LU505464B1 - A pan-KRAS inhibitor compound - Google Patents
A pan-KRAS inhibitor compound Download PDFInfo
- Publication number
- LU505464B1 LU505464B1 LU505464A LU505464A LU505464B1 LU 505464 B1 LU505464 B1 LU 505464B1 LU 505464 A LU505464 A LU 505464A LU 505464 A LU505464 A LU 505464A LU 505464 B1 LU505464 B1 LU 505464B1
- Authority
- LU
- Luxembourg
- Prior art keywords
- int
- alkylene
- compound
- mmol
- reaction
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 158
- 229940124785 KRAS inhibitor Drugs 0.000 title abstract description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- 101000713575 Homo sapiens Tubulin beta-3 chain Proteins 0.000 claims description 3
- 102100036790 Tubulin beta-3 chain Human genes 0.000 claims description 3
- 101000633680 Homo sapiens Tetratricopeptide repeat protein 37 Proteins 0.000 claims description 2
- 102100029210 Tetratricopeptide repeat protein 37 Human genes 0.000 claims description 2
- 208000007004 trichohepatoenteric syndrome Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 32
- 206010028980 Neoplasm Diseases 0.000 abstract description 29
- 201000010099 disease Diseases 0.000 abstract description 28
- 201000011510 cancer Diseases 0.000 abstract description 13
- 230000001404 mediated effect Effects 0.000 abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 10
- 208000027866 inflammatory disease Diseases 0.000 abstract description 8
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 125
- 238000006243 chemical reaction Methods 0.000 description 122
- 125000002947 alkylene group Chemical group 0.000 description 115
- -1 nitroxides Chemical class 0.000 description 72
- 239000000243 solution Substances 0.000 description 66
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 62
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 125000004432 carbon atom Chemical group C* 0.000 description 58
- 230000014759 maintenance of location Effects 0.000 description 53
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 49
- 229910001868 water Inorganic materials 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 37
- 239000007787 solid Substances 0.000 description 35
- 125000000753 cycloalkyl group Chemical group 0.000 description 34
- 238000004128 high performance liquid chromatography Methods 0.000 description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- 125000000217 alkyl group Chemical group 0.000 description 32
- 239000000543 intermediate Substances 0.000 description 30
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 28
- 238000000034 method Methods 0.000 description 27
- 239000012074 organic phase Substances 0.000 description 27
- 229910052760 oxygen Inorganic materials 0.000 description 27
- 229910052717 sulfur Inorganic materials 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 125000005842 heteroatom Chemical group 0.000 description 26
- 150000003839 salts Chemical class 0.000 description 26
- 125000001424 substituent group Chemical group 0.000 description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 229910052739 hydrogen Inorganic materials 0.000 description 24
- 239000001257 hydrogen Substances 0.000 description 24
- 125000003118 aryl group Chemical group 0.000 description 22
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- 239000002994 raw material Substances 0.000 description 20
- 229910052736 halogen Inorganic materials 0.000 description 19
- 150000002367 halogens Chemical class 0.000 description 19
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 125000001072 heteroaryl group Chemical group 0.000 description 18
- 125000000623 heterocyclic group Chemical group 0.000 description 17
- 239000000203 mixture Substances 0.000 description 17
- 125000004122 cyclic group Chemical group 0.000 description 16
- 238000010898 silica gel chromatography Methods 0.000 description 16
- 125000003545 alkoxy group Chemical group 0.000 description 15
- 229910052799 carbon Inorganic materials 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
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- 125000006413 ring segment Chemical group 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 description 12
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 12
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- 102100030708 GTPase KRas Human genes 0.000 description 11
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 125000001188 haloalkyl group Chemical group 0.000 description 11
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- 102000008016 Eukaryotic Initiation Factor-3 Human genes 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
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- 125000004429 atom Chemical group 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 8
- LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical compound CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 description 8
- 101000810330 Arabidopsis thaliana Eukaryotic translation initiation factor 3 subunit E Proteins 0.000 description 8
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 7
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 7
- 238000011161 development Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
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- 238000000746 purification Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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- 229940125782 compound 2 Drugs 0.000 description 6
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
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- 239000003112 inhibitor Substances 0.000 description 5
- 230000000155 isotopic effect Effects 0.000 description 5
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 5
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- 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 5
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- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a pan-KRAS inhibitor compound represented by formula (I) or formula (II) and a pharmaceutical composition containing the compound, and the use of compound of formula (I) or formula (II) for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune- mediated disease.
Description
BL-5785
A pan-KRAS inhibitor compound LU505464
The present invention relates to a compound, in particular to a highly active pan-
KRAS inhibitor and its use.
Background technique
RAS is one of the most frequently mutated genes in human tumors, and its mutation occurs in about 30% of tumor patients, among which KRAS accounts for about 85% of RAS mutations. KRAS mutations exist in 88% of pancreatic cancer, 50% of colorectal adenocarciuoma, and 32% of lung adenocarcinoma. The development of targeted KRAS inhibitors has great clinical significance and value.
KRAS is a membrane-bound protein with GTPase activity, which eycles between a GDP-bound inactive conformation and a GTP-bound active conformation through nucicotide exchange, performing the function of a "molecular switch". KRAS in the
GTP-bound state can activate multiple downstream signaling pathways including
RAF-MEK-ERK and PEK-AKT, and regulate life processes such as cell growth, prolifération, differentiation and apoptosis.
KRAS mutations (such as GI2C, G12D, GIZV, G13D, etc.) will affect the hydrolysis of GTP mediated by GTPase activating proteins (GAPS), increase KRAS in the GTP-bound activated state, and over-activate downstream signaling pathways, eventually ead to the occurrence and development of tumors. However, since the
KRAS protein lacks a corresponding hydrophobic pocket suitable for drag binding, and its affinity with GTP and GDP is at the picomolar level (-20pMD), it is very difficult to develop iniubitors that competitively bind to KRAS KRAS has been considered an undruggable target for the past decades.
In May 2021, AMGS10 was approved by the FDA for the treatment of locally advanced or metastatic non-small cell lung cancer carrving the KRASCUS mutation, breaking the history of KRAS being "undruggable”. However, the G120 mutation only accounts for a small portion of GRAS mutations For mutations at other sites of
KRAS, there is still a lack of satisfactory and effective inhibitor compounds, and a large number of clinical needs have not been met. Therefore, the development of effective pan- KRAS inhibitor compounds are a need in the art, 1
BL-5785
Contents of the invention LU505464
The invention provides a pan-KRAS inhibitor. Such structures are different from existing KRASY!2C inhibitors that act through covalent binding, but instead mediate the formation of a ternary complex between ubiquitous intracellular chaperones (such as
Cyclophilin A) and KRAS proteins. The formation of the ternary complex can block the combination of KRAS and its downstream effector molecules (such as RAF) through steric blockage, inhibit the activation of MAPK and PI3K-AKT signaling pathways, thereby inhibiting the occurrence and development of tumors, and play a role in the treatment of tumors and other diseases.
In one aspect, the present invention provides a compound with a structure of formula (I) or formula (II) or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof: er °, ren
R3 N= 3
N >
Re— SS a am à
Wh O
Ras 9 (D or "ve O )
N° Gf Ue
Ra N= Po”
N >
RE Hd
Rs Rs} AN
Ro ‘N eR
Rs" © (ID) wherein:
Rı represents Cı-Ce alkyl, -(Ci-C6 alkylene)-(C3-Cs cycloalkyl), -(C1-C6 alkylene)-(4-8 membered heterocycloalkyl), -(C1-Cs alkylene)-ORa, -(C1-C6 alkylene)-
SRa or -(C1-C6 alkylene)-NRaRa’; 2
BL-5785
Rz represents halogen, cyano, Ci-Cs alkyl, -(Co-Cs alkylene)-(Cs-Cs LU505464 cycloalkyl), or -(Co-Cs alkylene)-(4-8 membered heterocycloalkyl), which may optionally be substituted by 0, 1 or 2 of the following substituents: -ORa, -SRa, or -
NRaRa’;
Rs represents hydrogen, -O(Co-Cs alkylene)Ra, -S(Co-Cs alkylene)Ra, -N(Co-
Cs alkylene)Ra(Co-Cs alkylene)Ra , which may optionally be substituted by 0, 1 or 2 if ofthe following substituents: -ORa, -SRa, or NRaRa’;
Cy1 represents C3-C12 cycloalkyl or 4-12 membered heterocycloalkyl;
Rı each independently represents hydrogen, halogen, oxo, Ci-Cs alkyl, -(Co-
Cs alkylene)(Cs-Cs) cycloalkyl, -(Co-Cs alkylene)(4-8 membered) heterocycloalkyl, - (Co-Cs alkylene)ORa, -(Co-Cs alkylene)SRa, -(Co-Cs alkylene)NRaRa’, -(Co-Cs alkylene)CORa, -(Co-Cs alkylene)COORa, -(Co-Cs alkylene)CONRaRa’, -(Co-Cs alkylene) NRaCORa’, -(Co-Cs alkylene) OCONRaRa’, -(Co-Cs alkylene)
NRaCONRaRa’, -(Co-Cs alkylene)SORa, -(Co-Cs alkylene)S(O):Ra, -(Co-Cs alkylene)NRaS(O)»Ra’, -(Co-Cs alkylene)CN, -(Co-Cs alkylene)(C6-C10 aryl) or -(Co-
Cs alkylene)(5-12 membered heteroaryl); wherein, R4 on the two C atoms of Cy1 together with the C atoms connected thereto and the atoms between the two C atoms can form a 3-8 membered ring, and the 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or two R4 on the same C atom of Cy; together with the C atom connected thereto can form a 3-8 membered ring, and the 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or
S;
Rs, Re’ each independently represents hydrogen, halogen, Ci-Cs alkyl, C3-Cs cycloalkyl or -(Co-Cs alkylene)CN;
Rs, Rs’ each independently represents hydrogen, halogen, Ci-Cs alkyl, -(Co-Cs alkylene)(Cs-Cs) cycloalkyl, -(Co-Cs alkylene)CN, -(Co-Cs alkylene)ORa, -(Co-Cs alkylene)SRa, -(Co-Cs alkylene)NRaRa’, or Rs, Rs’ form a 3-8 membered ring together with the C atoms connected thereto, and the 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;
W represents NR7, CR7R7’, O or S, wherein,
R7, R7’ each independently is selected from: hydrogen, Ci-C6 alkyl, -(Co-Cs alkylene)(Cs-Cg cycloalkyl), -(Co-Cs alkylene)(4-12 membered heterocycloalkyl), - (Co-Cs alkylene)CN, -(Co-Cs alkylene)ORa, -(Co-Cs alkylene)SRa, -(Co-Cs 3
BL-5785 alkylene)NRaRa’, -(Co-Cs alkylene)C(O)Ra, -(Co-Cs alkylene)C(O)ORa, -(Co-Cs | -U505464 alkylene)C(O)NRaRa’, -(Co-C6 alkylene)OC(O)NRaRa’, -(Co-Cs alkylene)NRaC(O)Ra’, -(Co-Cs alkylene)S(O)Ra, -(Co-Cs alkylene)S(O)»Ra, or R7, R7’ can form a 3-8 membered ring with the C atom connected thereto, and the ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;
Rsa, Rgb, Rec, Red each independently is selected from: hydrogen, halogen, oxo,
C1-Cs alkyl, -(Co-Cs alkylene)(C3-Cg cycloalkyl), -(Co-Cs alkylene)(4-8 membered heterocycloalkyl), -(Co-Cs alkylene)CN, -(Co-Cs alkylene)ORa, -(Co-C6 alkylene)SRa, -(Co-Cs alkylene) = NRaRa’, -(Co-Cs alkylene)C(O)ORa, -(Co-Cs alkylene)C(O)NRaRa’, -(Co-C6 alkylene)OC(O)NRaRa’, -(Co-Cs alkylene)NRaC(O)Ra’, -(Co-Cs alkylene)S(O)Ra, -(Co-Cs alkylene)S(O)»,Ra; or R8a and R8b or R8c and R8d connected to the same C atom can form a 4-8 membered ring with the C atom connected thereto, and the ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or two of Rga, Rgb, Rec, Red that are not connected to the same C atom with the C atoms connected thereto and the atoms between the two
C atoms form a 4-8 membered ring, and the ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or one of Rsa, Rsb, Rec, Rad forms a 4-8 membered ring with R7 or R7’ on adjacent or non-adjacent W, and the ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S, and when one of
Rsa, Rgb, Rec, Red forms a 4-8 membered ring with R7 or R7’ on the adjacent W, the ring may optionally contain 0, 1, 2 or 3 unsaturated bond; when W is S, the S atom can be oxidized to -S(O)-- or -S(O) (NH)-; wherein, p represents 0, 1, 2, 3 or 4; m, n each independently represents 1, 2 or 3;
Ro, Ro’ each independently represents hydrogen, Ci-Cs alkyl, -(Co-Cs alkylene)(Cs-Cg cycloalkyl), -(Co-Cs alkylene)(4-12 membered heterocycloalkyl), - (Ci-Cs alkylene)ORa, -(Ci-Cs alkylene)SRa, -(Ci-Cs alkylene)NRaRa’, -(Ci-Cs alkylene)CN, -(Ci-C¢ alkylene)C(O)Ra, -(Co-Cs alkylene)C(O)ORa, -(Co-Cs alkylene)C(O)NRaRa’, -(Co-C6 alkylene)OC(O)NRaRa’, -(Co-Cs alkylene)NRaC(O)Ra’, -(Co-Cs alkylene)S(O)Ra, -(Co-Cs alkylene)S(O).Ra, which may optionally be substituted by 0, 1 or 2 substitutents selected from the following: - (C1-Cs alkylene)ORa, -(C1-C6 alkylene)SRa, -(Ci-Cs alkylene)NRaRa’; 4
BL-5785
Ra, Ra’ each independently represents hydrogen, C1-C6 alkyl, Cs-Cs cycloalkyl, 4- LU505464 8 membered heterocycloalkyl; wherein, when Ra and Ra’ are connected to the same N atom, the Ra and Ra’ and the commonly connected N atom can form a 4-8 membered ring, the 4-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; the alkyl, cycloalkyl, heterocycloalkyl, alkylene each independently can be substituted by 0, 1, 2, 3, 4, 5 or 6 halogen atoms.
