherein R, R2, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula file:
N/ \ / N’R
922%)\NX -:X1
IIIe
wherein R, R2, X1, and X2 are as previously .
In some aspects, the compound has general Formula IIIf:
wherein R, R2, X1, X2, and X3 are as previously defined.
In some aspects, the compound has general Formula IVa:
x g
f 0
N \ /
R2 /fl)QNN
X H (R1) ‘3/
wherein R, R1, R2, X1, X2 and y are as previously .
In some aspects, the compound has general Formula IVb:
wherein R, R1, R2, X, and y are as previously defined.
In some aspects, the compound has general Formula IVc:
R2 / NW0ow
\N H IVc
wherein R, X, and R2 are as usly defined.
In some aspects, the compound has general Formula IVd:
x if:
/ 0
N \ /
R flNFN2
X \Xl
IVd
wherein R, R2, X1, and X2 are as previously defined.
WO 05860
In some aspects, the compound has l Formula IVe:
wherein R, R2, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula 1sz
IVf
wherein R, R2, X1, X2, and X3 are as previously defined.
In some aspects, the compound has general Formula Va:
xfitx’l H y Va
wherein R, R1, R2, X1, X2 and y are as previously defined.
In some aspects, the compound has general Formula Vb:
/ O
n R, R1, R2, and y are as previously defined.
In some aspects, the compound has general Formula Vc:
”WW 0
n R and R2 are as previously defined.
In some aspects, the compound has general a Vd:
wherein R, R2, X1, and X2 are as usly defined.
In some aspects, the compound has general Formula Ve:
wherein R, R2, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula Vf:
\ N
/ \ o
x2~><3 N
Xi >\ k“N
wherein R, R2, X1, X2, and X3 are as previously defined.
In some aspects, the compound has general Formula VIa:
thxi EAN/ N
( at)
’ VIa
wherein R, R1, R2, X1, and X2 are as previously defined.
In some aspects, the compound has l Formula VIb:
R QfiiN/i g:
y v1b
wherein R, R1, R2, and y are as previously defined.
In some aspects, the compound has general Formula VIc:
RZ / \\ /l'\E / C)
\N N N N
H K/N\R
wherein R and R2 are as previously defined.
2017/040093
In some aspects, the compound has general Formula VId:
wherein R, R2, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula VIe:
a.X1 N
VIe
wherein R, R2, X1, and X2 are as previously .
In some aspects, the compound has general Formula VIf:
wherein R, R2, X1, X2, and X3 are as previously defined.
In some aspects, the compound has general Formula VIIa:
WX” N N 3
XL N \R
\X1 H
VIIa
wherein R, R2, X1, and X2 are as previously .
In some aspects, the compound has general Formula VIIb:
VIIb
wherein R, R2, X1, X2, and X3 are as previously defined.
In some aspects, the compound has general Formula VIIIa:
szzN
N/ \ N%N
X"-":X1
VIIIa
wherein R2, X1, and X2 are as previously defined.
In some aspects, the compound has general a VIIIb:
/ Om
N N
Rifl>:'__"'“N
XZ-lrxi NH
VIIIb
wherein R2, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula VIIIc:
N/\ “"‘N
Rzfl:HmN
VIIIc
wherein R2, X1, and X2 are as previously .
In some aspects, the compound has general a VIIId:
VIIId
wherein R2, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula VIIIe:
/ N
flit>:N
X2"? VIIIe
wherein R2, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula VIIIf:
/ \ N N
N N
——_—-N o
ngxl VIIIf
wherein R2, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula IXa:
\ O
A \ \
X":X1 fi
wherein R, R2, X1, and X2 are as previously defined.
In some aspects, the compound has general a IXb:
~71”\\ :
X/LNA>\xmlh, New/kw l
<———-—“A?» IXb
wherein R, R2, X1, X2, and X3 are as previously .
In some aspects, the compound has general Formula Xa:
wherein R, R2, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula Xb:
wherein R, R2, X1, X2, and X3 are as previously defined.
In some aspects, the compound has general Formula XIa:
wherein R, R2, X1, and X2 are as previously defined.
In some aspects, the nd has general Formula XIb:
N x N"
xzflflxg N
// \ N
X1 ~~~~
\ l I
wherein R, R2, X1, X2, and X3 are as previously .
In some aspects, the compound has general Formula XIIa:
N)\\ i .
x3§x1 N
XIIa
wherein R, R2, X1, and X2 are as previously defined.
In some s, the compound has general Formula XIIb:
XIIb
wherein R, R2, X1, X2, and X3 are as previously defined.
In some aspects, the compound has general Formula XIIIa:
WM \ N
)(thl
XIIIa
wherein R2, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula XIIIb:
XIIIb
n R2, X1, X2, and X3 are as previously defined.
In some aspects, the compound has general Formula XIVa:
XIVa
wherein X, R2, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula XIVb:
XIVb
wherein X, R2, X1, X2, and X3 are as previously defined.
In some aspects, the compound has general Formula XVa:
wherein R, R2, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula XVb:
wherein R, R2, X1, X2, and X3 are as usly defined.
In some aspects, the compound has general a XVIa:
XVIa
n R2, X1, and X2 are as previously defined,
2017/040093
In some aspects, the compound has general Formula XVIb:
XVIb
wherein R2, X1, X2, and X3 are as previously defined.
In some aspects, the compound has general Formula XVIIa:
wherein R, R2, X1, and X2 are as previously defined.
In some aspects, the compound has general a XVIIb:
XVIIb
wherein R, R2, X1, X2, and X3 are as previously defined.
In some aspects, the compound has general Formula XVIIIa:
7 N
X '—~..X12g E N N
y XVIIIa
n R1, R2, R10, X1, X2, X3, and y are as previously defined.
In some s, the compound has general Formula XVIIIb:
R /\N\ W/NE \
(R1), XVIIIb
wherein R, R1, R2, R10 and y are as previously defined.
In some aspects, the compound has l a XVIIIc:
R2:N\ fixN/fi
XVIIIc
wherein R, R2 and R10 are as previously defined.
In some aspects, the compound has general Formula XVIIId:
R2 / \ /’U\ /
X2136 E N N
XVIIId
wherein R, R2, R10, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula XVIIIe:
R2 / \ l
X 'zrxi2 E N
XVIIIe
wherein R, R2, R10 X1, and X2 are as previously defined.
2017/040093
In some aspects, the nd has general Formula XIVa:
{jg/W).x2:\NH
X. .
XIXa
wherein R2, X1, and X2 are as previously defined.
In some aspects, the compound has general a XIXb:
R2flXk{Cw
\X I
XIXb
wherein R2, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula XIXc:
N/\N
X xx]
XIXC
wherein R2, X1, and X2 are as previously defined.
In some s, the compound has general Formula XIXd:
XIXd
wherein R2, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula XIXe:
R‘------------NHx2=x1(KN/”“037
XIXe
wherein R2, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula XXa:
Rzfl )\N/x:X1\WdNRxxaN
wherein R, R2, X1, and X2 are as previously defined.
In some s, the compound has general Formula XXb:
[N \ 4N”
X2”"X3x)fip JN
>\N ~~‘.
\/ m
wherein R, X1, X2, and X3 are as previously defined.
In some aspects, the compound has l Formula XXc:
Rgfl N\N/X::X1H N
XXc
wherein R, R2, X1, and X2 are as previously defined.
In some aspects, the compound has l Formula XXd:
wherein R, X1, X2, and X3 are as previously defined.
In some aspects, the compound has general Formula XXIa:
RZfl”N2‘
X “X1 N
XXIa
wherein R2, X1, and X2 are as previously defined.
In some s, the compound has general Formula XXIb:
--...._ \\ ”'/\
xzw—fl \ i
I >\ )NI/ )xtj/N
\3 g
k I ””J/
XXIb
wherein X1, X2, and X3 are as previously defined.
In some aspects, the compound has general a XXIIa:
XXIIa
wherein R2, X1, and X2 are as previously defined.
In some aspects, the compound has general Formula XXIIb:
N N
sz—mxs \ / N
XXIIb
n X1, X2, and X3 are as previously defined.
WO 05860 2017/040093
In some aspects, the compound has general Formula :
R2flfi)‘N 640N/vw,
X2a.X1
XXIIIa
wherein R, R2, X1, and X2 are as previously defined,
In some aspects, the compound has general Formula XXIIIb:
X2WX) /
ll] >\ N
\N , NwN:R
XXIIIb
wherein R, X1, X2, and X3 are as previously defined.
In some embodiments, the compound is selected from a Formula presented above and
X1 is N and X2 is CH. In other ments, the compound is selected from a Formula
presented above and X1 is N and X2 is N. In other embodiments, the compound is selected
from a Formula presented above and X1 is CH and X2 is CH. In other embodiments, the
compound is selected from a Formula presented above and X1 is CH and X2 is N.
In some embodiments, the compound is selected from a Formula presented above and
X1 is N, X2 is CH, X3 is CH, and X4 is CH. In other embodiments, the compound is selected
from a Formula presented above and X1 is CH, X2 is N, X3 is CH, and X4 is CH. In other
embodiments, the compound is selected from a Formula presented above and X1 is CH, X2 is
N, X3 is N, and X4 is CH. In other embodiments, the compound is selected from a Formula
ted above and X1 is CH, X2 is N, X3 is CH, and X4 is N. In other embodiments, the
nd is selected from a Formula presented above and X1 is N, X2 is CH, X3 is N, and
X4 is CH. In other embodiments, the compound is selected from a Formula presented above
and X1 is N, X2 is CH, X3 is CH, and X4 is N.
In some embodiments, the compound is selected from a Formula ted above and
_R2*_N P* (RX’I )t
R2 is wherein P* is a 4- to 8-membered mono- or bicyclic
saturated heterocyclyl group and R”, R"1 and t are as previously defined.
In some embodiments, the compound is selected from a a presented above and
—R2*—N P* (RX1)t
R2 is wherein P* is a 4- to 8-membered mono— or bicyclic
saturated heterocyclyl group, RX1 is hydrogen or unsubstituted C1-C4 alkyl and R2* is as
previously defined.
In some embodiments, the compound is selected from a Formula presented above and
I {\A $&&»’\
min “5‘“:g m
R2 is selected from 0 A” ’ \
, x ,
‘; A»!
l 3““ xx} §\N/\\]
0 L\/i\l §\NA]
\{’ s
s ’8
\V \7/ L\/N\ and
‘ ‘C
o N N—
In some embodiments, the compound is selected from a Formula presented above and
:»,
%, «x N/\l SK
‘3‘ i LVN W
1:wais selected from, \v” N\, and
In some embodiments, the compound is selected from a a presented above
and R is alkyl.
In some ments, the compound is selected from a Formula presented above
and R is hydrogen.
In some embodiments Rx is further substituted with a substituent chosen from:
-(alkylene)m-CN, —(alkylene)m-OR5*, lene)m-S(O)n—R5*,
-(alkylene)m-NR3*R4*, -(alkylene)m-C(O)—R5*, -(alkylene)m-C(=S)R5*,
-(alkylene)m-C(=O)O R5*, -(alky1ene)m-OC(=O)R5*, -(alkylene)m-C(S)—OR5*,
-(alkylene)m-C(O)—NR3*R4*, -(alkylene)m-C(S)—NR3*R4*,
—(alkylene)m-N(R3*)—C(O)—NR3*R4*, lene)m-N(R3*)—C(S)—NR3*R4*,
-(alkylene)m-N(R3*)—C(O)—R5*, -(alkylene)m-N(R3*)—C(S)—R5*,
—(alkylene)m-O—C(O)—NR3*R4*, lene)m-O—C(S)—NR3*R4*,
-(alkylene)m-802—NR3*R4*, -(alkylene)m-N(R3*)—SOz—R5*,
-(alkylene)m-N(R3*)—SOz—NR3*R4*, -(alkylene)m-N(R3*)—C(O)—OR5*,
-(alkylene)m-N(R3*)—C(S)—OR5*, and -(alkylene)m-N(R3*)—SOz—R5*;
R3* and R4* at each occurrence are independently selected from:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl,
heterocycloalkyl, kyl, or heteroarylalkyl any of which may be optionally independently
substituted with one or more Rx groups as allowed by valance; or R3* and R4* together with
the en atom to which they are attached may combine to form a cyclo ring optionally
independently substituted with one or more RX groups as allowed by valance.
R5* is independently selected at each occurrence from:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl, lkyl, heterocyclo, aryl, heteroaryl,
cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally
independently substituted with one or more RX groups as allowed by valance;
2017/040093
In some embodiments the compound of the present invention is selected from:
R2 (12), 1:12 (112), R2
3‘ O
«.2 \ N
/R N N O
N\ J >60 \ / N
HEN/LN 3;; N Ni \
, 1 C?
HM (R) HN/L‘N/ N
(1112), R2 (1V2),
HN HN
‘ \R!,') N ~N ( R )
/ I? y / /
\ 1 3’
(V12), i2? (V112), R3 (V1112), R2
0 R1
X MIR i j
/ \ /
N N
N \
FM ( R‘) )‘N
i W1
1 HM (I R
HN )y
f N / N
1 \
(IXz), R2 (Xz), R2 (XIz),
(XVIz), R’2 (XVIIz) R2 (XVIIIz), and
R2 (XIXz);
n:
N" N
E ‘1 N
R2 IS selected from,. \V" 7” LVN\ and
00-;
In an ative embodiment, the compound of the present invention is selected from:
N\\/ N
IN/R N)\\/ z
7L0 N
H~ 7*
( R1 N
/ [i] )y /
2 2
R (XX), R
NfQTW NC]
)\N ,
\BVQ )\N W0
HN (R1)y HN (R1)
/ N / N
\ \
R2 (XXII),and R2 (XXIII),
wherein:
R2 is selected from,
0 NCN—
\_/ §
II. TERMINOLOGY
Compounds are described using standard nomenclature. Unless defined otherwise, all
technical and scientific terms used herein have the same meaning as is commonly understood
by one of skill in the art to which this invention belongs.
The nds in any of the as described herein include racemates,
enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N—
oxides, isomers; such as rotamers, as if each is specifically described.
The terms “a” and “an” do not denote a limitation of quantity, but rather denote the
ce of at least one of the referenced item. The term “or” means “and/or”. Recitation of
ranges of values are merely intended to serve as a shorthand method of referring individually
to each separate value falling within the range, unless otherwise indicated herein, and each
separate value is incorporated into the specification as if it were individually recited herein.
The endpoints of all ranges are included within the range and independently able. All
methods described herein can be med in a le order unless otherwise indicated
herein or otherwise clearly contradicted by context. The use of examples, or exemplary
language (e.g., “such as”), is intended merely to better illustrate the invention and does not
pose a tion on the scope of the invention unless otherwise claimed. Unless defined
otherwise, technical and ific terms used herein have the same meaning as is commonly
tood by one of skill in the art to which this invention belongs.
The present invention includes compounds of Formula 1, Formula II, Formula III
Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X,
a XI, a XII, Formula XIII, Formula XIV, Formula XV, a XVI, Formula
XVII, Formula XVIII, and Formula XIX with at least one desired isotopic substitution of an
atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are
atoms having the same atomic number but different mass numbers, i.e., the same number of
protons but a different number of neutrons.
Examples of isotopes that can be orated into compounds of the invention include
isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine
such as 2H, 3H, 11C, 13C, 14C, 15N, 18F 31P, 32P, 358, 36CI, and 125I respectively. In one non-
limiting embodiment, isotopically labelled compounds can be used in metabolic studies (with
14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques,
such as positron emission tomography (PET) or single-photon emission computed tomography
) including drug or substrate tissue bution assays, or in radioactive treatment of
patients. In particular, an 18F labeled compound may be particularly desirable for PET or
SPECT studies. Isotopically labeled compounds of this invention and prodrugs f can
generally be ed by canying out the procedures disclosed in the schemes or in the
examples and preparations described below by substituting a readily available isotopically
labeled reagent for a otopically labeled reagent.
By way of general e and without limitation, isotopes of hydrogen, for example,
deuterium (2H) and tritium (3H) may be used anywhere in described structures that achieves
the desired . Alternatively or in addition, isotopes of carbon, e.g., 13C and 14C, may be
used.
Isotopic substitutions, for example ium substitutions, can be partial or te.
Partial deuterium substitution means that at least one hydrogen is substituted with deuterium.
In certain embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any
location of interest. In one non-limiting embodiment, deuterium is 90, 95 or 99% enriched at
a desired location.
In one non-limiting embodiment, the substitution of a hydrogen atom for a ium
atom can be provided in any of a I, Formula II, a III Formula IV, Formula V,
Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII,
Formula XIII, Formula XIV, Formula XV, Formula XVI, a XVII, Formula XVIII,
a XIX, Formula XX, Formula XXI, Formula XXII, or Formula XXIII. In one non-
limiting embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within
a group selected from any of R, R1, R2, R3, R4, R5, R6, R7, R8, R9, and RX. For example, when
any of the groups are, or contain for example through substitution, methyl, ethyl, or methoxy,
the alkyl residue may be ated (in non-limiting embodiments, CDH2, CD2H, CD3,
CH2CD3, CD2CD3, D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 etc). In
certain other embodiments, when two substituents are combined to form a cycle the
unsubstituted carbons may be deuterated.
The compound of the present invention may form a solvate with solvents (including
water). Therefore, in one non-limiting embodiment, the invention includes a solvated form of
the compound. The term "solvate" refers to a molecular complex of a compound of the present
invention (including a salt thereof) with one or more solvent molecules. Non-limiting
examples of solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic
solvents. The term "hydrate" refers to a molecular complex comprising a nd of the
invention and water. Pharmaceutically acceptable es in accordance with the invention
include those wherein the solvent may be isotopically substituted, e. g. D20, tone, d6-
DMSO. A solvate can be in a liquid or solid form.
A dash ("-") that is not n two letters or s is used to te a point of
attachment for a substituent. For example, -(C=O)NH2 is attached through carbon of the keto
(C=O) group.
“Alkyl” is a branched or straight chain saturated aliphatic hydrocarbon group. In one
non-limiting embodiment, the alkyl group contains from 1 to about 12 carbon atoms, more
generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one non-
limiting embodiment, the alkyl contains from 1 to about 8 carbon atoms. In certain
embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges as used
herein indicate an alkyl group having each member of the range described as an independent
species. For example, the term C1-C6 alkyl as used herein indicates a straight or branched alkyl
group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is
described as an independent species. For example, the term C1-C4 alkyl as used herein indicates
a straight or ed alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to
mean that each of these is bed as an independent species. Examples of alkyl include, but
are not limited to, methyl, ethyl, yl, pyl, n-butyl, isobutyl, sec-butyl, t-butyl, n—
pentyl, isopentyl, tert—pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-
dimethylbutane, and 2,3—dimethylbutane. In an alternative embodiment, the alkyl group is
optionally substituted. The term ” also encompasses cycloalkyl or carbocyclic groups.
For example, when a term is used that includes “alk” then “cycloalkyl” or cyclic” can
be considered part of the definition, unless unambiguously excluded by the context. For
example, and without limitation, the terms alkyl, alkoxy, haloalkyl, etc. can all be considered
to include the cyclic forms of alkyl, unless unambiguously excluded by context.
“Alkenyl” is a linear or branched aliphatic hydrocarbon groups having one or more
carbon-carbon double bonds that may occur at a stable point along the chain. The specified
ranges as used herein indicate an alkenyl group having each member of the range described as
an ndent species, as described above for the alkyl moiety. Examples of alkenyl radicals
include, but are not limited to ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
The term “alkenyl” also embodies “cis” and “trans” alkenyl geometry, or altematively, “”E and
“Z” alkenyl geometry. In an alternative embodiment, the alkenyl group is optionally
substituted. The term “Alkenyl” also encompasses cycloalkyl or carbocyclic groups sing
at least one point of unsaturation.
“Alkynyl” is a branched or straight chain tic arbon group having one or
more -carbon triple bonds that may occur at any stable point along the chain. The
specified ranges as used herein indicate an alkynyl group having each member of the range
bed as an independent species, as described above for the alkyl . Examples of
l include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-
pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, l-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and
5-hexynyl. In an alternative embodiment, the alkynyl group is ally substituted. The term
“Alkynyl” also encompasses cycloalkyl or carbocyclic groups possessing at least one point of
unsaturation.
“Halo” and “Halogen” is fluorine, chlorine, bromine or iodine.
“Haloalkyl” is a branched or straight-chain alkyl groups substituted with 1 or more halo
atoms described above, up to the maximum ble number of halogen atoms. es of
haloalkyl groups include, but are not limited to, ethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,
ochloromethyl, dichlorofluoromethyl, difluoroethyl, opropyl, dichloroethyl and
dichloropropyl. “Perhaloalkyl” means an alkyl group having all hydrogen atoms replaced with
halogen atoms, Examples include but are not limited to, trifluoromethyl and pentafluoroethyl.
“Haloalkoxy” indicates a haloalkyl group as defined herein attached through an oxygen
bridge n of an l radical).
As used herein, “aryl” refers to a radical of a monocyclic or clic (e.g., bicyclic
or lic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 7t electrons shared in a cyclic
array) having 6—14 ring carbon atoms and zero heteroatoms provided in the aromatic ring
system (“Ce—14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”;
e.g., ). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”, e.g.,
yl such as 1—naphthyl and 2—naphthyl). In some embodiments, an aryl group has 14
ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the
aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups
wherein the radical or point of attachment is on the aryl ring, and in such instances, the number
of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. The
one or more fused carbocyclyl or heterocyclyl groups can be 4 to 7 or 5 to 7-membered
saturated or partially unsaturated carbocyclyl or heterocyclyl groups that optionally contain 1,
2 or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon
and boron, to form, for example, a 3,4-methylenedioxyphenyl group. In one non-limiting
embodiment, aryl groups are pendant. An example of a pendant ring is a phenyl group
tuted with a phenyl group. In an alternative embodiment, the aryl group is optionally
substituted as described above. In certain embodiments, the aryl group is an unsubstituted C67
14 aryl. In certain embodiments, the aryl group is a substituted C6714 aryl. An aryl group may
be optionally tuted with one or more functional groups that include but are not limited to,
halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo.
The term “heterocyclyl” (or “heterocyclo”) includes saturated, and partially saturated
heteroatom—containing ring radicals, where the heteroatoms may be ed from nitrogen,
sulfur and oxygen. Heterocyclic rings comprise monocyclic 6-8 membered rings, as well as 5-
16 membered bicyclic ring systems (which can include bridged fused and Spiro-fused ic
ring systems). It does not include rings containing -O-O-.—O-S- or -S-S— portions. Said
2017/040093
“heterocyclyl” group may be optionally substituted with 1 to 3 substituents that include but are
not limited to, yl, Boc, halo, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino.
Examples of saturated heterocyclo groups include saturated 3- to 6-membered
heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, irnidazolidinyl,
inyl, pyrrolinyl, piperazinyl], saturated 3 to 6-membered heteromonocyclic group
containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-
membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms
[e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include but are not
limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. es of
partially saturated and saturated heterocyclo groups include but are not limited to, pyrrolidinyl,
irnidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, linyl,
tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[l,4]dioxanyl, indolinyl,
isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-
dihydroquinolyl, 1,2,3,4- tetrahydro-isoquinolyl, 1 ,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a—
hexahydro-lHaza—fluorenyl, 5,6,7- ro-l,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-
2H-benzo[l,4]oxazinyl, benzo[l,4]dioxanyl, 2,3- dihydro—lH-lk’-benzo[d]isothiazolyl,
dihydropyranyl, dihydrofuryl and othiazolyl.
Heterocyclo groups also include radicals Where heterocyclic radicals are
fused/condensed with aryl radicals: such as unsaturated condensed heterocyclic group
containing 1 to 5 nitrogen atoms, for e, indoline, oline, unsaturated condensed
heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, rated
condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and
saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to
2 oxygen or sulfur atoms.
The term oaryl” s aryl ring systems that contain one or more heteroatoms
ed from O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized,
and nitrogen atom(s) are optionally quarternized. Examples include but are not d to,
unsaturated 5 to 6 membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, such
as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, IH-l ,2,3-triazolyl, 2H-l,2,3-triazolyl];
unsaturated 5- to 6-membered heteromonocyclic groups containing an oxygen atom, for
e, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered monocyclic groups
containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc; rated 5- to 6-membered
heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for
e, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-
oxadiazolyl], rated 5 to 6—membered heteromonocyclic groups containing 1 to 2 sulfur
atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl,
thiadiazolyl, 1,2,5-thiadiazoly1].
The term “sulfonyl”, whether used alone or linked to other terms such as alkylsulfonyl,
denotes respectively divalent radicals -SOz-.
The terms “carboxy” or “carboxyl”, Whether used alone or with other terms, such as
“carboxyalkyl”, denotes —C(O)—OH.
The term “carbonyl”, Whether used alone or with other terms, such as “aminocarbonyl”,
denotes -C(O)-.
The term carbonyl” denotes an amide group of the formula -C(O)—NH2.
The terms “heterocycloalkyl” denotes heterocyclic-substituted alkyl ls. Examples
include but are not d to, piperidylmethyl and morpholinylethyl.
“Arylalkyl” is an aryl group as defined herein attached through an alkyl group. Non—
limiting examples of arylalkyl groups include: 3 “’ I .
315V.
“Heteroarylalkyl” is a heteroaryl group as defined herein attached h an alkyl
“Aryloxy” is an aryl group as defined herein attached through a —O- linker. Non-
QR);
limiting examples of aryloxy groups include: 310 and ‘50
As used herein, “carbocyclyl”, c ‘carbocyclic”, cycle” or “cycloalkyl” is a
saturated or partially unsaturated (i.e., not aromatic) group containing all carbon ring atoms
WO 05860
and from 3 to 14 ring carbon atoms (“C3714 carbocyclyl”) and zero heteroatoms in the non—
aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms
(“C3710 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 9 ring carbon atoms
(“C3_9 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms
(“C378 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms
(“C377 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms
(“C376 carbocyclyl”). In some ments, a carbocyclyl group has 4 to 6 ring carbon atoms
(“C476 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms
(“C576 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms
(“C5710 yclyl”). Exemplary C376 carbocyclyl groups include, without limitation,
cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5),
cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like.
Exemplary C3—3 carbocyclyl groups include, without limitation, the entioned C3_6
carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7),
cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), and the like. Exemplary C3710
carbocyclyl groups include, without limitation, the aforementioned C378 carbocyclyl groups as
well as cyclononyl (C9), onenyl (C9), ecyl (C10), cyclodecenyl (C10), and the like.
As the foregoing examples illustrate, in certain ments, the carbocyclyl group can be
saturated or can contain one or more carbon—carbon double or triple bonds. In an alternative
embodiment, “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined
above, is fused with one or more heterocyclyl, aryl or heteroaryl groups wherein the point of
attachment is on the yclyl ring, and in such instances, the number of carbons continue to
designate the number of carbons in the carbocyclic ring system. In an alternative embodiment,
each instance of carbocycle is optionally substituted with one or more tuents. In n
embodiments, the yclyl group is an unsubstituted C3714 carbocyclyl. In certain
embodiments, the carbocyclyl group is a substituted C3714 carbocyclyl.
“Cycloalkylalkyl” is an cycloalkyl group as defined herein attached through an alkyl
group. Non-limiting examples of cycloalkylalkyl groups include: 9 7
wax/O
The term “oxo” as used herein contemplates an oxygen atom attached with a double
bond.
III. METHODS OF TREATMENT
In one aspect, a method of treating a proliferative disorder in a host, including ,
is provided comprising administering an effective amount of a compound of Formula I,
Formula II, Formula III Formula IV, a V, a VI, Formula VII, Formula VIII,
Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, a XIV, Formula XV,
Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI,
Formula XXII, Formula XXIII, a XXIV, or Formula XXV.
or its pharmaceutically acceptable salt, N—oxide, deuterated derivative, g, and/or
a pharmaceutically acceptable composition thereof as described herein optionally in a
pharmaceutically acceptable carrier. Non-limiting examples of disorders e tumors,
s, disorders related to abnormal cellular proliferation, inflammatory disorders, immune
disorders, and autoimmune disorders.
A compound of Formula I, Formula II, Formula III a IV, Formula V, Formula
VI, Formula VII, Formula VIII, Formula IX, a X, Formula XI, a XII, Formula
XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX,
Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV
is useful as therapeutic agents when administered in an effective amount to a host, including a
human, to treat , cancer , non-solid, diffuse, hematological, etc), abnormal cellular
proliferation, immune disorder, inflammatory disorder, blood disorder, a myelo- or
lymphoproliferative disorder such as B- or T-cell lymphomas, multiple myeloma, breast
, prostate cancer, AML, ALL, ACL, lung cancer, pancreatic cancer, colon cancer, skin
cancer, melanoma, Waldenstrom’s macroglobulinemia, Wiskott-Aldrich syndrome, or a post—
transplant lymphoproliferative disorder; an autoimmune disorder, for example, Lupus, Crohn’s
Disease, Addison disease, Celiac disease, dermatomyositis, Graves disease, ditis,
multiple sclerosis, pernicious anemia, reactive arthritis, or type I diabetes, a disease of
cardiologic malfunction, including hypercholesterolemia, an infectious disease, including a
viral and/or bacterial infection; an inflammatory condition, ing asthma, chronic peptic
ulcers, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, or hepatitis.
Exemplary proliferative disorders include, but are not limited to, benign growths,
neoplasms, tumors, cancer (Rb positive or Rb ve), autoimmune disorders, atory
disorders graft-versus-host rejection, and fibrotic disorders.
Non-limiting examples of cancers that can be treated according to the present ion
include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal
cancer, arcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma,
iosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g.,
cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast,
papillary carcinoma of the breast, y cancer, medullary carcinoma of the breast), brain
cancer (e.g., meningioma, glioma, e.g., astrocytoma, oligodendroglioma; oblastoma),
bronchus cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma),
choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal
cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, eliosarcoma
(e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g.,
uterine cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma of the esophagus,
Barrett’s adenocarinoma), Ewing’s sarcoma, eye cancer (e.g., intraocular melanoma,
retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g., stomach
adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and
neck squamous cell oma, oral cancer (e.g., oral squamous cell carcinoma (OSCC), throat
cancer (e.g., laryngeal cancer, pharyngeal , nasopharyngeal cancer, oropharyngeal
cancer)), hematopoietic s (e. g, ia such as acute cytic leukemia (ALL) —
also known as acute lymphoblastic leukemia or acute lymphoid leukemia (e.g., B—cell ALL,
T—cell ALL), acute myelocytic leukemia (AML) (e.g., B—cell AML, T—cell AML), chronic
myelocytic leukemia (CML) (e.g., B—cell CML, T—cell CML), and chronic lymphocytic
ia (CLL) (e.g., B—cell CLL, T—cell CLL); lymphoma such as n lymphoma (HL)
(e.g., B—cell HL, T—cell HL) and non—Hodgkin lymphoma (NHL) (e.g., B—cell NHL such as
diffuse large cell lymphoma (DLCL) (e.g., diffuse large B—cell lymphoma (DLBCL)),
follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma
(CLL/SLL), mantle cell lymphoma (MCL), marginal zone B—cell mas (e.g., —
associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B—cell lymphoma,
c marginal zone B—cell lymphoma), primary mediastinal B—cell lymphoma, Burkitt
lymphoma, lymphoplasmacytic lymphoma (i.e., “Waldenstrém's macroglobulinemia”), hairy
cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B—lymphoblastic
ma and primary central nervous system (CNS) lymphoma; and T—cell NHL such as
precursor T—lymphoblastic lymphoma/leukemia, peripheral T—cell lymphoma (PTCL) (e.g.,
cutaneous T—cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome),
mmunoblastic T—cell lymphoma, extranodal natural killer T—cell lymphoma,
enteropathy type T—cell lymphoma, subcutaneous panniculitis—like T—cell lymphoma,
anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described
above, and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma
chain disease, mu chain disease), hemangioblastoma, inflammatory oblastic tumors,
cytic amyloidosis, kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell
carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer
(e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), all cell lung cancer
(NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e. g., systemic
mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder
(MPD) (e.g., themia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid
metaplasia (AMM) aka. brosis (MF), chronic idiopathic myelofibrosis, chronic
myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic
syndrome (HES)), neuroblastoma, neurofibroma (e. g., neurofibromatosis (NF) type 1 or type
2, schwannomatosis), neuroendocrine cancer (e.g., enteropancreatic ndoctrine
tumor (GEP—NET), carcinoid tumor), arcoma, ovarian cancer (e.g., cystadenocarcinoma,
ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma,
pancreatic cancer (e. g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm
, Islet cell tumors), penile cancer (e.g., Paget’s disease of the penis and scrotum),
pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate
adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g.,
squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma
(BCC)), small bowel cancer (e.g., appendix cancer), soft tissue sarcoma (e. g., malignant fibrous
histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST),
chondrosarcoma, rcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland
carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma),
thyroid cancer (e.g., papillary carcinoma of the d, papillary thyroid carcinoma (PTC),
medullary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget’s
disease of the vulva).
In another embodiment, the er is myelodysplastic syndrome (MDS).
In certain embodiments, the cancer is ahematopoietic cancer. In n embodiments,
the hematopoietic cancer is a ma. In certain embodiments, the hematopoietic cancer is
a leukemia. In n embodiments, the leukemia is acute myelocytic leukemia (AML).
In certain embodiments, the proliferative er is a myeloproliferative neoplasm. In
certain ments, the myeloproliferative neoplasm (MPN) is primary myelofibrosis
(PMF).
In certain embodiments, the cancer is a solid tumor. A solid tumor, as used herein, refers
to an al mass of tissue that usually does not contain cysts or liquid areas. Different types
of solid tumors are named for the type of cells that form them. Examples of classes of solid
tumors include, but are not limited to, sarcomas, carcinomas, and mas, as described
above herein. Additional examples of solid tumors include, but are not limited to, squamous
cell oma, colon cancer, breast cancer, prostate cancer, lung cancer, liver cancer,
pancreatic cancer, and melanoma.
In certain ments, the condition treated with a compound of Formula I, Formula
II, Formula III Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX,
Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula
XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula
XXII, Formula XXIII, Formula XXIV, or Formula XXV is a disorder related to abnormal
cellular proliferation.
Abnormal cellular proliferation, notably roliferation, can occur as a result of a
wide variety of factors, including genetic mutation, infection, exposure to toxins, autoimmune
disorders, and benign or malignant tumor ion.
There are a number of skin disorders associated with cellular hyperproliferation.
Psoriasis, for example, is a benign disease of human skin generally characterized by plaques
covered by thickened scales. The disease is caused by increased proliferation of epidermal cells
of unknown cause. c eczema is also associated with icant hyperproliferation of the
epidermis. Other diseases caused by hyperproliferation of skin cells include atopic dermatitis,
lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma and squamous
cell carcinoma.
Other hyperproliferative cell disorders include blood vessel proliferation disorders,
fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors and cancers.
Blood vessel proliferative ers include angiogenic and vasculogenic disorders.
eration of smooth muscle cells in the course of development of plaques in vascular tissue
cause, for example, restenosis, retinopathies and atherosclerosis. Both cell migration and cell
proliferation play a role in the ion of atherosclerotic lesions.
ic ers are often due to the abnormal ion of an extracellular matrix.
Examples of fibrotic disorders include hepatic cirrhosis and mesangial proliferative cell
disorders, Hepatic cirrhosis is characterized by the increase in extracellular matrix constituents
resulting in the ion of a hepatic scar. Hepatic cirrhosis can cause diseases such as
cirrhosis of the liver. An increased extracellular matrix ing in a hepatic scar can also be
caused by viral infection such as hepatitis. Lipocytes appear to play a major role in hepatic
cirrhosis.
Mesangial disorders are brought about by abnormal proliferation of mesangial cells.
Mesangial hyperproliferative cell disorders include s human renal diseases, such as
glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic micro-
angiopathy syndromes, transplant rejection, and glomerulopathies.
Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid
tis is generally considered an autoimmune disease that is thought to be associated with
activity of autoreactive T cells, and to be caused by autoantibodies produced against collagen
and IgE.
Other disorders that can include an abnormal cellular erative ent include
Bechet’s syndrome, acute respiratory distress syndrome (ARDS), ic heart disease, post-
dialysis syndrome, leukemia, acquired immune ncy syndrome, vasculitis, lipid
histiocytosis, septic shock and inflammation in general.
In certain embodiments, a compound of the present invention and its pharmaceutically
acceptable derivatives or pharmaceutically acceptable formulations containing these
compounds are also useful in the prevention and treatment ofHBV infections and other related
conditions such as anti-HBV antibody positive and HBV-positive conditions, chronic liver
inflammation caused by HBV, cirrhosis, acute tis, fulrninant hepatitis, chronic persistent
hepatitis, and e. These compounds or ations can also be used lactically to
prevent or retard the progression of clinical illness in individuals who are anti-HBV antibody
or tigen positive or who have been d to HBV.
In certain embodiments, the condition is associated with an immune response.
Cutaneous contact hypersensitivity and asthma are just two examples of immune
responses that can be ated with significant morbidity. Others include atopic dermatitis,
eczema, Sjogren's Syndrome, including keratoconjunctivitis sicca secondary to Sjogren's
Syndrome, ia areata, allergic responses due to arthropod bite reactions, Crohn's disease,
aphthous ulcer, intis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus
erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may
result in any one or more of the ing symptoms or signs: itching, swelling, s,
blisters, crusting, ulceration, pain, scaling, cracking, hair loss, scarring, or oozing of fluid
involving the skin, eye, or mucosal membranes.
In atopic dermatitis, and eczema in general, immunologically mediated leukocyte
infiltration cularly infiltration of mononuclear cells, lymphocytes, neutrophils, and
eosinophils) into the skin importantly contributes to the pathogenesis ofthese es. Chronic
eczema also is ated with significant hyperproliferation of the epidermis.
Immunologically mediated leukocyte infiltration also occurs at sites other than the skin, such
as in the airways in asthma and in the tear producing gland of the eye in keratoconjunctivitis
sicca.
In one non-limiting embodiment compounds ofthe present invention are used as topical
agents in treating contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis,
Sjogren's Syndrome, including keratoconjunctivitis sicca secondary to Sjogren‘s Syndrome,
alopecia areata, allergic responses due to arthropod bite reactions, Crohn's disease, aphthous
ulcer, iritis, ctivitis, keratoconjunctivitis, ulcerative colitis, , allergic asthma,
cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. The novel
method may also be useful in reducing the infiltration of skin by malignant leukocytes in
diseases such as mycosis fungoides. These compounds can also be used to treat an aqueous—
deficient dry eye state (such as immune ed conjunctivitis) in a patient suffering
therefrom, by administering the compound topically to the eye.
The term asia” or “cancer” is used throughout the specification to refer to the
pathological process that results in the formation and growth of a cancerous or malignant
neoplasm, i.e., abnormal tissue (solid) or cells (non-solid) that grow by cellular eration,
often more rapidly than normal and continues to grow after the stimuli that initiated the new
growth cease. Malignant sms show partial or complete lack of structural organization
and functional coordination with the normal tissue and most invade surrounding tissues, can
metastasize to several sites, are likely to recur after attempted removal and may cause the death
of the patient unless adequately treated. As used herein, the term neoplasia is used to describe
all cancerous disease states and embraces or asses the pathological process associated
with malignant hematogenous, ascitic and solid tumors. Exemplary cancers which may be
treated by the present disclosed compounds either alone or in ation with at least one
additional anti-cancer agent include us-cell carcinoma, basal cell carcinoma,
arcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder,
bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas,
te, and h; leukemias; benign and malignant lymphomas, ularly Burkitt’s
lymphoma and Non-Hodgkin's lymphoma, benign and malignant melanomas;
myeloproliferative diseases; sarcomas, including s sarcoma, hemangiosarcoma,
Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma,
gliomas, astrocytomas, oligodendrogliomas, ependymomas, stomas, neuroblastomas,
ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas,
meningeal sarcomas, neurofibromas, and Schwannomas, bowel cancer, breast cancer, prostate
cancer, cervical cancer, uterine cancer, lung cancer, ovarian , testicular cancer, thyroid
cancer, astrocytoma, esophageal cancer, atic cancer, stomach cancer, liver cancer, colon
cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas.