In some embodiments, Ri represents C1-C6 alkyl, -(Ci-Cs alkylene)-(Cs-Csg cycloalkyl) or -(Ci-Cs alkylene)-(4-8 membered heterocycloalkyl); preferably, Ri represents C1-Cç alkyl; more preferably, Ri represents C1-C3 alkyl.
In some embodiments, Rz represents Ci-Ce¢ alkyl, which may optionally be
O-Ra substituted by 0, 1 or 2 -ORa substituents; preferably, Ra represents a ; further 0— o— preferably, R represents X ; more preferably, Ro represents = ; wherein, * represents the site where Ra is connected to the part of formula (I) where connecting to Ro.
In some embodiments, R3 represents hydrogen or -O(C1-C6) alkyl, -O(Co-Cs alkylene) (Cs-Cs) cycloalkyl, -O(Co-Cs alkylene) (4-8 membered) heterocycloalkyl, which may optionally be substituted by 0 or 1 substituent selected from the following:
ORa, -SRa, or NRaRa’.
In some embodiments, Cy: represents C3-Cg cycloalkyl or 4-8 membered heterocycloalkyl.
In some embodiments, Rı each independently represents hydrogen, halogen, C1-
Cs alkyl, -(Co-Cs alkylene)ORa, -(Co-Cs alkylene)SRa, -(Co-Cs alkylene)NRaRa’, -(Co-
Cs alkylene)CONRaRa’, -(Co-Cs alkylene) NRaCORa’, -(Co-Cs alkylene)
OCONRaRa’, -(Co-Cs alkylene)CN, -(Co-Cs alkylene)(5-12 membered heteroaryl), or
R4 on the two C atoms of Cy1 together with the C atoms connected thereto and the
BL-5785 atoms between the two C atoms can form a 3-8 membered ring, the 3-8 membered ring LU505464 optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or Cy1 and two R4 on the same C atom together with the C atom connected thereto can form a 3-8 membered ring, the 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S.
In some preferred embodiments, R4 each independently represents hydrogen, halogen, C1-C6 alkyl, -(Co-Cs alkylene) CONRaRa’, -(Co-Cs alkylene)(5-12 membered heteroaryl), or R4 on the two C atoms of Cy: together with the C atoms connected thereto and the atoms between the two C atoms can form a 3-8 membered ring, and the 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or two R4 on the same C atom of Cy1 together with the C atom connected thereto can form a 3-8 membered ring, and the 3-8 membered ring optionally may contain 0, 1, 2 or 3 heteroatoms selected from N, O or S.
In some embodiments, Re, Re’ each independently represents hydrogen or C1-C6 alkyl; more preferably, Re, Re’ each independently represents hydrogen or methyl.
In some embodiments, Rs, Rs’ each independently represents hydrogen, C1-C6 alkyl, -(Co-Cs alkylene)CN, -(Co-Cs alkylene)ORa, -(Co-Cs alkylene)SRa or -(Co-C6 alkylene)NRaRa’.
In some embodiments, R7, R7’ each independently represents hydrogen, C1-C6 alkyl, -(Co-Cs alkylene)(C:-Cg cycloalkyl), -(Co-Cs alkylene)(4-12 membered heterocycloalkyl), -(Co-Cs alkylene)ORa, -(Co-Cs¢ alkylene)NRaRa’, -(Co-Cs alkylene)C(O)NRaRa’, -(Co-C6 alkylene)OC(O)NRaRa’, -(Co-Cs alkylene)NRaC(O)Ra’, -(Co-Cs alkylene)S(O)»Ra, or R7, R7’ can form a 3-8 membered ring with the C atom connected thereto, and the ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O, S.
In some embodiments, Rsga, Rsb, Rec, Red each independently is selected from: hydrogen, halogen, Ci-Cs alkyl, -(Co-Cs alkylene)(Cs-Cs cycloalkyl), -(Co-Cs alkylene)(3-8 membered heterocycloalkyl), -(Co-Cs alkylene)CN, -(Co-Cs alkylene)ORa, -(Co-Cs alkylene)SRa, -(Co-Cs alkylene)NRaRa’, -(Co-Cs alkylene)C(O)NRaRa’; or R8a and R8b or R8c and R8d connected to the same C atom can form a 4-8 membered ring with the C atom connected thereto, and the ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or two of Rsa, Reb, 6
BL-5785
Rec, Red that are not connected to the same C atom can form a 4-8 membered ring with LU505464 the C atoms connected thereto and the atoms between the two C atoms, and the ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or one of Rsa,
Rsb, Rec, Red forms a 4-8 membered ring R7 or R7’ on adjacent or non-adjacent W, and the ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S, and when one of Rga, Rgb, Rec, Red forms a 4-8 membered ring with R7 or R7’ on the adjacent W, the ring may optionally contain 0, 1, 2 or 3 unsaturated bond, preferably, the ring is an aromatic heterocycle.
In some embodiments, when W is not NR7, at least one of R7, R7’, Rga, Rsb, Rec,
Rsd or the ring formed between them includes at least one heteroatoms selected from
N, O or S, preferably N atom, more preferably secondary amine or tertiary amine.
In some embodiments, when W is O or S, at least one of Rga, Rsb, Rec, Red or the ring formed between them includes at least one heteroatoms selected from N, O or S, preferably N atom, more preferably secondary amine or tertiary amine.
In some embodiments, Ro, Ro’ each independently represents hydrogen, C1-C6 alkyl, -(Co-Cs alkylene)(C:-Cg cycloalkyl), -(Co-Cs alkylene)(4-12 membered heterocycloalkyl), -(Co-Cs alkylene)ORa, -(Co-Cs alkylene)SRa, -(Ci-Cs alkylene)NRaRa’ substituted by 0 or 1 substituent selected from -(C1-C6 alkylene)ORa, -(C1-Cs alkylene)SRa.
In some preferred embodiments, at least one of Ro, Ro’ contains at least one heteroatoms selected from N, O or S, preferably N atom, more preferably secondary amine or tertiary amine.
In some embodiments, p is preferably 0, 1 or 2, or m, n each independently is preferably 1 or 2.
In some embodiments, the structure -Cy1-(R4)p in formula (I) is selected from the following: 7
BL-5785 % 5 F F F > Sk) 4510 #, LU505464 #.(8) ic SI +, , x 5 EA AS ’
TY TRE De * (S) * * wy oN AS HO
CN LO Lo w” > 0) / (SONO S\N (5) (5) Di w" (9 m
N
7 ÿ SN I %, * * gn m4 qe “Ny HUA 76 oH 7 OH “Reo” / | —o / _ —OH Nr HO, 9 0 we, . 0 O N 5 * (Sfr) A 5 QG 6 x 8! be: NTH NP —0 o 9 N = O oO ,, 5,
NZ x, Y Y we a dd >. a or hoe TO C
N
~ wherein, * represents the site where -Cy1-(R4)p is connected to the part of formula (I) where connecting to -Cy1-(R4)p.
Rs * pr, Reb 8a m
N
Wan © . Red
In some embodiments, the structure 8c in formula (I) is selected from the following: 8
BL-5785 . . , . , LU505464 x x | Ÿ
À \ N N „N N „N „N „N ‘ ‘ oO ‘ N Oo o No \ 0 N o N O " 7 TdT ( y (
OH F
\
N \ Ÿ \ Ÿ Ÿ ’ „N N N — N 9 o_J / /
F ’ pH " " N F | V | ; \ \ - N \ \ N N m 0 - „N
N - , N oO
NS NS N © N ° oJ ) " °
N \ — ! + N\ , Ho * N ; ( CF, # N ; \ \
N \ N
Xe 0’ N OS NON ° LOY N
H —N oO N 0 / N oO # d a MeO MeO ” a OE ee Tg Mg od
N N „N { Ÿ RON 0
N 0° N oO N N ‚N N
T I Ju N o —N oO Hod
O N
% # a N # Fk * { —N 0° N —N L/"0 N NO / 0
NT O
1
Ni Ni N v9 \ Na \ es , , ; N N i n J © Sr © 7 9 N N CN o a © N° ( \
N N O N
I x À x al \ + + * Ÿ \ \ N
N N „N = ” iN { i o os 0. os o 955 9
N 0€ N N i HN oO N | oO N oO 0
N / r NT N- N- NT / Ne I I I !
Rs x pr, Reb 8a Nam \ ‚N
Wan © wherein, * represents the site where 8c is connected to the part of
Rs x pr, Reb 8a Nam \ ‚N
Wan © ; R Red formula (I) where connecting to 8c
Rs Rs # \
Re „N
In some embodiments, the structure in formula (IT) "9 is selected from 9
BL-5785 the following: LU505464 / \ Na! Na! Ne! N Ds I Ne! oO N oO \ Oo nn ZX 0° (9) \ Oo [e] N oO — VAN AN N RN —
F + F # F # pr * OH >; a
F \ F V \ / A De NS NS \ Na! / N > or o N Ho, N— ON NAO RN © oN + \_/ / —N \_7 “© F > OH # ä >o * ä \ F Ÿ Ÿ \ Na „N N N N
N \_/
AN C6 N
Rs Rs # \ wherein, * represents the site where "9 is connected to the part of
Rs Rs # \ . Re! O formula (IT) where connecting to "9
In some embodiments, the compound of formula (I) has the structure of formula (IT), and the compound of formula (IT) has the structure of formula (IV):
O ©] O
TNO er
H
R
R, N= s 3
N >
Re— SS rs Rs — N
Ras NO Ré Ri „N
W n O
R Rad 8c formula (III),
BL-5785 ©) LU505464 (S)
Os NN O 0
H
0 R4
N pP
H
N=\ Rs
R, Ss
N >
Re / \ /
Ng
Rs Rs ON 4 Re R
Re ‚N
Rg' 9 9 formula (IV)
In another aspect, the invention provides compounds having the following structures:
Oy (a 99 oy (À 99 Oy 2 09 Oy 2 09
Fol J Ho Le Ho Le He Le
NA 2 La NA > My 7 My 7
N N N N
À — X — % — X —
N o _N ot N oN o”
ST N
Q,
Sig
SN 0 J HN-N HN-N, o a 9 y 0 Ny Hse 0 0 0 af —0, SP o © 0 nf HN © w= H —o ee —0 N= HN N LS Os)
N = ©) “0 5 ‘a, rN 2 8 Nf = J NS 4 Vw N ;
N= — N N X — d { J 5 — oN oN ZN o” C
N N OH
> 9 3.46)
Yan 5) vga
J ©) / HA o 9/70 (3) — (XD 3 ey
N= © 0 > N (5), 5 ©
LE { Se 4 q Jo { = X —
N ot
Ce
F oto) 0 Os © 0 Ose ex 2 0 F
THC, TVA, Phe d N f do N Vor d, N= N © F wl Ne Wa Le N SS
MN MN NA
N a J
N N N
_N 9 _N 9 _N 0
Os X 0 N Os e 0 N Os es 0 Os ex 0
SEL / SOI TOUL À SALE
N s a y 5 a = 5 N hg 5
Mg NA 9 FR Mg
N N N N
N — Y — X — N —
N N N N
_N oO _N oO _N 0 _N 0 oy 99 oa Oo: ol 09 oy ld 09 0 "eu À - o Hel Ll æ à MeN lef à "oN Jao
J, A NS J, wl N i; J Ne NT dr A N U == == > -
Mv Ng NA 7 > NA 9
N N N N
N — N — — —
N N N N
_N 9 _N 9 _N o _N 0 11
6 ol -~ 6) LU505464
Oy SN 9. Oy SN °° Oy SN °° Op NL à
N N
, 0 Hg Ah oH , o Ne ol © om , 0 Meg wl of , à Ne © oF q H 7e 0 BH Ve 0 H © q Ve 3 NA, 3 NA, Q NA, 3 NA, = N = N = N x
A NS NA NS
N N N N
À — X — X — x
N N N N
NL NO NO NO
Oy N20 à Oy 2 N20 à oy 2 N20 à 5 N 5 o Mel J à "mek À à MeN Je _ 0 A Ho ©
J NONE / NON / N vase J N © N= LN Og OL Lo Og n=l Hf 9 NA, ®\_0
Ss s
N = = = N = a4 NA Mg rN
N N N N a ( ( {
N N N N
AN ° _N o _N o N ° ; Go ©
Oy GA oy % DR 9 9 Os A N20 à Oy SP à /
H 3 H H A H N (5), (5), (5), . (5), so ope J wd 1 P Tue y ve @ N= 9 N= 18 0 3 N= ox N 3 N= ©
N = N SS N SS N LS vo Ny rN ÄZ rN rN
N N N N
7 4 — € — {
N N N N
NO NO NJ N° 6) | 6 ©
Oy GA °° Oy GA °° Oy NN 09 N_ Oy ON EIR / 0 N / 0 N / © AA / 09 VE
H H 0 H
Og N= Og N= 3 N= (Le Og FE ° 5 5 5
N > N = N > N >
A rN rN rN
N N N N
Lo 4 — 4 (J
N N N N
N o —N ° N _N o oc lo) Q "ON NS) 0. 6) ole) SN 6 ON 0. 1
M00 IN 90 / o fy N= Ja ir o H / 0 eo, À 0 / 0 ©) / al À ° N N o N 9 NTN 5 y Ne 9 nA ©) H ng n=l "M NY N A Ss ° N Los © 4 78 (À / SS _ 4 rN a —/ =/ _J N — X — N i — ‘N N N. 0 N _Nn fo _N_ or - A ooo) N | 6 oko = y" 0 N Og oto, 8 Oy o_o, > pt 0 0 o 0 hl © J o He I X Ce © A 0 J © 2 Te
NN 0 ©) H H 6, H nN LS NT n=l un nz N= X J N = = ff x a; SS AA; > © J > 0”
N =/ =/ N i + 4 — wo —N or N oN _n fo _N_ or
OWL om I No 4H IN pe 73 NNO N / NN / o Fe à / 0 al À, =, / o He =
Og NN 0 ye 9 NON 9 2 vo
N= ©) H ) n={ H ©) H
N 5 N N= N ; N N=
MN 7 47 SS rN = a 5
N ON AN AAN
+ 4 _J i — i J ‘N N N N
N 0 N oO N. o N. o
Yoo TN Te IW
J © > And J © I el o © 2 a J O02 eg a 5) ©)
WY nt TON WY n=l H © WY nd H a NG Nel H
NS 5 ARN 5 GNS 2S Ng oS + =/ =/ N — N — N — N — —N o” N. 0° N. 0 —N 0 or le oe) or. le) on a) he NT 99 5 Nt 99 3 y” Oo | , J N ; Pa NY o SAN de o Con Ae o Oo Ay 9 ON = 5 © H © ) © H ° ) oh "OD ©) n=(O H
N 6 N= ® N: N= 5 N N= N > oN 2 ARN 5 CA oS «4j = += =/ =/ N i J N — N — N —
No Nor N Jo N or
Te TNS NG THES / o Hel Le J ° Mol le J J o Ae 4 N © H © © oH 5 © 0. H > © N A ® Wd N= ® N N= ® N N= ® = \ X
A SS a =” CN > X AS > NT
EN N = N F 5
F
N Fe N hod N N _N o —N oO _N oO N oO
Ny © 0,66 À
Ye he SOS o 0 fg 1e J 0 Mol Le o 0 oh, pis
N ® ©) nd F F ©) nd A id Ww n= N ®
N N | > (NA 5 A nS 0 vw, oN = o NY
AN +; N Lone [A i — N —
N N o
N 0 9 ON 0 N oto) sr Ng 0: 61 Os ©) Os 6) SN a
BU EC Spike TON 99 / °o Ml Le o A / o "el / 9 U, 9 N o 2 he 9 Fae N" ©) N F Ca © À = 19 nd A F 19 nd H w@ 13 y ® N A 5 rN J 8 an; 8 aw, x N — = = N —
N N ï — N { — Ÿ — N co =
N o N o N ° ° f vr ST o
Ï ou fo 6) alo or fe) 0, Ve a 0 A A
H
J o "we Ao J 9 ok Jo J à Mg ho PA 0 hh “
A Ve vo H 19 nl # & N (3) n={ fH ® N S) n=l H 5 1-9 n= ® (4 SS a, SS AN SS A; =
N TON = N N bl — | — 4 — i _J
N N N \ rN o N © Jd NA © d WSO 9 — ou lo ou lo oo) 99 ole.) Og y ge °° X NN Oo
J o Hg Hh re o Hg ho re oO & he J Qa (3) Ae < 7 7 78 8 Ea Ci N nA C8 N nA ® N- n= HM ®
PA 8 4j 8 4 OS CN Ÿ n° =n N N N
Ÿ — i — N — N —
N N i \
X\ 3 {X 2 o o
Ho N— © —N NAO FON \ — —/ ou lo) 61
Oger ex ° Or ©) oO > SE SA 4 H 9 . H 9 / Oo” f / o Hel
J 0 ol Je J 0 ©, A J © A o Hono
NT © ©) © NAH p 9 nu ee N n= Te 2 n= Ye
Mf 5 aa SB C4 Ss FA LS
F =/ on = \ N
N i — Ÿ — N — w — or N So No No
N
No N00 TNT 00 A N 9 o 0 & wi © S o Hg A © J 0 & ue J © A A © N &, nd H F 3) Nel F F N ) n={ H F N 5 N= ®)
A) OS A 5 a. LS a. Ss — == == — N
N N N i — 0 i _J CN N — Ÿ —
N N - -
N © CN 0 LN 0 IN 0 oJ 0,6) ou do) oy GA 99 ole) 99 y ip 99 Ÿ Nt 99 d o Hg y © J o fg wl © o 0 (3) 9h © o 0 (3) y © f pe 78 © 8 nA 0 N= Ea ND IE ® NT nA ®
SA 5 AR} 5 MS 5 SA 5
MA =/ =/ N { — i — N — Ÿ — „N N —
N 0 HO Lo 9 Wo N 0 / / \
0 0 a LO) LU505464 a yee, eos NES
J à He er J 0 thd J 0 "A o 0 eg v9 nl # YF 19 nd A fé WY N= 4 H F N X = S ©
AA SS A 5 a Ny wo Nv — N — N N =} i —" i — N — N — oN No N Jo N) 0
N a
OS N 9 ou. lo TON 9
On. ©} oy © 09 Ÿ GA 99 J 0 Hg Ae
TNT / o Hall J © Tol Je ©) {0 © / 0 Mel Le 9 N°70 © N © N N i 3 N © & nl H > NY N= ® NA m5
N N (5) = ® N $ 5 oN 5 == N
N—¢ Yo > N = 5 N —
N 1 J ; —N 0
WT N oN “Nn oN
N 0 N ! ole Oy. le 6 oo 5 CR 99 Ÿ Gi 99
OO Ng J N 9 J 0 sly de J ° ol, Je
À N 9 X de Ps N © “ N ©
J 0 [CI © N © N. N=! ® N: N=! ®
Pe OÙ YF AR © N Den = CS >
N = 7 - = == 4 ss FFs oN N — i — = N À N N
J N —N 0 N 0 oN NSO T
N
/ 5 GA 99 GA 99 on fo 09 Oy ©) 99 o oO Hy ws © o o Hy Ho o à "© Le of o Hg y ©
N
N NA ~ WF Ea ne 9 nt H P 19 nd # VE = Ÿ SS CY Ÿ = A; 8 rN SS
N N = { J {J (+ { —
N N N N
0 0 s. oO 0:8 o 0=§ oO 0 HN
NT NT NT NT
! I ! ! 0, 0, Ss) 0, Ss) o 0 oly Mo J 0 sly Mg o 0 oN Hm y o Hal
N © N © N © 0 N°2 6 n=l HP ® , NH ® n={ HM ® © H © a 5 NA y SS A OS N N © _ _ rN yg SS
N ; N | on ‘ N N ‘à oN oN oN w — » No N. NC N o
Os a 04 J o "© 3 © J 0 Hg Ane d ° "oe 5
J © A 0A ) N= N f Ww nl H YF Ww NH f 19 we # P FA 5 KE 8 SY; SS 4 5 — ms —
X 7 = Ç 5 ; N { I
N ;
H i — N oN ON o N ©
N N
N o Ç U oA,
Ô ) I ! oO (5)
OO No TON 9 J N 9 PA ol due
SN 5 / o Hl Je S À Je © i © / à Fo Je 9 N 5 N © N N= ® 8 N - Na n 9 nd H 3 u n= As d ay, 5
J A Los |” meo 9 Vo SS MeO, C3 zZ > N
No 7 TON N Ÿ —
N Ÿ — N — N 0
N _N oO —N oO —N 0° odo) 0 lo) oo) 5 N
LEN SNL 5 5 N a S 0 oy Je
TON Fo / o Hol Le o 0 "ol Je o N © / 0 À, de 8 N © ©) N © N N= 3 N ® NZ nA æ N N= = oN gf nS
N = æ 4} AS (À # Np N oN 7 = N — > Oo -
TON { — i N 0°
OS yi fe y à, N r oO !
In another aspect, the present invention provides a pharmaceutical composition comprising a compound according to any one of the preceding claims or a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof. 14
BL-5785
In one aspect, the invention also provides use of the aforementioned compounds LU505464 or the pharmaceutically acceptable salts, isotope derivatives, stereoisomers or pharmaceutical compositions thereof in the preparation of medicine for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune mediated disease.
In another aspect, the invention also provides a method for preventing and/or treating cancer, tumors, inflammatory diseases, autoimmune diseases, or immune- mediated diseases, comprising administering to a patient in need a therapeutically effective amount of the aforementioned compounds or the pharmaceutically acceptable salts, isotope derivatives, stereoisomers or pharmaceutical compositions thereof.
It should be noted that, in this article, when referring to the "compound" of formula (D, formula (II), formula (III) and formula (IV), it generally also covers its stereoisomers, diastereomers,enantiomers, racemic mixtures and isotopic derivatives.
It is well known to those skilled in the art that a compound's salt, solvate, and hydrate are alternative forms of the compound, and they can all be converted into the compound under certain conditions. When referring to the compounds of formula (I), formula (II), formula (III) and formula (IV), generally, their pharmaceutically acceptable salts are also included, and furthermore, their solvates and hydrates are also included.
Similarly, when referring to a compound herein, its prodrugs, metabolites and nitroxides are also generally included.
The pharmaceutically acceptable salts of the present invention may be formed using, for example, the following inorganic or organic acids. "Pharmaceutically acceptable salt" means a salt which, within the scope of reasonable medical judgment, is suitable for use in contact with tissues of humans and lower animals, without undue toxicity, irritation, allergic reaction, etc., can be called a reasonable benefit / risk ratio.
The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or alone by reacting the free base or acid with a suitable reagent, as outlined below. For example, a free base function can be reacted with a suitable acid. Examples of pharmaceutically acceptable inorganic acid addition salts are amino acids with inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric) or organic acids (e.g., acetic, oxalic, maleic, tartaric, lemon acid,
BL-5785 succinic acid or malonic acid), or by using other methods known in the art such as ion LU505464 exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, lauryl sulfate, ethylate, formate, fumarate, glucoheptonate, glycerin phosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, bitter salt, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluene sulfonate, undecanoate, valerate, etc. Representative alkali or alkaline earth metal salts include those of sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, nontoxic ammonium salts, quaternary ammonium salts, and amine cations formed with counterions, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates and arylsulfonates.