Additional cancers which may be treated using the disclosed compounds according to the
present invention include, for example, acute granulocytic leukemia, acute lymphocytic
leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, arcoma,
adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma,
appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer,
bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem
glioma, breast , triple (estrogen, progesterone and HER-2) negative breast cancer, double
negative breast cancer (two of estrogen, progesterone and HER-2 are ve), single negative
(one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HERZ-
negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive
breast cancer, metastatic breast cancer, luminal A breast , luminal B breast cancer, Her2-
negative breast cancer, HERZ—positive or ve breast cancer, progesterone or-
ve breast cancer, progesterone receptor—positive breast cancer, ent breast cancer,
carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, c cytic
leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer,
craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal
carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal
, ewing sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer,
fibrosarcoma, gallbladder , c cancer, gastrointestinal cancer, gastrointestinal
carcinoid cancer, gastrointestinal stromal tumors (GIST), germ cell tumor glioblastoma
multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer,
hemangioendothelioma, Hodgkin ma, hypopharyngeal cancer, infiltrating ductal
carcinoma (IDC), infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC),
inal Cancer, intrahepatic bile duct cancer, invasive/infiltrating breast cancer, Islet cell
cancer, jaw , Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma,
leptomeningeal ases, leukemia, lip , liposarcoma, liver cancer, lobular carcinoma
in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast
cancer, medullary oma, medulloblastoma, melanoma, meningioma, Merkel cell
oma, mesenchymal chondrosarcoma, mesenchymous, mesothelioma atic breast
cancer, metastatic melanoma metastatic squamous neck , mixed gliomas, monodermal
teratoma, mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis
des, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck
cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin's lymphoma, non-small
cell lung cancer (NSCLC), oat cell cancer, ocular cancer, ocular melanoma,
oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma,
osteosarcoma, ovarian cancer, n epithelial cancer n germ cell tumor, ovarian
primary neal carcinoma, n sex cord stromal tumor, Paget's disease, pancreatic
cancer, papillary carcinoma, paranasal sinus cancer, parathyroid , pelvic cancer, penile
cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma,
pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary gland cancer, primary
l nervous system (CNS) lymphoma, prostate , rectal cancer, renal cell carcinoma,
renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone
sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine
, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma,
stomach cancer, synovial a, T-cell lymphoma, testicular cancer, throat cancer,
thymoma/thymic carcinoma, d cancer, tongue cancer, tonsil cancer, transitional cell
cancer, tubal cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer,
uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell
lineage acute lymphoblastic ia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-
LL), peripheral T-cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large
B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL,
Philadelphia some positive CML, juvenile myelomonocytic leukemia (JMML), acute
promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, Adult T—
cell chronic leukemia, diffuse large B cell lymphoma, follicular lymphoma, Mucosa—
Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma,
mediastinal large B cell lymphoma, nodal al zone B cell ma ; splenic
marginal zone lymphoma (SMZL), intravascular large B-cell lymphoma; primary effusion
lymphoma, or lymphomatoid granulomatosis,, B-cell prolymphocytic leukemia; splenic
lymphoma/leukemia, unclassifiable, splenic diffuse red pulp small B—cell lymphoma;
lymphoplasmacytic lymphoma; heavy chain diseases, for example, Alpha heavy chain e,
Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary
plasmacytoma of bone, extraosseous plasmacytoma, primary cutaneous follicle center
lymphoma, T cell/histocyte rich large B-cell lymphoma, DLBCL associated with chronic
inflammation, Epstein-Barr virus (EBV)+ DLBCL of the elderly; primary mediastinal (thymic)
large B-cell lymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell ma,
plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated entric,
Castleman disease, B-cell lymphoma, unclassifiable, with es intermediate between
diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate
between diffuse large B—cell lymphoma and classical Hodgkin lymphoma.
In another aspect, a method of increasing BIM expression (e. g., BCLC2L11 expression)
is provided to induce apoptosis in a cell comprising contacting a compound of the t
invention or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug
thereof with the cell. In certain ments, the method is an in vitro method. In certain
embodiments, the method is an in viva method. BCL2L11 expression is tightly regulated in a
cell. BCL2L11 s for BIM, a proapoptotic protein. 1 is downregulated in many
cancers and BIM is inhibited in many cancers, including chronic myelocytic leukemia (CML)
and non-small cell lung cancer (NSCLC) and that suppression of BCL2L11 expression can
confer resistance to tyrosine kinase inhibitors. See, e.g., Ng et al., Nat. Med. (2012) 18:521—
528.
In yet another aspect, a method of treating a condition associated with angiogenesis is
provided, such as, for example, a diabetic condition (e.g., diabetic pathy), an
inflammatory condition (e.g., rheumatoid arthritis), macular degeneration, obesity,
atherosclerosis, or a erative disorder, sing administering to a subject in need
thereof a compound of the present invention or a pharmaceutically acceptable composition,
salt, isotopic , or prodrug thereof.
In certain embodiments, the condition associated with angiogenesis is macular
degeneration. In certain embodiments, provided is a method of treating macular degeneration
comprising administering to a subject in need thereof a compound of the present invention or
a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof.
In certain embodiments, the condition associated with angiogenesis is y. As used
herein, “obesity” and “obese” as used herein, refers to class I obesity, class II obesity, class III
y and esity (e.g., being “over-weight”) as defined by the World Health
Organization. In certain embodiments, a method of treating obesity is provided comprising
administering to a subject in need thereof a compound of the present ion or a
pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof
In certain ments, the condition associated with angiogenesis is atherosclerosis.
In certain embodiments, provided is a method of ng atherosclerosis comprising
administering to a t in need thereof a compound of the present invention or a
ceutically able composition, salt, isotopic analog, or g thereof.
In certain embodiments, the condition associated with angiogenesis is a proliferative
disorder. In certain embodiments, provided is a method of treating a proliferative disorder
comprising administering to a subject in need thereof a compound of the present invention or
a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof.
IV. METHODS TO REDUCE THE SIDE EFFECTS D TO
CHEMOTHERAPY
In certain embodiments, nds of the present ion decrease the effect of
chemotherapeutic agent ty on CDK4/6 replication dependent healthy cells, such as
hematopoietic stem cells and hematopoietic progenitor cells her referred to as HSPCs),
and/or renal epithelial cells, in subjects, typically humans, that will be, are being, or have been
exposed to the chemotherapeutic agent (typically a DNA-damaging agent).
In one embodiment, the subject has been exposed to a chemotherapeutic agent, and,
using a compound described herein, the subj ect’s CDK4/6-replication dependent healthy cells
are placed in G1 arrest following exposure in order to mitigate, for example, DNA damage. In
one embodiment, the compound is administered at least 1/2 hour, at least 1 hour, at least 2 hours,
at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8
hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours,
at least 20 hours or more post chemotherapeutic agent exposure.
In one embodiment, the compound can allow for dose intensification (e.g., more
y can be given in a fixed period of time) in lly d chemotherapies, which will
translate to better efficacy. Therefore, the presently disclosed methods can result in
chemotherapy regimens that are less toxic and more effective.
In some embodiments, the use of a compound described herein may result in reduced
or substantially free of off—target effects, for example, related to inhibition of kinases other than
CDK4 and/or CDK6 such as CDK2. Furthermore, in certain embodiments, the use of the
compounds described herein should not induce cell cycle arrest in CDK4/6 replication
independent cells.
In some embodiments, the use of a nd described herein reduces the risk of
undesirable off-target effects including, but not limited to, long term toxicity, anti—oxidant
effects, and estrogenic effects. Anti-oxidant effects can be determined by standard assays
known in the art. For example, a nd with no significant anti-oxidant s is a
compound that does not significantly scavenge free-radicals, such as oxygen radicals. The
anti-oxidant effects of a compound can be ed to a compound with known anti-oxidant
activity, such as genistein. Thus, a compound with no significant anti-oxidant activity can be
one that has less than about 2, 3, 5, 10, 30, or 100 fold anti-oxidant activity relative to genistein.
Estrogenic ties can also be determined via known assays. For instance, a non-estrogenic
compound is one that does not significantly bind and activate the estrogen receptor. A
nd that is substantially free of estrogenic effects can be one that has less than about 2,
3, 5, 10, 20, or 100 fold estrogenic activity relative to a compound with estrogenic activity,
e. g., genistein.
V. METHODS TO TREAT ABNORMAL PROLIFERATION OF T-CELLS, B-
CELLS AND/OR NK—CELLS
In certain s, the invention includes the use of an effective amount of a compound
described , or its pharmaceutically acceptable salt, prodrug or isotopic variant optionally
in a pharmaceutical composition, to treat a host, typically a human, with a selected cancer,
tumor, hyperproliferative condition or an inflammatory or immune disorder. Some of the
disclosed compounds are highly active against T-cell proliferation. Given the paucity of drugs
for T-cell cancers and abnormal proliferation, the identification of such uses represents a
substantial improvement in the medical y for these diseases.
al proliferation of T-cells, B-cells, and/or NK-cells can result in a wide range
of es such as cancer, proliferative disorders and inflammatory/immune es. A host,
for example a human, afflicted with any of these disorders can be treated with an effective
amount of a compound as described herein to achieve a decrease in ms (a palliative
agent) or a decrease in the underlying disease (a disease modifying agent).
Examples include T-cell or NK-cell lymphoma, for example, but not limited to:
peripheral T-cell lymphoma; anaplastic large cell ma, for example anaplastic
lymphoma kinase (ALK) positive, ALK negative anaplastic large cell lymphoma, or primary
cutaneous anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell
lymphoma, for example mycosis fungoides, Sézary syndrome, y ous anaplastic
large cell lymphoma, y cutaneous CD30+ T-cell lymphoproliferative disorder, primary
cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, primary cutaneous
gamma-delta T-cell ma; primary cutaneous small/medium CD4+ T-cell lymphoma, and
matoid papulosis; Adult T-cell Leukemia/Lymphoma (ATLL); Blastic NK-cell
Lymphoma; Enteropathy-type T-cell lymphoma; Hematosplenic gamma—delta T-cell
Lymphoma; Lymphoblastic Lymphoma; Nasal ell Lymphomas; Treatment-related T-
cell lymphomas; for example lymphomas that appear after solid organ or bone marrow
transplantation; T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia;
Chronic lymphoproliferative disorder of NK—cells; Aggressive NK cell leukemia; Systemic
EBV+ T-cell lymphoproliferative disease of childhood (associated with chronic active EBV
infection); Hydroa vacciniforme-like ma; Adult T-cell ia/ lymphoma;
pathy-associated T-cell lymphoma; Hepatosplenic T-cell lymphoma; or Subcutaneous
panniculitis-like T-cell lymphoma.
In one embodiment, a compound disclosed herein, or its salt, prodrug, or isotopic
variant can be used in an effective amount to treat a host, for e a human, with a
lymphoma or lymphocytic or myelocytic proliferation disorder or abnormality. For example,
the compounds as described herein can be administered to a host suffering from a Hodgkin
Lymphoma or a Non-Hodgkin Lymphoma. For example, the host can be suffering from a Non-
Hodgkin Lymphoma such as, but not limited to: an AIDS-Related Lymphoma; Anaplastic
Large-Cell Lymphoma; Angioimmunoblastic Lymphoma; Blastic NK-Cell Lymphoma;
Burkitt’s Lymphoma; Burkitt—like Lymphoma (Small Non-Cleaved Cell ma); Chronic
Lymphocytic Leukemia/Small Lymphocytic Lymphoma; ous T-Cell Lymphoma;
Diffuse Large B-Cell Lymphoma; Enteropathy-Type T-Cell ma; Follicular
Lymphoma; splenic Gamma-Delta T-Cell ma; Lymphoblastic Lymphoma;
Mantle Cell Lymphoma; Marginal Zone Lymphoma; Nasal T-Cell Lymphoma; Pediatric
Lymphoma; Peripheral T-Cell Lymphomas; y Central s System Lymphoma; T—
Cell Leukemias; Transformed Lymphomas; Treatment-Related T—Cell Lymphomas; or
Waldenstrom's Macroglobulinernia.
Alternatively, a nd disclosed herein, or its salt, prodrug, or isotopic variant can
be used in an effective amount to treat a host, for example a human, with a Hodgkin
ma, such as, but not limited to: Nodular Sclerosis Classical Hodgkin’s ma
(CHL); Mixed Cellularity CHL; Lymphocyte-depletion CHL; Lymphocyte-rich CHL;
Lymphocyte Predominant Hodgkin Lymphoma; or Nodular Lymphocyte Predominant HL.
Alternatively, a nd disclosed herein, or its salt, prodrug, or isotopic variant can
be used in an ive amount to treat a host, for example a human with a specific B-cell
lymphoma or proliferative disorder such as, but not limited to: multiple myeloma; Diffuse large
B cell lymphoma; Follicular lymphoma; Mucosa—Associated Lymphatic Tissue lymphoma
(MALT); Small cell lymphocytic lymphoma;Mediastinal large B cell lymphoma; Nodal
marginal zone B cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL);
Intravascular large B-cell ma; Primary effusion lymphoma; or Lymphomatoid
granulomatosis;; B-cell prolymphocytic leukemia; Hairy cell leukemia; Splenic
lymphoma/leukemia; unclassifiable; Splenic diffuse red pulp small B-cell lymphoma; Hairy
cell leukemia—variant; Lymphoplasmacytic lymphoma; Heavy chain diseases; for example,
Alpha heavy chain disease; Gamma heavy chain disease; Mu heavy chain disease; Plasma cell
myeloma; Solitary plasmacytoma of bone; Extraosseous plasmacytoma; y cutaneous
follicle center lymphoma; T istiocyte rich large B-cell lymphoma; DLBCL associated
with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; Primary
mediastinal (thymic) large B-cell lymphoma; Primary cutaneous DLBCL; leg type; ALK+
large B-cell lymphoma; Plasmablastic lymphoma; Large B-cell lymphoma g in HHV8-
associated entric; Castleman disease; B-cell lymphoma; unclassifiable; with features
intermediate between diffuse large B-cell lymphoma; or B-cell lymphoma; sifiable; with
features intermediate between e large B-cell lymphoma and classical Hodgkin
lymphoma.
In one embodiment; a compound disclosed herein; or its salt; prodrug; or isotopic
t can be used in an ive amount to treat a host; for example a human with leukemia.
For e; the host may be suffering from an acute or chronic leukemia of a lymphocytic or
enous origin, such as, but not limited to: Acute lymphoblastic leukemia (ALL); Acute
myelogenous leukemia (AML); Chronic lymphocytic leukemia (CLL); Chronic myelogenous
leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL);
acute promyelocytic leukemia (a subtype of AML); large granular lymphocytic leukemia; or
Adult T-cell chronic leukemia. In one embodiment; the patient suffers from an acute
myelogenous leukemia; for example an erentiated AML (M0); myeloblastic ia
(M1; with/without minimal cell maturation); myeloblastic leukemia (M2; with cell
maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic ia
(M4 or M4 variant with eosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia
(M6); or megakaryoblastic leukemia (M7).
VI. PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS
An active compound described herein; or its salt; isotopic analog; or prodrug can be
administered in an effective amount to a host to treat any of the disorders described herein
using any suitable ch which achieves the desired therapeutic result. The amount and
2017/040093
timing of active compound administered will, of course, be ent on the host being treated,
the instructions of the supervising medical specialist, on the time course of the exposure, on
the manner of administration, on the pharmacokinetic properties of the ular active
compound, and on the judgment of the prescribing physician. Thus, because of host to host
variability, the dosages given below are a guideline and the physician can titrate doses of the
compound to achieve the treatment that the physician ers appropriate for the host. In
ering the degree of ent desired, the physician can balance a variety of factors such
as age and weight of the host, presence of preexisting disease, as well as presence of other
diseases.
The ceutical composition may be formulated as any pharmaceutically useful
form, e.g., as an aerosol, a cream, a gel, a pill, an injection or infusion on, a capsule, a
tablet, a syrup, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation
formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral
formulation, or an ophthalmic solution. Some dosage forms, such as tablets and capsules, are
subdivided into suitably sized unit doses containing appropriate quantities of the active
components, eg., an effective amount to achieve the desired purpose.
The therapeutically ive dosage of any active compound described herein will be
determined by the health care practitioner depending on the condition, size and age of the
patient as well as the route of delivery. In one non-limited embodiment, a dosage from about
0.1 to about 200 mg/kg has therapeutic y, with all weights being calculated based upon
the weight of the active compound, including the cases where a salt is employed. In one
embodiment the dosage is at about or greater than 0.1, 0.5, 1, 5, 10, 25, 50, 75, 100, 125, 150,
175, or 200 mg/kg. In some embodiments, the dosage may be the amount of compound needed
to e a serum concentration of the active compound of up to about 10 nM, 50 nM, 100
nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1 ”M, 5 ”M, 10
nM, 20 nM, 30 nM, or 40 uM.
In certain embodiments, the pharmaceutical composition is in a dosage form that
contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about
100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and
optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from
about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active
agent in a unit dosage form. Examples of dosage forms with at least 5, 10, 15, 20, 25, 50, 100,
200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt. The
pharmaceutical composition may also include a molar ratio of the active compound and an
additional active agent, in a ratio that achieves the d results.
Compounds disclosed herein or used as bed herein may be administered orally,
topically, parenterally, by tion or spray, sublingually, via implant, including ocular
implant, transdermally, via buccal administration, rectally, as an ophthalmic solution, injection,
including ocular ion, intraveneous, intramuscular, inhalation, intra—aortal, intracranial,
subdermal, intraperitioneal, subcutaneous, transnasal, gual, or rectal or by other means,
in dosage unit formulations containing conventional pharmaceutically acceptable carriers. For
ocular delivery, the compound can be administered, as desired, for example, via intravitreal,
intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial,
conjunctival, junctival, eral, periocular, transscleral, retrobulbar, ior
juxtascleral, circumcomeal, or tear duct injections, or through a mucus, mucin, or a mucosal
barrier, in an immediate or controlled release fashion or via an ocular device.
In accordance with the presently disclosed s, an oral stration can be in
any d form such as a solid, gel or liquid, including a solution, suspension, or emulsion.
In some embodiments, the nds or salts are administered by inhalation, intravenously,
or intramuscularly as a liposomal suspension. When administered through inhalation the active
compound or salt may be in the form of a plurality of solid particles or droplets having any
desired particle size, and for example, from about 0.01, 0.1 or 0.5 to about 5, 10, 20 or more
microns, and optionally from about 1 to about 2 microns. Compounds as disclosed in the
present invention have demonstrated good cokinetic and pharmacodynamics properties,
for instance when administered by the oral or intravenous routes.
The pharmaceutical formulations can comprise an active compound described herein
or a pharmaceutically acceptable salt thereof, in any pharmaceutically acceptable carrier. If a
solution is desired, water may sometimes be the carrier of choice for water-soluble compounds
or salts. With respect to the water-soluble compounds or salts, an organic vehicle, such as
ol, propylene glycol, polyethylene glycol, or mixtures thereof, can be suitable. In the
latter instance, the organic vehicle can contain a substantial amount of water. The solution in
either instance can then be sterilized in a suitable manner known to those in the art, and for
illustration by filtration through a 0.22-micron filter. uent to sterilization, the solution
can be dispensed into appropriate receptacles, such as depyrogenated glass vials. The
dispensing is ally done by an c method. Sterilized closures can then be placed on
the vials and, if d, the vial contents can be lyophilized.
Carriers include ents and diluents and must be of ently high purity and
sufficiently low toxicity to render them suitable for administration to the t being treated.
The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of
carrier employ ed in ction with the nd is sufficient to provide a practical quantity
of material for administration per unit dose of the compound.
Classes of carriers include, but are not limited to binders, buffering agents, coloring
agents, diluents, disintegrants, emulsifiers, flavorants, glidents, lubricants, vatives,
stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in
more than one class, for example ble oil may be used as a lubricant in some formulations
and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars,
starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Optional
active agents may be included in a pharmaceutical composition, which do not substantially
interfere with the activity of the compound of the present invention.
Additionally, auxiliary substances, such as wetting or emulsifying agents, biological
buffering substances, surfactants, and the like, can be present in such vehicles. A biological
buffer can be any solution which is cologically acceptable and which provides the
formulation with the desired pH, i.e., a pH in the physiologically acceptable range. Examples
of buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’s
buffered , and the like.
Depending on the intended mode of administration, the pharmaceutical compositions
can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets,
suppositories, pills, capsules, powders, liquids, suspensions, , ointments, lotions or the
like, preferably in unit dosage form suitable for single administration of a precise dosage. The
compositions will include an effective amount of the selected drug in combination with a
pharmaceutically acceptable carrier and, in addition, can include other ceutical agents,
adjuvants, diluents, buffers, and the like.
Thus, the compositions of the disclosure can be stered as pharmaceutical
formulations including those suitable for oral (including buccal and sub-lingual), , nasal,
l, pulmonary, vaginal or parenteral (including intramuscular, arterial, intrathecal,
subcutaneous and intravenous) administration or in a form suitable for stration by
inhalation or insufflation. The preferred manner of administration is intravenous or oral using
a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
For solid compositions, conventional nontoxic solid carriers include, for example,
pharmaceutical grades of mannitol, lactose, starch, ium stearate, sodium saccharin, talc,
cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically
administrable compositions can, for example, be prepared by dissolving, dispersing, and the
like, an active compound as described herein and optional pharmaceutical adjuvants in an
excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like,
to thereby form a solution or suspension. If d, the pharmaceutical composition to be
stered can also contain minor amounts of nontoxic auxiliary substances such as wetting
or emulsifying , pH buffering agents and the like, for example, sodium acetate, sorbitan
monolaurate, triethanolamine sodium acetate, anolamine oleate, and the like. Actual
methods of preparing such dosage forms are known, or will be apparent, to those skilled in this
art, for example, see ton’s Pharmaceutical es, referenced above.
In yet another embodiment is the use of permeation er excipients including
polymers such as: polycations (chitosan and its quaternary ammonium tives, poly-L-
arginine, aminated n); polyanions boxymethyl chitosan, poly-acrylic acid); and,
thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan—
thiobutylamidine, chitosan-thioglycolic acid, chitosan—glutathione conjugates).
For oral administration, the ition will generally take the form of a ,
capsule, a softgel capsule or can be an aqueous or nonaqueous solution, suspension or syrup.
Tablets and capsules are preferred oral administration forms, Tablets and capsules for oral use
can include one or more commonly used carriers such as lactose and corn . Lubricating
agents, such as magnesium stearate, are also typically added. Typically, the compositions of
the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable, inert
carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate,
dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Moreover, when desired
or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also
be incorporated into the mixture. Suitable binders e starch, n, l sugars such
as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia,
anth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the
like. Lubricants used in these dosage forms e sodium , sodium stearate, magnesium
stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators
include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
When liquid suspensions are used, the active agent can be combined with any oral, non-
toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like
and with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening
agents can be added as well. Other optional components for incorporation into an oral
formulation herein include, but are not limited to, preservatives, suspending agents, thickening
agents, and the like.
Parenteral formulations can be prepared in conventional forms, either as liquid
solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to
injection, or as emulsions. Preferably, sterile inj ectable suspensions are formulated according
to ques known in the art using suitable carriers, dispersing or g agents and
suspending agents. The sterile inj ectable formulation can also be a sterile inj ectable solution or
a suspension in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable
vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium
chloride solution. In addition, sterile, fixed oils, fatty esters or polyols are conventionally
employed as solvents or suspending media. In addition, parenteral administration can involve
the use of a slow e or sustained release system such that a constant level of dosage is
maintained.
Parenteral administration includes intraarticular, intravenous, intramuscular,
intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and ueous,
isotonic sterile injection ons, which can contain antioxidants, buffers, bacteriostats, and
solutes that render the ation ic with the blood of the intended recipient, and
aqueous and non—aqueous sterile suspensions that can e suspending , solubilizers,
thickening agents, stabilizers, and preservatives. Administration via n eral routes
can involve introducing the formulations of the disclosure into the body of a patient through a
needle or a catheter, propelled by a sterile syringe or some other mechanical device such as an
continuous infusion system. A formulation provided by the disclosure can be administered
using a syringe, injector, pump, or any other device recognized in the art for parenteral
administration.
In addition to the active compounds or their salts, the pharmaceutical formulations can
contain other additives, such as pH-adjusting additives. In particular, useful pH—adjusting
agents include acids, such as hydrochloric acid, bases or buffers, such as sodium e,
sodium acetate, sodium phosphate, sodium citrate, sodium , or sodium gluconate.
Further, the formulations can contain antimicrobial preservatives. Useful antimicrobial
preservatives include paraben, propylparaben, and benzyl alcohol. An antimicrobial
preservative is typically ed when the formulations is placed in a vial designed for multi-
dose use. The pharmaceutical formulations described herein can be lyophilized using
techniques well known in the art.
2017/040093
For oral administration a pharmaceutical composition can take the form of a solution
suspension, tablet, pill, capsule, powder, and the like. Tablets ning various excipients
such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with
various disintegrants such as starch (e. g., potato or tapioca starch) and certain complex silicates,
together with binding agents such as nylpyrrolidone, sucrose, gelatin and acacia.
Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc are
often very useful for tableting purposes. Solid compositions of a similar type may be employed
as fillers in soft and hard-filled gelatin capsules. als in this connection also include
lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous
suspensions and/or elixirs are d for oral administration, the compounds of the presently
disclosed host matter can be combined with various sweetening agents, flavoring agents,
coloring , emulsifying agents and/or suspending agents, as well as such diluents as water,
ethanol, propylene glycol, glycerin and various like combinations thereof.
In yet another embodiment of the host matter bed herein, there are provided
inj ectable, stable, sterile formulations sing an active compound as bed herein, or
a salt thereof, in a unit dosage form in a sealed container. The compound or salt is provided in
the form of a lyophilizate, which is capable of being reconstituted with a suitable
pharmaceutically acceptable carrier to form liquid formulation suitable for injection thereof
into a host. When the compound or salt is ntially insoluble, a sufficient amount of
emulsifying agent, which is physiologically acceptable, can be employed in sufficient quantity
to emulsify the compound or salt in an aqueous carrier. Particularly useful emulsifying agents
include phosphatidyl cholines and lecithin.
Additional embodiments provided herein include liposomal ations of the active
compounds disclosed herein. The technology for forming liposomal suspensions is well known
in the art. When the compound is an aqueous-soluble salt, using conventional liposome
technology, the same can be orated into lipid vesicles. In such an instance, due to the
water solubility of the active nd, the active compound can be substantially ned
within the hydrophilic center or core of the liposomes. The lipid layer employed can be of any
conventional composition and can either contain cholesterol or can be cholesterol-free. When
the active compound of interest is water-insoluble, again employing conventional liposome
ion technology, the salt can be substantially entrained within the hydrophobic lipid
bilayer that forms the structure of the liposome. In either instance, the liposomes that are
produced can be reduced in size, as h the use of standard sonication and nization
techniques. The liposomal ations comprising the active compounds disclosed herein
can be lyophilized to produce a lyophilizate, which can be reconstituted with a
pharmaceutically able carrier, such as water, to rate a liposomal suspension.
Pharmaceutical formulations also are provided which are le for administration as
an l by inhalation. These formulations comprise a solution or suspension of a desired
compound described herein or a salt f, or a plurality of solid les of the nd
or salt. The desired formulations can be placed in a small chamber and nebulized. Nebulization
can be accomplished by compressed air or by ultrasonic energy to form a plurality of liquid
droplets or solid particles comprising the compounds or salts. The liquid droplets or solid
particles may for example have a particle size in the range of about 0.5 to about 10 microns,
and ally from about 0.5 to about 5 microns. In one embodiment, the solid particles
provide for controlled release through the use of a degradable polymer. The solid particles can
be obtained by processing the solid compound or a salt thereof, in any appropriate manner
known in the art, such as by rnicronization. Optionally, the size ofthe solid particles or droplets
can be from about 1 to about 2 microns. In this respect, commercial nebulizers are available
to achieve this e. The compounds can be administered via an l suspension of
respirable particles in a manner set forth in US. Pat. No. 5,628,984, the disclosure of which is
incorporated herein by reference in its entirety.
Pharmaceutical ations also are provided which provide a controlled release of a
compound described herein, ing through the use of a degradable polymer, as known in
the art.
When the pharmaceutical formulations suitable for administration as an aerosol is in
the form of a liquid, the formulations can comprise a water-soluble active compound in a carrier
that comprises water. A surfactant can be present, which lowers the surface tension of the
formulations sufficiently to result in the formation of droplets within the desired size range
when hosted to nebulization.
The term "pharmaceutically acceptable salts" as used herein refers to those salts which
are, within the scope of sound medical judgment, suitable for use in contact with hosts (e.g.,
human hosts) without undue toxicity, tion, allergic response, and the like, commensurate
with a reasonable benefit/risk ratio, and effective for their intended use, as well as the
zwitterionic forms, where possible, of the compounds of the tly disclosed host matter.
Thus, the term "salts" refers to the relatively non-toxic, inorganic and organic acid
on salts of the presently disclosed compounds. These salts can be prepared during the
final ion and purification of the compounds or by separately reacting the purified
compound in its free base form with a suitable organic or inorganic acid and isolating the salt
thus formed. Basic compounds are capable of forming a wide variety of ent salts with
s inorganic and organic acids. Acid addition salts of the basic compounds are prepared
by contacting the free base form with a sufficient amount of the desired acid to produce the salt
in the conventional manner. The free base form can be regenerated by contacting the salt form
with a base and isolating the free base in the conventional manner. The free base forms may
differ from their respective salt forms in certain al properties such as lity in polar
solvents. Pharmaceutically acceptable base addition salts may be formed with metals or
amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of
metals used as s, e, but are not limited to, sodium, potassium, magnesium, calcium,
and the like. Examples of suitable amines include, but are not limited to, N,N‘-
dibenzylethylenediamine, procaine, choline, nolamine, ethylenediamine, N-
methylglucamine, and procaine. The base addition salts of acidic compounds are prepared by
contacting the free acid form with a sufficient amount of the desired base to produce the salt in
the conventional manner. The free acid form can be regenerated by contacting the salt form
with an acid and isolating the free acid in a conventional manner. The free acid forms may
differ from their respective salt forms somewhat in n physical properties such as solubility
in polar solvents.
Salts can be prepared from inorganic acids sulfate, pyrosulfate, bisulfate, sulflte,
bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide such as hydrochloric, nitric, phosphoric, sulfuric,
hydrobromic, hydriodic, phosphorus, and the like. Representative salts include the
hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate,
palmitate, stearate, laurate, borate, te, e, ate, te, citrate, maleate,
te, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate,
laurylsulphonate and isethionate salts, and the like. Salts can also be prepared from organic
acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted ic acids,
hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic
acids, etc. and the like. Representative salts include acetate, propionate, caprylate, isobutyrate,
oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate,
chlorobenzoate, methylbenzoate, obenzoate, phthalate, benzenesulfonate,
toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the
like. Pharmaceutically acceptable salts can include cations based on the alkali and ne
earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as
non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to,
WO 05860
ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,
trimethylamine, triethylamine, ethylamine, and the like. Also plated are the salts of
amino acids such as te, gluconate, galacturonate, and the like. See, for example, Berge
et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference.
Preferably, sterile inj ectable suspensions are formulated according to techniques known
in the art using suitable carriers, dispersing or wetting agents and ding agents. The sterile
injectable formulation can also be a e injectable solution or a suspension in a nontoxic
parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can
be employed are water, Ringer’s solution and isotonic sodium de solution. In addition,
sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or ding
media. In addition, parenteral administration can involve the use of a slow release or sustained
release system such that a constant level of dosage is maintained.
Preparations according to the disclosure for parenteral administration e sterile
aqueous or ueous solutions, sions, or emulsions. Examples of ueous
ts or vehicles are ene glycol, polyethylene glycol, vegetable oils, such as olive oil
and corn oil, gelatin, and inj ectable organic esters such as ethyl oleate. Such dosage forms can
also contain nts such as preserving, wetting, emulsifying, and dispersing agents. They
can be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating
sterilizing agents into the compositions, by irradiating the compositions, or by heating the
compositions. They can also be manufactured using sterile water, or some other sterile
inj ectable medium, immediately before use.
Sterile inj ectable ons are prepared by incorporating one or more ofthe compounds
of the disclosure in the required amount in the appropriate solvent with various of the other
ingredients enumerated above, as required, followed by filtered sterilization. Generally,
dispersions are prepared by incorporating the various sterilized active ingredients into a sterile
vehicle which contains the basic dispersion medium and the required other ingredients from
those enumerated above. In the case of sterile powders for the preparation of sterile inj e
solutions, the preferred methods of preparation are vacuum-drying and freeze-drying
techniques which yield a powder of the active ingredient plus any additional desired ingredient
from a previously sterile-filtered solution thereof. Thus, for example, a eral composition
suitable for administration by injection is prepared by stirring 1.5% by weight of active
ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with
sodium chloride and sterilized.
Formulations suitable for rectal administration are typically presented as unit dose
suppositories. These may be prepared by admixing the active sed compound with one or
more conventional solid carriers, for example, cocoa butter, and then shaping the resulting
mixture.
ations suitable for topical application to the skin preferably take the form of an
ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include
petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and
combinations of two or more thereof.
Formulations suitable for transdermal administration may be presented as discrete patches
adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period
of time. Formulations suitable for transdermal administration may also be delivered by
iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take
the form of an optionally buffered aqueous solution of the active compound. In one
embodiment, microneedle patches or devices are provided for delivery of drugs across or into
biological tissue, particularly the skin. The microneedle patches or devices permit drug delivery
at clinically relevant rates across or into skin or other tissue barriers, with minimal or no
damage, pain, or irritation to the tissue.
Formulations suitable for administration to the lungs can be delivered by a wide range
of passive breath driven and active power driven single/-multiple dose dry powder inhalers
(DPI). The devices most ly used for atory delivery e nebulizers, metered-
dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet
nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung
delivery device s on parameters, such as nature of the drug and its formulation, the site
of action, and pathophysiology of the lung.
Additional non-limiting examples of drug ry devices and methods include, for
example, 0203709 titled “Pharmaceutical Dosage Form For Oral Administration Of
Tyrosine Kinase Inhibitor” (Abbott Laboratories), US20050009910 titled “Delivery of an
active drug to the posterior part of the eye via subconjunctival or periocular delivery of a
prodrug”, US 20130071349 titled “Biodegradable polymers for ng intn ocular re”,
US 8,481,069 titled ine kinase pheres”, US 8,465,778 titled “Method of making
tyrosine kinase pheres”, US 8,409,607 titled “Sustained release intraocular implants
containing tyrosine kinase inhibitors and related methods”, US 738 and US
2014/0031408 titled “Biodegradable intravitreal ne kinase ts”, US 2014/0294986
titled “Microsphere Drug ry System for Sustained Intraocular Release”, US 8,911,768
titled “Methods For Treating pathy With Extended Therapeutic Effect” (Allergan, Inc);
US 6,495,164 titled “Preparation of injectable suspensions having improved injectability”
mes Controlled eutics, Inc); WO 2014/047439 titled “Biodegradable
Microcapsules Containing Filling Materia ” (Akina, Inc); WO 2010/132664 titled
“Compositions And Methods For Drug Delivery” (Baxter International Inc. Baxter Healthcare
SA); U820120052041 titled “Polymeric nanoparticles with enhanced drug loading and
methods of use thereof” (The Brigham and Women’s Hospital, Inc); US20140178475,
US20140248358, and US20140249158 titled peutic Nanoparticles Comprising a
Therapeutic Agent and Methods of Making and Using Same” (BIND eutics, Inc); US
5,869,103 titled “Polymer microparticles for drug delivery” (Danbiosyst UK Ltd); US
8628801 titled “Pegylated Nanoparticles” (Universidad de Navarra); US2014/0107025 titled
“Ocular drug delivery system” (Jade Therapeutics, LLC); US 6,287,588 titled “Agent
delivering system comprised of microparticle and biodegradable gel with an improved
releasing profile and s of use thereof”, US 6,589,549 titled “Bioactive agent ring
system comprised of microparticles within a biodegradable to improve release profiles”
(Macromed, Inc); US 6,007,845 and US 5,578,325 titled “Nanoparticles and microparticles of
non-linear hydrophilic hydrophobic multiblock copolymers” (Massachusetts Institute of
Technology); US20040234611, U820080305172, 0269894, and US20130122064
titled “Ophthalmic depot formulations for periocular or subconjunctival administration
(Novartis Ag); US 539 titled “Block polymer” Med, Inc); US 20070071756 titled
“Delivery of an agent to ameliorate inflammation” (Peyman); US 20080166411 titled
“Injectable Depot Formulations And Methods For Providing ned Release Of Poorly
Soluble Drugs sing Nanoparticles” (Pfizer, Inc.); US 6,706,289 titled “Methods and
compositions for enhanced delivery of bioactive molecules” (PR ceuticals, Inc); and
US 8,663,674 titled “Microparticle containing matrices for drug delivery” (Surmodics).
VII. COMBINATION THERAPY
The sed compounds of Formula 1, Formula II, Formula III Formula IV, Formula
V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula
XII, Formula XIII, a XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,
Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or
a XXV can be used in an effective amount alone or in combination with another
compound of the present invention or another bioactive agent to treat a host such as a human
with a disorder as described herein.
The disclosed compounds described herein can be used in an effective amount alone or
in combination with another compound of the present invention or another bioactive agent to
treat a host such as a human with a disorder as described herein.
The term “bioactive agent” is used to describe an agent, other than the selected
compound according to the present invention, which can be used in combination or alternation
with a compound of the present invention to achieve a desired result of therapy. In one
embodiment, the compound of the present invention and the bioactive agent are stered
in a manner that they are active in vivo during overlapping time periods, for example, have
time-period overlapping Cmax, Tmax, AUC or other pharmacokinetic parameter. In another
embodiment, the compound of the t invention and the bioactive agent are administered
to a host in need f that do not have overlapping pharrnacokinetic parameter, however,
one has a therapeutic impact on the therapeutic efficacy of the other.
In one aspect of this embodiment, the bioactive agent is an immune modulator,
including but not limited to a oint inhibitor, including as non-limiting examples, a PD-
1 inhibitor, PD-Ll inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3
inhibitor, V-domain Ig suppressor of T-cell activation ) inhibitors, small molecule,
peptide, nucleotide, or other inhibitor. In certain aspects, the immune modulator is an antibody,
such as a monoclonal antibody.
PD-l inhibitors that blocks the interaction of PD-l and PD-Ll by g to the PD-l
receptor, and in turn inhibit immune suppression include, for example, nivolumab (Opdivo),
pembrolizumab uda), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF-
06801591 (Pfizer), MEDIO680 (AstraZeneca), PDROOl (Novartis), 10 (Regeneron),
SHR—12-1 (Jiangsu i Medicine Company and Incyte Corporation), TSR-042 (Tesaro),
and the PD-Ll/VISTA inhibitor CA-170 (Curis Inc.) PD-Ll inhibitors that block the
interaction of PD-l and PD-Ll by binding to the PD-Ll receptor, and in turn inhibits immune
suppression, include for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and
MedImmune), KN035 mab), and EMS-936559 ol-Myers Squibb). CTLA-4
checkpoint tors that bind to CTLA—4 and inhibits immune suppression include, but are
not d to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884 and
AGEN2041 (Agenus). LAG-3 checkpoint inhibitors, include, but are not limited to, EMS-
986016 (Bristol-Myers ), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed),
LAG525 (Novartis), and the dual PD-l and LAG-3 inhibitor MGD013 Genics). An
example of a TIM-3 inhibitor is TSR-022 (Tesaro).