The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (such as acetone, methanol, ethanol and acetonitrile), adding an excess of organic acid or inorganic acid aqueous solution, so that the salt is precipitated from the resulting mixture, the solvent and remaining free acid are removed therefrom, and the precipitated salt is isolated.
The precursors or metabolites described in the present invention may be precursors or metabolites known in the art, as long as the precursors or metabolites are transformed into compounds through in vivo metabolism. For example, "prodrugs" refer to those prodrugs of the compounds of the present invention which, within the scope of sound medical judgment, are suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic response, etc., qualified as having a reasonable benefit/risk ratio and valid for its intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to yield the parent compound of the above formula, for example by in vivo metabolism, or N-demethylation of a compound of the invention. 16
BL-5785 "Solvate" as used herein means a physical association of a compound of the LUS05464 present invention with one or more solvent molecules, whether organic or inorganic.
This physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, solvates will be able to be isolated. Solvent molecules in solvates may exist in regular and/or disordered arrangements. Solvates may contain stoichiometric or non- stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution- phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
The "stereoisomerism" described in the present invention is divided into conformational isomerism and configurational isomerism, and configurational isomerism can also be divided into cis-trans isomerism and optical isomerism (that is, optical isomerism). Due to the rotation or twisting of carbon and carbon single bonds in organic molecules of a certain configuration, a stereoisomerism phenomenon in which each atom or atomic group of the molecule has a different arrangement in space, the common structures are alkanes and cycloalkanes. Such as the chair conformation and boat conformation that appear in the structure of cyclohexane. "Stereoisomer" means when a compound of the present invention contains one or more asymmetric centers and is thus available as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers. The compound of the present invention has an asymmetric center, and each asymmetric center can produce two optical isomers, and the scope of the present invention includes all possible optical isomers and diastereoisomer mixtures and pure or partially pure compounds . The compounds described herein may exist in tautomeric forms having different points of attachment of hydrogens by displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. All enantiomers, diastereoisomers, racemates, mesoforms, cis-trans isomers, tautomers, geometric isomers, epimers of compounds of formula (I) to formula (IV) and mixtures thereof are included in the scope of the present invention.
An "isotopic derivative" of the present invention refers to a molecule in which a compound is isotopically labeled. Isotopes commonly used for isotopic labeling are: 17
BL-5785 hydrogen isotopes, “H and *H; carbon isotopes: 'C, !*C and *C; chlorine isotopes: CI LU505464 and ‘’CI; fluorine isotopes: !*F; iodine isotopes: !°I and !°T, nitrogen isotopes: *N and
IN ; Oxygen isotopes: !°O, 170 and "*O and sulfur isotope S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues.
Especially deuterium *H and carbon ‘*C are more widely used due to their easy labeling and convenient detection. Substitution of certain heavy isotopes, such as deuterium (°H), can enhance metabolic stability, prolong half-life and thus achieve the purpose of reducing doses and provide therapeutic advantages. Isotopically labeled compounds are generally synthesized starting from labeled starting materials and carried out in the same way as non-isotopically labeled compounds using known synthetic techniques.
The present invention also provides the use of the compound of the present invention in the preparation of medicaments for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease or immune-mediated disease.
In addition, the present invention provides a pharmaceutical composition for preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, which comprises the present invention compounds as active ingredients. The pharmaceutical composition may optionally comprise a pharmaceutically acceptable carrier.
In addition, the present invention provides a method of preventing and/or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, which comprises administering the compound of the invention to the mammals in need thereof.
Representative examples of inflammatory, autoimmune, and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis , Other Arthritis
Conditions, Lupus, Systemic Lupus Erythematosus (SLE), Skin Related Disorders,
Psoriasis, Eczema, Dermatitis, Atopic Dermatitis, Pain, Pulmonary Disease, Lung
Inflammation, Adult Respiratory Distress Syndrome (ARDS) , pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, 18
BL-5785
Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's LU505464 syndrome, autoimmune thyroid disease, urticaria (rubella), multiple sclerosis, scleroderma, organ transplant rejection, xenograft, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B Cell Lymphoma, T Cell Lymphoma, Myeloma, Acute
Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Acute
Myeloid Leukemia (AML), Chronic Myelogenous Leukemia (CML), Hairy Cell
Leukemia, He Jie King's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), diffuse large
B-cell lymphoma, and follicular lymphoma.
Representative examples of cancer or tumor may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis carcinoma, hereditary nonpolyposis colorectal cancer, esophagus cancer, lip cancer, larynx cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, Papillary thyroid cancer, renal cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as Glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, Hodgkin lymphoma, non-
Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia ( ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder Carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, Osteosarcoma, chondrosarcoma, sarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, or plasmacytoma.
When the compound of the present invention or a pharmaceutically acceptable salt thereof is administered in combination with another anticancer agent or immune checkpoint inhibitor for the treatment of cancer or tumors, the compound of the present 19
BL-5785 invention or a pharmaceutically acceptable salt thereof can provide enhanced anticancer LU505464 effects .
Representative examples of anticancer agents useful in the treatment of cancer or tumors may include, but are not limited to, cell signal transduction inhibitor, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine,
Mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin , epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogs, methadone progesterone, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, leucovorin, sirolimus, sirolimus ester, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, britinib, cabozantinib, cediranib, crenolanib, kezhuotinib, dabrafenib, dabrafenib, Cotinib, danucitinib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, la Patinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motisanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tiratinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vimodegib, volasertib, alemtuzumab, bevacizumab, berentuzumab vedotin, catumaxumab Antibodies, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, PI3K inhibitor, CSF1R inhibitor,
A2A and/or A2B receptor antagonist, IDO inhibitor, anti-PD-1 antibody, anti-PD-L1 antibody, LAG3 antibody, TIM-3 antibody and an anti-CTLA-4 antibody, or any combination thereof.
When administered in combination with other therapeutic agents for the treatment of inflammatory disease, autoimmune disease and immune-mediated disease, the compounds of the present invention, or pharmaceutically acceptable salts thereof provide enhanced therapeutic effect.
Representative examples of therapeutic agents useful in the treatment of inflammatory, autoimmune, and immune-mediated diseases can include, but are not limited to, steroidal agents (e.g., prednisone, prednisone, prednisone, methylphenidate,
BL-5785 cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, LU505464 leflunomide, anti-TNFa agents (eg, etanercept, infliximab, adalib monoclonal antibody, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.), and antihistamines (e.g, diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one or more therapeutic agents selected from them can be included in the pharmaceutical composition of the present invention.
Other features of the invention will become apparent in the course of the description of exemplary embodiments of the invention which are given to illustrate the invention and are not intended to be limiting thereof. In the following examples the methods disclosed in the invention were used for preparation, separation and characterization.
The compounds of the present invention can be prepared in a variety of methods known to those skilled in the art of organic synthesis, the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or by variations thereof known to those skilled in the art may be used for the synthesis of the compounds of the present invention. Preferred methods include, but are not limited to, those described below. Reactions are performed in solvents or solvent mixtures appropriate to the kit materials used and to the transformations effected. Those skilled in the art of organic synthesis will appreciate that the functionality present on the molecule is consistent with the proposed transitions. This sometimes requires judgment to alter the order of synthetic steps or starting materials to obtain the desired compound of the invention.
Terms
Unless otherwise stated, the terms used in the present application, including the specification and claims, are defined as follows. If not stated otherwise, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used. In this application, the use of "or" or "and" means "and/or" if not stated otherwise.
In the specification and claims, a given chemical formula or name shall encompass all stereoisomers and optical isomers thereof and racemates in which such isomers exist.
Unless otherwise indicated, all chiral (enantiomers and diastereoisomers) and racemic forms are within the scope of the invention. Various geometric isomers of C=C double 21
BL-5785 bonds, C=N double bonds, ring systems, etc. may also exist in the compounds, and all LU505464 such stable isomers are encompassed by the present invention. The present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the invention and which may be isolated as a mixture of isomers or as separated isomeric forms. The compounds of the invention may be isolated in optically active or racemic forms. All methods used to prepare the compounds of the invention and intermediates prepared therein are considered part of the invention. When preparing enantiomeric or diastereomeric products, they may be separated by customary methods, for example by chromatography or fractional crystallization. Depending on the process conditions, the end products of the invention are obtained in free (neutral) or salt form. The free forms and salts of these end products are within the scope of the present invention. A compound can be converted from one form to another, if desired. A free base or acid can be converted into a salt; a salt can be converted into the free compound or another salt; a mixture of isomeric compounds of the invention can be separated into the individual isomers. The compounds of the invention, their free forms and salts, may exist in various tautomeric forms in which the hydrogen atoms are transposed to other parts of the molecule and thus the chemical bonds between the atoms of the molecule are rearranged. It is to be understood that all tautomeric forms which may exist are included within the present invention.
In the present invention, when the listed connecting groups do not specify the connecting direction, the connecting direction is arbitrary, for example when the L in
OC is -C(O)NH-, -C(O)NH- can both connect phenyl and cyclohexyl in the
OX reading order from left to right to form w=) , and connect phenyl and an cyclohexyl in the opposite reading order from left to right to form 70 The combination of the linking group and the connected group is only allowed if it results in a stable compound. In some preferred embodiments of the present invention, the reading order is from left to right.
Unless otherwise defined, the definitions of the substituents in the present invention are independent and not interrelated, for example (listed but not exhaustive), in one aspect, for the substituents Ra (or Ra") in different definitions of the substituents, the definitions are independent of each other. Specifically, when one definition is 22
BL-5785 selected for R* (or R¥) in one substituent, it does not mean that R? (or R*) has the same LU505464 definition in other substituents. More specifically, for example (but not exhaustively) for NR°R*, when R? (or R?) is defined from hydrogen, it does not mean that in -C(O)-
NR*R?, R? (or R*) must be hydrogen. In another aspect, when there is more than one
R? (or R?) in a certain substituent, these R* (or R¥) are also independent. For example, in the substituent -(CR*R*)m-O-(CR*R*)n-, when m+n is greater than or equal to 2, the m+n pieces of R* (or R*) are independent, and they can be have the same or different meanings.
Unless otherwise defined, when a substituent is noted as "optionally substituted", the substituent is selected from, for example, the following substituents, such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein 2 amino substituents are selected from alkyl radical, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl such as -SO,;NH,, substituted sulfonylamino, nitro, cyano, carboxyl, carbamoyl such as -CONH2, substituted carbamoyl such as -CONHalkyl, -CONHaryl, -CONHarylalkyl or two optional In the case of substituents from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclic, e.g. indolyl, imidazolyl, furyl, thienyl , Thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, etc. and substituted heterocyclyl.
The term "alkyl" as used herein is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
For example, "C1-Cs alkyl" means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl), and pentyl (e.g. n- pentyl, isopentyl, neopentyl). Alkyl may be unsubstituted or substituted, and when substituted, it may be substituted at any available point of attachment, the substituents being preferably selected from one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In this context, the alkyl group is preferably an alkyl group having 1 to 6, more preferably 1 to 4 carbon atoms.
The term "alkylene" as used herein is intended to include branched, straight-chain, 23
BL-5785 saturated aliphatic hydrocarbon radicals having the specified number of carbon atoms, LU505464 with or without cyclic alkyl groups, either from the same carbon atom or two different carbon atoms from the parent alkyl group. A residue derived from removing two hydrogen atoms from a carbon atom. For example, "Co-Cs alkylene" means an alkylene group having 0 (i.e, bonds), 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkylene include, but are not limited to, methylene (-CHz-), ethylene (-CH:CH»-), propylene (e.g.,-(CH»)s-, -(CHCH3)CH;-, -(CHCH:CH)-), butylene (eg, -(CHo)4-, -
CH,CH(CH:CH3)-, -CH,(CHCH,CH)- etc), pentylene (eg, -(CHys-, -
CH,CH(CH(CH3),)-, -CH,(CHCH:CH)CH»- etc.), hexylene (eg, -(CHa)s-, -
CH,CH,CH(CH(CH3),)-, -CH,(CHCH(CH;)CH)CHz-etc. In this disclosure, the alkylene group is preferably an alkylene group having 0-6, 0-4, 0-3, 1-6, 1-4, or 1-3 carbon atoms. In this disclosure, alkylene is preferably an alkylene group which does not contain a cyclic alkyl group.