W0 2018/005860
In yet r embodiment, one of the active compounds described herein can be
administered in an effective amount for the ent of abnormal tissue of the female
reproductive system such as breast, ovarian, endometrial, or uterine cancer, in ation or
alternation with an effective amount of an estrogen tor including but not limited to a
SERM tive estrogen receptor modulator), a SERD tive estrogen receptor degrader),
a complete estrogen receptor degrader, or another form of partial or complete estrogen
antagonist or agonist. Partial anti-estrogens like raloxifene and tamoxifen retain some estrogen—
like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases,
an estrogen-like action during breast cancer progression which actually stimulates tumor
growth. In contrast, fulvestrant, a complete strogen, is free of estrogen-like action on the
uterus and is effective in tamoxifen-resistant tumors. Non-limiting examples of anti-estrogen
compounds are provided in W0 2014/19176 assigned to Astra Zeneca, W02013/090921, W0
2014/203129, W0 2014/203132, and /0178445 assigned to Olema Pharmaceuticals,
and US. Patent Nos. 871, 8,853,423, and 8,703, 810, as well as Us 005286, wo
2014/205136, and . Additional non-limiting examples of anti—estrogen
compounds include: SERMS such as anordrin, xifene, estriol, chlorotrianisene,
clomiphene e, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene,
and fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole,
exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprorelin,
cetrorelix, allylestrenol, chloromadinone acetate, cyproterone acetate, delmadinone acetate,
dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate,
norethisterone acetate, progesterone, and spironolactone. Other estrogenic ligands that can be
used according to the present invention are described in U. S. Patent Nos. 4,418,068; 5,478,847;
,393,763; and 5,457,117, WO2011/156518, US Patent Nos. 8,455,534 and 8,299,112, US.
Patent Nos. 871; 8,853,423; 8,703,810; US 2015/0005286; and ,
/0175289, /0258080, , WO 84711; ;
; WO 2002/003992; WO 2002/003991; W0 2002/003990; WO
2002/003989; ; ; ; ;
; ; US 6821989; US 2002/0128276; US 6777424; US
2002/0016340; US 6326392; US 6756401; US 2002/0013327; US 6512002; US 6632834; US
2001/0056099; US 6583170; US 6479535; W0 1999/024027; US 6005102; EP 0802184; US
5998402; US 5780497, US 5880137, and .
In r embodiment, an active compound described herein can be administered in
an effective amount for the treatment of abnormal tissue of the male reproductive system such
as prostate or testicular cancer, in combination or alternation with an effective amount of an
androgen (such as testosterone) tor including but not limited to a selective androgen
receptor modulator, a selective en receptor degrader, a complete androgen receptor
degrader, or another form of partial or complete androgen antagonist. In one embodiment, the
prostate or testicular cancer is androgen-resistant. Non-limiting examples of anti-androgen
compounds are provided in WO 56518 and US Patent Nos. 534 and 8,299,112.
Additional non-limiting examples of anti-androgen compounds include: enzalutamide,
apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone,
drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.
In one embodiment, the bioactive agent is an ALK tor. Examples of ALK
inhibitors include but are not limited to Crizotinib, Alectinib, ceritinib, TAE684 (NVP-
TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-lOl), and
AP26113.
In one embodiment, the bioactive agent is an EGFR inhibitor. Examples of EGFR
inhibitors include erlotinib (Tarceva), ib (Iressa), ib (Gilotrii), rociletinib (CO—
1686), osimertinib (Tagrisso), olmutinib (Olita), inib (ASP8273), nazartinib (EGF816),
47775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272), avitinib (ACOOIO),
EAIO45, tarloxotinib 00; ), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-
7647, KD-019), inib, WZ-3146, WZ8040, CNX-2006, and dacomitinib 299804;
Pfizer).
In one embodiment, the bioactive agent is an HER-2 inhibitor. Examples of HER-2
inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.
In one embodiment, the bioactive agent is a CD20 inhibitor. Examples of CD20
inhibitors include obinutuzumab, mab, fatumumab, ibritumomab, tositumomab, and
ocrelizumab.
In one embodiment, the ive agent is a JAK3 inhibitor. Examples of JAK3
inhibitors include tasocitinib.
In one embodiment, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2
inhibitors include venetoclax, ABT-l99 (4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-l-
en-l-yl]methyl]piperazin-l-yl]-N-[[3-nitro[[(tetrahydro-2H-pyran-4—
hyl]amino]phenyl]sulfony1]-2—[(lH— pyrrolo[2,3-b]pyridinyl)oxy]benzarnide), ABT—
737 (4-[4- [ [2-(4-chlorophenyl)phenyl] methyl] piperazin- l -yl] -N- [4- -4—
(dimethylamino)phenylsulfanylbutanyl] amino] nitrophenyl]sulfonylbenzamide)
(navitoclax), ABT-263 ((R)(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l, l'-biphenyl]—
ethyl)piperazin-l -yl)-N-((4-((4-morpholino-l ylthio)butanyl)amino)—
3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (obatoclax mesylate,
(ZZ)[(5Z)[(3,5- dimethyl-lH-pyrrolyl)methylidene]methoxypyrrol
ylidene]indole; methanesulfonic acid))), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-
dihydronaphtho[2,3-d]thiazolylamino)-phenyl ester), pogosin, ethyl 2-aminobromo
(1-cyanoethoxyoxoethyl)-4H—chromenecarboxylate, Nilotinib-d3, TW-37 (N-[4-[[2—
(1,l-Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5 -[[2-(l -
ethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2), HA14-1, ATIOI,
sabutoclax, ic acid, or G3139 (Oblimersen).
In one aspect, a treatment regimen is provided comprising the administration of a
compound ofFormula 1, Formula II, Formula III Formula IV, Formula V, Formula VI, Formula
VII, a VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula
XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX,
Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV in
combination with at least one additional chemotherapeutic agent. The combinations disclosed
herein can be administered for beneficial, additive, or synergistic effect in the ent of
abnormal ar proliferative disorders.
In specific ments, the treatment regimen es the administration of a
nd ula 1, Formula II, Formula III Formula IV, Formula V, Formula VI, Formula
VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula
XIV, Formula XV, Formula XVI, a XVII, Formula XVIII, a XIX, Formula XX,
Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV in
combination with at least one kinase inhibitor. In one ment, the at least one kinase
inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’s tyrosine
kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.
PI3k inhibitors that may be used in the present invention are well known. Examples of
PI3 kinase inhibitors include but are not limited to Wortmannin, demethoxyviridin, perifosine,
idelalisib, Pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-l36,
duvelisib, GS-9820, BKMIZO, GDC-0032 (Taselisib), (2-[4-[2-(2-Isopropylmethyl-1,2,4—
triazolyl)-5,6-dihydroimidazo[1,2-d][l,4]benzoxazepinyl]pyrazol-l-yl]
methylpropanamide), MLN—l 1 17 ((2R)Phenoxy—2—butanyl hydrogen (S)-
methylphosphonate, or (oxo) {[(2R)—l-phenoxybutanyl]oxy}phosphonium)), BYL-
7’ l 9 ((ZS)-N1-[4-Methyl[2-(2,2,2-trifluoro-l,1-dimethylethyl)pyridinyl]thiazolyl]-
1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-Difluoro-N— {2-(methyloxy)—5-[4-(4—
ziny1)quinoliny1]pyridiny1}benzenesulfonarnide) (omipalisib), l ((::)
Methyl-2—(morpholiny1)(l-pheny1aminoethy1)-pyrido[1,2—a]-pyrimidinone),
GSK2636771 (2-Methy1(2-methy1-3 -(trifluoromethy1)benzyl)—6-morpholino-1H-
benzo[d]irnidazolecarboxy1ic acid dihydrochloride), 3 ((R)((1-(7-methy1
linooxo-4H-pyrido[1,2-a]pyrimidiny1)ethy1)amino)benzoic acid), TGR—
1202/RP5264, GS-9820 ((S)— (2-(2-aminopyrimidinyl)methy1
mohydroxypropan- 1 —one), GS-1101 (5-fluoropheny1-2—([S)][9H-purinylamino]—
propyl)-3H-quinazolinone), AMG—319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5-
dimethoxypheny1)arnino)quinoxaliny1)sulfamoy1)pheny1)-3—methoxy-4 methylbenzamide),
BAY80-6946 (2-amino-N-(7-methoxy(3-morpholinopropoxy)—2,3-dihydroimidazo[1,2-
c]quinaz), AS 252424 [5-(4-F1uorohydroxy-phenyl)—furan-2—y1]-meth—(Z)-ylidene]—
lidine-2,4-dione), CZ 24832 (5-(2-aminofluoro-[1,2,4]triazolo[1,5-a]pyridiny1)-N-
tert-butylpyridinesu1fonarnide), Buparlisib (5-[2,6-Di(4-morpholiny1) pyrimidinyl]
(trifluoromethyl)—2-pyridinamine), GDC-0941 (2-(1H-Indazoly1)[[4-(methy1su1fony1)—1-
piperazinyl]methyl](4-morpholiny1)thieno[3,2-d]pyrimidine), GDC-0980 ((S)(4-((2-(2-
aminopyrimidin—5 -y1)methylmorpholinothieno[3,2-d]pyrimidin-6 y1)methy1)piperazin-l—
yl)hydroxypropan-l-one (also known as RG7422)), SF1126 ((8S,14S,17S)
(carboxymethyl)—8-(3-guanidinopropyl)—17-(hydroxymethy1)-3,6,9,12,15-pentaoxo(4-(4-
oxopheny1-4H-chromenyl)morpholinoiurn)oxa—7,10,13,16-tetraazaoctadecan
oate), PF-052123 84 [[4-(Dimethy1amino) piperidinyl]carbony1]pheny1]-N’-[4-(4,6-
dimorpholiny1-1,3,5-triaziny1)pheny1]urea) (gedatolisib), LY3023414, BEZ235 (2-
Methy1 {4-[3-methy1oxo(quinoliny1)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-l-
y1]pheny1}propanenitri1e) (dactolisib), XL-765 (N-(3-(N—(3-(3,5-
dimethoxyphenylamino)quinoxalinyl)su1famoy1)pheny1)—3-methoxymethylbenzamide),
and GSK1059615 (5-[[4-(4-Pyridiny1)quinoliny1]methylene]-2,4-thiazolidenedione),
PX886 ([(3aR,6E,9S,9aR,10R,1 1aS)—6-[[bis(propeny1)amino]methylidene]hydroxy
(methoxymethyl)—9a,1 1a—dimethy1-1,4,7-trioxo—2,3,3a,9,10,11-
hexahydroindeno[4,5h]isochromen- 10-y1] acetate (also known as sonolisib)) LY294002,
AZD8186, PF-4989216, pilaralisib, ONE-317, PI-3065, PI-103, NU7441 (KU-57788), HS
173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, ,
PIK-93, AS—605240, BGT226 (NVP—BGT226), AZD6482, voxtalisib, alpelisib, IC-87114,
TG1100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293,
PIK-294, 3-MA hyladenine), AS—252424, 850, apitolisib (GDC-0980, RG7422),
and the structure described in W02014/071109.
In one embodiment, the compound of Formula 1, Formula II, a 111 Formula
IV, Formula V, a VI, Formula VII, a VIII, Formula IX, Formula X, Formula XI,
Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII,
Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII,
a XXIV, or Formula XXV is ed in a single dosage form with the PIk3 inhibitor.
BTK inhibitors for use in the present invention are well known. Examples of BTK
inhibitors include ibrutinib (also known as PCI-32765)(ImbruvicaTM)(1-[(3R)[4-amino
(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidinyl]piperidinyl]propenone),
dianilinopyrimjdine-based tors such as AVL-lOl and AVL-29l/292 (N-(3-((5-fluoro-2—
((4-(2-methoxyethoxy)phenyl)amino)pyrimidinyl)amino)phenyl)acrylamide) (Avila
Therapeutics) (see US Patent Publication No 2011/0117073, incorporated herein in its
entirety), Dasatinib ([N-(2-chloromethylphenyl)(6-(4-(2-hydroxyethyl)piperazinyl)-
2-methylpyrimidinylamino)thiazole—5-carboxarnide], LFM-A13 (alpha-cyano-beta-
hydroxy-beta-methyl-N-(2,5-ibromophenyl) propenamide), GDC-0834 ([R-N-(3-(6-(4-(1,4-
dimethy1oxopiperazinyl)phenylamino)methy1oxo-4,5-dihydropyrazinyl)
phenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-Z—carboxamide], CGI-560 4-(tert-butyl)—
N—(3-(8-(phenylamino)imidazo[1,2-a]pyrazinyl)phenyl)benzamide, CGI-1746 (4-(tert—
butyl)—N-(2-methyl(4—methyl((4-(morpholinecarbonyl)phenyl)amino)—5-oxo-4,5-
dihydropyrazinyl)phenyl)benzamide), CNX-774 (4-(4-((4-((3-acrylamidophenyl)amino)
fluoropyrimidin-2—yl)amino)phenoxy)-N-methylpicolinamide), CTA056 zyl(3-
(piperidinyl)propyl)(4-(pyridinyl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one),
34 ((R)-N-(3-(6-((4-(1,4-dimethy1oxopiperazin-Z-yl)phenyl)amino)methyl
oxo-4,5-dihydropyrazinyl)methylphenyl)—4,5,6,7—tetrahydrobenzo[b]thiophene
carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(1,4-dimethyloxopiperazin
yl)phenyl)amino)—4-methyloxo-4,5-dihydropyrazinyl)methylphenyl)—4,5,6,7-
tetrahydrobenzo[b]thiophene-2—carboxamide), HM-71224, ACP-196, ONO-4059 (Ono
Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazolyl)phenyl)amino)(((lR,ZS)
aminocyclohexyl)amino)pyrimidine—5-carboxamide hydrochloride), QL-47 (l -(1-
acryloylindolinyl)—9-( 1 -methyl- 1 H-pyrazolyl)benzo [h] [l ,6]naphthyridin-2(lH)—one),
and RN486 (6-cyclopropylfluoro(2-hydroxymethyl{1-methyl[5-(4-methyl-
piperazin-l-y1)-py1idinylamino]-6—oxo-1,6-dihydro-py1idinyl}-pheny1)—2H—isoquinolin-
1-one), and other molecules capable of ting BTK activity, for example those BTK
inhibitors sed in Akinleye et ah, Journal of Hematology & Oncology, 2013, 6:59, the
entirety of which is incorporated herein by reference. In one embodiment, the compound of
2017/040093
Formula I, Formula II, Formula III Formula IV, Formula V, Formula VI, Formula VII, Formula
VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula
XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI,
Formula XXII, Formula XXIII, Formula XXIV, or Formula XXV is combined in a single
dosage form with the BTK tor.
Syk inhibitors for use in the present invention are well known, and include, for e,
Cerdulatinib (4-(cyclopropylamino)((4-(4-(ethylsulfonyl)piperazin-1—
yl)phenyl)amino)pyrimidinecarboxamide), entospletinib (6-(1H-indazolyl)-N—(4-
morpholinophenyl)imjdazo[1,2—a]pyrazinarrnne), fostamatinib ([6-({5-Fluoro[(3,4,5-
trimethoxyphenyl)amino]pyrimidinyl}amino)-2,2-dimethyloxo-2,3-dihydro-4H-
pyrido[3,2-b] [1,4] yl]methyl dihydrogen ate), fostamatinib disodium salt
(sodium (6-((5-fluoro((3,4,5 -trimethoxyphenyl)amino)pyrimidinyl)amino)-2,2-
dimethyloxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate), BAY 61-3606 (2-
(7-(3,4-Dimethoxyphenyl)-imidazo[1,2—c]pyrimidinylamino)-nicotinamide HCl), R0902]
(6-[(1R,2S)Amino-cyclohexylamino](5,6-dimethyl-pyridinylamino)-pyridazine
carboxylic acid amide), imatinib (Gleevac, 4-[(4-methylpiperazinyl)methyl]—N—(4—methy1-
3-{[4-(pyridinyl)pyrimidinyl]amino}phenyl)benzamide), staurosporine, GSK143 (2-
(((3R,4R)aminotetrahydro-2H-pyran—4-yl)amino)(p-tolylarnino)pyrimidine—5-
carboxamide), PP2 (1-(tert-butyl)—3-(4-chlorophenyl)-lH-pyrazolo[3,4-d]pyrimidinamine),
PRT-060318 (2-(((1R,2S)aminocyclohexyl)amino)—4-(m-tolylamjno)pyrimidine
carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazolyl)phenyl)amino)(((lR,2S)
yclohexyl)amino)pyrimidine-S-carboxamide hydrochloride), R112 (3,3'—((5-
fluoropyrimidine-2,4-diyl)bis(azanediy1))diphenol), R348 (3-Ethyl-4—methylpyridine), R406
(6-((5-fluoro((3,4,5-trimethoxyphenyl)amino)pyrimidinyl)amino)-2,2-dimethyl-2H—
[3,2-b] [1,4]oxazin-3(4H)—one), piceatannol (3-Hydroxyresveratol), YM193306(see
Singh et a1. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med.
Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER—27319 (see Singh et a1. Discovery
and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-
3643 incorporated in its entirety herein), Compound D (see Singh et a1. Discovery and
Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643
incorporated in its entirety ), PRT060318 (see Singh et a1. Discovery and Development
of Spleen Tyrosine Kinase (SYK) Inhibitors, J , Med. Chem. 2012, 55, 643 incorporated
in its entirety herein), luteolin (see Singh et a1. Discovery and Development of Spleen Tyrosine
Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 643 incorporated in its entirety
herein), apigenin (see Singh et al. ery and Development of Spleen Tyrosine Kinase
(SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein),
quercetin (see Singh et al. Discovery and Development of Spleen ne Kinase (SYK)
Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), fisetin (see
Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med.
Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), myricetin (see Singh et al.
Discovery and pment of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012,
55, 643 incorporated in its entirety herein), morin (see Singh et al. Discovery and
Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643
incorporated in its entirety herein). In one embodiment, the nd of Formula 1, Formula
II, Formula III Formula IV, a V, Formula VI, Formula VII, Formula VIII, Formula IX,
Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, a
XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula
XXII, Formula XXIII, Formula XXIV, or Formula XXV is combined in a single dosage form
with the Syk inhibitor.
In one ment, the at least one additional chemotherapeutic agent is a protein cell
1 (PD-1) inhibitor. PD-l inhibitors are known in the art, and include, for example,
nivolumab (BMS), pembrolizumab (Merck), pidilizumab (CureTech/Teva), AMP-244
mmune/GSK), EMS-936559 (EMS), and 36 (Roche/Genentech). In one
embodiment, the compound of Formula 1, Formula II, Formula 111 Formula IV, Formula V,
Formula VI, a VII, Formula VIII, Formula IX, Formula X, a XI, Formula XII,
Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,
Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or
Formula XXV is combined in a single dosage form with the PD-l inhibitor.
In one embodiment, the at least one additional chemotherapeutic agent is a B-cell
lymphoma 2 (Bcl-2) protein inhibitor. BCL-2 inhibitors are known in the art, and include, for
example, ABT- l 99 (4-[4- [ [2-(4-Chlorophenyl)-4,4-dimethylcyclohexen-l -
yl]methyl]piperazin-l-yl]-N-[[3-nitro[[(tetrahydro-2H-pyran
yl)methyl]amino]phenyl]sulfonyl][(lH- pyrrolo[2,3-b]pyridinyl)oxy]benzamide), ABT-
737 (4-[4- [ [2-(4-chlorophenyl)phenyl] methyl] piperazinyl] -N- [4- [[(2R)
(dimethylarnino)phenylsulfanylbutanyl] amino] nitrophenyl]sulfonylbenzarnide),
ABT-263 ((R)(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l, l'-biphenyl]
yl)methyl)piperazinyl)-N-((4-((4-morpholino(phenylthio)butanyl)amino)—
3((trifluoromethy1)sulfony1)phenyl)sulfonyl)benzamide), GX15-070 (obatoclaX te,
(ZZ)[(SZ)[(3,5- dimethyl-lH-pyrrolyl)methylidene]methoxypyrrol
ylidene]indole; methanesulfonic acid))), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-
dihydronaphtho[2,3-d]thiazolylarnino)-phenyl , pogosin, ethyl 2-aminobromo
(1-cyanoethoxyoxoethyl)—4H-chromenecarboxylate, Nilotinib-d3, TW-37 (N-[4-[[2—
imethylethy1)pheny1]sulfonyl]phenyl]-2,3,4-trihydroxy -5 -[[2-(1-
methylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2), or G3139 (Oblimersen).
In one embodiment, the nd of Formula 1, a II, Formula III Formula IV, Formula
V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula
XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,
Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, or
Formula XXV is combined in a single dosage form with the at least one BCL-2 inhibitor.
In one embodiment, a combination described herein can be further combined with an
additional therapeutic to treat the cancer. The second therapy can be an immunotherapy. As
discussed in more detail below, the compound of Formula I, Formula II, a 111 Formula
IV, a V, Formula VI, a VII, Formula VIII, Formula IX, Formula X, Formula XI,
Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII,
Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII,
Formula XXIV, or Formula XXV can be conjugated to an antibody, radioactive agent, or other
targeting agent that directs the compound to the ed or abnormally proliferating cell. In
r embodiment, the combination is used in combination with another pharmaceutical or
a biologic agent (for example an antibody) to increase the efficacy of treatment with a
combined or a synergistic approach. In an embodiment, combination can be used with T-cell
vaccination, which lly involves immunization with inactivated autoreactive T cells to
eliminate a cancer cell population as bed herein. In another embodiment, the
combination is used in combination with a bispecific T-cell Engager (BiTE), which is an
antibody designed to aneously bind to c antigens on endogenous T cells and cancer
cells as described herein, linking the two types of cells.
In one embodiment, the bioactive agent is a MEK inhibitor. MEK inhibitors are well
known, and e, for example, trametinib/GSK1120212 (N-(3-{3-Cyclopropyl[(2-fluoro-
4-iodophenyl)amino]—6,8-dimethyl-2,4,7-trioxo—3,4,6,7-tetrahydropyrido[4,3—d]pyrimidin-
1}pheny1)acetamide), selumetinib (6-(4-bromochloroanilino)fluoro-N-(2—
hydroxyethoxy)methylbenzimidazolecarboxamide), pimasertib/AS703026/MSC
1935369 ((S)-N-(2,3-dihydroxypropyl)((2-fluoro-4— iodopheny1)amino)isonicotinamide),
XL-518/GDC-0973 (l-({3,4-difluoro[(2-fluoro enyl)amino]phenyl}carbonyl)—3-
[(2S)-piperidin-2—yl]azetidinol), refametinib/BAY869766/RDEAl 19 (N-(3,4-difluoro-2—
(2-fluoroiodophenylamino)methoxyphenyl)(2,3-dihydroxypropyl)cyclopropane-1 -
amide), PD-0325901 (N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro[(2-fluoro
iodophenyl)amino]— benzamide), TAK733 ((R)(2,3-Dihydroxypropyl)—6-fluoro(2-
fluoroiodophenylamino)—8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione),
MEKl62/ARRY438162 (5 - [(4—Bromofluorophenyl)amino] fluoro-N—(2—
hydroxyethoxy)methyl-1H-benzimidazole—6-carboxamide), R05126766 (3-[[3-Fluoro
(methylsulfamoylamino)pyridyl]methyl]methyl-7—pyrimidinyloxychromenone),
WX-554, R04987655/CH4987655 (3,4-difluoro((2-fluoroiodophenyl)amino)-N—(2-
hydroxyethoxy)—5-((3-oxo-l,2-oxazinan-2yl)methyl)benzami de), or AZD8330 (2-((2-fluoro
iodophenyl)amino)—N—(2 hydroxyethoxy)-1 ,5-dimethyloxo-l,6-dihydropyridine
carboxamide), EtOH, PD184352 40), GDC-0623, BI-847325, cobimetinib,
PD98059, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088.
In one embodiment, the bioactive agent is a Raf inhibitor. Raf inhibitors are known
and include, for example, Vemurafinib [[5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-
3-yl]carbonyl]-2,4-difluorophenyl]propanesulfonamide), sorafenib tosylate (4-[4-[[4-
chloro(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine
carboxamide,4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropanyl)-N-(4-methyl(3-
methyloxo-3,4—dihydroquinazolinylamino)phenyl)benzamide), NVP-BHG712 (4-
(1-methyl(pyridinyl)-lH-pyrazolo[3,4-d]pyrimidinylamino)—N—(3-
(trifluoromethyl)phenyl)benzamide), RAF-265 (1-methyl[2-[5-(trifluoromethyl)-1H-
imidazolyl]pyridin-4—yl]oxy-N—[4-(trifluoromethyl)phenyl]benzimidazolamine), 2-
Bromoaldisine (2-Bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf Kinase
Inhibitor IV oro(2-phenyl(pyridinyl)—1H-imidazolyl)phenol), Sorafenib N-
OXide (4-[4-[[[[4-Chloro-3(trifluoroMethyl)phenyl]aMino]carbonyl]aMino]phenoxy]—N-
Methyl-2pyridinecarboxaMide l-Oxide), PLX—4720, dabrafenib 18436), GDC-0879,
RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, 496, LY3009120, and
GX818 (Encorafenib).
In one embodiment, the additional therapy is a onal antibody (MAb). Some
MAbs stimulate an immune response that destroys cancer cells. Similar to the antibodies
produced naturally by B cells, these MAbs “coat” the cancer cell e, triggering its
destruction by the immune system. For example, bevacizumab targets vascular endothelial
growth factor(VEGF), a protein secreted by tumor cells and other cells in the tumor’s
microenvironment that promotes the development of tumor blood vessels. When bound to
zumab, VEGF cannot ct with its cellular receptor, preventing the signaling that
leads to the growth of new blood vessels. Similarly, cetuximab and panitumumab target the
epidermal growth factor receptor (EGFR), and trastuzumab targets the human epidermal
growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors
prevent the ed receptors from sending their normal -promoting signals. They may
also trigger apoptosis and activate the immune system to destroy tumor cells,
Another group of cancer therapeutic MAbs are the immunoconjugates. These MAbs,
which are mes called immunotoxins or antibody-drug conjugates, t of an antibody
attached to a cell-killing substance, such as a plant or bacterial toxin, a chemotherapy drug, or
aradioactive molecule. The antibody s onto its ic antigen on the e of a cancer
cell, and the cell-killing substance is taken up by the cell. FDA-approved conjugated MAbs
that work this way include ado-trastuzumab emtansine, which targets the HER-2 molecule to
deliver the drug DMI, which inhibits cell proliferation, to HER-2 expressing metastatic breast
cancer cells.
Immunotherapies with T cells engineered to recognize cancer cells via bispecific
antibodies (bsAbs) or chimeric antigen receptors (CARS) are approaches with potential to
ablate both dividing and non/slow-dividing subpopulations of cancer cells.
Bispecific antibodies, by simultaneously recognizing target antigen and an activating
receptor on the surface of an immune effector cell, offer an opportunity to redirect immune
or cells to kill cancer cells. The other ch is the generation of chimeric antigen
ors by fusing ellular antibodies to intracellular signaling domains. Chimeric
antigen receptor-engineered T cells are able to cally kill tumor cells in a MHC-
independent way
In some embodiments, the combination can be administered to the subject in further
combination with other herapeutic agents. If convenient, the combination described
herein can be administered at the same time as another chemotherapeutic agent, in order to
simplify the treatment regimen. In some embodiments, the combination and the other
chemotherapeutic can be provided in a single formulation. In one embodiment, the use of the
compounds described herein is combined in a therapeutic regime with other agents. Such
agents may include, but are not limited to, tamoxifen, midazolam, letrozole, bortezomib,
anastrozole, goserelin, an mTOR inhibitor, a PI3 kinase inhibitors, dual mTOR-PI3K
inhibitors, MEK inhibitors, RAS inhibitors, ALK inhibitors, HSP inhibitors (for example,
HSP70 and HSP 90 inhibitors, or a combination thereof), BCL-2 inhibitors, apopototic
inducing compounds, AKT inhibitors, including but not limited to, MK-2206, GSK690693,
sine, (KRX—0401), GDC—0068, Triciribine, AZD5363, Honokiol, PF-04691502, and
Miltefosine, PD-l inhibitors ing but not limited to, Nivolumab, CT-Ol l, MK-3475,
BMS936558, and 4 or FLT-3 inhibitors, ing but not limited to, P406, Dovitinib,
Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLN518), ENMD-2076, and KW-
2449, or combinations thereof.
In one embodiment, the bioactive agent is an mTOR inhibitor. es of mTOR
tors include but are not limited to rapamycin and its analogs, everolimus (Afinitor),
temsirolimus, ridaforolimus, sirolimus, and deforolimus. Examples ofMEK inhibitors include
but are not limited to tametinib/GSK1120212 {3-Cyclopropyl[(2-fluoro
iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin—l(2H-
yl}phenyl)acetamide), selumetinob (6-(4-bromochloroanilino)fluoro-N—(2-
hydroxyethoxy)methy1benzimidazolecarboxamide),
pimasertib/AS703026/MSC l 935369 ((S)-N-(2,3-dihydroxypropyl)-3 -((2-fluoro-4—
iodophenyl)amino)isonicotinamide), XL-518/GDC-0973 (l-({3,4-difluoro[(2-fluoro-4—
iodophenyl)amino]phenyl}carbonyl)[(ZS)-piperidinyl]azetidinol),
refametinib/BAY869766/RDEA119 (N-(3,4-difluoro(2-fluoroiodophenylamino)
methoxyphenyl)—l-(2,3-dihydroxypropyl)cyclopropane—l-sulfonamide), PD-0325901 (N-
[(2R)—2,3-Dihydroxypropoxy]-3,4-difluoro[(2-fluoroiodophenyl)amino]-benzamide),
TAK733 ((R)—3-(2,3-Dihydroxypropyl)fluoro(2—fluoroiodophenylamino)
methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEKl 62/ARRY438162 (5-[(4-Bromo
fluoropheny1)amino]fluoro-N-(2-hydroxyethoxy)—1-methyl-lH-benzimidazole—6
carboxamide), R05126766 (3-[[3-Fluoro-2—(methylsulfamoylamino)pyridyl]methyl]
methylpyrimidinyloxychromen-Z-one), WX-554, R04987655/CH4987655 (3,4-
difluoro((2-fluoroiodophenyl)amino)-N-(2-hydroxyethoxy)((3-oxo-l,2-oxazinan-2
yl)methyl)benzamide), or AZD8330 (2-((2-fluoroiodophenyl)amino)-N-(2-
hydroxyethoxy)—1,5-dimethyloxo-l,6-dihydropyridinecarboxamide).
In one ment, the ive agent is a RAS inhibitor. Examples ofRAS inhibitors
include but are not limited to Reolysin and siGlZD LODER.
In one embodiment, the bioactive agent is an ALK inhibitor. Examples of ALK
inhibitors include but are not d to Ciizotinib, AP26113, and LDK37 8.
In one embodiment, the bioactive agent is a HSP inhibitor. HSP inhibitors include but
are not limited to Geldanamycin or 17—N—Allylamino-l7-demethoxygeldanamycin (17AAG),
and Radicicol. In a particular embodiment, a compound described herein is administered in
combination with letrozole and/or tamoxifen. Other herapeutic agents that can be used
in combination with the compounds bed herein include, but are not limited to,
chemotherapeutic agents that do not require cell cycle activity for their anti-neoplastic effect.
Additional bioactive compounds e, for example, everolimus, trabectedin,
abraxane, TLK 286, AV-299, DN—101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD
6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin,
anib, ARQ-197, 7, MLN8054, FHA—739358, R-763, AT-9263, a FLT-3
inhibitor, a VEGFR inhibitor, an aurora kinase inhibitor, a PIK-l modulator, an HDAC
inhibitor, a c-MET tor, a PARP inhibitor, a Cdk inhibitor, an IGFR-TK inhibitor, an anti-
HGF antibody, a focal adhesion kinase inhibitor, a Map kinase (mek) inhibitor, a VEGF trap
antibody, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171,
batabulin, umab, zanolimumab, edotecarin, tetrandrine, can, tesmilifene,
oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, B10 140,
CC 8490, cilengitide, gimatecan, ILl3-PE38QQR, INC 1001, IPdRi KRX-0402, lucanthone,
LY317615, neuradiab, vitespan, Rta 744, de 102, anel, atrasentan, Xr 311, psin,
ADS-1003 80, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin,
liposomal doxorubicin, 5’-deoxyfluorouridine, vincristine, temozolomide, ZK—304709,
seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-[4-[2-(2-amino-4,7-
dihydrooxo-lH-pyrrolo[2,3-d]pyrimidinyl)ethyl]benzoyl]-, disodium salt, heptahydrate,
camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, azole, exemestane,
letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab,
11, CHIR-25 8); 3-[5-(methylsulfonylpiperadinemethyl)-indoly1-quinolone, vatalanib,
AG—013736, 05, goserelin acetate, leuprolide acetate, triptorelin pamoate,
yprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene,
bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272,
erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, 9, PKI-166, 016,
Ionafamib, EMS-214662, tipifamib, amifostine, NVP-LAQ824, suberoyl analide hydroxamic
acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide,
amsacrine, anagrelide, L—asparaginase, Bacillus Calmette—Guerin (BCG) vaccine, adriamycin,
bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine,
clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin,
lstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide,
gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, ib, leuprolide, levamisole,
lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin,
2017/040093
mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin,
ycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide,
testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, l3-cis-retinoic acid,
phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-
deooxyuridine, ne arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol,
valrubicin, mithramycin, Vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3,
neovastat, EMS—275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-
12, IM862, tatin, Vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine,
trastuzumab, denileukin ox, gefitinib, bortezimib, paclitaxel, cremophor—free paclitaxel,
docetaxel, epithilone B, 7550, EMS-310705, droloxifene, 4-hydroxytamoxifen,
pipendoxifene, ERA-923, arzoxifene, trant, acolbifene, lasofoxifene, idoxifene, TSE—
424, HMR-3339, ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352,
cin, 2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578,
BC-210, LY294002, 23, LY292696, LY293684, LY293646, wortmannin, ZM336372,
L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating
factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating
factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated eron alfa—2b,
interferon alfa—2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab,
hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid,
nazole, interleukin-2, megestrol, immune globulin, nitrogen mustard,
methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine,
bexarotene, tositumomab, arsenic de, cortisone, editronate, mitotane, cyclosporine,
liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-l
receptor antagonist, setron, aprepitant, hydramine, hydroxyzine,
metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone,
methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron,
pegfilgrastim, erythropoietin, n alfa, darbepoetin alfa and mixtures thereof.
In one embodiment, a compound of Formula 1, Formula II, Formula 111 Formula IV,
Formula V, Formula VI, Formula VII, a VIII, Formula IX, Formula X, Formula XI,
Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII,
a XVIII, a XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII,
Formula XXIV, or Formula XXV bed herein can be combined with a chemotherapeutic
selected from, but are not limited to, Imatinib mesylate (Gleevac®), Dasatinib (Sprycel®),
Nilotinib (Tasigna®), Bosutinib (Bosulif®), Trastuzumab (Herceptin®), Pertuzumab
(PerjetaTM), Lapatinib (Tykerb®), ib (Iressa®), Erlotinib (Tarceva®), Cetuximab
(Erbitux®), Panitumumab (Vectibix®), anib (Caprelsa®), Vemurafenib (Zelboraf®),
Vorinostat (Zolinza®), Romidepsin (Istodax®), Bexarotene (Tagretin®), Alitretinoin
(Panretin®), Tretinoin (Vesanoid®), zomib (KyprolisTM), Pralatrexate yn®),
Bevacizumab (Avastin®), Ziv-aflibercept (Zaltrap®), Sorafenib (Nexavar®), Sunitinib
(Sutent®), Pazopanib (Votrient®), Regorafenib (Stivarga®), and Cabozantinib
(CometriqTM).
In certain aspects, the additional therapeutic agent is an anti—inflammatory agent, a
herapeutic agent, a radiotherapeutic, additional therapeutic agents, or
immunosuppressive agents.
Suitable chemotherapeutic agents include, but are not limited to, radioactive molecules,
toxins, also referred to as cytotoxins or cytotoxic agents, which includes any agent that is
detrimental to the viability of cells, agents, and liposomes or other vesicles containing
chemotherapeutic compounds. General anticancer ceutical agents include: Vincristine
(Oncovin®) or liposomal Vincristine (Marqibo®), Daunorubicin (daunomycin or
Cerubidine®) or doxorubicin (Adriamycin®), Cytarabine (cytosine arabinoside, ara—C, or
r®), L-asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®),
Etoposide (VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Pun'nethol®),
Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, thasone (Decadron),
imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and
ponatinib (IclusigTM). Examples of additional suitable chemotherapeutic agents include but
are not limited to l-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopunne, 6—
thioguanine, actinomycin D, adriamycin, eukin, alkylating agents, allopurinol sodium,
altretamine, amifostine, anastrozole, anthramycin , anti-mitotic agents, cis—
dichlorodiamine um (II) (DDP) tin), o dichloro platinum, anthracycline, an
antibiotic, an antimetabolite, asparaginase, BCG live (intravesical), thasone sodium
phosphate and betamethasone acetate, bicalutamide, bleomycin e, busulfan, calcium
leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine ,
mbucil, Cisplatin, Cladribine, Colchicin, conjugated estrogens, Cyclophosphamide,
hosphamide, Cytarabine, Cytarabine, cytochalasin B, Cytoxan, Dacarbazine,
omycin, dactinomycin (formerly actinomycin), daunirubicin HCL, ucbicin
citrate, denileukin diftitox, Dexrazoxane, Dibromomannitol, oxy anthracin dione,
Docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol, E. coli L-asparaginase,
WO 05860
emetine, epoetin-(x, Erwim'a L-asparaginase, esterified estrogens, estradiol, ustine
phosphate sodium, ethidium bromide, ethinyl iol, etidronate, etoposide citrororum factor,
etoposide ate, fllgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil,
flutamide, folinic acid, gemcitabine HCL, glucocorticoids, goserelin acetate, gramicidin D,
etron HCL, hydroxyurea, idarubicin HCL, ifosfamide, interferon (x-2b, irinotecan HCL,
letrozole, leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine, lomustine,
maytansinoid, rethamine HCL, medroxyprogesterone acetate, megestrol acetate,
melphalan HCL, mercaptipurine, mesna, methotrexate, methyltestosterone, mithramycin,
rnitomycin C, mitotane, mitoxantrone, mide, octreotide acetate, ondansetron HCL,
paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL, plimycin, polifeprosan 20
with carmustine implant, porfimer , ne, procarbazine HCL, nolol,
rituXimab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone,
tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL, ifene citrate,
trastuzumab, tretinoin, icin, stine sulfate, Vincristine sulfate, and Vinorelbine
tartrate.
onal therapeutic agents that can be administered in combination with a compound
disclosed herein can include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2,
finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522),
cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib,
figitumumab, atacicept, rituximab, alemtuzumab, eukine, atlizumab, tocilizumab,
temsirolimus, everolimus, lucatumumab, dacetuzumab, HLLl, huN901-DM1, atiprimod,
natalizumab, omib, carfilzomib, marizornib, tanespimycin, saquinavir mesylate,
vir, nelfinavir mesylate, indinavir e, belinostat, panobinostat, mapatumumab,
lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, talmapimod, 0,
enzastaurin, tipifamib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin,
celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991,
ribociclib (LEEOl 1), amebaciclib (LY2835219), HDM201, trant (Faslodex), exemestane
(Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and
ramucirumab (IMC-1121B).
In one aspect of the present invention, a compound described herein can be combined
with at least one suppressive agent. The immunosuppressive agent is preferably
selected from the group consisting of a eurin inhibitor, e.g. a cyclosporin or an
ascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR
inhibitor, e. g. rapamycin or a derivative thereof, e. g. Sirolimus (RAPAMUNE®), Everolimus
(Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e. g, ridaforolimus,
azathioprine, h IH, a SIP receptor modulator, e.g. fmgolimod or an ue thereof,
an anti IL-8 antibody, mycophenolic acid or a salt thereof, e. g. sodium salt, or a prodrug thereof,
e. g. Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE , Prednisone,
ATGAM®, THYMOGLOBULIN®, Brequinar , OKT4, TIOB9.A-3A, 33B3.I, 15—
deoxyspergualin, tresperimus, Leflunomide ARAVA®, Ig, anti-CD25, anti-ILZR,
Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate,
dexamethasone, ISAtX-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA4lg (Abatacept),
belatacept, LFA3lg,, etanercept (sold as ® by Immunex), adalimumab (Humira®),
IO infliximab (Remicade®), an anti-LFA-I antibody, natalizumab (Antegren®), Enlimomab,
gavilimomab, antithymocyte immunoglobulin, siplizumab, Alefacept efalizumab, pentasa,
zine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac
and thacin, aspirin and ibuprofen.
In certain embodiments, a compound described herein is administered to the subject
prior to treatment with another chemotherapeutic agent, during treatment with another
chemotherapeutic agent, after stration of another chemotherapeutic agent, or a
combination thereof.
In some embodiments, the compound of Formula 1, a II, Formula 111 Formula
IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI,
Formula XII, Formula XIII, a XIV, Formula XV, Formula XVI, Formula XVII,
Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII,
Formula XXIV, or Formula XXV can be administered to the subject such that the other
chemotherapeutic agent can be administered either at higher doses (increased
chemotherapeutic dose intensity) or more frequently (increased chemotherapeutic dose
density). ense chemotherapy is a chemotherapy treatment plan in which drugs are given
with less time between treatments than in a standard chemotherapy treatment plan.
Chemotherapy dose intensity represents unit dose of chemotherapy stered per unit time.
Dose intensity can be increased or decreased through altering dose stered, time interval
of administration, or both.
In one embodiment of the invention, the compounds described herein can be
stered in a concerted regimen with another agent such as anon-DNA—damaging, targeted
anti-neoplastic agent or a hematopoietic growth factor agent. It has been recently reported that
the untimely administration of hematopoietic growth s can have serious side effects. For
example, the use of the EPO family of growth factors has been associated with arterial
hypertension, cerebral sions, hypertensive encephalopathy, thromboembolism, iron
deficiency, influenza like syndromes and venous thrombosis. The G—CSF family of growth
factors has been associated with spleen enlargement and rupture, respiratory ss syndrome,
allergic reactions and sickle cell complications. As such, in one embodiment, the use of the
compounds or methods described herein is combined with the use of hematopoietic growth
factors including, but not limited to, granulocyte colony stimulating factor (G—CSF, for
example, sold as en stin), Neulasta (peg-filgrastin), or lenograstin), granulocyte—
macrophage colony stimulating factor (GM—CSF, for example sold as molgramostim and
sargramostim (Leukine)), M-CSF (macrophage colony stimulating factor), opoietin
(megakaryocyte growth development factor (MGDF), for example sold as Romiplostim and
Eltrombopag) interleukin (IL)-12, interleukin-3, interleukin-ll (adipogenesis inhibiting factor
or oprelvekin), SCF (stem cell factor, steel factor, kit-ligand, or KL) and erythropoietin (EPO),
and their derivatives (sold as for example epoetin-0t as Darbopoetin, Epocept, Nanokine, Epofit,
Epogin, Eprex and Procrit, epoetin-B sold as for example NeoRecormon, Recormon and
Micera), epoetin-delta (sold as for example Dynepo), epoetin- omega (sold as for example
), epoetin zeta (sold as for example Silapo and Reacrit) as well as for example t,
EPOTrust, Erypro Safe, Repoeitin, Vintor, Epofit, Erykine, Wepox, Espogen, Relipoeitin,
Shanpoietin, Zyrop and EPIAO). In one embodiment, the compound of Formula I, Formula II,
Formula III Formula IV, Formula V, a VI, Formula VII, Formula VIII, Formula IX,
Formula X, Formula XI, a XII, Formula XIII, Formula XIV, Formula XV, Formula
XVI, Formula XVII, a XVIII, Formula XIX, Formula XX, a XXI, Formula
XXII, a XXIII, Formula XXIV, or Formula XXV is administered prior to administration
of the hematopoietic growth factor. In one embodiment, the hematopoietic growth factor
administration is timed so that the nd’s effect on HSPCs has dissipated. In one
embodiment, the growth factor is administered at least 20 hours after the administration of a
nd described herein.
If d, multiple doses of a compound described herein can be administered to the
subject. Alternatively, the subject can be given a single dose of a compound described .
In one aspect of the invention, a compound disclosed herein can be beneficially
administered in combination with any therapeutic regimen entailing radiotherapy,
chemotherapy, or other therapeutic agents. In additional embodiments the compounds
disclosed herein can be beneficially administered in combination with therapeutic agents
ing auto—immune disorders.
VIII. SYNTHESIS
The compounds described herein can be prepared by s known by those skilled in
the art. In one non-limiting example the disclosed compounds can be made by the following
schemes.
The disclosed compounds can be made by the following general schemes:
my N
.N N/
N/ N
St 1 N>\ l
ep Lag/k}; \>
fl; N
‘GAN:
LG, N g 0.961. 60% impel
A4 A-Z
N/ N
NW” l ‘>
\ ‘~
Stepsy. : E: \> Q . /J\ N
A A view HN N
______.,_ L61 N N """MRTW 17 OPG;
A—4 A5
«A N OLG ‘l
l N/ N
Step5 PGZNN/K‘NN/j: \N) \H
Step6 PG2‘N/KN l “N C)
9&7 J: “oped, I7 ‘09:;
R. :5
2 i N
............................... N N NHR
l ”l“ E
OH 7 “Min
Rx R —
N O
N / I
———> HN N N NW
9%? C37
A-‘lfl
Scheme 1A
As demonstrated in Scheme 1A, compounds that adhere to Formula 1 can be prepared
from readily ble purines. In Step 1, an appropriately substituted purine A-1 can be reacted
with an appropriate substituted olefin at elevated temperature in the presence of an
metallic catalyst in organic solvent to furnish A-2. LG1 and LG2 are leaving groups
known by those skilled in the art. In one ment, LG1 and LG2 are chloro. PG1 is a
protecting group known by those skilled in the art. In one embodiment, PG1 is TBDMS. In one
embodiment, the solvent is toluene. In one embodiment, the catalyst is Au(I) salt bound to
appropriate ligands. In one embodiment, the temperature is greater than 80°C. The olefin shown
in Scheme 1 is a non-limiting example and other olefins may be used by those skilled in the art
to generate derivatives of structure A-2. In Step 2, LG2 is replaced by another leaving group
LG3 to yield A-3. In one embodiment, LG3 is amino, -NH2. In Step 3, LG3 is removed by
methods known to those skilled in the art to generate structure A-4. In a limiting example, LG3
is ed by hydrogen. In Step 4, structure A—4 is coupled with an appropriately substituted
amine at elevated temperature in the presence of base and an organometallic catalyst in organic
solvent. In one embodiment, the amine is pyridin-Z-amine. In one embodiment, the base is
potassium t-butoxide. In one ment, the catalyst is Pd(OAc)2 attached to a [1,1'-
biphenyl]yldi-tert-butylphosphane . In one embodiment, the temperature is greater
than 60°C. In one embodiment, the t is toluene. Structure A-5 is then protected with a
ting group known to those in the art. In one embodiment, PG2 is trityl. Structure A-6 is
then transformed to structure A-7 in Step 6 according to methods known in the art. In one
embodiment, LG1 is phenyl. In Step 7, PG1 is d by methods known in the art to afford
A-8. l A-8 is then converted to a leaving group, LG2 in Step 8 to afford compound A-9.
In one embodiment, LG2 is bromo. In Step 9, LG2 is displaced to form A-10 which is a
compound of Formula I.
WO 05860 2017/040093
Step 3
Step 5
Step 7
Scheme 1B
As demonstrated in Scheme 1B, compounds that adhere to Formula II can be prepared
from readily available starting materials such as B-l. In Step 1, B-l is protected with protecting
group PG1 known by those skilled in the art to furnish B-2. In one embodiment, PG1 is TBDMS.
In Step 2, B-2 is reacted with an appropriately substituted e in the presence of a Lewis
acid to generate B-3. In one embodiment, the Lewis acid is boron trifluoride etherate. The
epoxide shown in Scheme 2 is anon-limiting example and other epoxides may be used by those
skilled in the art to access derivatives ofB-3. In Step 3, alcohol B-3 is protected with protecting
group PG2 to furnish B-4. In one embodiment, PG2 is TBDMS. B-4 is then converted to
structure B-S by methods known in the art. LG is a leaving group known by those in the art. In
one embodiment, LG is phenyl. In Step 6, PG; is d according to s known in the
art to yield B-7. In Step 7, B-7 is cyclized by methods known in the art to generate lactam B-
8. In Step 8, sulfide B-8 is ed to afford B-9. Sulfone B-9 is then displaced by an
appropriately substituted amine to produce compound B-10 which is a compound of Formula
H ,PG1 [P61
LG1AN/ / ifs/LNx / / /
R7—-NH2 Hr? l\.
6-? 3-2 (3-3
PG: P81
' N
S- 3 N’ N \
l : ng
x :
R7 I ,
(3-4
(2-5
N OLG 2
Stepfi “if? MW Step6 PG7‘N/L\N/ /
l OPG3
(1-?
F31 E
\l 0
\j \ O I'\. \
i P82\NAN/s / {ting AL «2 f?
Step1 IN
.,,, Step 8 IN-«g
' W .N/ Hi?!
A? o -’
R7 <
33-8 {3-9
Scheme 1C
As demonstrated in Scheme IC, compounds that adhere to Formula III can be prepared
from readily available pyrimidines. In Step 1, an riately substituted pyrimidine C-l is
protected with a protecting group, PGi, known to those skilled in the art to furnish C-2. In one
embodiment, PGi is trityl. LG1 is a leaving group known by those skilled in the art. In one
embodiment, LG1 is chloro. In Step 2, C-2 is coupled with an appropriately substituted amine
at elevated temperature in the presence of base and an organometallic catalyst in organic
solvent to yield structure C-3. In one embodiment, the amine is pyridin-Z-arnine. In one
embodiment, the base is potassium t—butoxide. In one embodiment, the catalyst is Pd(OAc)2
attached to a [1,1'-biphenyl]—2-yldi-tert-butylphosphane ligand. In one embodiment, the
temperature is greater than 60°C. In one ment, the solvent is toluene. In Step 3, structure
C-3 is protected with protecting group PG2 known to those d in the art to generate
structure C-4. In one ment, PG2 is trityl. In Step 4, C-4 can be reacted with an
appropriate substituted epoxide in the presence of a Lewis acid to produce structure C-S. In
one embodiment, the Lewis acid is trifluoroboron etherate. The epoxide shown in Scheme 3 is
a miting example and other es may be used by those d in the art to generate
derivatives of structure C-S. In Step 6, alcohol C-S is protected with protecting group PG3
known to those d in the art to generate C-6. In one embodiment, PG3 is TBDMS. In Step
6, C-6 is transformed to structure C-7 according to methods known in the art where LG2 is a
leaving group. In one embodiment, LG2 is phenyl. In Step 7, C-7 is cyclized to afford lactam
C-8 according to methods known in the art. In Step 8, PGi and PG2 are removed to furnish
nd C-9 which is a compound of Formula III.
L‘Gg O
N/KYO Step1 i\ Step2
: (j, HNJLN”
m1} /I /i\>/ /
LG; N _ l
N R’---NH2
{3-1 [5-2 [3:3
“Mr ‘~ 0
we )L ,;> N
“LimaSte 3 1‘» /
~~ 3: 4
If N “it“, p61, A x /
N/\ o OLG3
Step 5 ‘G ”NAN/d /
Step 6 O
WWW—a» OPGZ
RT I
$997 Pel‘pg/LKN/ ‘ / NHR Step 8 A f - / _(
Scheme 1D
As demonstrated in Scheme 1D, nds that adhere to Formula III can be prepared
from readily ble pyrimidines. LGi and LG2 are g groups known by those skilled in
the art. In one embodiment, LGi and LG2 are chloro. In Step 1, LG2 is d according to
methods known in the art to h structure D-2. In Step 2, D-2 is coupled with an
appropriately substituted amine at ed temperature in the presence of base and an
organometallic catalyst in organic solvent to yield structure D-3. In one embodiment, the amine
is pyridin-Z-amine. In one embodiment, the base is potassium t—butoxide. In one embodiment,
the catalyst is Pd(OAc)2 attached to a [l,1'-biphenyl]yldi-tert-butylphosphane ligand. In one
embodiment, the temperature is greater than 60°C. In one embodiment, the solvent is toluene.
In Step 3, structure D-3 is protected with protecting group PGi known by those skilled in the
art. In one embodiment, PGi is trityl. In Step 4, pyrimidine D-4 is reacted with an appropriately
substituted epoxide in the presence of a Lewis acid to produce structure D-5. In one
embodiment, the Lewis acid is trifluoroboron etherate. The epoxide shown in Scheme 3 is a
non-limiting example and other epoxides may be used by those skilled in the art to generate
derivatives of structure D-S. In Step 5, alcohol D-S is protected with protecting group PG2
known to those skilled in the art to generate D-6. In one embodiment, PG2 is TBDMS. In Step
6, D-6 is transformed to structure D-7 according to methods known in the art where LG3 is a
leaving group. In one ment, LG3 is phenyl. In Step 7, ester D-7 is converted to amido
species and the PG2 is subsequently removed to furnish the free alcohol which is then converted
to leaving group LG4 by methods known in the art to produce ure D-8. In one
ment, LG4 is bromo. In Step 9, D-8 is cyclized by methods known in the art to afford
lactam D-9 which is a compound of Formula III.
:3: \ Step? HNJLN/ f Step2 PG“ A ,j
R? R7
£2 £43
N \ N ‘\ 5
48103 3‘9”
——+ PG1\:/li\ / /
{3qu i , /
o I? N CH “f N CFC-32
é R7 k”! RI L\/I
E~4 E—5
Step5
Scheme 1E
As demonstrated in Scheme 1E, compounds that adhere to Formula III can be prepared
from readily available dines. In structure E-l, LGi is a leaving group known by those
skilled in the art. In one embodiment, LGi is . In Step 1, E-l is coupled with an
appropriately substituted amine at elevated temperature in the presence of base and an
organometallic catalyst in organic solvent to yield structure E-2. In one embodiment, the amine
is pyridin-Z-amine. In one embodiment, the base is potassium xide. In one embodiment,
the catalyst is Pd(OAc)2 attached to a [l,1'-biphenyl]-2—yldi-tert-butylphosphane ligand. In one
embodiment, the temperature is r than 60°C. In one embodiment, the solvent is toluene.
In Step 2, E-2 is protected with a ting group, PGi, known to those skilled in the art to
furnish E-3. In one embodiment, PGi is trityl. In Step 3, E-3 can be reacted with an
appropriately substituted epoxide in the presence of a Lewis acid to e structure E-4. In
one embodiment, the Lewis acid is trifluoroboron te. The epoxide shown in Scheme 5 is
a non-limiting example and other epoxides may be used by those skilled in the art to generate
derivatives of structure E-4. In Step 4, alcohol E-4 is protected with protecting group PG2
known to those skilled in the art to generate E-S. In one embodiment, PG2 is TBDMS. In Step
, E-S is transformed to structure E-6 according to methods known in the art where LGi is a
leaving group. In one embodiment, LGi is phenyl. In step 6, ester E-6 is ormed to an
amido species and PG2 is removed to yield E-7. In Step 7, the alcohol is converted to leaving
group LG2 known by those skilled in the art. In one embodiment, LG2 is bromo. In Step 8, E-
8 is ed to afford lactam E-9 which is a compound of Formula III.
,NHz [PG
N Step1
N \ N/(K‘YN Stecz l /E /
J; , 5 4K?
/ -----------------------------I» Hit N
LG N LG N R,
F“! F~2 R3
Step3 N Whips
N \ Step4 NE \E
W pal, N,» /
m,“ AL ,, J
FE! N ‘
C) a OH
R, R7 (R1),
. g R i)?” , 3:
F4 5’ F—5
PG. we
Ni N;
N \ l N \
MEL“,- PG1\N/JLN/ Pu1\N,il\N/’’j/ {I h
’1 ,,
Step6 ~
LG”: W '
E ‘\ L81
7 1 ' 1“
(My R tR‘}
-2.7
[PG H
N N \ R
Ste 7 i N=N~NHPh StepB HNAN/I {3 PG1\i\j/J\N/ ( / N
l: ‘\ CN E I
I7 7
I R
R" A
R R1) I R!)
3/ y
Scheme 1F
As demonstrated in Scheme 1F, compounds of Formula IV can be ed from
y available starting materials such as F-l. In Step 1, F-l is protected by methods known
by those skilled in the art to furnish F -2. In one embodiment, LG is ne. In one
embodiment PG is trityl. In Step 2, F-2 undergoes SNAr nucleophilic addition, yielding F-3.
In Step 3, F-3 is protected to afford F-4. In Step 4, an appropriately substituted F-4 can be
reacted with an appropriate substituted epoxide to furnish F-5. In Step 5, the hydroxyl of F-5
is converted to an appropriate leaving group to afford F-6. In Step 6, F-6 is converted to azide
F-7. In Step 7, F-7 undergoes nucleophilic attack to install a cyano group and yield F-8. In
Step 8, F-8 is cyclized by s known by those skilled in the art to afford F-9 which is a
compound of Formula IV.
(5-4 35
Step? PGW: N “\V):0 51698 HE}; K<szo
Scheme 1G
As demonstrated in Scheme 1G, compounds ofFormulaV can be prepared from readily
available starting materials such as G-l. In Step 1, G—l is ted by methods known by those
skilled in the art to furnish G -2. In one embodiment, LG is chlorine. In one embodiment PG
is trityl. In Step 2, G-2 undergoes SNAr nucleophilic addition, yielding G-3. In Step 3, G—3 is
protected to afford G-4. In Step 4, an appropriately substituted G—4 can be reacted With an
appropriate substituted olefin at elevated temperature in the presence of an organometallic
catalyst in organic solvent to furnish G-S. In one embodiment, the solvent is toluene. In one
ment, the catalyst is Au(I) salt bound to appropriate ligands. In one embodiment, the
temperature is greater than 80°C. The olefin shown in Scheme 1G is a non-limiting example
and other olefins may be used by those skilled in the art to te derivatives of structure G-
. In Step 5 G-S is converted to azide G-6. In Step 6, G-6 is undergoes nucleophilic attack to
install a cyano group and yield G—7. In Step 7, G-7 is cyclized by methods known by those
skilled in the art to afford G-8. In Step 8, G-8 is ected to afford G—9 which is a compound
of Formula V.
Step3
CN 0 o
.EAT\ WWw Step1 N \ NA“ H2N\/U\ ,
/K ,a/x. ~ I ---------------------------a»
LG h. NHZ / ____________________9{1,
‘-G M NH? AL /
LG N Halo
(1 O Q
N - DPG
i La: /
-u . ton N
H Y i ill/m”
U o
“-4 H5 ._o o
0 0
Step6 ‘\ Sep'l'
N N \ ’1!\ steps
—_“* i """"""""""""" N'
/ ‘)wa [JL / (39¢ l
,. :i """"""""""""1* .I
I LG1
LG N LG N
‘ fi LSANA’Q/
\IO 0 O
" 0
H 7 H-8 H 9
0H ,3
\ k ly M? \ )n r ,
---------------------------------------------------------->,, j: / if} N/Y F5
u H 11
Ste09 at: N Er LGAN/
"1 O VET)“' \Ei’
H41} " flLGz
PG1 o y
0 Q
step N \ R7,NH2 NM
———9 LrJ/L‘Nl I l i
/ O r” Q
N “mm—"4” ’j‘m-“Y_ H13
Ste.) 12
N L N
MF3 R, V,
{RU l N“?
{R‘-
y \ ‘
H42 Formula VI
Scheme 1H
As demonstrated in Scheme 1H, compounds of Formula VI can be prepared from
readily available ng materials such as H-1. In Step 1, H-1 is ted to a ketone by
methods known by those skilled in the art to furnish H-2. In one embodiment, LG is chlorine.
In Step 2, H -2 is converted to an appropriate halide for uent displacement, yielding H
-3. In Step 3, halide H-3 is displaced by glycine to afford H-4. H-4 is then protected to afford
structure H -5 by methods known in the art. In one embodiment PG is ethyl, In Step 5 H-5 is
converted to zwitterion H-6. In Step 6, H-6 is cyclized by methods known in the art to yield
H-7. In one embodiment silyl is TMS. In Step 7, H-7 is dehydrated to afford H-8. In Step 8,
H-8 is converted to an appropriate leaving group containing compound H-9. In one
WO 05860
ment LGl is hydroxyl. In Step 9, the secondary amine is protected and then the LG]
of H—9 is displaced by an appropriately substituted amine to produce compounds of Formula
H010. In one embodiment PGl is a carbamate. In Step 10, the hydroxyl group of H-10 is
converted to an appropriate leaving group to afford H-ll. In Step 11, H-ll is cyclized to afford
H-12. In Step 12 SNAr nucleophilic addition of an amine displacing the leaving group of H-
12 affords a compound of Formula VI.
Ci NH2
WPAuOTf N/JEN -N
N\> DMSCE/k(53m01%) NH4OH it. N\> kN”: ~o.BDMS HZO/MeOH or
or N N OTBDMS
1 i
To!uene 85°C 3
.,_ N
\ NJ; m: l N
4 5
\ z 0
aux/”75%) N/
1 ng“'P T..F
0:013:23 : 1.221339“
; \.NAN Ph N 3
-----------------------------#- OCUD
NEt3 fioraoMs 2 CECOQ'F’h N: (Shmom
l 2% E NWN
1. NH?” MeOH Ph" \
N \N N NH; F’Pi'13.CBr4 SuxN NAN NHZ
DC‘JI i ’\
2.TBAF, A : Br
OH N,
N/ E 6}
K I \ ------
N2 3 R2 g
1. NaH Nit:N4;
2 AcOH MeOH © On-
Scheme 2
As exemplified in Scheme 2, An appropriately substituted purine (1) is dissolved in
toluene and treated with tert-butyl(cycloheX-l-en-l-ylmethoxy)dimethylsilane in the presence
of tic PhsPAuOTf at elevated temperature to produce 2. Compound 2 is subsequently
aminiated with ammonium hydroxide to furnish amine 3. The amino moiety is then removed
by conversion to the corresponding diazonium salt with nitrous acid followed by subsequent
reduction with hydrophosphinic acid to yield 4. An riately substituted amine is then
coupled with 4 at elevated temperature in the presence of base (NaOt—Bu) and a palladium
WO 05860
source such as Pd(OAc)2 with an appropriate ligand to generate 5. This species is then protected
with trityl chloride to produce compound 6. The trityl-protected species is then ted with
an lithium reagent and quenched with an appropriately substituted electrophile to furnish
compound 7. Amidation of 7 with ammonia, followed by subsequent deprotection of the silyl
ether with TBAF yields an amido alcohol 8 that is converted to bromo species 9 with
triphenylphosphine and carbon romide. Finally, cyclization of the alkyl bromide with the
amide moiety, followed by acidic deprotection of trityl affords the title compound 10 which is
a representative compound of Formula I.
WO 05860 2017/040093
Q OTBDMS
A EBDMS
N 1 ,N N/ M
HN TBDMSCI N N' BFS'OEtZ \\
H3CSAN/‘NN:>
l /L\x \
imidzole N
H3CS \N 0 H308 “OH
11 12
EBDMS 1. n-BuLi, THF
N” N, TBDMSCI, N\ 00C fl 9TBDMS
imidazole H393 N OTBDMS 2. CICth
1.TBAF, DCM NJ’L‘N’N OPh Pd/C,H2
- \
2. Pool3 H3cs’”‘NJk .\
o EtOH
HO
1. BOCZO, K2C03,
1_ NH3, MeOH
H cs
2- Pphfv CBr4 3
2. Oxone, ZO
(\r 2
sz\ N HC'
N-Boc
e, 100°C
Scheme 3
As exemplified in Scheme 3, Compound 11 is first protected with TBDMSCl to yield
silyl ether 12 which reacts with an appropriately substituted epoxide in the presence of a
suitable Lewis acid to produce alcohol 13. Silylation of 13 affords 14 and subsequent lithiation
of the ic ring with an n—butyllithium followed by treatment with an appropriately
substituted electrophile produces 15. Treatment of 15 with excess TBAF removes both silyl
ethers and the free amide is then converted to chloride 16 with POC13. Chloride 16 is reduced
to compound 17 in the presence of finely dispersed palladium on carbon with molecular
hydrogen as the reductant. Treatment of 17 with ammonia in ol followed by a
subsequent reaction with PPh3 CBr4 yields an intermediate bromide that undergoes cyclization
in the presence of base such as NaH under elevated temperature to afford lactam 18. The amide
is protected as a carbamate with BOC2O and the sulfide is uently oxidized to the sulfone
by the action of oxone in aqueous media buffered to approximately pH 4.5. This ure
furnishes compound 19 which readily undergoes aromatic substitution with an appropriately
substituted amine at elevated temperature to generate 20. The Boc protecting group is then
removed under acidic ions to yield title compound 21 which is a representative
compound of Formula II.
MHZ <3}th
H 13 (“Kg N \Ai
N \ ClCDhs MAE/N sz /
)L ,«
A / ‘ “'“’ i 5;); / N
,. DCM N533 _
C! N CI‘ N Pd{OAc)g NaOi~Bu,
22 P(tBu)J
23 {‘5
Q"-"Q \ 24
Toluene, 110°C
{1:53:13
. N
.____E_E__Cf:E-_3_________.,.
W: pA “E \ 2 81,0512
x /
Don/Hera3 ‘
N o
\ 25
0.0m
i ‘ ESPhg
n...
N Ol-‘E‘:
N \ \ N
TBDMSCE
Phgci )L /\/ :.n:::;l.::'l—IF PhaCNJ‘LN
irnidazole l? “‘OTBDMS __-_,.. GTBDMS
2. CECOzF’h
/ /
E 3N 28L
CPhs
1.NE-{3.MeOH P313ch,1; /_<rH AcOH,MeOT—l
—---------------a»
2.TBAF
KAN 80°C
3.CBr,;,PPh3
4.NaH
$2. R2 3o
Scheme4
As exemplified in Scheme 4, Compound 22 is protected with trityl chloride in the
presence of base to furnish 23. An appropriately substituted amine is then coupled with 23 at
elevated temperature in the presence of base (NaOt—Bu) and a palladium source such as
Pd(OAc)2 with an appropriate ligand to te 24. uent protection of 24 with trityl
chloride yields 25 which is then reacted with an appropriately substituted epoxide in the
ce of a suitable Lewis acid to produce alcohol 26. Silylation of 26 readily affords 27
which is transformed into nd 28 by n-butyllithium and an appropriately tuted
electrophile. Amidation of 28 is effected by methanolic ammonia and the silyl ether is
ected in the presence of TBAF. This procedure affords an intermediate alcohol that is
converted to the corresponding bromide by CBr4 and PPh3 that undergoes cyclization in the
presence of base such as NaH to yield compound 29. The trityl groups are then deprotected
with acid under elevated temperatures to furnish 30 which is a representative compound of
Formula 111.
(WT/MHZ N
N \ £3in AL / / CiCPhg
ca/E‘N/ ’/ N
Pdcoamg u, :53! DCM, NEt3
P(t~8u) EN
31 \
02,.BR“ E2. E TBDMSC!
Phase“ /
N¢~ PthNina" /
O ' 13H OTBDMS
imidazole
. 1 N
3 O
“--‘=TMF
1.NH3,MeOH PhaciNi; 2’?
DOC—rt “Hz
2. TBAF
2. CECOZPh /' N </ 9H
FE? 3?
can, PPha mm
mm _
2. AcGH‘ MeOH
R2 38
Schemes
As exemplified in Scheme 5, Compound 31 is y coupled to an appropriately
substituted amine at elevated temperature in the presence of base (NaOt—Bu) and a palladium
source such as Pd(OAc)2 with an appropriate ligand to generate 32. The amino moiety is then
protected with trityl chloride to furnish 33 which reacts with an appropriately substituted
epoxide in the presence of a suitable Lewis acid to produce alcohol 34. Silylation of alcohol 34
produces 35 which is ormed to compound 36 by n-butyllithium and an appropriately
substituted ophile. Ester 36 is then converted to an amide by methanolic ammonia and
the silyl ether is cleaved in the presence of TBAF to yield 37. Bromination of alcohol 37 with
CBr4 and PPh3 affords bromide 38 which readily undergoes ation in the presence of base
to produce a cyclic lactam. This intermediate lactam is treated with acid at elevated temperature
to remove the trityl protecting group which furnishes compound 39 which is a representative
compound of Formula 111.
N fig o
\ '
o R2 /
N \ Poi/C H3. Etoei
/ HN N/
i / --------------------------------- NEAR/O
C‘! N/ Pd(OAcb NaOt—Bu. A
C! N ’
Paul-Bu)? l
40 41 V
<1 42
Tcfiuerae, 11930
W33= Phsct ‘ /.J N
1 N c, WNA
.3 .
, E/ N i
V /
R2 N7
o 0%
.\ ‘l. n-BULL THE:
TED:JISC! PhsC‘NAN/_ i
PhacN11? ,i/ Q
000 “r? '
imidazoie UTBDMS W
/ ECKKTQWW / XOTBDMS
E 1N V
\ ' \’ 45
NWOH N.CN13; < “N [1NH
EBAF
/ 2 ACOH MeOH C>
3. arm, PPhg
R2 47
Scheme 6
As exemplified in Scheme 6, Compound 40 is reduced with finely dispersed palladium
on carbon in the presence of molecular hydrogen to furnish loridate 41. An
riately substituted amine is then d with 41 at elevated temperature in the presence
of base Bu) and a palladium source such as )2 with an appropriate ligand to
generate 42. Compound 42 is then protected with trityl de to yield 43 which is then
reacted with an appropriately substituted epoxide in the presence of a suitable Lewis acid to
produce alcohol 44. Silylation of alcohol 44 produces 45 which is transformed to compound
WO 05860
46 by n—butyllithium and an appropriately substituted electrophile. Ester 46 is then converted
to an amide by methanolic ammonia and the silyl ether is cleaved in the presence of TBAF.
Subsequent bromination of the ediate alcohol with CBr4 and PPh3 affords bromide 47
which readily undergoes cyclization in the presence of base to produce a cyclic lactam. This
intermediate lactam is treated with acid at elevated temperature to remove the trityl ting
group which hes compound 48 which is a representative compound of Formula 111.
cw WNW ’CPhE
'3 N
I N N \
N )«\
ClCPhq I‘x' \. V
R2 JL / /
/ A / / HN N
N,» DOM N._-3n cg N Pd(OAc)2 NaOf-Bu, 1
59 1211231112 IN 51
dom- \
Toluene, 110°C
J. Org. Chem, Vol. 65. No. 4, 2000
(312113?”h3
.3 N
_____1: 33 3 3131:2113, 131-30512
33 3A“; “j
DOM, MEN 3 ‘N N” 3’
a 52 i
R2 R2
53131133309113
"2momma-~ / N—NNHPS‘. 1_ n-BuLJ,THF
h 5233,: / 12.3333,133:
0°C“
imidazoie ‘ \‘OTBDMS ——* OTBDMS
2.113131: l
R; 55
Cl’hg H
N:N—1111111 133*Ni/E’NNl NH
/ /
1 TBAF DCM 333330WEE/f H0! ON, «J."-0
2 si 115136001:
/ N <
N 6m
3 £15vaDMSO l
\ V
R2 56 R2 57
Scheme7
As exemplified in Scheme 7, Compound 49 is protected with trityl de in the
presence of base to yield 50. An appropriately substituted amine is then coupled with 50 at
elevated temperature in the presence of base (NaOt—Bu) and a palladium source such as
Pd(OAc)2 with an appropriate ligand to generate 51. Subsequent trityl protection of 51
fumishes 52 which reacts with an appropriately substituted epoxide in the presence of a suitable
Lewis acid to produce alcohol 53. Silylation of53 readily affords 54 which is transformed into
compound 55 by n-butyllithium and phenylazide. The siyl ether is then cleaved with TBAF
and the resulting alcohol is tosylated and displaced by NaCN to yield e 56. Heating
compound 8 at elevated temperature in the ce of acid cleaves the trityl protecting groups
and es hydrolysis of the nitrile and azo moieties to generate lactam 57 which is a
entative compound of Formula IV.
. N
. N \ \
ClCPhg “3% \ Riki‘v (I?
Marm = /= HN N
DcM,NEt3,3 _ BEAN/\j‘l Pd{OAc)2NaOf-Bu, 33pm
H Ph3c ’/ N
F-‘(t—Bu)
58 i I
59 \
'Toluene, 110°C
1 BnCi, NEt3 Brx film' '
NANmN
2. ACGH 60°C f6:Ph3r‘Auoff(5 mo! Io) i
c V (5OTBDWES Toluene 85°C
4 \\
:A.-B“03:1,L' THri" /\/>—N=NNHPt NA; N:N»NHl-hI)
'; 1
8anIANAN “HEAR DOM
————»“’ OTBDMS 0N
2N3Ph 2.03r4J-N2h3 / N
3.NaCN,DMSO l
\ \V.»
R2 64
N \ \
60°C
Scheme 8
As exemplified in Scheme 8, Compound 58 is protected with trityl chloride in the
ce of base to yield 59. An riately tuted amine is then coupled with 59 at
elevated temperature in the presence of base (NaOt-Bu) and a palladium source such as
Pd(OAc)2 with an appropriate ligand to generate 60. Subsequent tion of 3 with benzyl
chloride and ediated hydrolysis of the pre-existing trityl protecting group yields 61.
Compound 61 is then reacted with tert-butyl(cycloheX-l-en-l-ylmethoxy)dimethylsilane in the
presence of catalytic Ph3PAuOTf at elevated temperature to produce 62. Treatment of 62 with
n-butyllithium followed by phenylazide furnishes 63. The silyl ether is deprotected with TBAF
and the resulting alcohol is transformed into an alkyl halide with PPh3 and CB4 and is displaced
by NaCN to produce nitrile 64. Hydrolysis of the nitrile and azo moieties in the presence of
acid at elevated temperature es cyclization to lactam 65. Reductive cleavage of the
benzyl protecting group by finely dispersed palladium with molecular en affords
compound 66 which is a representative compound of Formula V.
CN 1. MeMr‘Br
\ .3
_T_l:‘l_F_DOC"-“El NM\ 1‘ rlNOZ: H20
. ----> /M HgNV’lLOH
Cl N NH-2.
HO! (aq)*10C (Si/1N 5L“H2 2 HBF4. reflux Ci/T‘NAF DMF K2C03
68 reflux
o O o
3% 1-SOCE2 3e02, t~BuOOH
A / OH ' 0E1 E
‘ i\ l/ / QB
N ___ a
_- CI N NHW )NL \
ttUH,F.l. r,w N EAT/i/ .
71 ‘
NEE (SN/1% “ED”... ”% K2003
OH CIAN/ fififlwl" a: :
...................... : I» A ,
TMSCE N/fif _ / OH
HOH Erik:
MeOHngo Cl N N
TMSG 0 ‘30ch
1. TBDMSCI, NaH i};
HATU, DEPEA 2. BriCE, Kt (SI/1‘“
DMF NaH, DMF OTBDMS
dioxane, H20
100%)
H2.Pd/‘C i ..
cDH GVN
Scheme 9
As exemplified in Scheme 9, Compound 67 is chilled to reduced temperatures and
treated with methyl magnesium bromide. Acidic workup of the on mixture yields 68.
Diazotination of 68 with nitrous acid ed by subsequent treatment with HBF4 at elevated
temperatures produces fluoride 69. This intermediate is heated with glycine in the presence of
base to furnish 70. Carboxylic acid 70 is converted to the acid chloride and esterified with
EtOH to afford ethyl ester 71. Oxidation of the secondary nitrogen to nitrone 72 is
accomplished with SeOz and t—BuOOH. Cyclization of 72 with TMSCl in the ce of base
yields 73 which is reduced with Pd/C in the presence of molecular hydrogen to generate amine
74. Ethyl ester 74 is then hydrolyzed with aqueous base and simultaneously ted with Boo
to afford carboxylic acid 75. Acid 75 is then coupled with an appropriately substituted amine
to yield amide 76. The tertiary alcohol is silylated with TBDMSCl and the amide is benzylated
with sodium hydride and benzyl bromide to furnish 77. Hydrolysis of B00 and the silane
protecting group in aqueous acid produces a tertiary carbocation that undergoes cyclization at
elevated temperature to produce 78. Chloride 78 is then coupled with an riately
substituted amine to generate 79 which undergoes a Pd catalyzed reduction to cleave the benzyl
protecting group which yields compound 80 which is a representative compound of Formula
\ ,. s N N ix»
3 N a e
ref H l“ NP
81 33
Ellisi , Q 0
‘S/JxNZ/KN5 C0C3‘ e1 __............,,. “7W
\s \N” N‘
. . _,\SAN E :M
,4 in p
34 85
o 0
o lo
\ ”I ‘~
/=: \
N ixH: MAX‘ NH
N NH_ \ / N , \ 42—»;
\ / N ' NH w N
--------------*> N ”NH )~~;\
"—m—“W Om;
S I/\ (/1 W HN l
\ ,1, 0
/~ l? \’j
a? 88
89 N"3
Scheme 10
As shown in Scheme 10, bromide 81 is converted to aldehyde 82 followed by
subsequent cyclization and oxidation to furnish carboxylic acid 83. Acid 83 is then transformed
to an alkyl ester 84 and transamidated to yield amide 85. ection of the ting group
P produces 86 which oes aminal formation in the presence of a ketone to generate aminal
87. Sulfonation of 87 affords 88 which subsequently undergoes nucleophilic aromatic
substitution to furnish desired compound 89 which is a representative compound of Formula
VII.
iii-i2 M
NH; N300
NW0 NBOC -~N
H N / / “.1
+ NW—NH tdepr‘otect
W Mfg—N
PM >2” ——p
2. giyoxcii F“
Ci R7HN
3. RNH2
9t) 91 92
Tetrahedron, 52(29), 6855-5861; 2006
1.Anti—Cancer Drug Design . 8(6), 439—631.
2. indian i of Chemistry, Section B: fjrganic try Including Medicinal Chemistry (1983),
228(12), 1233-5.
Scheme 11
As shown in Scheme 11, commercially available chloride 90 is coupled with an
appropriate amine Via philic aromatic substitution to afford intermediate 91. Amine 91
is then deprotected, subjected to cyclization in the presence of glyoxal, and coupled with the
desired amine to yield compound 92 which is a entative compound of a VIII.
NO: NO NH-
N02 N800 if 2
iCi N300
N ./\ 1 deprotect
- NH_ NQN MN>": :f: *
-------I> .....
N >—N 2. cyciizeto
aminoimidazoie. 05>—
typioaiiy with
94 cyanogen bromide 95
i—BuOK, THF NzN NzN
mum-ma» N82H2s n2V4
/ \\ >§N -----------)u» l \\ >‘\“N
96 N N N N 97
R?__NH_
>=~ -*A A
C! R'HN
Jourwa'ofMe=dic'r~a'C'rie>rni,try 46(1) 1519-- 182; 2003 U3. Pai.Appi. Pubi.,20040192686
Journal of Organic Chemistry. 79(16) 7520-'7'31; 2014.
sis (8) 855—857': E997
Science of Synthesis, ’17" 357-447; 26-04
Scheme 12
Alternatively compounds of Formula VIII can be formed as shown in Scheme 12.
Commercially available chloride 93 is coupled with an appropriate amine via nucleophilic
ic substitution to afford intermediate 94. Amine 94 is then deprotected and subjected to
cyclization in the presence of cyanogen bromide or an analogous reagent to afford compound
95. Compound 95 is further cyclized in the presence of a base to afford compound 96, which
is reduced and subjected to an appropriately substituted amine to afford nd 97, which
is a compound of Formula VIII.