The term "cycloalkyl" refers to a monocyclic, polycyclic or branched cyclic alkyl group. For example, Cz-C12 cyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Polycyclic, such as bicyclic and tricyclic cyclic alkyl groups include bridged, spiro or fused cyclic cycloalkyl groups. Cycloalkyl may be unsubstituted or substituted, and when substituted, it may be substituted at any available point of attachment, the substituents being preferably selected from one or more of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkyl, oxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In the invention, the cycloalkyl group is preferably a C3-C12 cycloalkyl group, and more preferably a Cs-Cs cycloalkyl group.
Similarly, the term "heterocycloalkyl" refers to a one-membered cyclic structure in which at least one carbon atom of the cycloalkyl ring is replaced by a heteroatom selected from the group consisting of N, O, S and P. The N atoms may be optionally quaternized, and the N and S atoms may be optionally oxidized (i.e., NO, SO, and SO»).
It includes monocyclic heterocyclic, bicyclic heterocyclic and tricyclic heterocyclic systems, wherein the bicyclic heterocyclic and tricyclic heterocyclic systems include spirocyclic heterocyclic, paracyclic heterocyclic and bridged heterocyclic.
Heterocycloalkyl may be unsubstituted or substituted, and when substituted, it may be substituted at any available point of attachment, the substituents being preferably selected from one or more of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, 24
BL-5785 haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. In the present invention, LU505464 the heterocycloalkyl group is preferably a 4-12-membered heterocycloalkyl group, and more preferably a 4-8-membered heterocycloalkyl group.
In the present invention, the term “cyclic ring” refers to a polycyclic group formed by two or more cyclic structures sharing two adjacent atoms with each other.
In the present invention, the term “bridged ring” refers to a polycyclic group in which two rings in the system share two or more ring atoms.
In the present invention, the term “spiro ring” refers to a polycyclic group in which one carbon atom (called a spiro atom) is shared between single rings.
The term "alkenyl" denotes a straight or branched chain hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms. For example, "C,-Cs alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, e.g. vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Herein, alkenyl is preferably C,-Cs alkenyl.
The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl group.
Monocyclic cyclic alkenyl refers to C3-Cg cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornenyl. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyl groups include bridged, spiro or condensed ring cyclic alkenyl groups.
The term "alkynyl" denotes a straight or branched chain hydrocarbon group containing one or more triple bonds and generally having a length of 2 to 20 carbon atoms. For example, "C,-C¢ alkynyl" contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1- butynyl, and the like. Herein, the alkynyl group is preferably a C,-Cs alkynyl group.
The term "alkoxy" or "alkyloxy" refers to -O-alkyl. " C1-C6 alkoxy" (or alkyloxy) is intended to include C1, Cz, C3, Ca, Cs, Ce alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), and tert- butoxy. Herein, the alkoxy group is preferably an alkoxy group having 1 to 6, more preferably 1 to 4 carbon atoms. Similarly, "alkylthio" or "thioalkoxy" means a sulfur- bridged alkyl group as defined above having the specified number of carbon atoms; for example, methyl-S- and ethyl-S-. Alkoxy may be unsubstituted or substituted, and when substituted, it may be substituted at any available point of attachment, the substituents being preferably selected from one or more of deuterium, halogen, hydroxyl, amino,
BL-5785 cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. LU505464
The term “carbonyl” refers to an organic functional group (C=0) consisting of two atoms, carbon and oxygen, linked by a double bond.
The term "aryl", alone or as part of a larger moiety such as "aralkyl", "arylalkoxy" or "aryloxyalkyl", refers to a single cyclic, bicyclic or tricyclic ring system having a total of 5 to 12 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetralin base. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring, non- limiting examples of which include benzyl, phenethyl, and the like. The fused aryl group can be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring. The dashed lines drawn from the ring system indicate that bonds can be attached to any suitable ring atom. Aryl groups may be unsubstituted or substituted, and when substituted, they may be substituted at any available point of attachment, the substituents being preferably selected from one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
The term "heteroaryl" means a stable 5-membered, 6-membered, or 7-membered aromatic monocyclic ring or aromatic bicyclic ring or a 7-membered, 8-membered, 9- membered, 10-membered, 11-membered, 12-membered aromatic polycyclic heterocycle, which is fully unsaturated or partially unsaturated, and contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; and includes cycloalkane or heterocycloalkane with a structure in which aromatic rings such as benzene rings or heteroaromatic rings such as pyridine are condensed. The position of the structure as a substituent may be located on a cycloalkane, a heterocycloalkane, an aromatic ring or a heteroaryl ring. Nitrogen and sulfur heteroatoms can be optionally oxidized. The nitrogen atom is substituted or unsubstituted (i.e. N or NR, where R is H or another substituent if defined). A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. The nitrogen in the heterocycle can optionally be quaternized.
Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and 26
BL-5785
O atoms in the heterocycle is not greater than one. Heteroaryl groups may be LU505464 unsubstituted or substituted, and when substituted, they may be substituted at any available point of attachment, the substituents being preferably selected from one or more of halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. When the term "heterocycle" is used, it is intended to include heteroaryl. Examples of heteroaryl groups include, but are not limited to, acridinyl, azetidinyl, aziocinyl, benzimidazolyl, benzofuryl, benzothiofuranyl, benzothienyl, benzooxa azolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2, 3-b] tetrahydrofuryl, furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridyl, indolenyl, indolinyl, Indolazinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuryl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoindolyl quinolinyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, diazanaphthyl, octahydroisoquinoline oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl , oxazolidinyl, oxazolyl, oxazolopyridyl, oxazolidinyl, diazaphenyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl , phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinyl, 4-piperidinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridimidazolyl, pyridothiazolyl, pyridyl , pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H- quinazinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydroquinolyl, 6H-1,2 5-thiadiazinyl, 1,2 ,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthryl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, thienooxa Azolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, quinolinyl, isoquinolyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzo Imidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3 -Dihydro-benzofuryl, chromanyl, 1,2,3,4-tetrahydro- quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl. The term "heteroaryl" may also include biaryl structures formed by the above-defined "aryl" and a monocyclic "heteroaryl", such as but not limited to "-phenyl bipyridyl-", "- "phenyl bipyrimidyl", 27
BL-5785 "_pyridyl biphenyl", "-pyridyl bipyrimidyl-", "-pyrimidyl biphenyl-"; wherein the 14505464 present invention also includes condensed ring and spiro compound containing, for example, the above-mentioned heterocycles.
The term "substituted" as used herein means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valences are maintained and that the substitution results in a stable compound. A cyclic double bond, as used herein, is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N or N=N).
In this disclosure, one or more halogens may be each independently selected from fluorine, chlorine, bromine, and iodine. "Halo" or "halogen" includes fluoro, chloro, bromo and iodo. "Haloalkyl"/"haloalkylene" is intended to include branched and straight chain saturated alkyl/alkylene groups having the indicated number of carbon atoms substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2.2 2-trifluoroethyl, heptafluoro propyl and heptachloropropyl.
Examples of haloalkyl also include "fluoroalkyl" intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with 1 or more fluorine atoms. "Halocycloalkyl"/"haloheterocycloalkyl" is intended to include cycloalkyl/heterocycloalkyl having the indicated number of carbon atoms substituted with one or more halogens. In the present invention, the halogen atom is preferably fluorine or chlorine, more preferably fluorine. "Haloalkoxy" or "haloalkyloxy" means a haloalkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. For example, "haloC1-C6 alkoxy" is intended to include C1, Ca, C3, Ca, Cs, Cs haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2, 2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" denotes a haloalkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge; for example trifluoromethyl-S- and pentafluoroethyl -S-.
In the present disclosure, the expression Cx1-Cx is used when referring to some substituent groups, which means that the number of carbon atoms in the substituent groups may be x1 to x2. For example, Co-Cs means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, C1-Cg means that the group contains 1, 2, 3, 4, 5, 6,7 or 8 carbon atoms, C,-Cg means that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms, 28
BL-5785
C3-Cs means that the group contains 3, 4, 5 , 6, 7 or 8 carbon atoms, C4-Cg means that LU505464 the group contains 4, 5, 6, 7 or 8 carbon atoms, Co-Cs means that the group contains 0, 1, 2, 3, 4 , 5 or 6 carbon atoms, C1-C6 means that the group contains 1, 2, 3, 4, Sor 6 carbon atoms, C2-Cs means that the group contains 2, 3, 4, 5 or 6 carbon atoms, C3-C6 means that the group contains 3, 4, 5 or 6 carbon atoms.
In this disclosure, the expression "x1-x2 membered ring" is used when referring to cyclic groups such as aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, which means that the number of the ring atoms of the group can be x1 to x2. For example, the 3-12 membered cyclic group may be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms may be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 3-6-membered ring means that the cyclic group can be 3, 4, 5 or 6-membered ring, and the number of ring atoms can be 3, 4, 5 or 6 ; 3-8 membered ring means that the cyclic group can be 3, 4, 5, 6, 7 or 8-membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7 or 8; 3-9 membered ring means that the cyclic group can be a 3, 4, 5, 6, 7, 8 or 9-membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8 or 9; 4-7 membered ring means that the cyclic group can be a 4, 5, 6 or 7-membered ring, and the number of ring atoms can be 4, 5, 6 or 7; 5-8-membered ring means that the cyclic group can be 5, 6, 7 or 8- membered ring, the number of ring atoms can be 5, 6, 7 or 8, 5-12 membered ring means that the ring group can be 5, 6, 7, 8, 9, 10, 11 or 12-membered ring, the number of ring atoms can be 5, 6, 7, 8, 9, 10, 11 or 12; 6-12 membered ring means that the ring group can be 6, 7, 8, 9, 10, 11- or 12-membered rings, the number of ring atoms may be 6, 7, 8, 9, 10, 11 or 12. The ring atoms may be carbon atoms or heteroatoms, for example selected from N, O and S. When the ring is heterocyclic, the heterocyclic ring may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, for example selected from N, O and S of heteroatoms.
Where nitrogen atoms (e.g. amines) are present on compounds of the invention, these nitrogen atoms can be converted to N-oxides by treatment with oxidizing agents (e.g. mCPBA and/or hydrogen peroxide) to obtain other compounds of the invention .
Accordingly, both shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxides to obtain the derivatives of the present invention.
When any variable occurs more than one time in any composition or formula of a compound, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R, then said group may be optionally substituted with up to three R groups, and R at each 29
BL-5785 occurrence is independently selected from the definition of R. Also, combinations of LU505464 substituents and/or variables are permissible only if such combinations result in stable compounds.
The term "patient" as used herein refers to an organism being treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, ape, monkey, equine, bovine, porcine, canine, feline, etc.) and most preferably refer to humans.
The term "effective amount" as used herein means an amount of a drug or agent (i.e., a compound of the invention) that will elicit a biological or medical response in a tissue, system, animal or human being sought, e.g, by a researcher or clinician.
Furthermore, the term "therapeutically effective amount" means an amount which results in improved treatment, cure, prevention or alleviation of a disease, disorder or side effect, or a reduction in the rate of disease or disorder progression. An effective amount may be given in one or more administrations, applications or doses and is not intended to be limited by a particular formulation or route of administration. The term also includes within its scope amounts effective to enhance normal physiological function.
As used herein, the term "treating" includes any effect that results in amelioration of a condition, disease, disorder, etc, such as alleviation, reduction, regulation, amelioration or elimination, or amelioration of the symptoms thereof.
The term "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions and/or dosage forms: within the scope of sound medical judgment, they are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, and/or other problems or complications, commensurate with a reasonable benefit/risk ratio.
The phrase "pharmaceutically acceptable carrier" or “pharmaceutical carrier” as used herein means a pharmaceutical substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g. lubricant, talc, magnesium stearate, calcium stearate, or zinc stearate, or stearic acid) or solvent-encapsulated substances involved in the carrying or transport of a subject compound from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
The term "pharmaceutical composition" means a composition comprising a compound of the present invention together with at least one other pharmaceutically
BL-5785 acceptable carrier. "Pharmaceutically acceptable carrier" means a medium generally LU505464 accepted in the art for delivering a biologically active agent to an animal, particularly a mammal, including (i.e) an adjuvant, excipient or vehicle, such as a diluent , preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, which depends on the mode of administration and the nature of the dosage form.
Certain pharmaceutical and medical terms
The term "acceptable", as used herein, means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.
The term "cancer", as used herein, refers to an abnormal growth of cells that cannot be controlled and, under certain conditions, is capable of metastasizing (spreading).