NH; N800
treat with acid to
remove Boo group m
and convert acetai N
to the aldehyde ‘1. air oxidation
mmmnm-Db PM mum-nib >3—"N
7. RH“7-
zwmm
191 102
Scheme 13
As shown in Scheme 13, bischloride 98 is coupled with an amine via nucleophilic
ic substitution to furnish intermediate 99 which then undergoes amidation in the
presence of a carboxylic acid to produce amide 100. Removal of B00 triggers intramolecular
cyclization to yield intermediate 101 which is then oxidized upon re to air or other
ts and coupled with a desired amine to afford target 102 which is a compound ofFormula
WO 05860
OWN HumR
“3‘33 NH
N f0 N NH
(Cl/k53M (,IL‘ / mm»
‘ )1“ HI, N 0
C! N l‘i Ll N
103 1055
/—’/ \ R7-NH2 \ N 0
Br QE/k/‘ii:H: WNWR R7 HH
‘N N N
wo2012 082997
Scheme 14
As shown in Scheme 14, protected heterocycle 103 is reacted with an electrophile as
known in the art to furnish intermediate 104 which then undergoes ection to produce
amide 105. Nucleophilic attack of dibromoethane by 105 followed by intramolecular
cyclization affords 106 which is coupled with a desired amine to afford compound 107 which
is a compound of Formula I.
”far" i“):X /J\ / HszR7 ./l\ / Cessum acetate, NHG
X. N NH H?- N NH Cu, MeOH, DMSO
‘ mum—nav-
NHBGC R7 NHBQC
us.‘ 1' at. ~ i Pub 4L100225a’9 ’ V52
103 109
N/le-lg N\ 0
HN/kN/ e H NH N/ N OH 1i Deproteot
F E
R7 NHBoc R7 NIHIBoe 2. Laotam
formation
110 111
NWN O
: X, X1 are halogens
i an M
HN N N
Scheme 15
As shown in Scheme 15, protected heterocycle 108 is coupled with a desired amine to
furnish intermediate 109. Intermediate 109 is then converted to an anilino compound 110 as
known in the art. The anilino compound 110 is sed into an oxalate derivative 111 which
is subsequently deprotected and cyclized to form compound 112, which is a compound of
Formula I.
0 W0
NH ”Gk/MHZ HZNWR'7
N \ N ------------------------------------b» 5'
PM TiCM, messi‘lylene
JOC 59, 17, 1994, Pag355084—7
Scheme 16
As shown in Scheme 16, known compound 113 can be reacted with an amino ketal to
form compound 114. Compound 114 is subsequently reacted with a desired amine to form
compound 115, which is a representative compound of Formula XI.
116 117 118
Bioorg, Med Chem. Lett.
18, 2008, pp 5015-1?
HZNwR7’
>”—“N 0H “mum,
CI R”!
------------------------------1>
119 120
Scheme 17
General Procedure for the Synthesis of Diazepinones 118. A mixture of the suitable 2-
arninobenzophenone derivative 116 (6.0 mmol) in pyridine (40 mL) containing 9.0 mrnol of
e tive 117 is refluxed for 20 h under nitrogen. The on mixture is concentred
under reduced pressure, poured into ice—water and ted with CH2C12. The organic layer is
washed with 0.1 N HCl, dried over Na2S04, and evaporated in vacuo. The residue is purified
by flash-chromatography eluting with the suitable solvent to afford the ed compounds,
which after re-crystallization from the appropriate solvent gives 118.
Diazepinone 118 is then coupled with a dine to afford 119 which is subjected to
an appropriate amine in a nucleophilic attack to afford 120, which is a compound of Formula
XII.
In the following schemes methyl piperazines products and intermediates are
synthesized. One skilled in the art, will appreciate that a variety of different heterocycles could
be used in place of methylpiperazine (such as zine, isopropylpiperazine, morpholine, etc)
by selection of the heteroaryl amine reactant in the following schemes.
c ,0? o
o O UQKO O\
H H NH2 0
\ O
N \ “o N\.xvmc /’ ”/0 / A
/l\ /E NazleN Wk” /
c!5 M NH
c; N Cl
NH l?”
' BO“
Bow j 0’ m); ECI
p l
_0 CE!
121 122 123
124 125 \
Scheme 18
Scheme 18 provides a synthetic preparation of compound 126 of Formula I. First
commercially available dichloride 121 undergoes nucleophilic addition to install a diamine
moiety and afford 122. Intermediate 122 is then reduced to an anilino compound and
uently reacted with either methyl chloromethoxyacetate, methyl 2,2,2-
thoxyacetate, methyl 2,2,2-tn'chloroacetimidate, or a similar t to afford cyclization
precursor 124. 124 is then deprotected and subsequently undergoes intramolecular cyclization
to afford 125 which then undergoes nucleophilic attack to afford final compound 126.
Br N’Waf
-0 /§{ 14005 N“ Br' i
N o VA .4 o
<_____/—
3" o/ki
\ ‘1 #W a; OH_ 3’” 5 N
sfiN \ 9 N T I
OH 1
[/j a a
Journai of i-Ieieroeyclic Chemistry, \v/
127 2003, V0140, #2 [1219-2213
129 130
NfljBra: N/sjara; x O /
, , CH
CN ,1
Br \NHBOC
I‘x/ K‘J
132 133
Br SH
SAN/I =grams , $AN/,ixi'AI/ :omoms _______________,.,,
"-9“ ! : :
GNNHBQC @NHBCC
0 Cl
\\ /\
S, O Q Sf’k}.../\
/~\M
NR! 0 #82)” NA:( 0
\ f)‘# “rams ./=\ ,
”x —b~
N }~‘NM\
., /\ ”,BOC S)\N ,R x
/b " I“; r.‘ «80c H
/ I $21 <\_,.
138 138
[fail/fl O REV/Syria? \ls I}:
/3/ ‘N \ as N\ 45.1.!" NH NOW], "Jh
—*" ’l
x l‘d i’
aw w /~ <’ fiso I ,J
/ L \
Patent: W02015/180642 A1, 2015 ;
on in patent: aph 00%; 00160 XN‘K
139 LN/
140 141 '\ 142
Scheme 19
Scheme 19 provides a synthetic preparation of compound 142 of Formula III. First
aldehyde 127 and carboxylic acid 128 are reacted as described in the Journal of Heterocyclic
Chemistry to afford compound 129. Compound 129 is oxidized to 130 and then subsequently
alpha brominated to bromide 131. Bromide 131 undergoes nucleophilic attack to afford cyano
species 132 and then subsequent reduction and protection to afford the carbamate protected
compound 133. Compound 133 is silyl ted to 134 and then dehalogenated to afford thiol
135. Thiol 135 is converted to ester 136 by reaction of an alpha brominated ester and then is
subsequently ected (137) and ed to ketone intermediate 138. Ketone 138
undergoes intramolecular cyclization to afford 140 which then is oxidized as known in the art
to sulfone 141. e 141 undergoes nucleophilic attack to afford compound 142.
Br B NW8?
{:0 uf"\ 14C DC /l
)LNJTT’‘- *'f1 NI; \5 ii O
‘N ’
/ mm—w /
+ er mm—abL s
\...../2
$ N l
/s OH 5
= .
Journal of Heterocyclic Chemistry, J
127 2003, voE.40, #2 {1219—224
129 130
N \g
I ,A,‘
x \ NHBoc
132 133
Ely OH
N,A\ Ni.\ 3/1ka Voraoms _,, SAN”; VOTBDMS 1,,
------------------an» q !
@NHBOC @NHBOC
('Jl Q
of?) O\ (3)0
£N:‘\/ O -0
o NEXT) 0
”a‘TBDMS _/=~. n
N OH x/Lpf‘f m...»
fix a ~ 4
/-.S N / NH
Bocr'Nl" &J
Patent: WOZMSHBOS—Q A1, 2015 : N"‘\
Location in patent: Paragraph 0099; 00100 ; L )-
147 148 149 N\ 15f)
Scheme 20
Scheme 20 es a synthetic preparation of compound 150 of Formula 111. First
aldehyde 127 and ylic acid 128 are reacted as described in the Journal of cyclic
Chemistry to afford compound 129. nd 129 is oxidized to 130 and then subsequently
alpha brominated to e 131. Bromide 131 undergoes nucleophilic attack to afford cyano
species 132 and then subsequent reduction and protection to afford the carbamate protected
compound 133. Compound 133 is silyl protected to 134 and then dehalogenated to afford
hydroxyl 143. Hydroxyl 144 is converted to ester 145 by reaction of an alpha brominated ester
and then is subsequently deprotected (146) and oxidized to ketone intermediate 147. Ketone
147 oes intramolecular cyclization to afford 148 which then is oxidized as known in the
art to sulfone 149. Sulfone 149 undergoes nucleophilic attack to afford compound 150.
N/.\‘~ NO;
iperoxide
NO Kr‘N i
N/W 2 N33 N‘WNOZ u N’WNOZ LDA,THF
\ A ('6‘ ,CN
[41 \JL/l \/“\/i 8 N
\ Br CN as
S N \ “S N’AV 8 NA“. Bioorganic&Medicinal N
Chemistry Letters 8 g
(1998) 205-208 /’
151 152 153 154
EtOt—i/HCI
55% j}
x» \q/JLM/ / "'1W ,.
c. .
COZEI
A‘s/ii
NF\‘\ [1’
[EMF/YER >650
)L r’ ’1,
.....................p. ‘N
\N L,I
\:=(
158 159
Scheme 21
Scheme 21 provides a synthetic preparation of compound 160 of Formula IV.
Commercially available nd 151 is brominated in a radical reaction to afford 152 which
then can be displaced by a philic source of cyano (such as potassium cyanide) to afford
cyano 153. Cyano 153 is then deprotonated as described in BMCL to afford alkene 154. Alkene
154 is coupled with a metal such as zinc to afford ester 155, Ester 155 is then reduced with
another metal (such as iron) to afford aniline 156. Aniline 156 then undergoes intramolecular
ation to afford pyrazolopyrimindine 157 which then undergoes a base catalyzed
intramolecular ation to afford the trifused cycle 158. nd 158 is then oxidized to
the sulfone 159 which is subsequently displaced with an appropriate amine in the presence of
an appropriate base to afford the final compound 160.
0 Benzoyl peroxide;
Na-ZDZEHE.0H+. F’EE')’\-3 -. :
. KLN/DMF3 Nx§ [\CN
—+v kw/ M35; N’N AB?
Cf, \nx—fl ELK: ’ ----------------------I» :I ——» I ,
‘ ' healing \
~3... \s N“ ‘cs N‘s/«N ‘0; \s ‘N‘ CI
161 EP1754708 7 “=2 153
164 165
oozzve
H;N /’
>‘x NWA‘C‘N Nb“ \
\s’l‘V‘V‘WH it PM” /\ \
’ N, 3"“ ”‘3'“ ”202
~. ! CI5 ~ \QAN/- c‘’0245M .eaun ' mm
’ ‘, itmg
\COZMe ”' [K’X<V \s N
[M vI <,2? “M \ I
Agricultural and Biological
Chemistry, 1981 vol 45.
165 , 157
#9 p. 2031 -2035 "63
, ~
\g \N N u -------------x» 13w. ;—o
\ I} (/‘N < /
169 u) we
Scheme 22
Scheme 22 provides a synthetic preparation of compound 170 of Formula V.
Commercially available reagent 161 is ted to base and head as described in EP1754706
to afford 162. Compound 162 is then chlorinated as known in the art to afford 163. Compound
163 undergoes bromination in a radical reaction to afford bromide 164. Bromide 164 undergoes
nucleophilic attack with a cyano source (such as ium cyanide) to afford cyano 165.
Cyano 165 is subjected to an amine to afford 166 and then intramolecular cyclization s
167 as known in the art. Compound 167 undergoes intramolecular cyclization again to afford
168 then subsequent oxidation to afford 169. The selectivity of the oxidation can be controlled
by choice of reagents. Sulfone 169 is then displaced in a philic SNAr type reaction to
afford 170.
172 17:
PG PG H
I N
fq‘ \
\ \ i\l
\: h "O
\Ffo N =0 /\ N
N2 J —: 1.: N \\
~—» /~ N 3
C! I N HNH <
V ‘37 R‘ 3-
174 175 176
Scheme 23
Scheme 23 provides an alternative synthetic preparation of compounds of Formula V.
NC COGEt. _ coca 0
COQH
C H/N HM________“j '
BOG b 'I' \
BOG O 0——
--------»» é mun—a» “mun—«n» ---------------->—
17? 17g
Helvetica Chimica Acta,
1998,voi.81,#12 0A
312218-2243
O O
O I
I ‘~.
o W\ . 0
HN [TR
HM NHZNHZH20
“‘ ’
/ Nap; HN o EtOH Hw—
Boo / x
—-n- Boc -------------------.3» Soc. ----—--»
rap-1475094; (2004);
131 182 133
N OH
\ ‘3’
HMwkm-
"W,”fir/go ,N\
HN "szN
HN‘ —
. P0013
______________.,
305' x ' ‘ ”
NHz /
a Hill->4 Him—u N a,»
0C a.
1”\2 Boo
V \l
wozo 1 0/43633; (2010)
184 135 186
N 11 JL NH
HN N . / [‘1‘]
:H‘: HN Ni‘r/QN PD; .——
A v
«— A I/
HM dkA,“ ~ N 5/ ———> HQN N s” ——» :N
\ >
l l s \
l\v/l K/ \
18'? 188 139
N )L
"N er. A
,Nm NH ,9” ,
193 191
Scheme 24
Scheme 24 provides a tic preparation of compound 191 of Formula XV.
Compound 177 undergoes reduction of the cyano group followed by protection of the resultant
amine to afford protected compound 178. nd 178 is saponifled (typically by sodium
hydroxide) to afford compound 179. Compound 179 is converted to the Weinreb amide 180 by
reaction of the Weinreb salt and an excess of base, or alternatively by coupling the Weinreb
salt in the presence of HATU or a similar reagent. The Weinreb amide is then reacted with a
nucleophilic methyl source, such as methyl lithium or methyl magnesium bromide to afford a
ketone 181. Ketone 181 is deprotonated and condensed to afford compound 182 which
undergoes uent cyclization with hydrazine to form pyrazole 183 which undergoes
uent lation of a nitro group to afford compound 184. Compound 184 is reduced to
amine 185 as performed in W02010/43633 which is then cyclized to afford 186. Compound
186 is chlorinated with any suitable reagent (such as POCl3) to afford chloride 187. Chloride
187 is then dehalogenated with a proton source to afford 188. Compound 188 is coupled to an
appropriate acid and then undergoes olecular cyclization to afford compound 189.
Compound 189 is oxidized to compound 190 and undergoes subsequent nucleophilic attack to
afford compound 191.
IX. EXEMPLARY COMPOUNDS
WO 05860
WO 05860
WO 05860
WO 05860
WO 05860
WO 05860
WO 05860
WO 05860
WO 05860
WO 05860
WO 05860
0 s
N N
N “N
N f N N / N / Jim/4
N m NH
)ELN/ )LN/ )&N
HN HN “N
N N N
/ \ / \ / \
x \7/
X. EXAMPLES
General Methods:
1H NMR spectra were recorded on a 300 MHz Fourier transform Brt'rcker spectrometer.
Spectra were obtained from samples prepared in 5 mm diameter tubes in CDCl3, CD3OD or
DMSO-de. The spin multiplicities are indicated by the symbols 5 et), d (doublet), t
(triplet), m (multiplet) and, br (broad). Coupling constants (J) are reported in Hz. MS spectra
were obtained using electrospray ionization (ESI) on an Agilent Technologies 6120 quadrupole
MS apparatus. The reactions were generally d out under a dry nitrogen here using
Sigma-Aldrich anhydrous ts. All common chemicals were purchased from commercial
sources.
Compounds of the present invention with stereocenters are drawn ic for
convenience. One skilled in the art will recognize that pure enantiomers can be prepared by
methods known in the art. Examples of methods to obtain optically active materials include at
least the following.
i) physical separation of crystals—a technique whereby macroscopic ls of the
individual enantiomers are manually separated. This technique can be used if ls of the
separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are Visually
distinct;
ii) simultaneous crystallization—a technique whereby the dual enantiomers are
separately llized from a solution of the racemate, possible only if the latter is a
conglomerate in the solid state;
iii) enzymatic resolutions—a technique whereby partial or complete tion of a
te by virtue of differing rates of reaction for the enantiomers with an enzyme;
iv) enzymatic asymmetric synthesis—a synthetic technique y at least one step
of the sis uses an enzymatic on to obtain an enantiomerically pure or enriched
synthetic precursor of the desired enantiomer;
v) chemical asymmetric synthesis—a synthetic technique whereby the desired
enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry
(i.e.; chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries;
vi) diastereomer separations—a technique whereby a racemic compound is reacted with
an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers
to diastereomers. The ing diastereomers are then separated by chromatography or
crystallization by virtue oftheir now more distinct structural differences and the chiral auxiliary
later removed to obtain the desired omer;
vii) first- and second-order asymmetric transformations—a technique whereby
diastereomers from the te equilibrate to yield a preponderance in solution of the
diastereomer from the desired enantiomer or where preferential crystallization of the
diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in
principle all the material is converted to the crystalline diastereomer from the desired
enantiomer. The desired enantiomer is then released from the diastereomer;
viii) kinetic resolutions—this que refers to the achievement of partial or complete
resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue
ofunequal reaction rates ofthe enantiomers with a chiral; non-racemic reagent or st under
kinetic conditions;
ix) enantiospecific synthesis from non-racemic precursors—a tic technique
whereby the desired enantiomer is ed from non-chiral starting als and where the
stereochemical integrity is not or is only minimally compromised over the course of the
synthesis;
x) chiral liquid chromatography—a technique y the enantiomers of a racemate
are separated in a liquid mobile phase by virtue of their differing interactions with a stationary
phase (including via chiral HPLC). The stationary phase can be made of chiral material or the
mobile phase can n an additional chiral material to provoke the differing interactions;
xi) chiral gas chromatography—a technique whereby the racemate is volatilized and
omers are separated by virtue of their differing interactions in the gaseous mobile phase
with a column containing a fixed non-racemic chiral adsorbent phase;
xii) extraction with chiral solvents—a technique whereby the enantiomers are separated
by virtue of preferential dissolution of one enantiomer into a particular chiral solvent;
xiii) transport across chiral membranes—a technique whereby a racemate is placed in
contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one
containing the racemate, and a driving force such as concentration or pressure differential
causes preferential transport across the ne barrier. Separation occurs as a result of the
non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to
pass through.
Chiral chromatography, including ted moving bed chromatography, is used in
one embodiment. A wide y of chiral stationary phases are commercially available.
e 1. Preparation of substituted 2-amin0pyridines.
l-Methyl(6-nitr0pyridyl)piperazine
MN/ \, / ’R
To 5-bromonitropyridine (4.93 g, 24.3 mmole) in DMF (20 mL) was added N—
piperazine (2.96 g, 1.1 eq) followed by the addition of DIPEA (4.65 mL, 26.7 mmole).
The contents were heated at 90 0C for 24 hrs. After the addition of ethyl e (200 mL),
water (100 mL) was added and the layers were separated. Drying followed by concentration
afforded the crude product which was purified on a silica gel column using (0-10%)
thanol.
1H NMR (DMSO- d6) 5 8.26 (s, 1H), 8.15 (1H, d, J = 9.3 Hz), 7.49 (1H, d, J = 9.4 Hz), 3.50
(m, 4H), 2.49 (m, 4H), 2.22 (s, 3H).
5-(4-Methylpiperazinyl)pyridinamine
"mm-"N/\/"“\M,N
To 1-methyl(6-nitro—3-pyridyl)piperazine 3.4 g in ethyl acetate (100 mL) and
ethanol (100 mL) was added 10% Pd/c (400 mg) and then contents stirred under hydrogen (10
psi) overnight. After filtration through Celite®, the solvents were evaporated and the crude
product was purified over silica gel using DCM/ 7N Ammonia in MeOH (0- 5%) to afford 5-
(4—methylpiperazinyl)pyridinamine (2.2 g).
lHNMR (DMso- d6) 5 7.56 (1H, d, J = 3 Hz), 7.13 (1H, m), 6.36 (1H, d, J = 8.8 Hz), 5.33 (brs,
2H), 2.88 (m, 4H), 2.47 (m, 4H), 2.16 (s, 3H).
Iert-Butyl 4-(6-aminopyridyl)piperazine—l-carboxylate
The compound was ed as described in A1.
To onitropyridine (1.2 g, 5.9 mmole) in DMSO (4 mL) was added 1-(4-
piperidyl)piperidine (1.0 g, 5.9 mole) and triethylamine (0.99 mL, 7.1 mole), The contents
were heated to 120 0C in a CEM Discovery microwave system for 3 hours. The crude reaction
was then loaded over a silica gel column and eluted with DCM/methanol (0—20%) to afford 2-
nitro[4-(1-piperidyl)—1-piperidyl]pyridine as an oil (457 mg).
1H NMR (600 MHz, DMSO-d6) 5 ppm 1.26 - 1.36 (m, 2 H) 1.43 (m, 6 H) 1.76 (m, 2 H) 2.37
(m, 5 H) 2.94 (t, J=12.74 Hz, 2 H) 4.06 (d, J=13.47 Hz, 2 H) 7.41 (dd, J=9.37, 2.64 Hz, 1 H)
8.08 (d, J=9.37 Hz, 1 H) 8.20 (d, J=2.64 Hz, 1 H).
5— [4-(1-Piperidyl)piperidyl]pyridin-Z-amine
-[4-(1-Piperidyl)piperidyl]pyridinamine was prepared in a manner similar to that
used in the synthesis of 5-(4-methylpiperazinyl)pyridinamine.
1H NMR (600 MHz, 6) 5 ppm 1.13 - 1.37 (m, 6 H) 1.40 - 1.63 (m, 6 H) 1.71 (m, 2 H),
2.24 (m, 1H) 2.43 (m, 2 H) 3.33 (d, J=12.30 Hz, 2 H) 5.31 (s, 2 H) 6.33 (d, J=8.78 Hz, 1 H)
7.10 (dd, J=8.78, 2.93 Hz, 1 H) 7.55 (d, J=2.64 Hz, 1 H). LCMS (E81) 261 (M + H).
4-[1-(6-Nitropyridyl)—4—piperidyl] morpholine
WCQH
4-[(6-Nitr0-pyridyl)--piperidyl] morpholine was synthesizedin a manner similar
to that used1n the synthesis of 2-nitro[4-(1-pipeIidyl)piperidy1]pyridine.
1H NMR (600 MHz, DMSO-d6) 5 ppm 1.41 (m, 2 H) 1.82 (m, 2 H) 2.42 (m, 5 H) 2.98 (t,
J=12.44 Hz, 2 H) 3.52 (s, 4 H) 4.04 (d, J=12.88 Hz, 2 H) 7.42 (d, J=9.37 Hz, 1 H) 8.08 (d,
J=9.08 Hz, 1 H) 8.21 (s, 1 H).
0rpholin0-l-piperidyl) pyridin-Z-amine
-(4-Morpholinopiperidyl)pyridinamine was prepared in a manner similar to that
used in the synthesis of5-(4-methylpiperaziny1)pyridinamine.
1H NMR (600 MHz, 6) 5 ppm 1.34 - 1.52 (m, 2 H) 1.78 (m, 2 H) 2.14 (m, 1 H) 2.43
(m, 4 H) 3.32 (d, J=12.30 Hz, 4 H) 3.47 - 3.59 (m, 4 H) 5.32 (s, 2 H) 6.34 (d, J=8.78 Hz, 1 H)
7.11 (dd, J=8.93, 2.78 Hz, 1 H) 7.47 - 7.62 (m, 1 H). LCMS (ESI) 263 (M + H).
4-[1-(6-Nitropyridyl)-4—piperidyl] thiomorpholine
,/ \ / 1
4-[(6-Nitro-3—pyridy1)-piperidy1] rpholine was synthesized in a manner
similar to that usedin the synthesis of 2—nitro[4-(1-piperidyl)piperidyl]pyridine.
1H NMR (600 MHz, DMSO-d6) 5 ppm 1.40 - 1.52 (m, 2 H) 1.71 (m, 2 H) 2.49 - 2.55 (m, 4 H)
2.56 - 2.63 (m, 1 H) 2.68 - 2.75 (m, 4 H) 2.88 — 2.98 (m, 2 H) 4.09 (d, J=13.18 Hz, 2 H) 7.42
(dd, J=9.22, 3.07 Hz, 1 H) 8.08 (d, J=9.37 Hz, 1 H) 8.20 (d, J=3.22 Hz, 1 H).
5-(4-Thiom0rpholin0-l-piperidyl) pyridin-Z—amine
-(4-Thiom0rpholin0piperidyl) pyridinamine was prepared in a manner similar
to that used in the synthesis of 5—(4-methylpiperaziny1)pyridinamine.
1H NMR (600 MHz, DMSO-d6) 5 ppm 1.47 - 1.59 (m, 2 H) 1.65 (m, 2 H) 2.22 - 2.38 (m, 1 H)
2.50 - 2.59 (m, 6 H) 2.68 - 2.82 (m, 4 H) 3.33 (d, J=12.00 Hz, 2 H) 5.31 (s, 2 H) 6.33 (d, J=9.08
Hz, 1 H) 7.10 (dd, J=8.78, 2.93 Hz, 1 H) 7.55 (d, J=2.64 Hz, 1 H). LCMs (ESI) 279 (M + H).
o(1-piperidyl)pyridine
2—Nitro(1-piperidyl) pyridine was synthesized in a manner similar to that used in the
synthesis of 2-nitr0[4-(1-piperidyl)piperidyl]pyridine.
1H NMR (600 MHz, DMSO-d6) 5 ppm 1.56 (m, 6 H) 3.49 (d, J=4.39 Hz, 4 H) 7.30 - 7.47 (m,
1 H) 8.02 - 8.12 (m, 1 H) 8.15 - 8.26 (m, 1 H).
-(1-Piperidyl)pyridin-2—amine
-(1-Piperidyl) pyridin-2—amine was prepared in a manner similar to that used in the
synthesis of 5-(4-methylpiperazinyl)pyridinamine.
1H NMR (600 MHz, DMSO-d6) 5 ppm 1.39 - 1.46 (m, 2 H) 1.51 - 1.62 (m, 4 H) 2.75 - 2.92
(m, 4 H) 5.30 (s, 2 H) 6.34 (d, J=8.78 Hz, 1 H) 7.09 (dd, J=8.78, 2.93 Hz, 1 H) 7.54 (d, J=2.93
Hz, 1 H). LCMS (E81) 178 (M + H).
itropyridyl) thiomorpholine
/ \ / \
r402
4-(6-nitropyridyl) thiomorpholine was synthesized in a manner similar to that used
in the synthesis of 2-nitro[4-(1-piperidyl)piperidyl]pyridine.
1H NMR (600 MHz, DMSO-d6) 5 ppm 2.56 - 2.69 (m, 4 H) 3.79 - 3.92 (m, 4 H) 7.43 (dd,
J=9.22, 3.07 Hz, 1 H) 8.10 (d, J=9.37 Hz, 1 H) 8.20 (d, J=2.93 Hz, 1 H).
-Thiomorpholinopyridin-Z-amine
3/ \N / \
-Thiomorpholinopyridin-Z-amine was ed in a manner similar to that used in the
synthesis of 5-(4-methylpiperaziny1)pyridinamjne.
1H NMR (600 MHZ, DMSO-d6) 5 ppm 2.59 - 2.73 (m, 4 H) 3.04 - 3.20 (m, 4 H) 5.41 (s, 2 H)
6.35 (d, J=8.78 Hz, 1 H) 7.10 (dd, J=8.78, 2.93 Hz, 1 H) 7.57 (d, J=2.64 Hz, 1 H). LCMS
(E81) 196 (M + H).
tert-Butyl (4R)(6-nitropyridyl)-2,5—diazabicyclo[2.2.1]heptane-2—carboxylate
tert—Butyl (4R)(6-nitropyridy1)—2,5-diazabicyclo[2.2. 1]heptane—2-carboxy1ate
was synthesized in a manner similar to that used in the synthesis of 2-nitro[4-(1-piperidy1)-
1-piperidyl]pyridine.
1H NMR (600 MHz, DMSO-d6) 5 ppm 1.33 (d, J=32.21 Hz, 11 H) 1.91 (m, 2 H) 3.15 (d,
J=10.25 Hz, 1 H) 3.58 (m, 1 H) 4.46 (m, 1 H) 4.83 (s, 1 H) 7.16 (s, 1 H) 7.94 (s, 1 H) 8.05 -
8.16 (m, 1 H).
tert-Butyl —(6-aminopyridyl)—2,S-diazabicyclo [2.2.1]heptane—2—carboxylate
131m
WO 05860
tert—Butyl (4R)(6-aminopyridyl)-2,5-diazabicyclo[2.2.1]heptanecarb0xylate
was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazin
yl)pyridinamine.
1H NMR (600 MHz, DMSO-d6) 5 ppm 1.31 (d, J=31.91 Hz, 11 H) 1.83 (m, 2 H) 2.71 - 2.82
(m, 1 H) 3.44 (ml H) 4.30 (d, 2H) 5.08 (s, 2 H) 6.35 (d, J=8.78 Hz, 1 H) 6.77 - 6.91 (m, 1 H)
7.33 (s, 1 H). LCMS (ESI) 291 (M + H).
N,N-dimethyl(6-nitropyridyl) piperidinamine
N,N—dimethyl(6-nitr0pyridyl)piperidinamine was synthesized in a manner
r to that used in the synthesis of 2—nitro[4-(1-piperidyl)piperidyl]pyridine.
1H NMR (600 MHz, DMSO-d6) 5 ppm 1.30 - 1.45 (m, 2 H) 1.79 (m, 2 H) 2.14 (s, 6 H) 2.33
(m, 1 H) 2.92 - 3.04 (m, 2 H) 4.03 (d, J=13.76 Hz, 2 H) 7.42 (dd, J=9.22, 3.07 Hz, 1 H) 8.04 -
8.11 (m, 1 H) 8.21 (d, J=2.93 Hz, 1 H).
—[4-(Dimethylamino)piperidyl] pyridin-Z—amine
>434}
-[-4(dimethylamino)- 1-p—iperidyl]pyridin-amine was preparedin a manner r to
that usedin the synthesis of 5-(4-methylpiperaziny1)pyridinamine.
1H NMR (600 MHz, DMSO-d6) 5 ppm 1.35 - 1.50 (m, 2 H) 1.69 - 1.81 (m, 2 H) 2,00 - 2.10
(m, 1 H) 2.11 - 2.22 (s, 6 H) 3.17 - 3.36 (m, 4 H) 5.19 - 5.38 (s, 2 H) 6.34 (d, J=8.78 Hz, 1H)
7.10 (dd, J=8.78, 2.93 Hz, 1 H) 7.55 (d, J=2.63 Hz, 1 H). LCMS (E81) 221 (M + H).
4-(6-Nitr0pyridyl) morpholine
fl/WKMU
4-(6-Nitropyridyl) morpholine was synthesized in a manner similar to that used in
the sis of 2-nitro[4-(l-piperidyl)piperidyl] pyridine.
S-Morpholinopyridin-Z-amine
,/"“\,/K
\/____
-Morpholinopyridinamine was prepared in a manner similar to that used in the
synthesis of 5-(4—methylpiperazinyl) pyridin—2—amine.
1H NMR (600 MHz, CHCl3-d) 5 ppm 2.91 - 3.00 (m, 4 H) 3.76 - 3.84 (m, 4 H) 4.19 (br. s., 2
H) 6.45 (d, J=8.78 Hz, 1 H) 7.12 (dd, J=8.78, 2.93 Hz, 1 H) 7.72 (d, J=2.93 Hz, 1 H).
-(4-Isobutylpiperazin-l-yl) n-Z—amine
{Q/___.\
1-Isobutyl(6-nitropyridyl)piperazine was synthesized in a manner similar to that
used in the synthesis of 2-nitro[4-(1-piperidyl)piperidyl]pyridine which was then
converted 5-(4-isobutylpiperazinyl)pyridinamine in a manner similar to that used in the
sis of 5-(4-methylpiperazinyl)pyridinamine.
1H NMR (600 MHz, CHCl3-d) 5 ppm 0.88 (d, J=6.73 Hz, 6 H) 1.71 - 1.84 (m, 1 H) 2.10 (d,
J=7.32 Hz, 2 H) 2.46 - 2.58 (m, 4 H) 2.97 - 3.07 (m, 4 H) 4.12 (s, 2 H) 6.45 (d, J=8.78 Hz, 1
H) 7.14 (dd, J=8.78, 2.93 Hz, 1 H) 7.75 (d, J=2.93 Hz, 1 H). LCMs (E81) 235 (M + H).
-(4-Isopropylpiperazin-l-yl) pyridin-Z-amine
/ t;
N142
H\.._/ m—
1-Isopropyl(6—nitropyridyl)piperazine was sized in a manner similar to that
used in the synthesis of 2-nitro[4-(1-piperidyl)piperidyl]pyridine which was then
converted to s0pr0pylpiperazinyl)pyridinamine in a manner similar to that used in
the synthesis of5-(4-methylpiperazinyl)pyridinamine.
1H NMR (600 MHz, CHCl3-a) 5 ppm 1.06 (d, J=6.44 Hz, 6 H) 2.59 - 2.75 (m, 5 H) 2.97 - 3.10
(m, 4 H) 4.13 (s, 2 H) 6.45 (d, J=8.78 Hz, 1 H) 7.15 (dd, J=9.08, 2.93 Hz, 1 H) 7.76 (d, J=2.93
Hz, 1 H). LCMS (E81) 221 (M + H).
-[(2R,6S)-2,6-Dimethylmorpholinyl]pyridin-Z-amine
Nit-12
(2S,6R)-2,6-Dimethyl(6-nitropyridyl)morpholine was synthesized in a manner
similar to that used in the synthesis of 2-nitro—5-[4-(1-piperidyl)piperidyl]pyridine which
WO 05860
was then converted to 5-[(2R,6S)-2,6-dimethylmorpholinyl]pyridinamine in a manner
similar to that used in the synthesis of 5-(4-methylpiperazin-l-yl)pyridinamine. 1H NMR
(600 MHz, CHCl3-a) 5 ppm 1.20 (d, J=6.44 Hz, 6 H) 2.27 - 2.39 (m, 2 H) 3.11 - 3.21 (m, 2 H)
3.70 - 3.84 (m, 2 H) 4.15 (s, 2 H) 6.45 (d, J=8.78 Hz, 1 H) 7.12 (dd, J=8.78, 2.93 Hz, 1 H) 7.72
(d, J=2.63 Hz, 1 H). LCMS (E81) 208 (M + H).
-[(3R,SS)-3,5-Dimethylpiperazin-l-yl]pyridin-Z-amine
HN N'QNH;
(3S,5R)-3,5-Dimethyl(6-nitropyn'dyl)piperazine was synthesized in a manner
similar to that used in the synthesis of 2-nitro[4-(1-piperidyl)-l-piperidy1]pyridine which
was then converted to 5-[(3R,5S)-3,5-dimethylpiperazinyl]pyridinamine in a manner
similar to that used in the synthesis of 5-(4-methylpiperazinyl)pyridinamine. 1H NMR
(600 MHz, CHCl3-d) 8 ppm 1.09 (d, J=6.44 Hz, 6 H) 2.20 (t, J=10.83 Hz, 2 H) 2.95 - 3.08 (m,
2 H) 3.23 (dd, J=l 1.71, 2.05 Hz, 2 H) 4.13 (s, 2 H) 6.45 (d, J=8.78 Hz, 1 H) 7.14 (dd, ,
2.93 Hz, 1 H) 7.73 (d, J=2.63 Hz, 1 H). LCMS (E81) 207 (M + H).
e 2: Compounds of the Present Invention:
Final Structure Name
1Cmpd # lO,10-dimethyl((5 -(4-
methylpiperazin- l -yl)pyridin
no)-6,6a,9, l O-tetrahydro—
5H-pyrazino[l',2': rido[2,3-
d]pyrimidine-5,7(8H)-dione
, l 0-dimethyl((5 -(4-
methylpiperazin- l -yl)pyridin
yl)amino)-6,6a,9,10-tetrahydro—
5H-pyrazino[1',2': l,6]pyrido[2,3-
d]pyrimidin-7(8H)-one
2'-((5-(4-methylpiperazin- l -
yl)pyridinyl)amino)—6',6a',8',9'-
tetrahydrospiro[cyclohexane-1,10'-
pyrazino[l ',2': l,6]pyrido[2,3-
d] pyrimidine] -5',7'-dione
Final Structure Name
Cmpd #
2'-((5-(4-methy1piperazin
y1)pyridiny1)amino)—6',6a',8',9'-
tetrahydrospiro[cyclohexane-1,10'-
pyrazino[1',2':1,6]pyrid0[2,3-
midin] -7'(5'H)-one
2'-((5-(4-methy1piperazin
y1)pyridin-Z-yl)arnino)-6‘,6a’,8',9'-
tetrahydrospir0[cyclopentane-
1,10'-
pyrazin0[1',2':1,6]pyrido[2,3-
d] pyrimidine] -5',7'-dione
6 2-((5-(4-methylpiperazin
y1)pyridiny1)amino)-6,6a,9,10-
ydro-SH-
pyrazino[1',2’:1,6]pyrido[2,3-
d]pyfimidine-5,7(8H)-dione
7 2-((5-(4-methylpiperazin
y1)pyridiny1)amino)-
6,6a,7,8,9,10-hexahydro-5H-
pyrimido[5,4-c]quinolizin-S-one
ethyl 2-((5-(4-methy1piperazin
y1)pyridinyl)amino)-5 -0XO-
6,6a,7,8,9,10-hexahydro-5H-
pyrimido[5,4-c]quin01izine
carboxylate
N—(S ethylpiperazin
yl)pyridinyl)—8',9'—
dihydrospiro[cyc10hexane-1, 10'-
pyrido[1,6-a:2,3-d']dipyrimidin]—
2'-amine
WO 05860
Example 3: Biological Data for Compounds of the Present Invention:
Biological Table 1
ical Table 2
F1nal Compound CDK7/CycH/
cmpd MATl
# ICso (uM)
Example 4. Preparation of Final Compounds
Scheme 25: Synthesis of 2'-((5—(4-Methylpiperazin-l-yl)pyridin-2—yl)amino)
-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1,2-e]purin]-6'-one (Compound 10)
NO~ NH
NO2 4 aim: 2
Cir: NaHC<33 N \
A / :1ch093
C! N NH NHjCi
St9;? 1 NH 8!ep?" HfilH StGD?‘
Bee Soc
193 194
\Njfiig/ /‘(“$ij
”(jfiH )3
NMP BINAF’
100 0t: M“
Step 4 Step 5
195 196 R:N/
CQMPGUND 10
Step 1: Synthesis of tert-Butyl ((1-((2-chloro-5—nitropyrimidin-4—
yl)amino)cyclohexyl)methyl)carbamate (193)
To a solution of 2,4-dichloronitropyrimidine (192, 3 g, 15.5 mmol), utyl ((1-
yclohexyl)methyl)carbamate (3.5 g, 15.5 mmol) in THF (20 mL) was added followed
by NaHCO3 (4.0 g, 47.6 mmol). After stirring at room temperature for 3 hours, the reaction
mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL). The organic
layer was separated and washed with brine, dried over MgSO4, filtered and concentrated in
vacuo. The resulting residue was purified by column chromatography to afford teIt-butyl ((1-
((2-chloronitropyrimidinyl)amino)cyclohexyl)methyl)carbamate (193, 3.5 g, 9.1 mmol).
MS : m/z 386 [M + H]+.
Step 2: Synthesis of tert—Butyl ((1-((5-aminochloropyrimidin
yl)amin0)cyclohexyl)methyl)carbamate (194)
To a solution of tert-butyl ((1-((2-chloronitropyrimidinyl)amino)cyclohexyl)
methyl)carbamate (193, 3 g, 7.8 mmol) in EtOH (30 mL) was added Fe powder (6 g, 107 mmol)
and sat. aq. NH4Cl (1 mL). The reaction mixture was refluxed overnight. After cooling to room
temperature, the on mixture was filtered and the filtrate was concentrated to afford the
crude product, which was purified by column chromatography to afford tert—butyl ((1-((5—
aminochloropyrimidin yl)amino)cyclohexyl)methyl)carbamate (194, 2.2 g, 6.2 mmol).
MS (ESI+): m/Z 356 [M + H]+,
Step 3: sis of Methyl 2—((4-((1-(((tert-but0xycarbonyl)amin0)methyl)
exyl)amino)chloropyrimidin-S-yl)amino)—2—oxoacetate (195)
To a solution of tert-butyl ((1-((5-aminochloropyrimidinyl)amino)
cyclohexyl)methyl)carbamate (194, 2 g, 5.6 mmol) in THF (10 mL) was added methyl 2-
chlorooxoacetate (0.7 g, 5.7 mmol) and NaHCO3 (3 g, 35.7 mmol). After stirring at room
temperature for 4 h, the reaction mixture was quenched with H20 (20 mL) and extracted with
EtOAc (20 mL). The organic layer was separated and washed with brine, dried over MgSO4,
filtered and concentrated in vacuo. The resulting residue was purified by column
chromatography to afford methyl 2-((4-((1-(((tert-
butoxycarbonyl)amino)methyl)cyclohexyl)amino) chloropyrimidin-S-yl)arnino)-2—
tate (195, 2.5 g, 5.6 mmol). MS (ESI): m/z 442 [M + H]+.
Step 4: Synthesis of 2'-Chloro—7',8'-dihydr0-6'H-spiro[cyclohexane—
1,9'-pyrazino[l,2-e]purin]-6'-0ne (196)
A solution of methyl 2-((4-((1-(((tert—butoxycarbonyl)amino)methyl)cyclohexyl)
amino)chloropyrimidinyl)amino)oxoacetate (195, 1.5 g, 3.4 mmol) in NMP (50 mL)
was stirred at 100 0C for 5h. The on mixture was cooled to room temperature and purified
by column chromatography to afford 2'-chloro-7',8'- dihydro-6'H-spiro[cyclohexane-1,9'-
pyrazino[l,2-e]purin]—6'—one (196, 300 mg, 1.0 mmol). MS (ESI +): m/z 292 [M + H]+.
Step 5: Synthesis of 2'-((5-(4-Methylpiperazinyl)pyridinyl)amino) -7',8'-dihydro-
6'H-spiro[cyclohexane—1,9'-pyrazino[1,2-e]purin]-6'-one (COMPOUND 10)
Under N2 atmosphere, to a solution of 2'-chloro-7',8'-dihydro—6‘H- spiro[cyclohexane—
1,9'-pyrazino[l,2-e]purin]— 6'-one (196, 300 mg, 1.0 mmol), 5-(4-methylpiperazin-l-
yl)pyridin- 2-amine (193 mg, 1.0 mmol), a)3 (92.23 mg, 0.1 mmol) and BINAP (125.4
mg, 0.2 mmol) in toluene (25 mL) was added LHMDS (1.5 mL, 1 M in THF). The reaction
mixture was kept at 100 °C overnight. After g to room temperature, the reaction mixture
was quenched with water (25 mL) and extracted with EtOAc (25 mL). The organic layer was
separated and concentrated in vacuo. The resulting e was purified by prep TLC to provide
2'-((5—(4-methylpiperazin-1—yl)pyridiny1) amino)—7',8'-dihydro-6’H—spiro[cyclohexane-1,9'—
pyrazino[l,2-e]purin]—6'—one (COMPOUND 10, 1.1 mg, 0.0025mmol). MS (ESI +): m/Z 448
[M + H]+, 1H NMR (300 MHz, MeOD ): 5 8.05 - 7.95 (m, 2H), 7.86 (d, J: 9.0 Hz, 1H), 7.49
(d, J: 8.4 Hz, 1H), 4.03 (s, 2H), 3.28 - 3.22 (m, 4H), 3.08 - 2.91 (m, 2H), 2.78 - 2.70 (m, 4H),
2.42 (s, 3H), 1.82 - 1.70 (m, 5H),1.47 - 1.39 (m, 3H).
Scheme 26: Synthesis of 2aR)((5-(4-Methylpiperazinyl)pyridin
yl)amino)-1,3,4,4a,5,12a—hexahydropyrimido[5',4':4,5]pyrrolo[1,2—a]quinoxalin-
6(2H)—one (COMPOUND 22)
o OEt C OB
HQN \NH_ _>1 _/<
_ <1“a
hchoJ. H, HN N! HAUL , / N NH (Brecht)
z N \chuA
--------------------0» a» N\ ——---———;a» N\ r
~ N
THF N
DMF o) DMAF‘ DCM
Mao ’
_ Mes
step 1 _____ Step 2 Step 3
Step 4
137 198 199 200
O gm O
«BEE-113:»- QM. g O
_ ‘
le Tf o TEA2
' ' “Al/V
P" PM”H3151? “flail/w
4“!» NEoc .NBoc )1 #‘N NBoc
Mes N ---------------------a» V153)L~N4’“N- WW
~ Mes N
_____
GCN‘ DMF \
Step 5 Step ‘l
261 202 203
er” NH
Tt'A 0
All/t:- .
\ o
A‘T \ \j/F \ \t
0cm Mc,./\N¢L‘I\J W TN
q“ CpgA 0%)sz \N W LHMDS
.....................in» /:;\x . —----------h» h'\£
DCN‘: '3 toluene
) / ”N“
Step., ..... A)
_ _,
I Step 8 Step 9 /
__.,
204 235 Tank.»[\mN
commune 22
Step 1: sis of aR)-Octahydroquinoxalin-2(1H)-one (198)
To a mixture of (1R,2R)—cyclohexane-l,2-diamine (197, 1 g, 8.75 mmol) and NaHCO3
(2.2 g, 26.2 mmol) in THF (40 mL) at 0 0C was added a solution of methyl oacetate
(1.34 g, 8.75 mmol) in THF (20 mL) in se. After stirring at 0 °C for 2 h, the reaction
mixture was warmed to room temperature and stirred for an additional 1 h. The reaction mixture
was then quenched with water (40 mL) and extracted with EtOAc (50 mL X 2). The combined
organic phases were dried over MgSO4, filtered and concentrated in vacuo. The resulting
residue was purified by column tography to provide (4aR,8aR) -octahydroquinoxalin—
2(1H)-one (198, 700 mg, 4.54 mmol).
Step 2: Synthesis of Ethyl 2-(methylthio)((4aR,8aR)-3—oxooctahydroquinoxalin-1(2H)-
yl)pyrimidinecarboxylate (199)
To a solution of (4aR,8aR)-octahydroquinoxalin-2(1H)—one (198, 4.7 g’ 30.5 mmol) in
DMF (140 mL) was added ethyl chloro(methylthio)pyrimidine carboxylate (7 g, 30.1
mmol) and K2CO3 (12.6 g, 91.2 mmol). After stirring at 80 0C for 2 h, the reaction mixture was
cooled to room temperature, quenched with water (250 mL) and extracted with EtOAc (150
mL X 2). The combined organic phases were washed with water (100 mL x 2) and brine (100
mL). After concentration in vacuo, the resulting residue was purified by column
chromatography to afford ethyl 2-(methylthio)((4aR,8aR) oxooctahydroquinoxalin-
1(2H)-yl)pyrimidine—5—carboxylate (199, 7.6 g, 21.6 mmol) as a white solid. MS (ESI+): m/z
351 [M + H]+.
Step 3: Synthesis of tert—Butyl(4aR,8aR)—4-(5-(ethoxycarbonyl)
(methylthio)pyrimidinyl)oxooctahydroquinoxaline-1(2H)-carboxylate (200)
To a solution of ethyl 2-(methylthio)-4—((4aR,8aR)oxooctahydroquinoxalin-1
(2H)-yl)pyrimidinecarboxylate (199, 7.6 g, 21.6 mmol) in DCM (200 mL) was added BoczO
(7.1 g, 32.5 mmol) and DMAP (7.9 g, 64.7 mmol). After stirring at room temperature for 12 h,
the reaction mixture was quenched with water (250 mL) and extracted with DCM (100 mL x
2). The combined c phases were washed with water (50 mL), brine (50 mL), dried over
MgSO4, and concentrated in vacuo. The resulting residue was purified by column
chromatography to provide utyl(4aR,8aR)—4-(5 -(ethoxycarbonyl)
(methylthio)pyrimidinyl)oxooctahydroquinoxaline-l(2H)—carboxylate (200, 8,0 g, 17.7
mmol) as a colorless oil. MS (ESI+): m/z 451 [M + H]+.
Step 4: Synthesis of tert-Butyl 12aR)hydroxy(methylthio) 0x0-
1,2,3,4,4a,12a-hexahydropyrimido[5',4':4,5]pyrrolo[1,2—a]quinoxaline-5(6H)-
carboxylate (201)
To a solution of tert-butyl (4aR,8aR)(5-(ethoxycarbony1)(methylthio)
pyrimidinyl)—2-oxooctahydroquinoxaline-l(2H)-carboxylate (200, 7.0 g, 15.5 mmol) in
THF (100 mL) at 0 °C was added DBU (3.5 g, 23.0 mmol). The on was gradually warmed
to room temperature. After stirring for 2 h, the reaction mixture was concentrated in vacuo.
The resulting e was purified by column chromatography to provide tert-butyl
(4aR, 12aR)hydroxy-l0-(methylthio)—6-oxo-1,2,3 ,4,4a,12a—
hexahydropyrimido[5',4':4,5]pyrrolo[l,2-a]quinoxaline-5(6H)-carboxylate (201, 4.8 g, 11.8
mmol) as a green solid. MS (ESI+): m/z 405 [M + H]+.
Step 5: Synthesis of tert-Butyl 2aR)-lO-(methylthi0)0xo(((
trifluoromethyl)sulfonyl)oxy)-1,2,3,4,4a,12a-hexahydropyrimido[5',4':4,5]pyrrolo[1,2-
a] quinoxaline-5(6H)-carboxylate (202)
To a solution of tert-butyl (4aR,12aR)hydroxy(methylthio)oxo-
1,2,3,4,4a, 1 2a-hexahydropyrimido [5',4' : 4,5] py rrolo[ 1 ,2-a] quinoxaline-5 (6H)—carboxylate
(201, 200 mg, 0.49 mmol) and Et3N (0.3 mL, 216 mmol) in DCM (5 mL) at 0 °C was added
Tf20 (209 mg, 0.74 mmol). The reaction was gradually warmed to room temperature. After
stirring for 2 h, the reaction mxiture was concentrated in vacuo. The resulting residue was
purified by column chromatography to provide tert-butyl (4aR,12aR)—10-(methylthio)oxo—
rifluoromethyl)sulfonyl)oxy)-1,2,3,4,4a,12a—hexahydropyrimido[5',4':4,5]pyrrolo[1,2-
a] aline-5(6H)-carboxylate (202, 180 mg, 0.34 mmol). MS : m/Z 536 [M + H]+.
Step 6: sis of tert—Butyl (4aR,12aR)(methylthio)—6-oxo—1,2,3,4,4a,12a-
hexahydropyrimido [5',4' :4,5] pyrrolo[1,2—a] quin0xaline-5(6H)—carboxylate (203)
Under N2 atmosphere, to a solution of utyl (4aR,12aR)(methylthio)-6
-oxo(((trifluoromethyl)sulfonyl)oxy)-1,2,3 ,4,4a,12a-
hexahydropyrimido[5’,4':4,5]pyrrolo[1,2-a]quinoxaline-S(6H)—carboxylate (202, 250 mg, 0.47
mrnol) and Pd(PPh3)4 (54 mg, 0.47 mmol) in DMF (5 mL) was added Et3SiH (81.4 mg, 0.70
mmol). After stirring at 50 0C for 12 h, the reaction mixture was quenched with water (20 mL)
and extracted with EtOAc (10 mL X 3). The combined organic layers were washed with water
(5 mL x 2) and brine (5 mL), dried over MgSO4, and concentrated in vacuo. The resulting
e was purified by column chromatography to provide tert—butyl (4aR,12aR)—10-
lthio) oxo-1,2,3,4,4a,12a-hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxaline-
5(6H)-carboxylate (203, 70 mg, 0.18 mmol).
Step 7: Synthesis of (4aR,12aR)(Methylthio)-1,3,4,4a,5,12a-
hexahydropyrimido [5',4' :4,5] pyrrolo[1,2—a] quinoxalin-6(2H)-0ne (204)
To a solution of tert-butyl (4aR,12aR)(methylthio)oxo-1,2,3,4,4a,12a—
hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxaline-5(6H)—carboxylate (203, 70 mg, 0.18
mrnol) in DCM (1.5 mL) was added TFA (0.5 mL). After stirring at room temperature for 2 h,
the reaction mixture was neutralized with saturated aqueous NaHCO3 (20 mL) and extracted
with DCM (10 mL x 3). The combined organic phases were dried over MgSO4 and
concentrated in vacuo. The resulting residue was purified by column tography to
provide (4aR,12aR)(methylthio)-1,3,4,4a,5,12a-hexahydropyrimido[5',4':4,5]pyrrolo[1,2-
a] quinoxalin-6(2H)-one (204, 70 mg, 0.24 mmol).
Step 8: Synthesis of (4aR,12aR)(Methylsulfonyl)—1,3,4,4a,5,12a -
hexahydropyrimido [5',4' :4,5] pyrrolo[1,2—a] quinoxalin-6(2H)—0ne (205)
To a solution of (4aR,12aR)—10-(methylthio)-1,3,4,4a,5,12ahexahydropyrimido
:4,5]pyrrolo[l,2-a]quinoxalin-6(2H)-one (204, 70 mg, 0.24 mmol) in
DCM (5 mL) was added m—CPBA (126 mg, 0.73 mmol). After stirring at room temperature for
12 h, the on mixture was neutralized with saturated aqueous NaHCO3 (5 mL) and
extracted with DCM (10 mL X 2). The combined organic phases were dried over MgSO4, and
trated in vacuo. The resulting residue was purified by column chromatography to
provide (4aR,12aR)-lO-(methylsulfonyl)—l,3,4,4a,5,12a—
hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxalin-6(2H)-one (205, 30 mg, 0.09 mmol).
MS: m/Z 321 (MH+).
Step 9: Synthesis of (4aR,12aR)((5-(4-Methylpiperazinyl)pyridin-2 -yl)amino)—
1,3,4,4a,5,12a-hexahydr0pyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxalin-6(2H)—0ne
(COMPOUND 22)
To a on of 5-(4-methylpiperazin-l-yl)pyridinamine (180 mg, 0.94 mmol) in
toluene (10 mL) at 0 °C was added LHMDS (1.1 mL, 1.1 mol, 1 M in THF). After stirring at
0 0C for l h, a solution of (4aR,12aR)-lO-(methylsulfonyl)—l,3,4,4a,5,12a—
hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxalin-6(2H)-one (205, 300 mg, 0.94 mrnol) in
toluene (5 mL) was added. The reaction was kept at 80 0C for 12 h. After g to room
temperature, the reaction mixture was quenched with saturated aqueous NaHCO3 (5 mL) and
extracted with DCM (10 mL x 3). The ed organic phases were dried over MgSO4, and
concentrated in vacuo. The resulting residue was purified by column chromatography to
provide ((4aR,12aR)—10—((5 -(4—methylpiperazinyl)pyridin-2—yl)arnino)—1,3,4,4a,5,12a-
hexahydropyrimido[5',4':4,5]pyrrolo[1,2-a]quinoxalin-6(2H)-one (COMPOUND 22, 3.0 mg,
0.007 mmol). MS (ESI+): m/Z 433 [M + H]+, 1H NMR (300 MHz, MeOD + CDCl3): 5 9.35 (s,
1H), 8.69 (d, J: 8.1 Hz, 1H), 8.52 (d, J: 3.0 Hz, 1H), 7.95 (dd, J: 9.0, 3.0 Hz, 1H), 7.80 (s,
1H), 4.62 - 4.44 (m, 2H), 4.23 - 4.13 (m, 1H), 3.78 (t, J: 4.8 Hz, 4H), 3.25 (t, J: 4.8 Hz, 4H),
2.97 (s, 3H), 2.75 - 2.60 (m, 1H), 2.52 — 2.40 (m, 2H), 2.26 - 2.04 (m, 4H).
Scheme 27: Synthesis of (4aS,12aS)((5-(4-Methylpiperazinyl)pyridin
yl)amino)-1,3,4,4a,5,12a-hexahydropyrimid0[5',4':4,5]pyrrolo[l,2—a]quin0xalin-
6(2H)-one (COMPOUND 23)
197 Step 1 Step 2 Step 3
266 207 208
CH CT”
0 O . .
. fi_ ”"Ky ”W E13$1H, Den, :HF
—-—i9’- N\
}\ /N‘ )\\ 'TT’QQfF'EA
N NBGC
Pd(PPh)4
x. /L 1”
N PM, NEE-SC
Mes N , ——a» Mes (j WWW”
Step4 Step5
299 210
R \ O
)1 WNBQ"" ——"" Ti/YV \
N \ {/0
M 3 \s » ' w
e O NF
EECM Mes/\N R . DEAR/SK W
/ ‘b
0cm /
Step6 Step 7 \
211 212 213
N/l CAN-a\ N,“
LHMDS )5N
toiuene
, "fig
Step8 Na
R4.”'9
CGMPOUND 23
COMPOUND 23 was prepared according to the experimental procedure described in
Scheme 26 for the synthesis of COMPOUND 22. MS (ESI+): m/z 433 [M + H]+; 1H NMR
(300 MHz, MeOD + : 5 8.81 (s, 1H), 8.13 - 8.10 (m, 1H), 7.96 (d, J: 2.7 Hz, 1H),7.48
— 7.44 (m, 1H), 7.24 (s, 1H), 4.01 - 3.94 (m, 2H), 3.66 — 3.63 (m, 1H), 3.29 - 3.25 (m, 4H), 2.81
— 2.78 (m, 4H), 2.48 (s, 3H), 2.19 - 2.08 (m, 2H), 1.99 — 1.86 (m, 2H), 1.71 - 1.46 (m, 3H).
Scheme 28: Synthesis of (4aS,12aR)((5-(4-Methylpiperazinyl)pyridin
yl)amin0)—1,3,4,4a,5,12a—hexahydropyrimido[5',4' :4,5] pyrrolo[1,2—a] quinoxalin-6(2H)—
one (COMPOUND 24)
O o
0 “GE? C‘ 4
K2432; ,2? M”
-"- Nat-K303 N (Bog-20 /---- Oil-<0
HN NH NH N ----N New
--------------------o -----------;>» ,fu-N
>\__N :2 ——----——)a> /
\ J THF 3 S DMF a) DMAF‘, DOM
MesI . N 2””Rm
197 Steer Step? \_/ Step3 z”
214 215 216
OH on
O ”V1 0
DBU,TE-IF \ V N \ men«we;
——-)> )L. f' vaO‘ TEA \
‘ ‘ N/J‘N WPPM‘ \
N Nch N800
Step4 14128 N ,,
--------------------------iv» M63
new: '
""" Step5 Step6
217 218
O O
Pill/:TM /\ .0
N‘ \rw
TFA 1 ‘?i
.. .ANwN NH m-CPBA \NH
.-\:JCM~ 3::j -——a>» m,
DCM “C!
Step 7 Step 8 {:3
219 229 221
\i 31H
Ni \ NY ‘1
LHMDS K/
mm» HN
toluene [TN
,. /
ire-pg8.. K \\
\«NNV
commune 24
COMPOUND 24 was ed according to the experimental described in Scheme
26 for the synthesis of COMPOUND 22. MS (ESI+): m/z 433 [M + H]+; 1H NMR (300
MHz, MeOH + CDC13): 5 8.83 (s, 1H), 8.34 (s, 1H), 7.96 (s, 1H), 7.52 - 7.47 (m, 1H), 7.20
(s, 1H), 4.19 — 4.13 (m, 2H), 3.64 (s, 1H), 3.29 - 3.26 (m, 4H), 2.80 - 2.78 (m, 4H), 2.48 (s,
3H), 2.15 - 1.99 (m, 4H),1.95 - 1.83 (m, 3H).
Scheme 29: Synthesis of N-(S-(4-Methylpiperazinyl)pyridinyl)-5'H
-spir0[cyclohexane-1,6'-imidazo[2",1":3',4']pyrazino[1',2':1,5]pyrrolo[2,3—d]pyrimidin]-
9'-amine (COMPOUND 25)
wx, 8, ' we
rent/fl:\
HN 6; N2“-N \ ’
’ AIDA JN Orig» NW N”) TFA, toluene N J"
‘11'
/4::\1 j HCN (J HN
19 2 reflux
\/ N
reflux /
(134‘ Step4 ‘“-
42Mpg
Step 2
4 \ r, ,1
222 223 ND 25
Step 1: Synthesis of N6'-(2,2-Diethoxyethyl)—N2'-(5-(4-methylpiperazin-l-yl) pyridin
yl)-8'H-spir0 [cyclohexane- 1,9'-pyrazin0 [1',2' : 1,5] pyrrolo [2,3-d]pyrimidine] -2',6'-
diamine (223)
To a solution of N-(5-(4-methylpiperazinyl)pyridinyl)-6'-(methylthio)—8'H-
spiro[cyclohexane-1,9’-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-2’-arnine (222, 100 mg,
0.20 mmol) in toluene (5 mL) was added 2,2—diethoxyethanamine (100 mg, 0.37 mmol).
After stirring under reflux for 48 h, the reaction mixture was cooled to room temperature and
concentrated in vacuo. The resulting residue was purified by prep TLC to afford N6'—(2,2—
diethoxyethyl)-N2'-(5-(4-methylpiperazinyl)pyridinyl)-8'H-spiro[cyclohexane-1,9'-
pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]—2',6'—diamine (223, 70 mg, 0.12 mmol). MS
(ESI+): m/z 562 [M + H]+.
Step 2: sis of N-(S-(4-Methylpiperazinyl)pyridinyl)-5'H-spiro[cyclohexane-
l,6'-imidazo[2",1":3',4']pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-9'-amine
(COMPOUND 25)
To a solution of N6'-(2,2-diethoxyethy1)-N2'-(5-(4-methylpiperazinyl)pyridinyl)—
8'H-spiro[cyclohexane-l,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-2',6'-diamine (223,
65 mg, 0.11 mmol) in toluene (3 mL) was added TFA (3 drops). After ng under reflux for
1 h, the reaction mixture was cooled to room temperature and concentrated in vacuo. The
resulting residue was purified by prep TLC to afford N-(5-(4-methylpiperazinyl)pyridin
yl)-5'H-spiro[cyclohexane-1,6'-imidazo[2",1":3',4']pyrazino[1’,2':1,5]pyrrolo[2,3-
d]pyrimidin]—9'-amine UND 25, 6.9 mg, 0.015 mmol). MS (ESI+): m/Z 470 [M +
H]+;1H NMR (300 MHz, MeOD): 6 8.74 (s, 1H), 8.06 (d, J= 12.0 Hz,1H), 7.98 (d, J= 3.3 Hz,
1H), 7.58 (dd, J: 9.9, 4.2 Hz, 1H), 7.24 (d, J: 1.2 Hz, 1H),7.18(d,J=1.2 Hz, 1H), 7.04 (s,
1H), 4.55 (s, 2H), 3.41 - 3.37 (m, 4H), 3.16 - 3.12 (m, 6H), 2.73 (s, 3H), 1.95 - 1.86 (m, 5H),
1.75 - 1.44 (m, 3H).
Scheme 30: Synthesis of N-(5—(4—Methylpiperazinyl)pyridinyl)-8'HSpiro
hexane—1,9'-imidazo[2,1-h]pteridin]-2'-amine (COMPOUND 26)
NH \ N“
TFA Ni/‘jNH 2 2 N
N! \ glyoxa|,ElOH fl /‘;§
A / ” "MCI N N N
Cl N NH DCM CI N NH
80 OC ......f
'3” Step 1 ””2 Step 2
224 225 226
NAT)NNlN N
Pd/C Pd2(dba)3
t0 Uene| ONE/j *1N/ /\\ BINAP / N
N N n GNJN
Step 3 Step 4 N21
COMPOUND 26
Step 1: Synthesis of N4-(1-(Aminomethyl)cyclohexyl)chloropyrimidine—4,5-diamine
(225)
To a solution of tert—butyl ((1-((5 -aminochloropyrimidin
yl)amino)cyclohexyl)methyl)carbamate (224, 300 mg, 0.84 mmol) in DCM (10 mL) was added
TFA (3 mL). After stirring at room temperature for 2 h, the reaction mixture was neutralized
with saturated aqueous NaHCO3 and extracted with DCM (10 mL x 3). The combined organic
phases were dried over MgSO4, filtered and trated in vacuo to provide N4—(1—
(aminomethyl)cyclohexyl)—2-chloropyrimidine—4,5-diamine (225, 200 mg, 0.78 mmol), which
was used for the next step without r purification.
Step 2: sis of 2'-Chloro-6',8'-dihydro-5'H—spiro[cyclohexane-1,9'-imidazo[2,1-
h]pteridine] (226)
To a solution of N4—(l-(aminomethyl)cyclohexyl)chloropyrimidine-4,5-diamine
(225, 200 mg, 0.78 mmol) in EtOH (10 mL) was added glyoxal (113 mg, 0.?8 mmol). After
stirred at 80 0C for 2 h, the reaction mixture was concentrated in vacuo. The resulting residue
was purified by column chromatography to provide 2’-chloro-6',8'—dihydro-5’H-
spiro[cyclohexane-l,9'-imidazo[2,l-h]pteridine] (226, 80 mg, 0.29 mmol). MS (ESI+): m/Z 278
[M + H]+.
Step 3: Synthesis of 2'-Chloro-8'H-spir0[cyclohexane-l,9'—imidazo[2,1-h]pteridine] (227)
To a solution of 2'-chloro-6',8'-dihydro-5'H-spiro[cyclohexane-1,9'—imidazo[2,l-
h]pteridine] (226, 60 mg, 0.22 mmol) in e (5 mL) was added Pd/C (10 mg). After stirred
at 110 0C for 12 h, the reaction mixture was filtered. The filtrate was concentrated in vacuo.
The resulting residue was purified by column chromatography to provide 2'-chloro-8'H-
spiro[cyclohexane-l,9'-imidazo[2,l-h]pteridine] (227, 20 mg, 0.07 mmol). MS (ESI+): m/Z 276
[M + H]+.
Step 4: Synthesis of N-(S-(4-Methylpiperazinyl)pyridinyl)-8'H-spiro
[cyclohexane-1,9'-imidazo[2,1-h]pteridin]-2'-amine (COMPOUND 26)
Under N2 atmosphere, to a solution of 2'-chloro-8'H-spiro[cyclohexane-1,9'-
imidazo[2,1-h]pteridine] (227, 80 mg, 0.29 mmol), 5-(4-methylpiperazinyl)pyridinamine
(55 mg, 0.29 mmol), Pd2(dba)3 (26.4 mg, 0.03 mmol) and BINAP (35.2 mg, 0.06 mmol) in
e (20 mL) was added LHMDS (0.4 mL, 0.4 mmol). After stirred at 100 0C for 12 h, the
reaction mixture was cooled to room ature, quenched with water (10 mL) and extracted
with EtOAc (10 mL). The organic phase was separated and concentrated in vacuum. The
resulting residue was d by column chromatography to provide N-(5 -(4-methylpiperazin—
1-yl)pyridinyl)—8'H-spiro[cyclohexane- l idazo[2, l -h] pteridin]—2'—amine
(COMPOUND 26, 11.1 mg, 0.02 mmol). MS : m/z 432 [M + H]+, 1H NMR (300 MHz,
MeOD): 5 8.47 (s, 1H), 8.03 - 8.09 (m, 2H), 7.90 (s, 1H), 7.39 - 7.43 (m, 1H), 4.00 (s, 2H),
3.28 — 3.36 (m, 4H), 2.88 (d, J: 12.6 Hz, 2H), 2.76 - 2.82 (m, 4H), 2.49 (s, 3H), 1.68 - 1.89
(m, 5H), 1.28 - 1.47 (m, 3H).
Scheme 31: Synthesis of 2'-((5-(4-Methylpiperazinyl)pyridinyl)
amino)—5'H—spir0[cyclohexane-1,9'-imidazo[2,1—h]pteridin]-6'(8'H)—0ne (COMPOUND
42H-
229 {‘13 N \ NH2
7N /J\ /
it \ \ HI?! N NH
j NH
: .———'p~ .
/ ri/NN NH
C' N ”H ‘ i
Pesgmbab
”EH Q 6301;
BINAP, LHMDS
toluene, 110 °C (N
228 :3pr 1 KM 23:: 231
O H m
a: fig 0
N x V0 N f” / _
HN N HH 0 ~N NH )5“; ‘N
NH, W )‘N‘N J
HCVMeOH
/ N HN\ r DMSO H“;
\a ------------------------ m g m ”'>
Step3
. W)\ 100 c0 K2C03,E1C)H \g
[N] 80°C SfepS
l: l\j
N 232 Step4 i N), 233 {K
E \N [\l
\ commune 27 \
Step 1: Synthesis of tert—Butyl ((1-((2-((5-(4-methylpiperazinyl)pyridinyl)amino)—5-
nitropyrimidinyl)amin0)cyclohexyl)methyl)carbamate (230)
Under N2 atmosphere, to a mixture of tert-butyl 2-chloronitropyrimidin
Ul yl)amino)cyclohexyl)methyl)carbamate (228, 1.0 g, 2.6 mmol), 5-(4-methylpiperazin-l-
yl)pyridinamine (229, 0.6 g, 3.1 mmol), Pd2(dba)3(120 mg, 0.13 mmol), and BINAP (160
mg, 0.25 mmol) in toluene (30 mL) was added LHMDS (0.52 mL, 1 M in THF). The reaction
was kept at 100 0C overnight and was then quenched with water (50 mL) and extracted with
EtOAc (50 mL). The organic layer was separated and concentrated in vacuo. The resulting
residue was purified by column tography to afford tert—butyl ((1-((2-((5-(4—
methylpiperazin-l -yl)pyridinyl)amino)—5 -nitropyrimidin
yl)amino)cyclohexyl)methyl)carbamate (230, 400 mg, 0.74 mmol). MS : m/z 542 [M +
H]+.
Step 2: Synthesis of tert-Butyl 5-amin0((5-(4-methylpiperazin-l-yl) pyridin-2—
yl)amino)pyrimidinyl)amino)cyclohexyl)methyl)carbamate (231)
To a solution of tert-butyl ((1-((2-((5-(4-methylpiperazinyl)pyridinyl)amino)
nitropyrimidinyl)amino)cyclohexyl)methyl)carbamate (230, 180 mg, 0.33 mmol) in EtOH
(10 mL) was added Fe powder (200 mg, 3.57 mmol) and aqueous NH4Cl solution (1 mL). After
stirring under reflux overnight, the reaction mixture was cooled to room temperature, filtered
and concentrated in vacuo to afford the crude product, which was purified by column
chromatography to afford utyl 5—amino((5-(4-methylpiperazinyl)pyridin—2—
yl)amino)pyrimidinyl)amino)cyclohexyl)methyl)carbamate (231, 40 mg, 0.08 mmol). MS
(ESI+): m/Z 512 [M + H]+.
Step 3: Synthesis of N4-(1-(Aminomethyl)cyclohexyl)-N2-(5-(4-methylpiperazin
yl)pyridinyl)pyrimidine-2,4,5-triamine (232)
A on of tert-butyl ((1-((5-amino((5-(4-methylpiperazinyl)pyridin
yl)amino)pyrimidinyl)amino)cyclohexyl)methyl)carbamate (231, 270 mg, 0.53 mmol) in
sat. HCl/MeOH solution (5 mL) was stirred at room ature for 3 h. Then the mixture was
trated in vacuo. To the ing residue was added MeOH (5 mL) and K2C03 (300 mg).
The mixture was heated to reflux for 1 h. After cooling to room temperature, the mixture was
filtered and the filtrate was concentrated to afford N4-(1-(aminomethyl)cyclohexyl)—N2-(5 -(4-
methylpiperazinyl)pyridin-2—yl)pyrimidine-2,4,5-triamine (232, 180 mg, 0.44 mmol),
which was used for the next step without further purification. MS (ESI): m/z 412 [M + H]+.
Step 4: Synthesis of 2'-((5-(4-Methylpiperazinyl)pyridinyl)amino)—
dihydro-5'H—spiro[cyclohexane—1,9'-imidazo[2,1-h]pteridin]-6'(6a'H)—one (233)
To a mixture of N4-(1-(aminomethyl)cyclohexyl)-N2-(5-(4-methylpiperazin-l-
yl)pyridinyl)pyrirnidine-2,4,5-t1iarnine (232, 170 mg, 0.41 mmol), K2CO3 (300 mg, 2.17
mmol) in EtOH (3 mL) was added a solution of ethyl 2-oxoacetate (85 mg, 0.83 mmol) in
toluene (0.1 mL). After stirring at 80 °C for 2 h, the reaction mixture was filtered and the filtrate
was concentrated to afford the residue, which was purified by prep TLC to afford 2'-((5-(4-
methylpiperazinyl)pyridinyl)amino)-7', 8‘-dihydro-5'H-spiro[cyclohexane-1,9'-
imidazo[2,1-h]pteridin]-6'(6a'H)—one (233, 80 mg, 0.18 mmol). MS (ESI +): m/Z 450 [M + H]+.
Step 5: Synthesis of 2'-((5-(4-Methylpiperazinyl)pyridinyl)amino)— 5'H-
Spiro[cyclohexane—1,9'-imidazo[2,1-h]pteridin]-6'(8'H)—0ne (COMPOUND 27)
A solution of 2'-((5-(4-methylpiperazin-1—yl)pyridinyl)amino)-7',8'-dihydro-5’H—
spiro[cyclohexane-1,9'-imidazo[2,1-h]pteridin]-6'(6a'H)-one (233, 65 mg, 0.14 mmol) in
DMSO (2 mL) was kept at 100 °C for 6 h. After cooled to room temperature, the reaction
mixture was purified by prep TLC to afford 2'-((5-(4-methylpiperazinyl)pyridin-2—
yl)amino)-5'H-spiro[cyclohexane-1,9'-imidazo[2,1-h]pteridin]-6'(8'H)-one (COMPOUND
27, 6.1 mg, 0.014 mmol). MS (ESI +): m/z 448 [M + H]+, 1H NMR (300 MHz, DMSO-d6 +
D20): 5 8.04 (s, 1H), 7.97 (s, 1H), 7.93 (d, J: 9.6 Hz, 1H), 7.46 (d, J: 8.7 Hz, 1H), 3.91 (s,
2H), 3.10 - 3.05 (m, 2H), 3.05 - 3.03 (m, 2H), 3.00 - 2.96 (m, 2H), 2.84 - 2.76 (m, 5H), 2.02 -
1.96 (m, 2H),1.72 - 1.61 (m, 5H), 1.40 - 1.30 (m, 3H).
Scheme 32: Synthesis of 2'-((5-(4-Methylpiperazinyl)pyrimidinyl)
amino)-7',8'-dihydro-6'H—spir0[cyclohexane—1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-
d]pyrimidin]-6'-one (COMPOUND 28)
NH2 ”4
Pd2(dba)3, Pd(OAc)2, 11m~\ NH
NH’)
z- t--BL£ONa, N \N , )\N
A if
John—phos E H1“
/ {332002
——»- ——~»~ M K
W 1009(34811 N
Step1 ~
Br E 3 8119/32
234 235 {:4}
COMPOUND 28“
Step 1: Synthesis of 5-(4-Methylpiperazin-l-yl)pyrimidinamine (235)
Under N2 atmosphere, to a solution of 5-bromopyrimidin-2—amine (234, 2 g, 11.5
mmol) in toluene (200 mL) was added l-methylpiperazine (32 g, 3195 mmol), t-BuONa (1.8
g, 18.7 mmol), Pd2(dba)3 (520 mg, 0.57 mmol) and John-phos (680 mg, 2.28 mmol). After
stirred at 100 °C for 48 h, the reaction mixture was concentrated in vacuo. The resulting residue
was purified by column chromatography to provide 5-(4-methylpiperazin-1—yl)pyrimidin-2—
amine (235, 200 mg, 1.0 mmol). MS (ESI+): m/Z 194 [M + H]+.
Step 2: sis of 2'-((5-(4-Methylpiperazinyl)pyrimidinyl)amin0)- 7',8'-dihydro-
6'H-spiro[cyclohexane- yrazino[1 ',2' : 1,5] pyrrolo [2,3-d] pyrimidin] -6'-one
(COMPOUND 28)
Under N2 atmosphere, to a solution of ethylpiperazinyl)pyrimidinamine
(235, 13 mg, 0.07 mmol), 2'-chloro-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'—
pyrazino[l',2':1,5]pyrrolo[2,3-d]pyrimidin]—6'-one (20 mg, 0.07 mmol) in dioxane (40 mL) was
added Pd(OAc)2 (3 mg, 0.01 mmol), X-Phos (6 mg, 0.01 mmol) and CS2CO3 (45 mg, 0.14
mmol). After stirred at 100 0C for 4 h, the reaction mixture was cooled to room temperature,
quenched with water (20 mL) and extracted with EtOAc (10 mL X 3). The combined c
phases were dried over NazSO4, concentrated in vacuo. The resulting residue was purified by
prep TLC to provide 2'-((5-(4-methy1piperaziny1)pyrimidiny1)arnino)-7',8'-dihydro-6'H-
spiro[cyclohexane-1,9’-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6’-one (COMPOUND 28,
2.8 mg, 0.0063 mmol). MS : W2 448 [M + H]+, 1H NMR (300 MHz, MeOD): 5 8.89 (s,
1H), 8.40 (br s, 2H), 7.26 (s, 1H), 3.77 (s, 2H), 3.29 - 3.20 (m, 4H), 3.07 (t, J: 11.4 Hz, 2H),
2.80 - 2.72 (m 4H), 2.45 (s, 3 H), 2.00 - 1.90 (m, 2 H), 1.86 — 1.76 (m, 3 H), 1.60 - 1.47 (m,
3H).
Scheme 33: Synthesis of 2'-((5—(4-Methylpiperazinyl)pyridinyl)amino)—
6'H-spiro[cyclohexane—1,9'-pyrazino[ 1',2' : 1,5] pyrrolo [2,3-d] pyrimidine] (7'H)-
dione (COMPOUND 30)
NHZ I /
. éé/J\0Et
i O NH2 ------
\ /Z38 [:2 O
N N 'NH m N NH NH
J11 / / / 2
__;.. M
$1 N fii‘ H
NaHCCh, C. PdCb(PPh3h, >63,
DMfiq ' Cm.DWEA,THF
Step 1 Step 2
ALNM______< N \ \ [0
“fix g -----1”
or N N 0E HOAc, H20 l/L, / NaCEOZ,
TBAF Ci N
g Q§_ ”c: NaHgPO4
——-3P W
THF HZN Step 4 Step 5
Step3 Z
fi/Ndfflgr./ \ 4?
PfiOAm2, NH
9 X-phos, WM ”{2}
(if; (3329,03 HN Ir 0
/ twic
N NH
)an N /
#0 i6
\‘K‘
829,06
f N~
fi compouwnso
Step 1: Synthesis of Chloroiodopyrimidinyl)amino)cyclohexane
carboxamide (237)
2017/040093
To a solution 2,4-dichloroiodopyrimidine (236, 26 g, 94.6 mmol) and 1-
aminocyclohexane-l-carboxamide (15 g, 105.4 mmol) in DMAc (260 mL) was added NaHCO3
(33 g, 392.8 mmol). After stirring at 80 0C for 12 h, the reaction e was cooled to room
ature, quenched with water (700 mL) and extracted with EtOAc (300 mL x 3). The
combined organic phases were washed with water (200 mL X 2), brine (100 mL) and dried over
anhydrous NazSO4. After concentration, the resulting residue was purified by column
chromatography to provide 1-((2-chloroiodopyrimidinyl)amino)cyclohexane
carboxamide (237, 12 g, 31.5 mmol). MS (ESI+): m/z 381 [M + H]+.
Step 2: Synthesis of 1-((2-Chloro-S-(3,3-diethoxypropynyl)pyrimidin
yl)amin0)cyclohexane—l-carboxamide (239)
Under N2 atmosphere, to a solution of 1-((2-chloroiodopyrimidin-4—
yl)amino)cyclohexanecarboxarnide (237, 4 g, 10.5 mmol) and DIPEA (2.7 g, 20.9 mmol) in
THF (170 mL) was added CuI (200 mg, 1.05 mmol) and Pd(PPh3)2Clz (294 mg, 0.42 mmol).