Cancers of this type include, but are not limited to, solid tumors (e.g., bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (e.g., thyroid), prostate, skin (melanoma), or blood cancer (such as non-leukemic leukemia).
The term "administration in combination" or similar terms, as used herein, refers to the administration of several selected therapeutic agents to a patient, in the same or different modes of administration at the same or different times.
The term "enhancing" or "capable of enhancing", as used herein, means that a desired result is capable of being increased or prolonged, either in potency or duration.
Thus, in relation to enhancing the therapeutic effect of a drug, the term "capable of potentiating” refers to the ability of the drug to increase or prolong its potency or duration in the system. As used herein, "potency value" refers to the ability to maximize the enhancement of another therapeutic drug in an ideal system.
The term "immune disease" refers to a disease or condition of an adverse or deleterious reaction to an endogenous or exogenous antigen. The result is usually dysfunction of the cells, or destruction thereof and dysfunction, or destruction of organs or tissues that may produce immune symptoms.
The term "subject" or "patient" includes mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as orangutans, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, and pigs, domestic animals such as rabbits and dogs; experimental animals include 31
BL-5785 rodents, such as rats, mice and guinea pigs. Non-mammalian animals include, but are LU505464 not limited to, birds, fish, and the like. In a preferred aspect, the selected mammal is a human.
The term "treatment", "course of treatment" or "therapy" as used herein includes alleviating, suppressing or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing and/or treating a sign caused by a disease or a symptom.
As used herein, a certain compound or pharmaceutical composition, after administration, can improve a certain disease, symptom or condition, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.
General process
When the preparation route is not included, the raw materials and reagents used in the present invention are known products, which can be synthesized according to methods known in the art, or can be obtained by purchasing commercially available products. All commercially available reagents were used without further purification.
Room temperature means 20-30°C.
There is no special description in the reaction examples, and the reactions are all carried out under a nitrogen atmosphere. The nitrogen atmosphere refers to a nitrogen balloon of about 1 L connected to the reaction flask.
The hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times. The hydrogen atmosphere means that the reaction bottle is connected with a hydrogen balloon of about 1L.
Microwave reactions use the Biotage® Initiator+ Microwave Reactor.
The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and mass spectroscopy (MS). NMR shifts (6) are given in units of 10° (ppm). The determination of NMR is to use (Bruker AscendTM 32
BL-5785 500 type) nuclear magnetic analyzer, the measurement solvent is deuterated dimethyl LU505464 sulfoxide (DMSO-d6), deuterated chloroform (CDC13), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS). The following abbreviations are used for the multiplicity of NMR signals: s = singlet, brs = broad singlet, d = doublet, t = triplet, m = multiplet. Coupling constants are listed as J values, measured in Hz.
As to reverse-phase preparative chromatography, a Thermo (UltiMate 3000) reverse-phase preparative chromatograph was used. The flash column chromatography uses Agela (FS-9200T) automatic column passing machine, and the silica gel prepacked column uses Santai SEPAFLASH® prepacked column. Yantai Huanghai HSGF254 or
Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates, and the specifications used for thin-layer chromatography separation and purification products are 0.4mm to 0.5mm.
LC-MS analysis method is as follows: 1) Mass spectrometry method: Thermo Fisher MSQ PLUS mass spectrometer, ESI source, positive ion mode. Ion source parameter settings: drying gas temperature is 350 °C; drying gas flow rate is 10 L/min; MS Range: 120-1000. 2) Liquid phase conditions: Chromatographic column: Waters XBridge (3.5um, 5S0mmx4.6mm); mobile phase A is an aqueous solution containing 0.1% ammonium bicarbonate, mobile phase B is an acetonitrile solution, and perform linear gradient elution in the following table 1; Flow rate: 2 mL/min; column temperature: 30°C; UV detection wavelength: 214nm, 254nm, 280nm; injection volume 2uL.
Table 1. Gradient elution conditions
Tim mobile mobile min phase A/% phase B/% 0 9% 5 1.4 5 95 2.8 5 95 2.820 95 5 3 95 5
HPLC analysis method is as follows:
Chromatographic column: Waters XBridge phenyl (3.5um, 150mmx4.6mm); 33
BL-5785 mobile phase À is aqueous solution containing 0.1% ammonium bicarbonate, mobile LU505464 phase B is acetonitrile solution, and linear gradient elution is carried out in the following table 2; flow rate: 1 mL/ min; column temperature: 30°C; UV detection wavelength: 214nm, 254nm, 280nm; injection volume 2uL.
Table 2. Gradient elution conditions mobile mobile
Time/min phase A/% phase B/% 0 95 5 5 95 5 95 20.2 95 5 24 95 5
The synthetic method of some intermediates in the invention is as follows:
Intermediate 1 /
AcO 2 c (S) ©
NA HN-Boc
O ~°
B M
ON
H
Intermediate 1 was prepared by the following steps: 34
BL-5785 o TBDPSCI 0 0 0 LU505464
Ho > Vo” “idole taps ~ An — NaOH ___TPPPS-O/ or soo TBDPS- Se
INT-1a INT-1b INT-1¢ INT-1d
TBDPS JBDPS
Br ! 0, HO,
To ©
N Acetic anhydride
INT-1e Br 0 1) LiBH,, THF Br TBAF Br TEA,DMAP
AIELCI N 2) diludine, TSOH,DCM 3 THF S DCM
DCM N 3)LIOH,MeOH,H20 N N
INT-1f INT-1g INT-1h
Oo INT-1k oo” oO ha o=( N 5) I J
B
Ve, LOUE SA
Pd(dppfClz, ACOK 9 Boc _ dioxane o-B Pd(dppfCly, K,PO4 N= Ss ENT Boe
Br A Ÿ dioxane/H20 / >
N H N
INT-1i INT-1j INT-11
Q O
~~ < ja d
Q LC Pinacolborane 9 De
NIS S-Phos, Pd,dbaz, ACOK ovr N= HN-Boc — uene n= HN-Boc
B
N oO N
H H
INT-1m INT-1
Step 1: 2.2-dimethyl-3-hydroxypropionate methyl ester INT-1a (100 g, 756.7 mmol) was dissolved in 1L N,N-dimethylformamide, imidazole (128.8 g, 1.89 mol) was added, stirred to dissolve, and tert-butyldiphenylchlorosilane (228.8 g, 832.3 mmol) was added dropwise at room temperature. After the addition was complete, stirring was continued for 4 hours. After the reaction was complete, the reaction solution was poured into 3L of ice water, the suspension was extracted with ethyl acetate (1L*2), the organic phase was washed with water three times, and then concentrated under reduced pressure to obtain INT-1b as a colorless oil. It was directly used in the next step without purification. ESI-MS (m/z): 371.2 [M+H]".
Step 2: Add the raffinate INT-1b obtained in the previous step into 2L of methanol, add 360 g of 33% aqueous sodium hydroxide solution, and stir at room temperature for 17 hours. After the reaction was complete, add 1L of water, remove methanol under reduced pressure, extract the residue with petroleum ether (1L*5), adjust the pH value of the aqueous phase to 4~5 with hydrochloric acid after extraction, continue to stir for
BL-5785 30 minutes, filter with suction, and dry to obtain white solid INT-1c (269 g, yield 90%). LU505464
ESI-MS (m/z): 357.8 [M+H]".
Step 3: INT-1¢ (130 g, 364.6 mmol) was dissolved in 500 mL of dichloromethane, thionyl chloride (130.1 g, 1.09 mol, 79.4 mL) was added at room temperature, stirred at 60 °C for 3 hours. After the reaction was complete, dichloromethane and remaining thionyl chloride were removed under reduced pressure to obtain INT-1d as a light yellow oil, without purification, 200 mL of dichloromethane was added for use.
Step 4: INT-1e (64.8 g, 331 mmol) was dissolved in 400 mL of dichloromethane, 198 mL of diethylaluminum chloride solution (2M in hexanes) was added dropwise at 0 °C. During the dropping process, the temperature was controlled to be no more than © C. Stir the solution for 30 minutes after the dropwise addition, and add the obtained
INT-1d dichloromethane solution dropwise into the reaction flask. During the dropping process the temperature was controlled to be no more than 10 °C. After the dropping was complete, continue the stirring for 2 hours. After the reaction was complete, the reaction solution was poured into 1L of ice water, stirred for 30 minutes, concentrated under reduced pressure to remove dichloromethane. The residue was extracted with ethyl acetate (1L*2), washed with water, and the organic phase was spin evaporated to obtain a brown oil. The oil was added to 2L of petroleum ether/ethyl acetate=10/1 mixed solution, the solid was precipitated by stirring, and filtered by suction to obtain INT-1f as a yellow solid (139 g, yield 78%). ESI-MS (m/z): 534.8 [M+H]".
Step 5: INT-1f (100 g, 187.1 mmol) was dissolved in 500 mL tetrahydrofuran, lithium borohydride (12.2 g, 561.2 mmol) was added, and stirred overnight at 60 °C.
After the raw materials disappeared, the reaction solution was added to 200 mL of ice water to quench, extracted with ethyl acetate (500 mL*3), and the organic phase was washed with water, dried, concentrated under reduced pressure, and the residue was dissolved in 500 mL of dichloromethane, then 2,6-dimethyl- Diethyl 1,4-dihydro-3,5- pyridinedicarboxylate (28.4 g, 112.2 mmol) and p-toluenesulfonic acid (21.4 g, 112.2 mmol) were added thereto, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove methylene chloride, and the residue was dissolved in 500 mL of methanol, 14% lithium hydroxide aqueous solution (100 mL) prepared in 36
BL-5785 advance was added, and the solution was stirred at room temperature for 3 hours, and LU505464 filtered with suction to obtain a yellow solid INT-1g (84 g, collected rate of 86.3%).
ESI-MS (m/z): 520.2 [M+H]".
Step 6: INT-1g (50 g, 96 mmol) was dissolved in 250 mL tetrahydrofuran, tetrabutylammonium fluoride (IM inTHF, 197mL) was added, stirred overnight at 60°C.
After the reaction was complete, the reaction solution was added to 300 mL of water, extracted with ethyl acetate (200 mL*3), washed with water, and concentrated under reduced pressure to obtain a brown oil. Dissolve the obtained residue in 40 mL of methanol, add 20 mL of water, wash the mixed solution with petroleum ether (40 mL*5), concentrate under reduced pressure to remove methanol, and extract the residue with ethyl acetate (50 mL*2). The organic phase was washed with water and dried to obtain
INT-1h (25 g, yield 90.4%) as a pale yellow oil. ESI-MS (m/z): 282.8 [M+H]".
Step 7: Dissolve compound INT-1h (22 g, 77 mmol) in 100 mL of dichloromethane. Add 4-dimethylaminopyridine (467 mg, 3.82 mmol), triethylamine (23.2 g, 230 mmol), and add acetic anhydride (7.9 g, 77 mmol) dropwise at 0 °C. After the dropwise addition, the temperature was raised naturally, and the solution was stirred overnight. After the reaction was complete, the reaction solution was washed with water, dried, and concentrated to obtain a brown oil, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to obtain a light yellow oil INT-1i (22.5 g, Yield 90.7%). ESI-MS (m/z): 324.2 [M+H]".
Step 8: Compound INT-1i (40 g, 123.4 mmol) was dissolved in dioxane (400 mL), potassium acetate (30.3 g, 308.4 mmol), [1,1'-bis(diphenyl
Phosphine)ferrocene]palladium dichloride (10 g, 12.3 mmol), pinacol diborate (78.3 g, 308.4 mmol) were added to react at 90 °C for 3 hours under nitrogen protection, LCMS monitored the complete reaction of the raw materials, and the reaction solution was directly concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with water and brine, and the organic phase was purified by silica gel column chromatography to obtain white solid compound INT-1j (35 g, yield 76.4%).
ESI-MS (m/z): 372.5 [M+H]".
Step 9: Dissolve compound INT-1j (35 g, 94.3 mmol) and compound INT-1k (37.9 37
BL-5785 g, 103.7 mmol) in dioxane (300 mL) and water (30 mL), add potassium phosphate ( 50 LU505464 g, 235.7 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6.89 g, 9.43 mmol) to react overnight at 90 °C under nitrogen protection. LCMS monitored the complete reaction of the raw material, the reaction solution was directly concentrated under reduced pressure, the residue was dissolved in ethyl acetate (300 mL), washed with water and brine, and the organic phase was purified by silica gel column chromatography to obtain yellow oily compound INT-11 (28 g, yield 56.08%).