After stirring at room temperature for 10 min, a solution of 3,3-diethoxypropyne (238, 1.6
g, 12.5 mmol) in THF (5 mL) was added in dropwise and the reaction was stirred at room
temperature for 12 h. After tration of the mixture in vacuo, the resulting e was
purified by column chromatography to provide 1-((2-chloro(3,3-diethoxypropyn
yl)pyrimidinyl)amino)cyclohexane-l-carboxamide (239, 2.4 g, 6.3 mmol). MS (ESI+): m/z
381 [M + H]+.
Step 3: Synthesis of 1-(2-Cloro—6-(diethoxymethyl)—7H-pyrrolo[2,3-d] pyrimidin
yl)cyclohexane—1-carboxamide (240)
To a on of 1-((2-chloro(3,3-diethoxypropynyl)pyrimidin
yl)amino)cyclohexane-l-carboxamide (239, 2 g, 5.25 mmol) was added TBAF (20 mL, 20
mrnol, 1M in THF). After stirring at 60 0C for 2h, the reaction mixture was cooled to room
temperature, quenched with water (70 mL) and extracted with EtOAc (50 mL x 3). The
combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The
resulting residue was purified by column chromatography to provide 1-(2-chloro-6—
oxymethyl)-7H-pyrrolo[2,3-d]pyrimidinyl)cyclohexanecarboxamide (240, 400
mg, 1.05 mmol). MS (ESI+): m/z 381 [M + H]+.
Step 4: sis of 1-(2-Chlor0formyl-7H-pyrrolo[2,3-d]pyrimidinyl) cyclohexane—
l-carboxamide (241)
To a solution of l-(2-chloro(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin
yl)cyclohexane—1-carboxamide (240, 800 mg, 2.1 mmol) in THF (4 mL) was added water (4
mL) and HOAc (4 mL). After stirring at 60 0C for 2h, the on mixture was ed with
saturated aqueous NaHCOa and extracted with EtOAc (100 mL x 3). The combined organic
phases were dried over , filtered and concentrated in vacuo. The resulting residue was
d by column chromatography to provide 1-(2-chloroformyl-7H-pyrrolo[2,3-
d]pyrimidinyl)cyclohexanecarboxamide (241, 527 mg, 1.72 mmol).
Step 5: Synthesis of 2'-Chloro-6'H-spiro[cyclohexane—1,9'-pyrazino[1',2':1,5]
pyrrolo[2,3—d]pyrimidine]-6',8'(7'H)-dione (242)
To a solution of hloroformyl-7H-pyrrolo[2,3-d]pyrimidinyl) exane-
l-carboxamide (241, 100 mg, 0.33 mmol) in t-BuOH (5 mL) and acetonitrile (1 mL) was added
NaH2P04 (405 mg, 3.38 mmol) and 2-methylbutene (183 mg, 2.6 mmol ). The reaction
mixture was brought to 0 0C was a solution ofNaC102 (405 mg, 4.48 mmol) in water (10 mL)
was added dropwise. After stirring at room temperature for 12 h, the reaction mixture was
extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine,
dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by
column chromatography to provide 2'-chloro-6'H-spiro[cyclohexane-1,9'-
pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-6‘,8'(7'H)-dione (242, 95 mg, 0.31 mmol).
Step 6: Synthesis of 2'-((5-(4-Methylpiperazinyl)pyridinyl)amino)- 6'H-
spiro[cyclohexane—1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-6',8'(7'H)-dione
(COMPOUND 30)
Under N2 atmosphere, to a solution of 2'-chloro-6'H-spiro[cyclohexane-1,9'-
pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-6',8'(7'H)—dione (242, 100 mg, 0.33 mmol), 5-(4—
methylpiperazinyl)pyridin-2—amine (76 mg, 0.4 mmol) in dioxane (5 mL) was added
Pd(OAc)2 (7.4 mg, 0.03 mmol), CszCO3 (320 mg, 0.98 mmol) and X-Phos (62 mg, 0.13 mmol).
The reaction was stirred at 100 °C for 12 h. After cooled to room temperature, the reaction
mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 2). The
combined organic phases were concentrated in vacuo. The resulting residue was purified by
prep TLC to prodive 2'-((5-(4-methy1piperazinyl)pyridin—2-yl)
amino)-6'H-spiro[cyclohexane-l ,9'-pyrazino[l',2': 1,5]pyrrolo[2,3-d] pyrimidine] -6',8'(7'H)-
dione (COMPOUND 30, 2.9 mg, 0.0063 mmol). MS : W2 461 [M + H]+, 1HNMR (300
MHz, MeOD + CDCl3): 5 8.93 (s, 1H), 8.34 (s, 1H), 8.02 (s, 1H), 7.48 - 7.42 (m, 2H), 3.32 —
3.21 (m, 6H), 2.93 - 2.84 (m, 4H), 2.55 (s, 3H), 2.30 - 2.15 (m, 2H), 2.13 - 2.02 (m, 2 H), 2.00
—1.91(m, 1H),1.91 -1.78(m,2H), 1.70 - 1.59 (m, 1 H).
Scheme 34: Synthesis of 4-Methylpiperazinyl)pyridin-2—yl)-6'H-
Spiro[cyclohexane—1,9'-pyrazin0[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-2'-amine
(COMPOUND 31)
H3N (2001-1 LAH H205
Step 1
243 244
801330
[“1sz NHBOC
/ THF /
245 246
Step3
N/aé‘Ii 1
(mi/E: “LC:E’JE‘N/ DSSS Mamn- CHAN/ '
NH NH
0.1““1‘”
Ci DMA DOM
80 °C
Step 1 Step 2
248 249
NHBQC
///—NHBQC245 \ \
TBAF} THF N
NHBOC TFA
N “ma" x / N mm»
\ / N0
PdCE2(PPh3}2 >~N N
00 Cn a C; DCM
CULTEA C.
Step 3 Step 4 0 Step 5
253 251
/ \\
/ \ Pd(OAc)2
N l‘ HN
iN fiszCO3
2» N
N. may,
h If M
Q; 1,4—dioxane \
"“5.
3399 5 CQMPOUND 31
252 {:1}
Step 1: Synthesis of (l-Aminocyclohexyl)methanol Intermediate (244)
To a solution of 1-aminocyclohexane—1-carboxylic acid (243, 10 g, 69.9 mmol) in
ous THF (300 mL) at 5 °C was added LiAlH4 (8 g, 210.5 mmol) in portions over 30
min. The reaction was then refluxed for 12 h. After cooling to 5 0C with an ice-bath, to the
reaction mixture was added 8 mL of H20, 8 mL of 15% NaOH s, followed by addition
of 16 mL of H20. After the completion of addition, the mixture was stirred for 30 min.
Anhydrous magnesium sulfate (20 g) was added. After stirring for 1h, the mixture was filtered
and the filter cake was washed with EtOAc (50 mL). The filtrate was concentrated to provide
(1 -aminocyclohexyl)methanol (244, 5.2 g, 40 mmol) as a yellow oil, which was used in the
next step without further purification. MS (ESI+): m/z 130 [M + H]+.
Step 1: Synthesis of tert—Butyl prop-Z-yn-l-ylcarbamate Intermediate (246)
To a solution of -yn-l-amine (245, 2.1 g, 38.2 mmol) in THF (30 mL) was added
(Boc)20 (15 g, 68.8 mmol ). After stirring at room temperature for 1 h, the reaction mixture
was concentrated in vacuo to afford the residue, which was purified by column chromatography
with a gradient elution of hexane (100%) to hexane (80%) and EtOAc (20%) to provide tert-
butyl propyn—l—ylcarbamate (246, 4.1 g, 26.4 mmol); 1H NMR (300 MHz, CDCl3): 5 4.70
(s, 1H), 3.85 (d, J: 3.0 Hz, 2H), 2.15 (t, J: 2.7 Hz, 1H), 1.38 (s, 9H).
Step 1: Synthesis of (1-((2-Chloro—5-iodopyrimidinyl)amino) cyclohexyl)methanol
(248)
To a on of 2,4-dichloroiodopyrimidine (247, 2.7 g, 9.8 mmol) in DMA (20 mL)
was added (1-aminocyclohexyl)methanol (244, 1.4 g, 10.8 mmol) and NaHCO3 (5 g, 59.5 mol).
The reaction was stirred at 80 °C for 4 h. After cooling to room temperature, the reaction
mixture was quenched with water (40 mL) and extracted with EtOAc (50 mL x 2). The
ed organic phases were concentrated in vacuo to afford the residue, which was purified
by column chromatography to afford (1 -((2-chloroiodopyrimidin-4—
yl)amino)cyclohexyl)methanol (248, 1.5 g, 4.1 mmol). MS (ESI): m/Z 368 [M + H]+.
Step 2: Synthesis of 1-((2-Chloro—5-iodopyrimidinyl)amino)cyclohexane
carbaldehyde (249)
To a solution of (l-((2-chloroiodopyrimidinyl)amino)cyclohexyl)methanol (248,
1 g, 2.7 mmol) in DCM (50 mL) at room temperature was added PCC (1.1 g, 5.1 mmol). After
stirring at room temperature overnight, the solid was removed. The filter cake was washed with
DCM (100 mL) and the te was washed with ted sodium bicarbonate solution (50
mL). The organic layer was separated and concentrated in vacuo to afford the residue, which
was purified by column chromatography with a gradient elution hexane (95%) and EtOAc (5%)
to hexane (80%) and EtOAc (20%) to provide 1-((2-chloroiodopyrimidin
yl)amino)cyclohexane-l-carbaldehyde (249, 0.3 g, 0.8 mmol), MS (E81 +): m/z 366 [M + H]*.
Step 3: Synthesis of tert—Butyl Chloro—4—((1-formylcyclohexyl)amino) pyrimidin-S—
yl)propynyl)carbamate (250)
Under N2 atmosphere, to a solution of 1—((2-chloroiodopyrimidin
yl)amino)cyclohexane-l-carbaldehyde (249, 300 mg, 0.8 mmol) and TEA (165 mg, 1.6 mmol)
in anhydrous THF (15 mL) at room temperature was added Cul (15.5 mg, 0.1 mmol) and
PdC12(PPh3)2 (28.7 mg, 0.04 mmol), followed by the addition of tert-butyl propyn-l-
ylcarbamate (246, 165 mg, 1.1 mmol) dropwise. After stirring at room temperature overnight,
the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL).
The c layer was separated and washed with brine, dried over MgSO4, filtered and
trated in vacuo to afford the crude product, which was purified by column
chromatography to provide tert-butyl (3-(2-chloro((1-formylcyclohexyl)amino)pyrimidin-
-yl)propyn-l-yl)carbamate (250, 165 mg, 0.4 mmol). MS (ESI) m/Z 393 [M + H]+.
Step 4: Synthesis of tert—Butyl ((2—chloro—7—(l-formylcyclohexyl)-7H-pyrrolo [2,3-
d]pyrimidinyl)methyl)carbamate (251)
To a on of tert-butyl (3—(2-chloro-4—((1-formylcyclohexyl)amino)pyrimidin—S-
yl)propynyl)carbamate (250, 800 mg, 2.0 mmol) in anhydrous THF (5 mL) was added
TBAF (12 mL, 12 mmol, 1 M in THF). The reaction was stirred at 60 °C for 1 h. After cooling
to room ature, the reaction mixture was quenched with H20 (10 mL) and extracted with
EtOAc (10 mL). The organic layer was separated and washed with brine, dried over MgSO4,
filtered and concentrated in vacuo to afford the crude product, which was purified by column
chromatography to afford tert-butyl((2-chloro(1-formylcyclohexyl)-7H-pyrrolo[2,3-
d]pyrimidinyl)methyl)carbamate (251, 370 mg, 0.94 mmol). MS (ESI +): m/z 393 [M + H]+.
Step 5: sis of 2'-Chloro—6'H—spiro[cyclohexane-1,9'-pyrazino
[1',2':1,5]pyrrolo[2,3—d]pyrimidine] (252)
To a solution of utyl ((2-chloro(1-formylcyclohexyl)-7H-pyrrolo[2,3-
d]pyrimidinyl)methyl)carbamate (251, 100 mg, 0.25 mmol) in DCM(1 mL) was added TFA
(3 mL). After stirring at room temperature for 2 h, the reaction mixture was neutralized with
ted sodium bicarbonate on (5 mL) and extracted with EtOAc (5 mL x 2). The
combined organic phases were concentrated in vacuo and purified by prep TLC to afford 2'-
chloro—6'H-spiro[cyclohexane—1,9'-pyrazino[1’,2':1,5]pyrrolo[2,3-d]pyrirnidine] (252, 55 mg,
0.20 mmol) as awhite solid. MS (ESI +): m/z 275 [M + H]+.
Step 6: Synthesis of N-(5-(4-Methylpiperazinyl)pyridinyl)—6'H-spiro [cyclohexane—
1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-2'-amine (COMPOUND 31)
Under N2 atmosphere, to a solution of 2'-chloro-6'H-spiro[cyclohexane-1,9'-
pyrazino[l',2':l,5]pyrrolo[2,3-d]pyrimidine (252, 100 mg, 0.36 mmol) and 5-(4-
methylpiperazin—1—yl)pyridin-2—amine (80 mg, 0.41 mmol) in anhydrous 1,4—dioxane (5 mL)
was added Pd(OAc)2 (40 mg, 0.18 mmol), X-phos (100 mg, 0.21 mmol) and CszCO3 (520 mg,
1.60 mmol). The reaction mixture was stirred at 110 °C overnight. After cooling to room
temperature, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc
(20 mL). The organic phase was separated and concentrated in vacuo to afford the residue,
which was purified by prep HPLC to e N-(5-(4-methylpiperazinyl)pyridinyl)—6'H-
spiro[cyclohexane-l,9'-pyrazino[1',2':l,5]pyrrolo[2,3-d]pyrimidin]—2'-amine (COMPOUND
31, 15.2 mg, 0.03 mmol). MS (ESI +): m/z 431 [M + H]+, 1H NMR (300 MHz, CDC13 ): 5 8.68
(s, 1H), 8.30 (s, 1H), 8.22 (d, J: 9.3 Hz, 1H), 7.96 (d,J= 2.7 Hz, 1H), 7.93 (s, 1H), 7.25 (dd,
J: 9.0, 3.0 Hz,1H), 6.55 (s, 1H), 4.00 (s, 2H), 3.17 - 3.14 (m, 4H), 2.83 (td, J: 13.5, 4.2 Hz,
2H), 2.62 - 2.59 (m, 4H), 2.34 (s, 3H), 1.82 - 1,72 (m, 6H), 1.59 - 1.46 (m, 2H).
Scheme 35: Synthesis of 2'-((5-(4-Methylpiperazinyl)pyridinyl)amino)
-6',7'-dihydro-8'H—spiro [cyclohexane— 1,9'-pyrazino[1',2':1,5]pyrrolo[2,3—d]pyrimidin]-
8'-0ne (COMPOUND 33)
NR l //¢/l\OF1_.
”/iLN/ ——aa~
C! Cl
Peep-(Pm); \
253 out, DIPEA THF >—N 254
Step 1
Ci:..
N> \
<0 N \
A /I \o
. i JL %g N/n HOAQ, HZO m NhZOHHLE k
>20E O N
0);. N—QH mum—w)» C: N N
"""""""""""" O
Step 4 ; EEOH, 80 CC
--—O
”’0 ”'W')flywlc
Slat) 5
255 257 258
Baptism,, \
Zn NWQQ’KNH\ / N
‘\ \ ,
mm.» X-phos, “N
“1= NH m 0 _
)‘rq\ i N- I .........,..
Step 6 ,
r 2W4 V
Ci 0 Step 7 N \\
(\ commune 33
Step 1: Synthesis of 2,4-Dichloro(3,3-diethoxypropynyl)pyrimidine (254)
Under N2 atmosphere, to a solution of 2,4-dichloro-S-iodopyrimidine (253, 1 g, 3.65
mmol) and DIEA (1.42 g, 10.99 mmol) in THF (20 mL) was added Cul (70 mg, 0.37 mmol)
and 3)2Cl2 (100 mg, 0.14 mmol). After stirring at room temperature for 10 min, a
solution of 3,3-diethoxyprop-1—yne (470 mg, 3.67 mmol) in THF (5 mL) was added. After
ng at room temperature for 12 h, the reaction mixture was quenched with water (20 mL)
and extracted with EtOAc (20 mL x 2). The combined organic phases were concentrated in
vacuo. The resulting residue was purified by column chromatography to provide 2,4-dichloro-
5-(3,3-diethoxypropynyl)pyrimjdine (254, 1.1 g, 4.0 mmol).
Step 2: Synthesis of Methyl 1-((2-chloro(3,3-diethoxyprop-l-yn-l-yl) pyrimidin-4—
n0)cyclohexanecarb0xylate (255)
A solution of 2,4-dichloro(3,3-diethoxypropynyl)pyrimidine (254, 600 mg,
2.18 mmol) and methyl ocyclohexanecarboxylate (336 mg, 2.14 mmol) and DIEA
(619 mg, 4.8 mmol) in DMAc (20 mL) was stirred at 60 °C for 12 h. After g to room
temperature, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc
(30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over NazSO4
and concentrated in vacuo. The ing e was d by column chromatography to
afford methyl 1 -((2-chloro(3,3-diethoxypropyn-l-yl)pyrimidin-4—
yl)amino)cyclohexanecarboxylate (255, 200 mg, 0.50 mmol).
Step 3: Synthesis ofMethyl 1-(2-chloro(diethoxymethyl)—7H-pyrrolo [2,3-d]pyrimidin-
7-yl)cyclohexane-l-carboxylate (256)
To a solution of methyl 1-((2-chloro(3,3-diethoxyprop—l-ynyl)pyrimidin-4—
yl)amino)cyclohexane-l-carboxylate (255, 50 mg, 0.13 mmol) in THF (1 mL) was added
TBAF (0.4 mL, 0.4 mrnol, 1M in THF). After ng at 60 °C for 2 h, the reaction mixture
was quenched with water (15 mL) and extracted with EtOAc (10 mL X 3). The combined
organic phases were dried over NazSO4, filtered and trated in vacuo. The resulting
residue was purified by column chromatography to provide methyl l-(2-chloro
(diethoxymethyl)-7H—pyrrolo[2,3-d]pyrimidinyl)cyclohexane-1—carboxylate (256, 20 mg,
0.05 mmol). MS (ESI+): m/Z 396 [M + H]+.
Step 4: Synthesis of Methyl 1-(2-chloroformyl-7H-pyrrolo[2,3-d]pyrimidin-7 -
yl)cyclohexane-l-carboxylate (257)
To a solution of methyl l-(2-chloro(diethoxymethyl)—7H-pyrrolo[2,3-d]pyrimidin—
7-yl)cyclohexane-l-carboxylate (256, 300 mg, 0.75 mmol) in THF (4 mL) was added water (4
mL) and HOAc (4 mL). After stirring at 60 0C for 2 h, the reaction mixture was quenched with
saturated aqueous NaHCO3 and ted with EtOAc (100 mL x 3). The combined organic
phases were dried over NazSO4 and concentrated in vacuo. The resulting residue was purified
by column chromatography to provide methyl 1-(2-chloroformyl- 7H-pyrrolo[2,3-
d]pyrimidinyl)cyclohexanecarboxylate (257, 250 mg, 0.78 mmol).
Step 5: Synthesis of Methyl (E)(2-chloro((hydroxyimino)methyl) rrolo[2,3-
d]pyrimidinyl)cyclohexane—l-carboxylate (258)
To a solution of methyl 1-(2-chloroformyl-7H-pyrrolo[2,3-d]pyrimidin
yl)cyclohexane-l-carboxylate (257 , 250 mg, 0.78 mmol) in EtOH (2 mL) at room temperature
was added hydroxylamine hydrochloride (107 mg, 1.54 mmol). After stirring at 80 °C for 30
min, the reaction mixture was quenched with water (15 mL) and extracted with EtOAc (10 mL
x 3). The combined organic phases were dried over NazSO4, filtered and trated in vacuo.
The resulting residue was purified by column chromatography to provide methyl (E)(2-
2017/040093
chloro((hydroxyimino)methyl)-7H-pyrrolo[2,3-d]pyrimidinyl)cyclohexane
carboxylate (258, 220 mg, 0.65 mmol). MS (ESI+): m/z 337 [M + H]+.
Step 6: Synthesis of 2'-Chloro-6',7'-dihydro-8'H-spir0[cyclohexane- 1,9'-
pyrazin0[1',2' : 1,5] pyrrolo [2,3—d] pyrimidin]-8'-one (259)
Under N2 atmosphere, to a solution of methyl (E)—1-(2-chloro
((hydroxyimino)methyl)-7H-pyrrolo [2,3 -d]pyrimidinyl)cyclohexanecarboxylate (258,
200 mg, 0.59 mmol) in EtOH (4 mL) was added saturated aqueous NH4Cl (8 drops) and Zn
power (193 mg, 2.95 mmol). After stirring at 80 0C for 2 h, the reaction mixture was cooled to
room temperature and filtered. The filtrate was concentrated in vacuo. The ing residue
was purified by column chromatography to provide 2'-chloro-6',7'-dihydro-8'H-
spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]—8'—one (259, 150 mg, 0.52
mmol). MS (ESI-): m/z 289 [M - H]'.
Step 7: Synthesis of 2'-((5-(4-Methylpiperazinyl)pyridinyl)amino)-6',7'-dihydro-
iro hexane—1,9'-pyrazino[1',2' : 1,5] pyrrolo [2,3—d] pyrimidin] -8'-one
(COMPOUND 33)
Under N2 atmosphere, to a solution of ethylpiperazin-l-yl)pyrimidinamine
(40 mg, 0.21 mmol), 2'-chloro-6',7'-dihydro-8'H-spiro[cyclohexane-1,9'-
pyrazino[1',2':l,5]pyrrolo[2,3-d]pyrimidin]—8'-one (259, 50 mg, 0.17 mmol) in dioxane (4 mL)
at room temperature was added CszCO3 (160 mg, 0.49 mmol), Pd(OAc)2 (4 mg, 0.02 mmol)
and X-Phos (16 mg, 0.03 mmol). After stirring at 100 °C for 12 h, the reaction mixture was
cooled to room temperature and quenched with water (10 mL) and extracted with EtOAc (10
mL x 2). The combined organic phases were concentrated in vacuo. The ing residue was
purified by prep TLC to provide 2'-((5-(4-methylpiperazinyl)pyridin-2—yl)amino)—6',7'-
dihydro-8‘H-spiro[cyclohexane—1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-8'—one
(COMPOUND 33, 4.6 mg, 0.01 mmol). MS : m/Z 447 [M + H]+; 1H NMR (300 MHz,
MeOD): 5 8.64 (s, 1H), 8.12 (d, J: 9.4 Hz, 1H), 7.99 (s, 1H), 7.59 (d, J: 9.6 Hz, 1H), 6.38 (s,
1H), 4.64 (s, 2H), 3.42 - 3.33 (m, 4 H), 3.23 - 3.13 (m, 6 H), 2.75 (s, 3H), 2.25 — 2.02 (m, 4H),
1.91 - 1.72 (m, 3H), 1.67 - 1.45 (m, 1 H).
Scheme 36: Synthesis of 2'-((5-(4—Methylpiperazinyl)pyridin-2—yl)amino)—2,3,5,6,7',8'-
hexahydr0-6'H-spiro[pyran-4,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one
(COMPOUND 34)
EEOH,
Q TMECN N NH2 NH
E ‘b H:N 2
Ti(O-iPr)4 NNz A; {Beqzo Bod-{N
MM ——-IB>’
Q Step 1 Step 2 Step 3 Q
250 251 262 253
E
N \ Sgfi‘h __ Pd(PPrt§)ZCEZ,
cafl‘w” CU” ”WA
NH NHBOC
_________'____T_______,,.,,
c: N\ /
Step 4‘ Step 5
264 (JP—N
()Et HOAC, NE \ \ Ne-CIOZ,
TBAF GEN/I\/\><O_____ H20 (ZN/[\N/ NaH2P04
N H
, . . ,,
SteP 6 , Ste 7 fr-
p- SteP 8
BocHN o
Boczi-EN \/0
267 263
270 CQMPQUND 34
Step 1: Synthesis of 4-Amin0tetrahydro-2H—pyrancarbonitrile (261)
Under N2 atmosphere, to a solution of Ti(O-iPr)4 (68 g, 239 mmol) in NH3/EtOH (300
mL) at room temperature was added tetrahydro-4H-pyranone (260, 20 g, 200 mmol). After
ng at 20 0C for 2 h, the reaction was cooled to -5 0C. TMSCN (20.6 g, 208 mmol) was
added dropwise and the on was continued to stir at -5 °C for 3 h. The reaction was then
warmed to room temperature and stirred for 12 h. The reaction mixture was quenched with
water (20 mL), d, and the filter cake was washed with EtOH (20 mL x 2). The filtrate
was concentrated in vacuo. The resulting residue was purified by column tography to
provide 4-aminotetrahydro-2H-pyrancarbonitrile (261, 20.8 g, 165 mmol) as ayellow oil.
Step 2: Synthesis of 4-(Aminomethyl)tetrahydro-2H-pyran-4—amine (262)
To a suspension of LiAlH4 (9.1 g, 240 mmol) in MTBE (120 mL) at room temperature
was added 4-aminotetrahydro-2H-pyrancarbonitrile (261, 10 g, 80 mmol). After stirring at
40 0C for 2 h, the reaction mixture was quenched with water (9.1 mL) and 15 % aqueous NaOH
(9.1 mL), followed by the addition of water (27.3 mL). After stirring for 1h, the mixture was
filtered and the filter cake was washed with MTBE (20 mL x 2). The filtrate was concentrated
in vacuo to provide 4-(aminomethyl)tetrahydro-2H-pyranamine (262, 6 g, 46.1 mmol),
which was carried forward in the next step without further purification.
Step 3: sis of utyl inotetrahydr0-2H—pyranyl)methyl)carbamate
(263)
Under N2 atmosphere, to a solution of 4-(aminomethyl)tetrahydro-2H-pyranamine
(262, 6 g, 46.1 mmol) in DCM (230 mL) at -78 °C was added BOC20 (8.5 g, 39 mmol) dropwise
over 1 h. After stirring at -78 °C for an onal 2 h, the reaction was gradually warmed to
room temperature. 1 M HCl was added to adjust pH = 5. The aqueous phase was extracted with
EtOAc (200 mL). The aqueous phase was collected and ed to pH = 10 with 15% aqueous
NaOH and extracted with DCM (200 mL x 3). The combined organic phases were dried over
Na2SO4, filtered and concentrated to provide tert-butyl ((4—aminotetrahydro-2H-pyran
yl)methyl)carbamate (263, 6.05 g, 26.3 mmol).
Step 4: Synthesis of tert-Butyl ((4-((2-chlor0iodopyrimidin-4—yl)amino) tetrahydro-
2H-pyranyl)methyl)carbamate (265)
To a solution of 2,4-dichloroiodopyrimidine (264, 8.7 g, 31.6 mmol) and tert-butyl
((4-aminotetrahydro-2H-pyranyl)methyl)carbamate (263, 5 g, 21.7 mmol) in DMAc (200
mL) was added NaHCO3 (11.1 g, 132 mmol). After stirring at 80 °C for 12 h, the on
mixture was ed with water (50 mL) and extracted with EtOAc (300 mL x 3). The
combined organic phases were washed with water (200 mL x 2) and brine (100 mL), dried over
Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by column
chromatography to provide tert—butyl ((4-((2-chloro-5—iodopyrimidin—4—yl)amino)tetrahydro-
2H-pyranyl)methyl) carbamate (265, 5.02 g, 10.7 mmol).
Step 5: Synthesis of utyl ((4-((2—chloro—S—(3,3-diethoxyprop-l-yn- 1-yl) pyrimidin-4—
yl)amino)tetrahydro-2H-pyran-4—yl)methyl)carbamate (266)
WO 05860
Under N2 atmosphere, to a solution of tert—butyl((4-((2-chloroiodopyrimidin
no) tetrahydro-ZH—pyran—4-yl) methyl)carbamate (265, 5.70 g, 12.2 mmol) and DIEA
(3.11 g, 24.1 mmol) in THF (170 mL) was added Cul (228 mg, 1.2 mmol) and Pd(PPh3)2C12
(342 mg, 0.49 mmol). After ng at room temperature for 10 min, 3,3-diethoxypropyne
(1.9 g, 14.8 mmol) in THF (5 mL) was added dropwise and the reaction was stirred at room
temperature for 12 h. The reaction was quenched with water (20 mL) and extracted with EtOAc
(20 mL x 2). The combined organic phases were concentrated in vacuo. The resulting residue
was d by column chromatography to provide tert-butyl ((4-((2-chloro(3,3-
diethoxyprop-l -ynyl)pyrimidinyl)amino)tetrahydro-2H-pyranyl)methyl)carbamate
(266, 5.03 g, 10.7 mmol). MS (ESI+): m/Z 469 [M + H]+.
Step 6: Synthesis of tert-Butyl ((4-(2-chloro(diethoxymethyl)—7H-pyrrolo [2,3-
d] pyrimidinyl)tetrahydro—2H-pyran-4—yl)methyl)carbamate (267)
To a solution of tert-butyl ((4-((2-chloro(3,3-diethoxypropyn yl)pyrimidin
yl)amino)tetrahydro-2H-pyranyl)methyl)carbamate (266, 4.90 g, 10.4 mmol) in THF (50
mL) was added TBAF (50 mL, 50 mol, 1 M in THF). After stirring at 65 °C for 2 h, the
on was cooled to room temperature and quenched with water (150 mL). The aqueous
solution was extracted with EtOAc (100 mL x 3). The combined organic phases were dried
over Na2S04, filtered and concentrated in vacuo. The resulting residue was d by column
chromatography to provide tert-butyl ((4-(2-chloro(diethoxymethyl)—7H-pyrrolo[2,3-
d]pyrimidinyl)tetrahydro-2H-pyranyl)methyl)carbamate (267, 1.8 g, 3.84 mmol). MS
(ESI+): m/Z 491 [M+Na]+.
Step 7: Synthesis of utyl ((4-(2-chloroformyl-7H-pyrrolo[2,3-d] pyrimidin
yl)tetrahydro—2H—pyran-4—yl)methyl)carbamate (268)
To a solution of tert-butyl -chloro(diethoxymethyl)-7H-pyrrolo[2,3-
d]pyrimidinyl)tetrahydro-2H-pyranyl)methyl)carbamate (267, 800 mg, 1.71 mmol) in
THF (4 mL) was added water (4 mL) and AcOH (4 mL). After stirring at 60 0C for 2 h, the
reaction e was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc
(100 mL x 3). The combined organic phases were dried over NazSO4 and concentrated in
vacuo. The resulting residue was purified by column chromatography to provide tert-butyl ((4-
(2-chloroformyl-7H-pyrrolo[2,3-d]pyrimidinyl)tetrahydro-2H-pyran
yl)methyl)carbamate (268, 527 mg, 1.33 mmol).
Step 8: Synthesis of tert—Butyl 2'-chloro-6'-oxo-2,3,5,6-tetrahydro-6'H- spiro[pyran-4,9'-
pyrazino[1',2':1,5]pyrrolo[2,3—d]pyrimidine]-7'(8'H)— carboxylate (269)
To a solution of tert—butyl -chloroformyl-7H-pyrrolo[2,3-d]pyrimidin
yl)tetrahydro—2H-pyranyl)methyl)carbamate (268, 200 mg, 0.51 mmol) in t-BuOH (5 mL)
and acetonitrile (1 mL) at 0 0C was added NaH2P04 (610 mg, 5.08 mmol) and 2-methyl-2—
butene (280 mg, 3.99 mmol). Then a solution of NaClOz (360 mg, 3.98 mmol) in H20 (3 mL)
at 0 0C was added dropwise. After completion ofthe addition, the reaction was warmed to room
temperature and stirred for 2 h. The reaction mixture was quenched with water (10 mL) and
extracted with EtOAc (30 mL x 3). The combined organic phases were dried over NazSO4,
d and concentrated in vacuo. The resulting residue was purified by column
chromatography to provide tert—butyl 2'-chloro-6'—oxo-2,3,5,6-tetrahydro-6'H-spiro[pyran-4,9’-
pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-carboxylate (269, 130 mg, 0.33 mmol).
Step 9: Synthesis of tert—Butyl 2'-((5-(4-methylpiperazinyl)pyridinyl) amino)—6'-
0x0-2,3,5,6-tetrahydro-6'H-spiro[pyran-4,9'-pyrazino[1',2':1,5]pyrrolo[2,3-
d]pyrimidine]-7'(8'H)—carboxylate (270)
Under N2 atmosphere, to a mixture of tert-butyl 2'-chloro-6'-oxo-2,3,5,6-tetrahydro—
6'H-spiro[pyran-4,9'—pyrazino[l',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-carboxylate (269,
mg, 0.05 mmol), 5-(4-methylpiperazin-l-yl)pyridinamine (11 mg, 0.06 mmol) and
C52CO3 (33 mg, 0.10 mmol) in e (2 mL) was added Pd(OAc)2 (1.1 mg, 0.005 mmol) and
X-Phos (9.6 mg, 0.02 mmol). The reaction was stirred at 100 0C for 12 h. After cooling to room
temperature, the on was concentrated in vacuo. The resulting e was purified by prep
TLC to provide tert-butyl 2'-((5-(4-methylpiperazin-1—yl)pyridinyl)amino)—6'-oxo—2,3,5,6-
tetrahydro-6'H—spiro[pyran-4,9‘-pyrazino[1',2': 1,5]pyrrolo[2,3-d] pyrimidine] -7'(8'H)-
carboxylate (270, 10 mg, 0.02 mmol). MS (ESI+): m/z 549 [M + H]+.
Step 10: Synthesis of 2'-((5—(4-Methylpiperazinyl)pyridinyl)amin0)-2,3,5,6,7',8'-
hexahydro-6'H-spiro[pyran-4,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one
(COMPOUND 34)
To a solution of tert-butyl 2'-((5-(4-methylpiperazinyl)pyridinyl)amino)—6'-oxo-
2,3,5,6—tetrahy H-spiro[pyran-4,9'—pyrazino[1',2': 1,5]pyrrolo[2,3-d] pyrimidine] —7'(8'H)—
carboxylate (270, 10 mg, 0.02 mmol) in DCM (3 mL) at 0 0C was added TFA (1 mL) dropwise
over 5 min. After stirring for 2 h, the reaction e was neutralized with ted aqueous
NaHCO3 and extracted with /DCM = 1/3 (20 mL x 2). The combined organic phases
2017/040093
were dried over NazSO4 and concentrated in vacuo. The resulting residue was purified by prep
TLC to provide 2'-((5-(4-methy1piperaziny1)pyridiny1)arnino)—2,3,5,6,7',8'—hexahydro-
6'H-spir0[pyran-4,9'—pyrazin0[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-0ne (COMPOUND 34,
.9 mg, 0.01 mmol). MS (ESI+): m/z 449 [M + H]+; 1H NMR (300 MHz, MeOD + CDC13): 5
8.83 (s, 1H), 8.26 (d, J: 9.1 Hz, 1H), 7.99 (d, J: 2.8 Hz, 1H), 7.63 (s, 1H), 7.53 (dd, J: 9.2,
2.8 Hz, 1H), 4.09 (dd, J: 120,48 Hz, 2H), 3.90 (s, 2H), 3.70 (t, J: 12.0 Hz, 2H), 3.47 (td, J
= 13.4, 5.1 Hz, 2H), 3.33
- 3.29 (m, 4H), 2.92 - 2.82 (m, 4H), 2.54 (s, 3H), 1.94 (d, J: 13.2
Hz, 2H).
Scheme 37: Synthesis of 2'-(((1R,4R)(4-(Cyclopropylmethyl)piperazin- 1-
yl)cyclohexyl)amino)—7',8'-dihydro-6'H-spir0[cyclohexane-1,9'-
pyrazin0[1',2':1,5]pyrrolo[2,3—d]pyrimidin]-6'-one (COMPOUND 36) and 2'-(((IS,4S)
(4-(Cyclopropy
l)piperazinyl)cyclohexyl)amino)—7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-
pyrazino[1',2':1,5]pyrrolo[2,3—d]pyrimidin]-6'-0ne (COMPOUND 40)
BrimN,‘
1128:, an— N, Bn"'N,' "‘
Pd/C, HZ
f K2503 "r‘ Dec < N”'\
____,_,.,
x <\ -—-'
< DCM a 1 —” 4‘ DMF ”4 Step 6
0H ‘0
2 OH
we” 1 5‘9” Z4 , ~N>
271 272 273 (\J‘
NaHB(QAc)3
Bog Bog DOM NIB”
{“3 8””
K2003 TFA ””3 Step5 > Pd/C, H;
I ------------------§ ———bv~
~NH {24>—- : ...................an».
' v4> DCM 1) new: “3 \fl
"4“ Step 7
274 Step 3 4 Step 4 <{ N ~\,, '
' < /
m N
275 2'36
278 >
\ 12 fl:— F—-» =
N\ NH
N N ,7 NB<<
f' ‘3‘ Q '
, HM,
\ ,J' /'r"“
'Na\7 231 \fl compouuo 36
K. ’
N» TEA, 51cm W“3
X , "N
279 Step8 §
9 4
m‘ \
N NH
\\ / N " o
~N TEA, EtOH y»
230 4:) Step 9 \_> commune 40
Step 1: Synthesis of (1R,4R)(Dibenzylamino)cyclohexan-l-ol (272)
To a solution of (1R,4R)—4-aminocyclohexanol (270, 30 g, 261 mmol) and K2CO3
(80 g, 575 mmol) in DMF (250 mL) was added benzyl bromide (44 g, 257 mmol) dropwise
over 30 min. After stirring at room temperature overnight, the reaction mixture was poured into
2 L of ice-water. The precipitated solid was collected, washed with water (2 x 100 mL) and
dried to provide (1R,4R)(dibenzylamino)cyclohexanol (272, 69.3 g, 234 mrnol ). MS
(ESI+): m/Z 296 [M + H]+.
Step 2: Synthesis of enzylamino)cyclohexan-l-one (273)
To a solution of )(dibenzy1amino)cyclohexanol (272, 40 g, 136 mmol) in
DCM (250 mL) was added PCC (75 g, 348 mmol) and silica gel (75 g). After stirring at room
temperature overnight, the reaction mixture was filtered. The filter cake was washed with DCM
(50 mL x 2) and the filtrate was washed with 100 mL of saturated sodium bicarbonate solution.
The c layer was ted and concentrated in vacuo. The resulting residue was purified
by column chromatography with a gradient elution of hexane (90%) and EtOAc (10%) to
hexane (75%) and EtOAc (25%) to provide 4-(dibenzylamino)cyclohexan-l-one (273, 25 g,
85 mmol). MS (ESI+): m/z 294 [M + H]+.
Step 3: Synthesis of tert—Butyl 4-(cycl0propylmethyl)piperazine-l-carboxylate
To a solution of teIt-butyl piperazine—l-carboxylate (274, 32 g, 172 mmol) and
(bromomethyl)cyclopropane (25 g, 185 mmol) in DCM (100 mL) at room temperature was
added TEA (20 mL, 144 mmol). After stirring at room ature for 48 h, the reaction
mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was
purified by column chromatography to afford utyl 4-(cyclopropylmethyl)piperazine
carboxylate (275, 30 g, 124 mmol). MS (ESI): m/Z 241 [M + H]+.
Step 4: Synthesis of 1-(Cyclopropylmethyl)piperazine (276)
To a solution of tert-butyl 4-(cyclopropylmethyl)piperazinecarboxylate (275, 30 g,
124 mmol) in DCM (100 mL) was added TFA (50 mL). After stirring at room temperature
overnight, the reaction mixture was neutralized with saturated sodium bicarbonate solution
(500 mL) and extracted with DCM (200 mL x 2). The combined organic phases were dried
over MgSO4, filtered and trated in vacuo to e 1—(cyc1opropylmethyl)piperazine
(276, 13 g, 92 mmol), which was used carried forward in the next step without further
purification. MS (ESI +): m/z 141 [M + H]+.
Step 5: Synthesis of (1R,4R)-N,N-Dibenzyl(4-(cyclopropylmethyl) piperazin-lyl
)cyclohexanamine (277) and (1S,4S)-N,N-Dibenzyl(4-
(cyclopropylmethyl)piperazinyl)cyclohexanamine (278)
To a solution of 4-(dibenzylamino)cyclohexanone (273, 5 g, 17.0 mmol) and 1-
(cyclopropylmethyl)piperazine (276, 2.4 g, 17.1 mmol) in DCM (30 mL) was added HOAc (1
mL). NaHB(OAc)3 (20 g, 94.4 mmol) was then added in portions. After stirring at room
temperature for 48 h, the reaction mixture was neutralized with saturated sodium bicarbonate
on and extracted with DCM (50 mL x 3). The combined organic phases were dried over
MgSO4 and concentrated in vacuo. The resulting residue was d by column
chromatography to afford (1r,4r)—N,N-dibenzyl(4-(cyclopropy1methyl)piperazin
yl)cyclohexanamine (277, 670 mg, 1.6 mmol) and (1s,4s)-N,N-dibenzyl(4—
(cyc1opropylmethyl)piperaziny1)cyclohexanamine (278, 1.2 g, 2.9 mmol).
(1R,4R)-N,N-Dibenzyl(4-(cyclopropylmethyl)piperazinyl)cyclohexan-1—amine
(277): 1H NMR (300 MHz, CDC13 ): 5 7.29 - 7.26 (m, 4H), 7.24 - 7.18 (m, 4H), 7.15 - 7.10 (m,
2H), 3.53 (s, 4H), 2.81- 2.60 (m, 6H), 2.44 - 2.36 (m, 2H), 2.29 (d, J: 6.6 Hz, 2H), 1.96 - 1.88
(m, 4H), 1.58 - 1.29 (m, 4H), 1.21 - 1.10 (m, 2H), 0.88 - 0.77 (m, 1H), 0.50 - 0.42 (m, 2H),
0.10 - 0.02 (m, 2H).
(1S,4S)-N,N-Dibenzyl(4-(cyclopr0pylmethyl)piperazinyl)cyclohexanamine
(278): 1H NMR (300 MHz, CDC13 ): 5 7.29 - 7.27 (m, 4H), 7.23 - 7.18 (m, 4H), 7.14 - 7.09 (m,
2H), 3.57 (s, 4H), 2.96 - 2.49 (m, 8H), 2.40 (d, J: 6.6 Hz, 2H), 2.20 (s, 1H), 1.89 - 1.85 (m,
2H),1.77 - 1.66 (m, 2H),1.48 - 1.44 (m, 2H),1.26 - 1.17 (m, 3H),1.00 - 0.82 (m, 1H), 0.55 -
0.49 (m, 2H), 0.16 - 0.11 (m, 2H).
Step 6: Synthesis of (1R,4R)(4-(Cyclopropylmethyl)piperazinyl)cyclohexan
amine (279)
To a solution of (1R,4R)-N,N—dibenzyl(4-(cyclopropylmethyl)piperazin
yl)cyclohexanamine (277, 500 mg, 1.2 mmol) in IPA (30 mL) was added Pd/C (10%, 200
mg). The reaction mixture was stirred at 40 °C under 1.8 MPa of hydrogen pressure for 24 h.
After completion of the reaction, the mixture was filtered and the filtrate was concentrated to
e (1R,4R)(4-(cyclopropylmethyl)piperazinyl)cyclohexanamine (279, 160 mg,
0.67 mmol). MS (ESI +): m/Z 238 [M + H]+.
Step 7: sis of )(4-(Cyclopropylmethyl)piperazinyl)cyclohexanamine
(280)
(1S,4S)(4-(cyclopropylmethyl)piperazinyl)cyclohexan-l-amine (280) was
prepared from (1S,4S)—N,N—dibenzyl(4-(cyclopropylmethyl)piperazinyl)cyclohexan
amine (278) according to the experimental procedure as described in Step 6 for the synthesis
of (1R,4R)(4—(cyclopropylmethyl)piperazinyl)cyclohexanamine (279). MS (ESI +):
m/z 238 [M + H]+.
Step 8: Synthesis of 2'-(((1R,4R)(4-(Cyclopropylmethyl)piperazin
yl)cyclohexyl)amino)-7',8'-dihydro-6'H-spir0[cyclohexane-1,9'-
pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one (COMPOUND 36)
To a solution of (1R,4R)(4-(cyclopropylmethyl)piperazin-l-yl)cyclohexan-l—amine
(279, 40 mg, 0.17 mmol) and 2'-chloro-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-
pyrazino[1',2’:1,5]pyrrolo[2,3-d]pyrimidin]—6’-one (280, 40 mg, 0.14 mmol) in 95% EtOH (5
mL) was added TEA (0.3 mL). The reaction was stirred in a sealed tube at 140 0C overnight.
After cooling to room temperature, the reaction mixture was concentrated to the e, which
was d by prep TLC to provide 2'-(((1R,4R)(4-(cyclopropylmethyl)piperazin
10hexy1)amin0)-7',8'-dihydr0-6'H-spir0[cyclohexane-1,9'-
pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]—6'-one (COMPOUND 36, 4.3 mg, 0.008 mmol).
MS (ESI +): m/z 492 [M + H]+;1H NMR (300 MHz, MeOD ): 8 8.60 (s, 1H), 7.11 (s, 1H), 3.73
(s, 2H), 3.73 - 3.72 (m, 1 H), 3.04 (td, J=13.5, 3.9 Hz, 4H), 2.89 - 2.75 (m, 4H), 2.33 - 1.79
(m, 10H), 1.56 - 1.28 (m, 11H), 1.09 - 1.00 (m, 1H), 0.71 - 0.68 (m, 2H), 0.36 (s, 2H).
Step 9: Synthesis of 2'-(((1S,4S)(4-(Cyclopropylmethyl)piperazinyl)
cyclohexyl)amin0)—7',8'-dihydr0-6'H-spiro [cyclohexane- 1,9'-
pyrazin0[1',2':1,5]pyrrolo[2,3—d]pyrimidin]-6'-0ne (COMPOUND 40)
2'-(((1 S,4S)(4-(cyclopropylmethy1)piperaziny1)cyc10hexy1)arnin0)-7', 8'-dihydro-
6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one
(COMPOUND 40) was prepared according to the procedure in Step 8 for the synthesis of
COMPOUND 36. MS (ESI +): m/z 492 [M + H]+; 1H NMR (300 MHz, MeOD): 5 8.62 (s, 1H),
7.12 (s, 1H), 4.04 (s, 1H), 3.73 (s, 2H), 3.04 (td, J =13.5, 3.6 Hz,4H), 2.86 — 2,80 (m, 4H), 2.18
— 2.10 (m, 3H),1.95 —1.78(m,10H), 1.60 — 1.46 (m, 3H), 1.39 —1.29(m, 5H),1.13 — 1.02
(m, 1H), 0.71 — 0.68 (m, 2H), 0.36 (s, 2H).
Scheme 38: Synthesis of 2'-(((1R,4R)—4-(4-Methylpiperazinyl)cyclohexyl)
amin0)-7',8'-dihydro-6'H—spiro hexane-1,9'-pyrazino[1',2' : 1,5] pyrrolo[2,3-
d]pyrimidin]-6'-one (COMPOUND 37) and 1S,4S)(4-Methylpiperazin-l-yl)
cyclohexyl)amin0)—7',8'-dihydr0-6'H-spiro hexane- 1,9'-
pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-0ne (COMPOUND 41)
Bar“,
W» LAH
<24» ,Bn Dd/C H2
BYVIN’ P
THF ~
For fr.»
" ’ Step2 Step4
286 \i
[Bn Boo / x)
EFFN, \,.N
r \
kféo Nat-ia(oAc:}3
232 Step 1 .2,”
an N
{3 F3”
Bn'"N
“My ..AH Z 2 Pd/C, H2
.......................4., —-----------§9>
235 LN ‘HF
Boc {N
Step3 \WN\ ,
orepor
£3 ""%EXI'E£6'§
"BK Step6 {W
{rm/14H Q
HAN Na />~t\l 1“”
"- O ’94-!” <‘>2.! -~ NH
231 N I
*8 ’ )‘t—N
N'”\
«a ) TEA, EtOH H?»
”N\ Step 7
CQMPGUND 41
LNN”)
Step 1: Synthesis of tert—Butyl ,4R)(dibenzylamino)cyclohexyl)piperazine
ylate (284) and tert—Butyl 4-((1S,4S)—4—(dibenzylamino)cyclohexyl)piperazine
carboxylate (285)
To a solution of 4-(dibenzylamino)cyclohexan-l-one (282, 5 g, 17.0 mmol) and tert-
butyl piperazine-l-carboxylate (283, 3.17 g, 22.6 mmol) in DCM (30 mL) was added HOAc
(1 mL). NaHB(OAc)3 (20 g, 94.4 mmol) was then added in portions After stirring at room
temperature for 48 h, the reaction mixture was neutralized with saturated sodium bicarbonate
solution and extracted with DCM (50 mL X 5). The combined organic phases were dried over
anhydrous MgSO4 and concentrated in vacuo. The resulting e was purified by column
chromatography to afford utyl 4-((1R,4R)—4-(dibenzylamino)cyclohexyl)piperazine
carboxylate (284, 400 mg, 0.86 mmol) and tert-butyl 4-((1S,4S)—4—
(dibenzylamino)cyclohexyl)piperazine-l-carboxylate (285, 1.4 g, 3.02 mmol).
tert-Butyl 4-((1R,4R)—4-(Dibenzylamino)cyclohexyl)piperazine—l-carboxylate: 1H NMR
(300 MHz, CDC13 ): 5 7.29 - 7.20 (m, 8H), 7.15 - 7.10 (m, 2H), 3.54 (s, 4H), 3.41 - 3.29 (m,
4H), 2.47 - 2.33 (m, 4H), 1.95 - 1.81 (m, 4H), 1.38 (s, 9H), 1.31 - 1.06 (m, 6H).
tert-Butyl 4-((1S,4S)(dibenzylamino)cycl0hexyl)piperazine-l-carboxylate: 1H NMR
(300 MHz, CDC13 ): 5 7.31 - 7.21 (m, 8H), 7.15 - 7.10 (m, 2H), 3.54 (s, 4H), 3.38 - 3.32 (m,
3H), 2.60 — 2.46 (m, 1H), 2.36 — 2.26 (m, 4H), 2.20 - 1.99 (m, 2H), 1.92 — 1.87 (m, 2H), 1.78 —
1.66 (m, 2H), 1.38 (s, 9H), 1.28 - 1.14 (m, 4H).
Step 2: Synthesis of (1R,4R)-N,N-Dibenzyl(4-methylpiperazinyl)cyclohexan
amine (286)
To a on of tert-butyl ,4R)(Dibenzylamino)cyclohexyl)piperazine
carboxylate (284, 900 mg, 1.94 mmol) in anhydrous THF (20 mL) under ice-water bath was
added LiAlH4 (300 mg, 7.90 mmol) in portions. After completion of the addition, the reaction
mixture was refluxed for 3 h. After cooling to room temperature, the mixture was quenched
with 0.3 mL of water, 0.3 mL of 15% sodium hydroxide aqueous solution, ed by the
addition of 0.6 mL of water. The mixture was stirred for 30 min. and 1 g of anhydrous
magnesium sulfate was added and the reaction was stirred for 1h. After filtration, the filter cake
was washed with EtOAc (30 mL x 2). The filtrate was concentrated to afford the residue, which
was d by a column chromatography with a gradient elution of EtOAc (100%) to EtOAc
(83%) and MeOH (16%) and NH3.H20 (1%) to provide (1R,4R)-N,N-dibenzyl(4-
methylpiperaziny1)cyclohexanamine (286, 500 mg, 1.32 mmol). MS (ESI +): m/z 378 [M
+ H]+.
Step 3: sis of (1S,4S)-N,N-Dibenzyl(4-methylpiperazinyl)cyclohexanamine
(287)
(lS,4S)-N,N-dibenzyl-4—(4-methylpiperazinyl)cyclohexanamine (287) was
prepared from 4-((1S,4S)(dibenzylamino)cyclohexyl)piperazinecarboxylate (285)
according to the experimental procedure of Step 2 for the synthesis of (1R,4R)-N,N-dibenzyl—
ethylpiperazin-l-yl)cyclohexan-l-amine (286) MS (ESI +): m/z 378 [M + H]+,
Step 4: Synthesis of (1R,4R)—4—(4-Methylpiperazinyl)cyclohexanamine (288)
(1R,4R)—4-(4-methylpiperazinyl)cy an-l-amine (288) was prepared from
(1R,4R)—N,N-dibenzyl(4-methylpiperazinyl)cyclohexanamine (286) according to the
experimental procedure for the synthesis of (1R,4R)(4-(cyclopropylmethyl)piperazin
yl)cyclohexan-l-amine (279, Scheme 37, Step 6). MS (ESI +): m/Z 198 [M + H]+.
Step 5: Synthesis of (1S,4S)(4-Methylpiperazin-1—yl)cyclohexan-1—amine (289)
(1S,4S)(4-methylpiperazinyl)cyclohexanamine (289) was prepared from
(1S,4S)-N,N—dibenzyl—4-(4-methylpiperazin—1-yl)cyclohexan—1-arnine (287) according to the
experimental procedure for the synthesis of (1R,4R)(4-(cyclopropylmethyl)piperazin
yl)cyclohexan—1-amine (279, Scheme 37, Step 6). MS (ESI +): m/z 198 [M + H]+.
2017/040093
Step 6: Synthesis of 2'-(((1R,4R)(4-Methylpiperazinyl)cyclohexyl)amino)—7',8'-
dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one
(COMPOUND 37)
2'-(((1R,4R)—4—(4-methylpiperazin-1—y1)cyclohexyl)amino)—7’,8'-dihy H—
spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]py1imidin]-6'-one (COMPOUND 37)
was ed from (1R,4R)(4-methylpiperaziny1)cyclohexanamine (288) according to
the experimental procedure for the synthesis of COMPOUND 36 as shown in Step 8, Scheme
37. MS (ESI +): m/z 452 [M + H]+,1H NMR (300 MHz, MeOD ): 5 8.60 (s, 1H), 7.11 (s, 1H),
3.73 (s, 2H), 3.73 - 3,68 (m, 1 H), 3.03 (td, J=13.2, 3.3 Hz, 4H), 2.67 (br s, 3H), 2.33 - 2,28
(m, 2H), 2.19 - 2.13 (m, 2H),1.96 - 1.92 (m, 2H), 1.83 - 1.79 (m, 3H), 1.57 - 1.36 (m, 9H),1.31
- 1.25 (m, 5H).
Step 7: Synthesis of 2'-(((1S,4S)—4-(4—Methylpiperazinyl)cyclohexyl)amino)-7',8'-
dihydro-6'H-spir0[cyclohexane-1,9'-pyrazin0[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one
(COMPOUND 41)
2'-(((1S,4S)(4-methylpiperaziny1)cyclohexy1)amino)-7',8‘-dihydro-6'H-
spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]py1imidin]-6'-one (COMPOUND 41)
was prepared from (1 4-(4—methylpiperaziny1)cyclohexanamine (289) according to
the experimental procedure for the synthesis of COMPOUND 36 as shown in Step 8, Scheme
37. MS (ESI +): m/z 452 [M + H]+;1H NMR (300 MHz, MeOD): 5 8.64 (s, 1H), 7.14 (s, 1H),
4.06 (s, 1H), 3.73 (s, 2H), 3.00 (td, J = 13.2, 3.9 Hz, 4H), 2.69 (br s, 3H), 2.21— 2.11 (m, 3H),
1.96 —1.74(m, 12H), 1.60 —1.47(m, 3H), 1.33 — 1.29 (m, 5H).
Scheme 39: Synthesis of (1S,4S)Methoxy-2'-((5-(4-methylpiperazin-l-yl)
pyridin-2—yl)amino)-7',8'-dihydr0-6'H-spiro[cyclohexane—l,9'-
pyrazin0[1',2':1,5]pyrrolo[2,3—d]pyrimidin]-6'-0ne (COMPOUND 38) and (1R,4R)—4-
Methoxy—2'-((5-(4-methylpiperazin-1—yl)pyridinyl)amin0)-7',8'-dihydr0-6'HSpiro
[cyclohexane— 1,9'-pyrazin0[1',2': 1,5] pyrrolo[2,3-d] pyrimidin]-6'-0ne
(COMPOUND 39)
TMSCN,
M43, EtOH,
Té(O-iPr)4
818,04
N\ NH
\ NH? '3
. NH
-- 2
LIAIH4. HzN‘ (800)20 BOCHN
“mm-##— ————b-
8:45:35 326536
O\ \ O\
294 295 296
2 OE:
N\ /)-----NH§-----NHBoc
>.....N - 3)ZCS2, m
c: CUE
BacHN N}Lr15] “NE-i;-----NHBQC
TEA,TI-{F (:1
Step8
298 3&0
./'“\ /
C! N h
L, EC)
29:7 OH
. Pd<PPh3)2C52,
N\ / Nag—wane Cu: _
>#N -
*- N\
/ ----- Ni—{s-"NHBOC
CI TEAIHF >-N ‘
299 i
,0 391
05: “1WD:
N \ \ CIANJA‘N H
A / Nauoz\. TBAF!
c,= N N "Et HOA‘ H 0c; 2 l
......................a... WHW ___,., BocHN «0/ ——as»
Stepg BQCHN K/{VO/ ”rep '0
Step 11
332 364
TBAr- N \ NI\E \ NaCIQ,
\ ----- Hem H20 m/J‘ ’?‘*N H
BocHN uh/
.0 o
I [i
:N \
_ _T‘ \
N MNBOC N 5...;
N“ O
x N
x Faro/Ac); )LN/ N /
\ x H/
.,/E\ / (352003: N
W W
C; N N \Boc x-phos \ I, TFA, DOM
(~ : ——a-- / ----------»~ [,4
N \ N \
Step 12 L2- 0\ Step 13 \N O
f- x
O N 3 31:28 N~~.
\ 396 < } commune 33
N ‘NN
\ \
L1 o
j: \ \ ..../< 1
paroxxmz, I
/\ \«l
[N \ N
Cl NBoc N N 052003, N806 NH
!Mr \____= N 2
JV“ __,.X‘ph°5 1111;” O\ ’7 k /
'1'FA,DCM L. ”"5“ \/
(,> N
~——Ha> HN
4"“ )
:T Kr/)>‘ 0
Step 1: sis of 1,4-Di0xaspiro[4.5]decanol (291)
To a solution of 1,4-dioxaspiro[4.5]decanone (290, 10 g, 64 mmol) in MeOH (100
mL) at 0 °C was added NaBH4 (4.8 g, 128 mmol) in portions. The reaction was gradually
warmed to room temperature. After ng for 12 h, aqueous NaOH (26 mL, 2 N) was added.
The mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was
purified by column chromatography to provide 1,4-dioxaspiro[4.5]decanol (291, 9.7 g, 61.3
mmol).
Step 2: Synthesis of 8-Methoxy-1,4-di0xaspiro[4.5]decane (292)
To a solution of 1,4-dioxaspiro[4.5]decanol (291, 9.7 g, 61.3 mmol) in THF (150
mL) at 0 °C was added NaH (4.3 g, 184.0 mmol) in ns over 1 h. CH3I (43 g, 306.5 mmol)
was added. After completion of the addition, the reaction mixture was d for 12 h. The
reaction mixture was then cooled to room temperature, quenched with saturated aqueous
NH4Cl and extracted with EtOAc (200 mL x 2), the combined organic phases were washed
with water (50 mL), dried over NazSO4, d and concentrated in vacuo to afford 8-methoxy—
1,4-dioxaspiro[4.5]decane (292, 12 g, 69.7 mmol), which was used in the next step without
further purification.
Step 3: Synthesis of 0xycyclohexan-l-one (293)
A mixture of 8-methoxy—l,4-dioxaspiro[4.5]decane (292, 12.0 g, 69.7 mmol) and p-
TsOH (1 g, 5.26 mmol) in H20 (300 mL) was stirred at 100 °C for l h. After cooling to room
temperature, the on mixture was extracted with EtOAc (100 mL X 2). The combined
organic phases were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated
in vacuo to provide 4-methoxycyclohexan-l-one (293, 7.01 g, 54.7 mmol), which was used in
the next step without further purification.
Step 4: Synthesis of 1-Amin0methoxycyclohexanecarbonitrile (294)
1-aminomethoxycyclohexanecarbonitrile (294) was prepared according to the
synthesis of 4-methoxycyclohexanone (261) described in Step 1 of Scheme 36.
Step 5: Synthesis of 1-(Aminomethyl)methoxycyclohexanamine (295)
1-(aminomethyl)—4-methoxycyclohexanamine (295) was prepared from l-amino-4—
methoxycyclohexanecarbonitrile (294) according to the experimental procedure for the
synthesis of 4-(aminomethyl)tetrahydro—2H-pyranamine (262) bed in Step 2, Scheme
Step 6: Synthesis of tert—Butyl ((1-amin0meth0xycyclohexyl)methyl)carbamate (296)
Tert-butyl ((l-amino-4—methoxycyclohexyl)methyl)carbamate (296) was prepared
from l-(aminomethyl)methoxycyclohexanamine (295) according to the experimental
procedure for the synthesis of tert—butyl inotetrahydro—2H-pyranyl)methyl)carbamate
(263) shown in Step 3, Scheme 36.
Step 7: Synthesis of utyl (((1S,4S)((2-chloroiodopyrimidinyl) amino)—4—
methoxycyclohexyl)methyl)carbamate (298) and utyl 4R)—1-((2-chloro
iodopyrimidinyl)amin0)methoxycyclohexyl)methyl)carbamate (299)
To a solution 2,4-dichloroiodopyrimidine (297, 1013 g, 37.5 mmol) and utyl
((1—amin0—4-methoxycyclohexyl)methyl)carbamate (296, 9 g, 34.8 mmol) in DMAc (180 mL)
was added NaHCO3 (10.8 g, 128 mmol). After stirring at 80 0C for 12 h, the reaction was
quenched with water (500 ml) and extracted with EtOAc (300 mL x 3). The combined organic
layers were washed with water (200 mL x 2) and brine (100 mL). The organic layer was dried
over NazSO4, filtered and concentrated in vacuo. The resulting residue was purified by column
chromatography to provide tert—butyl (((lS,4S)-l-((2-chloroiodopyrimidinyl)amino)—4—
methoxycyclohexyl)methyl)carbamate (298, 3.2 g, 6.44 mmol) and tert-butyl (((1R,4R)((2-
chloroiodopyrimidinyl)amino)methoxycyclohexyl)methyl)carbamate (299, 5.1 g,
.3 mmol). MS (ESI+): m/Z 497 [M + H]+.
tert-Butyl (((1S,4S)((2-chloro-S-iodopyrimidinyl)amino)—4-
methoxycyclohexyl)methyl)carbamate (298): 1H NMR (300 MHz, CDCl3): 5 8.21 (s, 1H),
3.53 (d, J: 6.6 Hz, 2H), 3.49 (d, J: 6.3 Hz, 1H), 3.37 - 3.32 (m, 1H), 3.25 (s, 3H), 3.23 - 3.22
(m, 1H), 2.08 - 1.98 (m, 2H), 1.79 - 1.64 (m, 5H), 1.52 - 1.47 (m, 1H),1.36(s, 9H).
tert-Butyl (((1R,4R)((2-chlor0i0d0pyrimidinyl)amin0)
meth0xycyclohexyl)methyl)carbamate (299): 1H NMR (300 MHz, CD03): 6 8.22 (s, 1H),
3.56 (d, J: 6.6 Hz, 2H), 3.52 (s, 1H), 3.28 (s, 3H), 3.27 - 3.25 (m, 1H), 3.19 - 3.12 (m, 1H),
2.30 - 2.17 (m, 95 - 1.82 (m, 2H),1.79 - 1.65 (m, 2H), 1.45 - 1.39 (m, 2H),1.36(s, 9H).
Step 8: Synthesis of utyl (((IS,4S)((2-chloro(3,3-diethoxyprop-l-yn
imidinyl)amino)—4-methoxycyclohexyl)methyl)carbamate (300)
Under N2 atmosphere, to a solution of tert—butyl (((1s,4s)—1-((2-chloro
iodopyrimidin-4—yl)amino)methoxycyclohexyl)methyl)carbamate (298, 3.2 g, 6.45 mmol)
and Et3N (1.4 g, 13.8 mmol) in THF (70 mL) was added CuI (122 mg, 0.64 mmol) and
Pd(PPh3)2C12 (181 mg, 0.26 mmol). After the reaction was stirred at 20 0C for 10 min, 3,3-
diethoxyprop-l-yne (990 mg, 7.72 mmol) was added se and the reaction was stirred at
20 0C for 12 h. The reaction mixture was then quenched with water (100 mL) and extracted
with EtOAc (100 mL x 3). The combined organic phases were washed with brine (100 mL),
dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified by
column chromatography to provide tert—butyl (((1s,4s)—1-((2-chloro(3,3-diethoxyprop-l-yn-
1-yl)pyrimidinyl)amino)methoxycyclohexyl)methyl)carbamate (300, 2.60 g, 5.23
mmol),
Step 9: Synthesis of tert—Butyl (((1S,4S)(2-chlor0—6-(diethoxymethyl)—7H- pyrrolo[2,3-
d]pyrimidinyl)methoxycyclohexyl)methyl)carbamate (302)
To a solution of teIt-butyl (((ls,4s)-l-((2-chloro(3,3-diethoxyprop—1-yn-l-
imidinyl)amino)methoxycyclohexyl)methyl)carbamate (300, 2.60 g, 5.23 mmol)
in THF (50 mL) was added TBAF (25 mL, 25 mmol, 1 M in THF). After stirring at 65 0C for
2 h, the reaction mixture was cooled room ature, quenched with water (150 mL) and
extracted with EtOAc (100 mL x 3). The combined organic phases were dried over Na2SO4,
filtered and concentrated in vacuo. The resulting residue was purified by column
chromatography to e tert-butyl (((1s,4s)(2-chloro(diethoxymethy1)-7H-
pyrrolo[2,3-d]pyrimidinyl)-4—methoxycyclohexyl)methyl)carbamate (302, 1.2 g, 2.41
mmol).
Step 10: Synthesis of tert—Butyl (((1S,4S)—1-(2-chloroformyl-7H—pyrrolo [2,3-
d]pyrimidinyl)methoxycyclohexyl)methyl)carbamate (304)
To a solution of tert-butyl (((ls,4s)-1—(2-chloro(diethoxymethy1)-7H-pyrrolo[2,3-
d]pyrimidinyl)methoxycyclohexy1)methy1)carbamate (302, 1.2 g, 2.41 mmol) in THF (4
mL) was added H20 (4 mL) and HOAc (4 mL). After stirring at 60 0C for 2 h, the on was
quenched with saturated aqueous NaHCO3 and extracted with EtOAc (100 mL x 3). The
combined organic phases were dried over Na2S04, filtered and concentrated in vacuo. The
resulting residue was d by column chromatography to provide tert-butyl (((ls,4s)(2-
chloro—6-formyl-7H—pyrrolo[2,3-d]pyrimidin—7-yl)—4-methoxycyclohexy1)methy1)carbamate
(304, 700 mg, 1.66 mmol).
Step 11: Synthesis of tert—Butyl )-2'-chloro—4-methoxy-6'-oxo-6'H-spir0
[cyclohexane— 1,9'-pyrazin0 [1',2' : 1,5] pyrrolo[2,3-d]pyrimidine]-7'(8'H)—carboxylate
(306)
To a on oftert—butyl (((1S,4S)(2-chloroformy1-7H-pyrrolo[2,3-d]pyrimidin-
4-methoxycyclohexy1)methy1)carbamate (304, 240 mg, 0.57 mmol) in t—BuOH (15 mL)
and acetonitrile (3 mL) was added NaH2P04 (709 mg, 4.55 mmol) and 2-methy1butene (318
mg, 4.53 mmol ). After stirring at 0 °C for 5 min, a solution of NaClOz (318 mg, 3.52 mmol)
in H20 (3 mL) was added dropwise over 1 h. After warming to room temperature and stirring
for another 2 h, the reaction mixture was quenched with water (50 mL) and extracted with
EtOAc (30 mL x 3). The combined organic phases were dried over , filtered and
concentrated in vacuo. The resulting residue was purified by column chromatography to
provide tert—butyl (1 S,4S)-2'—ch1oro—4-methoxy-6'-oxo-6'H-spiro[cyclohexane-1,9'—
pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-carboxylate (306, 200 mg, 0.47 mmol).
Step 12: Synthesis of tert—Butyl (1S,4S)methoxy-2'-((5-(4-methylpiperazin
yl)pyridinyl)amino)-6'-oxo—6'H-spiro [cyclohexane— 1,9'-pyrazin0[1',2' : 1,5] pyrrolo [2,3-
d]pyrimidine]-7'(8'H)—carb0xylate (308)
Under N2 atmosphere, to a solution of tert-butyl (1S,4S)-2'-chloromethoxy-6'-
oxo-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-
carboxylate (306, 100 mg, 0.24 mmol), 5-(4-methylpiperazin-l-yl)pyridinamine (55.4 mg,
0.28 mmol) in dioxane (5 mL) was added CS2CO3 (232 mg, 0.71 mmol), Pd(OAc)2 (5.3 mg,
0.02 mmol) and X-Phos (59 mg, 0.12 mmol). After stirring at 100 °C for 12 h, the reaction was
quenched with water (10 mL) and extracted with EtOAc (10 mL X 2). The organic phases were
concentrated in vacuo and the resulting residue was purified by column chromatography to
provide tert-butyl (1 s,4s)methoxy-2'—((5 -(4-methylpiperazinyl)pyridinyl)amino)-6'-
oxo-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-
carboxylate (308, 50 mg, 0.09 mmol). MS (ESI+): m/Z 577 [M + H]+.
Step 13: Synthesis of (1S,4S)Methoxy—2'-((5-(4-methylpiperazin-l-yl) pyridin-Z-
yl)amin0)-7',8'-dihydro-6'H—spir0[cyclohexane—1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-
d]pyrimidin]-6'-0ne (COMPOUND 38)
To a solution of tert-butyl (1S,4S)methoxy-2'—((5-(4-methylpiperazinyl)pyridin-
mino)-6'-oxo-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-
7'(8'H)-carboxylate (308, 50 mg, 0.09 mmol) in DCM (3 mL) at 0 0C was added TFA (1 mL)
in dropwise. After stirring for 2 h, the reaction mixture was neutralized with saturated s
NaHCO3 and extracted with i-PrOH/DCM = 1/3 (20 mL x 2). The combined organic phases
were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified
by prep TLC to provide )—4-methoxy-2’-((5-(4-methylpiperazinyl)pyridinyl)
amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'—pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-
6'-one (COMPOUND 38, 6.7 mg, 0.01 mmol). MS : m/z 477 [M + H]+; 1H NMR (300
MHz, MeOD + CDCl3): 5 8.84 (s, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.51 - 7.41 (m, 1H), 7.27 (s,
1H), 3.78 (s, 2H), 3.46 (s, 3 H), 3.45 - 3.36 (m, 6 H), 3.23 - 3.06 (m, 5 H), 2.73 (s, 3H), 2.27 -
2.17 (m, 2H), 2.15 - 2.04 (m, 2H), 1.54 — 1.40 (m, 2H).
Synthesis of (1R,4R)Meth0xy-2'-((5-(4-methylpiperazinyl)pyridinyl)amino)—
7',8'-dihydro-6'H—spiro [cyclohexane-l,9'-pyrazin0 [1',2' : 1,5] o [2,3-d]pyrimidin] -6'-
one (COMPOUND 39)
COMPOUND 39 was prepared according to the experimental procedures in the synthesis of
ND 38. MS : m/z 477 [M + H]+; 1H NMR (300 MHz, MeOD + CDCl3): 5
8.82 (s, 1H), 8.39 (br s, 1H), 7.98 (d, J: 2.5 Hz, 1H), 7.55 (d, J: 9.7 Hz, 1H), 7.26 (s, 1H),
3.77 (s, 2H), 3.63 (s, 1H), 3.41 (s, 3H), 3.40 - 3.34 (m, 6H), 3.16 - 2.94 (m, 4H), 2.67 (s, 3H),
2.19 - 2.09 (m, 2H), 1.87 - 1.76 (m, 2H), 1.72 - 1.59 (m, 2H).
Example 5. miting Examples of Compounds
Table 3. Non-limiting Examples of Final Compounds
Compound Structure
WO 05860
WO 05860
WO 05860
WO 05860
WO 05860
WO 05860
WO 05860
WO 05860
WO 05860
Example 6: CDK4/6 tion In Vitro Assay
Selected compounds disclosed herein were tested in CDK4/cyclinDl, CDK2/CycA and
CDK2/cyclinE kinase assays by Nanosyn (Santa Clara, CA) to determine their inhibitory effect
on these CDKs. The assays were performed using microfluidic kinase detection technology
(Caliper Assay Platform). The compounds were tested in 12-point dose-response format in
singlicate at Km for ATP. Phosphoacceptor substrate peptide concentration used was 1 uM
2017/040093
for all assays and Staurosporine was used as the reference compound for all assays. Specifics
of each assay are as described below:
CDK2/CyclinA: Enzyme concentration: 0.2 nM; ATP tration: 50 uM;
Incubation time: 3 hr.
CDK2/CyclinE: Enzyme concentration: 0.28 nM; ATP concentration: 100 uM;
Incubation time: 1 hr.
CDK4/CyclinD1: Enzyme concentration: 1 nM; ATP concentration: 200 uM;
Incubation time: 10 hr.
Biolo_ical Table 3
Compd CDK4/
# Compound Structure Cyclin
D1 (LLM) D3 (HM) E(uM) A(HM) T(MM)
N~ 0.03
Nifl '{Nj/\- l
27 g 0 9.4 >100 >100 >100
WO 05860
WO 05860
WO 05860
39 0.06
40 O 0.09
\ NH
N /
\w-N/
R1?“'3
41 Q 0.14
\ NH
N /
LN””3
WO 05860
Claims (3)
1. A compound of Formula: R’HNQN/ 62:”\lély; or a pharmaceutically acceptable salt, e, isotopic derivative, prodrug, and/or a pharmaceutically acceptable composition thereof; wherein: X is NH, NR9, S, or O; yis 0,1,2, 3 or4, Z is CH, CR9, or N, Q is CH2 or CO; R is hydrogen, C1-C6alkyl, -(Co-C2alkyl)(C3-Cscarbocyclyl), -(Co-C2alkyl)(C3- Csheterocyclyl),-(Co-C2alkyl)(aryl), -(C0-C2alkyl)(heteroaryl), -COOalky1, -COOarylalkyl, or —COOH; each R1 is independently alkyl, aryl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups ally includes heteroatoms O, N, or S in place of a carbon in the chain and two Rl’s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3membered cycle or two Rl’s on adjacent ring atoms together with the ring ) to which they are attached optionally form a 6-membered aryl ring; R2 is —(alkylene)m—heterocyclo, —(alkylene)m—heteroaryl, —(alkylene)m—NR3R4, —(alkylene)m—C(O)—NR3R4; —(alkylene)m—C(O)—O-alkyl, —(alkylene)m—O—R5, —(alkylene)m—S(O)n—R5, or —(alkylene)m—S(O)n—NR3R4 any of which may be optionally independently tuted with one or more Rx groups as d by valance, and wherein two RX groups bound to the same or adjacent atom may optionally combine to form a ring; m is 0, 1, or 2, n is 0, l, or 2, R3 and R4 at each occurrence are independently selected from: (i) hydrogen or (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl; or R3 and R4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring, R5 is selected from: (i) hydrogen or (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl; Rx at each occurrence is independently selected from halo, cyano, nitro, oxo, alkyl, haloalkyl, l, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)m-OR5, -(alkylene)m-O-alkylene-OR5, -(alkylene)m-S(O)n—R5, -(alkylene)m-NR3R4, -(alkylene)m-CN, -(alkylene)m-C(O)—R5, —(alkylene)m-C(S)—R5, -(alkylene)m-C(O)—OR5, -(alkylene)m-O—C(O)—R5, -(alkylene)m-C(S)—OR5, -(alkylene)m-C(O)-(alkylene)m-NR3R4, -(alkylene)m-C(S)—NR3R4, -(alkylene)m-N(R3)—C(O)—NR3R4, -(alkylene)m-N(R3)—C(S)—NR3R4, -(alkylene)m-N(R3)— C(O)—R5> lene)m-N(R3)—C(S)—R5, lene)m-O—C(O)—NR3R4, —(alkylene)m—O—C(S)— NR3R4, -(alkylene)m—SOz—NR3R4, -(alkylene)m—N(R3)—SOz—RS, lene)m-N(R3)—SOz— NR3R4, -(a1kylene)m-N(R3)—C(O)—OR5) -(alky1ene)m-N(R3)—C(S)—OR5, or -(alky1ene)m- SOz—R5; R6 is selected independently at each instance from: hydrogen, halogen, alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, kyl, or heteroarylalkyl; R8 :28 R8 R8 R8 R8 N V Y R8 / l R3 / \ R8 / I / R7 is selected from: Y R8 R8 Ra , , , , X: X2 YR 7 X2 X2 / N» X- N \ 4/ 1/ 47 Y 4/ N x 1 Y X l X‘ X1 I Y x1 v x? Y\ x X2 X" / / [X 4’ Y 2:2 W3 :3” WO 05860 or R7 is selected from cycloalkyl, heterocycle, and alkyl, each of which cycloalkyl, cycle, and alkyl groups is optionally substituted with one or more substituents selected from amino, -NHR14, 15, hydroxyl, OR”, R6, and R2, R14 and R15 are independently selected from: hydrogen, alkyl, alkenyl, alkynyl, —C(O)H, -C(O)alkyl, -C(S)alkyl, aryl, —SOzalkyl, heteroaryl, arylalkyl, and heteroarylalkyl. Y is NH, O, S, or NR9, X1, X2, X3 and X4 are independently N or CR8, wherein at least one of X1, X2, X3, X4, and X5 are CR8; R8 is selected independently at each instance from: R6 and R2, n one R8 is R2; R9 is selected from: , -C(O)alkyl, -C(S)alkyl, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; and 10 is selected from: hydrogen, —COOalkyl, -COOarylalkyl, —COOH, -OH, —C(O)H, C(O)alkyl, -C(S)alkyl, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl.
2. The compound of claim 1 of Formula grin:”R\ or a pharmaceutically acceptable salt, e, isotopic derivative, prodrug, and/or a pharmaceutically acceptable composition thereof.
3. The compound of claim 1 of Formula WN’N“”I N m N”R HN ( R1) 7 y
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US62/357,630 | 2016-07-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ749590A true NZ749590A (en) |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10829490B2 (en) | Substituted dihydropyrazino[1 ′,2′:1,5]pyrrolo[2,3-d]pyrimidine-based antiproliferative agents | |
US10618905B2 (en) | Pyrimidine-based compounds for the treatment of cancer | |
US10654831B2 (en) | Antiproliferative pyrimidine-based compounds | |
US20210198256A1 (en) | Compounds for the degradation of brd9 or mth1 | |
US11261193B2 (en) | Morphic forms of G1T38 and methods of manufacture thereof | |
US10988479B1 (en) | Morphic forms of trilaciclib and methods of manufacture thereof | |
US20200331925A1 (en) | Heterocyclic compounds for the treatment of abnormal cellular proliferation | |
US11643416B2 (en) | Substituted 1′,2′-dihydro-3′H-spiro[cyclohexane-1,4′-pyrimido[5′,4′:4,5]pyrrolo[2,1-c][1,2,4]triazin]-3′-ones as cyclin-dependent kinase inhibitors | |
WO2019222521A1 (en) | Cdk inhibitors for the treatment of neoplastic disorders | |
CA3188313A1 (en) | Compounds for targeted degradation of ret | |
JP2024521791A (en) | EGFR degraders for treating cancer metastasis to the brain or CNS | |
NZ749590A (en) | Pyrimidine-based antiproliferative agents | |
US20190062340A1 (en) | Cortistatin analogs |