ESI-MS (m/z): 530.7 [M+H]".
Step 10: Dissolve compound INT-11 (28 g 529 mmol) in N,N- dimethylformamide (280 mL), add N-iodosuccinimide (11.9 g, 52.9 mmol) to react at 50°C for 2 hours. LCMS monitored the complete reaction of the raw materials, and the reaction solution was poured into water (800 mL), extracted with ethyl acetate (200 mL*2). The organic phase was washed with saturated brine, dried, filtered, and purified through a silica gel column chromatography to give a yellow solid compound INT-1m (22 g, yield 63.5%). ESI-MS (m/z): 656.6 [M+H]*.
Step 11: Compound INT-Im (5 g, 7.63 mmol), 2-dicyclohexylphosphine-2',6"- dimethoxy-biphenyl (939.4 mg, 229 mmol), tris(dimethoxy benzylacetone) dipalladium (838.1 mg, 0.915 mmol), potassium acetate (2.6 g, 26.7 mmol) were dissolved in toluene (100 mL), and pinacol borane (4.9 g, 38.1 mmol) was added under nitrogen protection, after the addition was complete, the reaction was carried out at °C for 5 hours under the protection of nitrogen. LCMS monitored the complete reaction of the raw materials. The reaction solution was filtered and purified by silica gel column chromatography to obtain a yellow oily compound INT-1 (4.5 g, yield 90%).
ESI-MS (m/z): 656.5 [M+H]". 38
BL-5785
Intermediate 2 LU505464
O
Wade)
HN—N
O
° (S)
NA HN-Boc
S
O, J >
B
O N
H
Intermediate 2 was prepared by the following steps: o , INT-2b 3. 5 = A 8 A Nor HO J fu O
S) | © HN-NH TFA (S) ;
LiOH'H2O N= HN—Boc \ LIOH'H0
N= ANB To SS TCFH, NMI AS THF/H20 4 = — ACN } NP
N
INT-1m INT-2a INT-2c
HO HO HN-N HNN 0 Pinacolborane / HN-N
A © vee o A S-Phos, Pd2dba3, AcOK 0 A ©
Ne 5 HN-Boc DCM N= = HN-Boc THF N= s HN —Boc — — I (
N H ° À
INT-2d INT-2e INT-2
Step 1: Compound INT-1m (12 g, 18.3 mmol) was dissolved in tetrahydrofuran (120 mL) and water (20 mL), lithium hydroxide monohydrate (3.84 g, 91.5 mmol) was added to react overnight at room temperature, LCMS monitored the complete reaction of raw materials, the reaction solution was directly concentrated under reduced pressure, the residue was dissolved in water (100 mL), the pH was adjusted to 4~5 with 4M hydrochloric acid, the solution was extracted with dichloromethane (100 mL*3), the organic phase was washed with water, and washed with salt water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain white solid compound INT-2a (10.6 g, yield 96.6%). ESI-MS (m/z): 600.7 [M+H]".
Step 2: Compound INT-2a (9.5 g, 15.9 mmol) and compound INT-2b (11.7 g, 31.7 mmol) were dissolved in acetonitrile (190 mL), NNNN "-
Tetramethylchloroformamidine hexafluorophosphate (6.67 g, 23.8 mmol) and 1- methylimidazole (6.51 g, 79.2 mmol) were added to react at 0 °C for 1 hour, and the 39
BL-5785 reaction of the raw materials was monitored by LCMS to be complete. The reaction LU505464 solution was poured into water (200 mL), extracted with dichloromethane (100 mL*3), the organic phase was washed with water, and purified by silica gel column chromatography to obtain compound INT-2¢ (9.6 g, yield 83.5%) as a yellow solid.
ESI-MS (m/z): 726.3 [M+H]".
Step 3: Dissolve compound INT-2¢ (9.6 g, 13.2 mmol) in tetrahydrofuran (100 mL) and water (10 mL), add lithium hydroxide monohydrate (1.39 g, 33.1 mmol), and react at room temperature for 4 hours. LCMS monitored the complete reaction of the raw materials. The reaction solution was directly concentrated under reduced pressure, the residue was dissolved in water (100 mL), the pH was adjusted to 4~5 with 4M hydrochloric acid, and a white solid precipitated. After being filtered, washed with water, and dried a white solid compound INT- 2d (8.3 g, 88.2% yield) was obtained.
ESI-MS (m/z): 712.6 [M+H]".
Step 4: Dissolve compound INT-2d (3.5 g, 4.9 mmol), 1-hydroxybenzotriazole (1.99 g, 14.8 mmol), 4-dimethylaminopyridine (1.8 g, 14. mmol) in dichloromethane (170 mL), N,N-diisopropylethylamine (6 mL, 34.4 mmol) was added at 0°C, then 1-(3- dimethylaminopropyl)-3-ethylcarbodieneamine hydrochloride (4.71 g, 24.6 mmol) was added to react overnight at room temperature. LCMS monitored the complete reaction of the raw materials. The reaction solution was washed with saturated ammonium chloride aqueous solution, dried over sodium sulfate, and purified by silica gel column chromatography to obtain a yellow solid compound INT-2e ( 2 g, yield 58.6%). ESI-
MS (m/z): 694.6 [M+H]".
Step 5: Compound INT-2e (500 mg, 0.721 mmol), 2-dicyclohexylphosphine- 2',6"-dimethyl-biphenyl (88.8 mg, 0.216 mmol), tris(dibenzylidene acetone) dipalladium (79 mg, 0.086 mmol), potassium acetate (247 mg, 2.52 mmol) were dissolved in tetrahydrofuran (20 mL), and pinacolborane (461 mg, 3.6 mmol) was added under nitrogen protection. After the addition was complete, the reaction solution was allowed to react at 50 °C for 3 hours under the protection of nitrogen.
LCMS monitored the complete reaction of the raw materials. The reaction solution was filtered and purified by silica gel column chromatography to obtain a yellow solid compound INT-2 (400 mg, yield 80%). ESI-MS (m/z): 694.6 [M+H]". 40
BL-5785
LU505464
Intermediate 3
O
1 {(S) )
HN—N © (S) © n= HN
S “Cs xe >
BH oO N
H
Intermediate 3 was prepared by the following steps: 0 o INT-3b 0 nes du des ne (S) / Le) / ©) vod / =)
O 0 “Cs 0
Oo LE TFA o A > © LE D
N= HN-Boc DOM N=\ N2 TCFH, NMI N= an = = ACN ~° > 7 | Ÿ | Ÿ
INT-2e INT-3a INT-3c
O,
HN—N
Pinacolborane ©) O
S-Phos, Pd2dba3, AcOK © LE L
THF NS HN +85) to 7
B oO N
H
INT-3
Step 1: Dissolve compound INT-2e (1.7 g, 2.45 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (5 mL), and react at room temperature for 2 hours. LCMS monitored that the reaction of the raw materials was complete, and the reaction solution was directly concentrated under reduced pressure, the residue was dissolved in DCM (50 mL), washed twice with saturated NaHCO; aqueous solution, the organic phase was washed with water, dried over sodium sulfate, filtered, and concentrated to obtain compound INT-3a (1.3 g, yield 89.4%) as a yellow solid. ESI-MS (m/z): 594.7 [M+H]".
Step 2: Compound INT-3a (1.3 g, 2.19 mmol) and compound INT-3b (0.24 g, 2.41 mmol) were dissolved in acetonitrile (30 mL) NNNN "- tetramethylchloroformamidine hexafluorophosphate (921.9 mg, 3.29 mmol), and 1- 41
BL-5785 methylimidazole (414 mg, 5.04 mmol) were added to react at 0 °C for 1 hour, LCMS LU505464 monitored the complete reaction of the raw materials, and the reaction solution was poured into water (50 mL), extracted with dichloromethane (50 mL*3). Wash the organic phase with water, mix the sample and pass through the column for purification to obtain white solid compound INT-3¢ (1.3 g, yield 87.9%). ESI-MS (m/z): 675.7 [M+H].
Step 1: Compound INT-3¢ (1.1 g, 1.63 mmol), 2-dicyclohexylphosphine-2',6'- dimethyl-biphenyl (200.5 mg, 0.188 mmol), tris(dibenzylidene acetone) dipalladium (179 mg, 0.195 mmol), potassium acetate (559 mg, 5.7 mmol) were dissolved in toluene (30 mL), and pinacol borane (1.04 g, 8.14 mmol) was added under nitrogen protection. The solution was allowed to react at 50 °C for 3 hours under nitrogen protection after the addition was complete. LCMS monitored the complete reaction of the raw materials, the reaction solution was filtered, and purified by silica gel column chromatography to obtain a yellow solid compound INT-3 (990 mg, yield 90%). ESI-
MS (m/z): 676.9 [M+H]".
Intermediate 4
O
1 {(S) )
HN—N © (S) ©
N= HN (0 0 = S NS)
B84 (R)
O N
H
Intermediate 4 was prepared by the following steps:
HN-N “09 HN-N HN-N
O ® 0 0 Pinacolborane © 0 i C7 Term, nm 1s "Lo a Soames 1s Tg, — ACH — J ne. ( /®
H N ON
INT-3a INT-4b INT4
Step 1: Compound INT-3a (2.2 g, 3.71 mmol) and compound INT-4a (0.47 g, 4.08 42
BL-5785 mmol) was dissolvd in dichloromethane (50 mL), N,N,N' at 0 °C , N'- LU505464 tetramethylchloroformamidine hexafluorophosphate (1.56 g, 5.56 mmol), and 1- methylimidazole (0.70 g, 8.53 mmol) were added to react at 0 °C for 1 hour. LCMS monitored the complete reaction of the raw materials, and the reaction solution was poured into water (50 mL), extracted with dichloromethane (50 mL*3), the organic phase was washed with water, and the sample was mixed and purified by column to obtain white solid compound INT-4b (2.3 g, yield 90.0%). ESI-MS (m/z): 690.2 [M+H]".
Step 2: Compound INT-4b (2.1 g, 3.05 mmol), 2-dicyclohexylphosphine-2',6'- dimethyl-biphenyl (375.0 mg, 0.91 mmol), tris(dibenzylidene acetone) dipalladium (334.6 mg, 0.365 mmol), potassium acetate (1.05 g, 10.7 mmol) were dissolved in toluene (30 mL), and pinacolborane (1.95 g, 15.2 mmol) was added under nitrogen protection. After the addition was complete, the reaction system was allowed react at °C for 3 hours under the protection of nitrogen. LCMS monitored the complete reaction of the raw materials. The reaction solution was filtered and purified by silica gel column chromatography to obtain a yellow solid compound INT-4 (1.8 g, yield 85.7%). ESI-MS (m/z): 690.3 [M+H]".
Intermediate S +0 (S)
NS Br © cr Seer
Intermediate 5 was prepared by the following steps: 43
BL-5785
LU505464 = 23 7 ©
Br OZ NTN Br Nalog KOsO, NB
Done Ho OS WE ©
A 07
INT-5a INT-5b INT-5c
O 0 asser Dr vos C
EtOH, H,0 lL THF
HO. # oS ror
INT-5d INT-6
Step 1: Compound INT-5a (20 g, 58.5 mmol) and vinyl borate pinacol ester (10.8 g, 70.2 mmol) were dissolved in 1,4-dioxane (120 mL) and water (12 mL), potassium carbonate (16.2 g, 117.0 mmol), [1,1’-bis(diphenylphosphino)ferrocene]palladium dichloride (2.12 g, 2.92 mmol) were added. The reaction solution was stirred over night at 60 °C under the protection of N:. LCMS monitored the complete reaction of raw materials. The reaction solution was distilled under reduced pressure to remove excess solvents. The residue was added with water (100 mL), extracted with ethyl acetate (100 mL*3), the organic phase was filtered, washed with water. The sample was mixed and passed through column for purification to obtain a white solid compound INT-5b (13 g, yield 92.0%). ESI-MS (m/z): 242.2 [M+H]".
Step 2: Compound INT-Sb (13 g, 53.69 mmol) was dissolved in 300 mLtetrahydrofuran, 100 mLwater was added. Upon stirring, sodium periodate (28.7 g, 134.2 mmol) and potassium osmate (157.50 mg, 536.9 umol) were added. The reaction solution was stirred for 3 hours. LCMS monitored the complete reaction of raw materials. Upon liquid seperation, the aqueous phase was extracted with ethyl acetate (50 mL*3), and the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to obtain a white solid compound INT-5¢ (11.2 g, yield 85.5%). ESI-MS (m/z): 244.5 [M+H]".
Step 3: Compound INT-5¢ (1 g, 4.10 mmol) was dissolved in 15mL ethanol and 10mL water. Then hydroxylamine hydrochloride (313.17 mg, 4.51 mmol) and sodium 44
BL-5785 acetate (613.26 mg, 4.51 mmol) were added. Upon stirring for 1 hour, LCMS monitored LU505464 the complete reaction of raw materials. The reaction solution was subjected to suction filtration to obtaine a light yellow solid compound INT-5d (1.06 g, yield 94.2%). ESI-
MS (m/z): 259.4 [M+H]".
Step 4: Compound INT-5d (1.06 g, 3.86 mmol) was dissolved in 15 mLtetrahydrofuran, N- chlorosuccinimide (1.20 g, 9.01 mmol) was added. The reaction solution was stirred at room temperature for 3 hours. LCMS monitored the complete reaction of raw materials. The reaction solution was added with water (30 mL), extracted with ethyl acetate (20 mL*3), and the organic phases were concentrated to obtain a light yellow solid compound INT-5 (1.1 g, yield 85.8%).
ESI-MS (m/z): 293.0 [M+H]".
Intermediate 6 /
Qe)
N
\
N
O
Boe
Intermediate 6 was prepared by the following steps:
A
© Boo) N Se
NN Br A
INT-6a
A SN
NaHCO+ DCM/H20, rt N a FN 9
OH N
Bod INT
INT-5
Step 1: Intermediate INT-6a (739.2 mg, 3.75 mmol) and Intermediate INT-5 (550 mg, 1.87 mmol) were dissolved in a mixed solvent of dichloromethane (7 mL) and water (7 mL), sodium bicarbonate (472.2 mg, 5.62 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. LCMS detected that the reaction was complete. The reaction system was added with saturated brine, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, and 45
BL-5785 dried over anhydrous sodium sulfate, filetered and concentrated. The residue was LU505464 purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain a white solid compound INT-6 (625 mg, yield 73.4%). ESI-MS (m/z): 454.6 [M+H].
Intermediate 7 /
N
\ „N
Boc- N ©
Intermediate 7 was prepared by the following steps: _0 0 B © Boo—N p= NTS
Br A
NN
INT-7a
A S
NaHCO3,DCM/H,0, rt N cITSN | 9
OH Boc”
INT-5 INT-7
Use INT-7a to replace Intermediate INT-6in the synthesis step of INT-6a, and use similar methods and reaction steps to obtain compound INT-7. ESI-MS (m/z): 426.4 [M+H].
Intermediate 8 /
Os)
N
\
N
O
Boc- N
Intermediate 8 was prepared by the following steps: 46
BL-5785
Lo LU505464 © h-BuLi, Methyltriphenyl- 1 me SN N > " phosphonium bromide OH
INT-8a INT-8b
Bod’.
INT-8
Step 1: Methyltriphenylphosphine bromide (2.54 g, 7.1 mmol) was dissolved in tetrahydrofuran (10 mL), and n-butyllithium (2.84 mL, 2.5M, 7.1 mmol) was added dropwise in an ice bath. The mixture was stirred in an ice bath for 1 hour. Then a solution of INT-8a (500 mg, 2.37 mmol) in tetrahydrofuran (2 mL) was added dropwise.
After the dropwise addition was completed, the reaction solution was raised to room temperature and stirred for 16 h. LCMS detected that the reaction was complete. The reaction system was added with saturated ammonium chloride solution, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain a white solid compound INT-8b (400 mg, yield 80.8%). ESI-MS (m/z): 210.4 [M+H]".
Step 2: Intermediate INT-8b (214 mg, 1.02 mmol) and Intermediate INT-5 (300 mg, 1.02 mmol) were dissolved in a mixed solvent of dichloromethane (5 mL) and water (5 mL), sodium bicarbonate (472.2 mg, 5.62 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. LCMS detected that the reaction was complete. The reaction system was added with saturated brine, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain a white solid compound INT-8 (350 mg, yield 73.4%). ESI-MS (m/z): 466.5 [M+H]". 47
BL-5785
Intermediate 9 LU505464
J
(S)
N
\ „N
O
N
Bod
Intermediate 9 was prepared by the following steps:
LO
0 - - INT-9a ANB
NT Br oc | DD
A —————— ie
NaHCO3,DCM/H,0, rt SN
CIN 0
OH
N
INT-5 Boc INT-9
Use INT-9a to replace INT-6a in the synthesis step of Intermediate INT-6, and use similar methods and reaction steps to obtain compound INT-9. ESI-MS (m/z): 440.4 [M+H]".
The synthesis method of the example compound in the present invention 1s as follows:
Example 1 (18,2S)-N-((63S,48,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(8-methyl-1- oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-11 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamide
Os NN O o o Hel he
J vA (S) N=
S
N >> y NI] — N \ — „N 48
BL-5785
Example 1 was prepared by the following steps: LU505464 _0
NS BT fo 09 N 99
INT-6 F T H Aa 7 À uy A
O =
J ! (0) d oO N C5 o N i
O A N
Ts NL er Ss | Err SS
I / = | K3PO4, dioxane, NF N NF > dg N H20, 70°C | 7 17
H
INT-3 N 1a N 1b
N N
Boc Bod (a pa 5, NL © 9 N° © "1 N I 1% Ay 4 uy Tf o N° o N° 5 3
HCHO,
TFA NaBH(OAc)3
DCM DCE, rt +
Pa | N LS | N Ps | N
ND) Ny) No)
SN 1c N 1 5 1 oO O oO
N N N
Step 1: Intermediate INT- 3 (342 mg, 0.51 mmol) and Intermediate INT- 6 (200 mg, 0.44 mmol) was dissolved in a mixed solvent of 1,4-dioxane (7 mL) and water (0.7 mL), [1,1°-bis(diphenylphosphino)ferrocene]palladium dichloride (64.4 mg, 0.088 mmol) and potassium phosphate (280 mg, 1.32 mmol) were added. The reaction system was replaced with nitrogen and then heated to 70 °C to stir for 12 h. After the reaction solution was cooled to room temperature, the reaction solution was filled with diatomaceous earth and the filtrate was concentrated. the residue was purified by silica gel column chromatography (dichloromethane/methanol= 20/1) to obtain a light yellow solid compound 1a (243.8 mg, yield 60%). ESI-MS (m/z): 923.5 [M+H]".
Step 2: Compound 1a (243.8 mg, 0.26 mmol) was dissolved in DMF (5 mL), cesium carbonate (169 mg, 0.52 mmol) was added, and then ethyl iodide (61 mg, 0.39 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 6 hours. LCMS detected that the reaction was complete. The 49
BL-5785 reaction system was added with saturated brine, extracted with ethyl acetate, the organic 505464 phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product of compound 1b (247 mg, yield 100%). ESI-MS (m/z): 951.5 [M+HJ*.
Step 3: The compound 1b (247 mg, crude product) was dissolved in dichloromethane (3 mL), at 0 °C trifluoroacetic acid (1 mL) was added dropwise to the reaction solution. The reaction solution was stirred at 0 °C for 1 hour. LCMS detected that the reaction was complete. The reaction system was added with saturated sodium bicarbonate aqueous solution to quench the reaction, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a light yellow solid compound 1c (199 mg, yield 90%). ESI-MS (m/z): 851.5 [M+H]".
Step 4: Compound 1c (80 mg, 0.094 mmol) was dissolved in 1,2-dichloroethane (2.5 mL), at room temperature aqueous solution of formaldehyde (23 mg, 0.282 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 10 minutes. Then triacetyl sodium oxyborohydride (120 mg, 0.56 mmol) was slowly added to reaction solution. The reaction solution was continued to stir at room temperature for 3 hours. LCMS detected that the reaction was complete. The reaction system was added with saturated ammonium chloride aqueous solution to quenche the reaction, extracted with dichloromethane, and the organic phases were combined and concentrated. The residue was purified by preparative liquid phase to obtain a white solid compound 1 (5mg, yield 6.2%) and epimer 1° (6.8 mg, yield 8.4%).
The absolute configurations drawn by the two compounds are based on empirical assumptions, compound 1 is an isomer with relatively long retention time in LC-MS and HPLC, and 1’ is an isomer with relatively short retention time in LC-MS and HPLC.
Compound 1
ESI-MS (m/z): 865.6 [M+H]'; LC-MS retention time RT=1.70 min. HPLC retention time RT= 12.25 min. 'H NMR (500 MHz, DMSO-d6) 8 8.98 (d, J = 2.3 Hz, 1H), 8.56-8.48 (m, 2H), 7.98 (d, J= 2.2 Hz, 1H), 7.81 (s, 1H), 7.76 (dd, J = 8.7, 1.6 Hz, 1H), 7.59 (d, J = 8.6
BL-5785
Hz, 1H), 5.56 (t, J= 9.1 Hz, 1H), 5.10 - 5.05 (m, 1H), 4.37-4.08 (m, 5H), 3.62-3.56 (m, | -U505464 2H), 3.32-3.29 (m, 4H), 3.27 (s, 3H), 3.17-3.13 (m, 1H), 3.03-2.96 (m, 1H), 2.78-2.72 (m, 1H), 2.44-2.39 (m, 1H), 2.35-2.26 (m, 2H), 2.19 (s, 3H), 2.11-2.05 (m, 1H), 1.86- 1.72 (m, 6H), 1.54-1.47 (m, 2H), 1.38 (d, J= 6.0 Hz, 3H), 1.09-1.03 (m, 4H), 0.96-0.83 (m, 7H), 0.58-0.52 (m, 1H), 0.36 (s, 3H).
Compound 1’
ESI-MS (m/z): 865.5 [M+H]'; LC-MS retention time RT=1.69 min. HPLC retention time RT= 12.14 min. "HNMR (500 MHz, DMSO-4) 8 9.00 (d, J = 2.2 Hz, 1H), 8.57-8.51 (m, 2H), 8.14 (d, J = 2.3 Hz, 1H), 7.81 (s, 1H), 7.75 (dd, J = 8.6, 1.7 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 5.55 (t, J= 9.1 Hz, 1H), 5.07-5.03 (m, 1H), 4.26-4.19 (m, 2H), 4.01-3.95 (m, 2H), 3.86-3.80 (m, 1H), 3.70-3.63 (m, 1H), 3.57-3.51 (m, 1H), 3.23-3.13 (m, 3H), 3.10 (s, 3H), 3.09-3.04 (m, 1H), 2.76 (s, 1H), 2.37-2.28 (m, 3H), 2.19 (s, 3H), 2.15-2.10 (m, 1H), 1.86-1.75 (m, 7H), 1.54-1.49 (m, 2H), 1.42-1.35 (m, 1H), 1.28-1.21 (m, SH), 1.14- 1.04 (m, 8H), 0.93 (s, 3H), 0.89-0.86 (m, 1H), 0.58-0.53 (m, 1H), 0.49 (s, 3H).
Example 2 (1S,28)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(2-methyl-5- oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-11 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)- pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamide xx °
O Sa Ao
J N "76 (S) N= y — N { — „N —N1/ 0
Example 2 was prepared by the following steps: 51
BL-5785
Lo LU505464
N N Br Q oO 7 9 NP © © N° 0 0 ©) > _ Bod ( Cs,CO3, Et { No
N= HN Pd(dpphCla, DMF, rt
S Ne ioxane
By. 4 > [>= oe Tome oR | 2 \
J N CH CN
INT-3 PZ 2a \ 2 ) 2b
EN N
O O
N N
Boc Boc a Oo GN Po Gi Oo
T N rar T N ed T N ed 0 NS HCHO, 0 NT 0 NT
TFA NaBH(OAc)4 +
DCM DCE, rt “af L, ne L, ne L,
NJ ) 2 NJ ) 2 N A ) 2
Un &
O O O
HN N N
/ /
Use INT-7 to replace INT-6 in the synthesis step of compound 1, and use similar methods and reaction steps to obtain compound 2 and epimer 2’. The absolute configurations drawn by the two compounds are based on empirical assumptions, and compound 2 is an isomer with relatively long retention time in LC-MS and HPLC, and 2’ is an isomer with relatively short retention time in LC-MS and HPLC.
Compound 2
ESI-MS (m/z): 837.6 [M+H]'; LC-MS retention time RT=1.68 min. HPLC retention time RT= 12.18 min. 'H NMR (500 MHz, DMSO-de) & 8.98 (d, J = 2.2 Hz, 1H), 8.53-8.49 (m, 2H), 7.98 (d, J= 2.2 Hz, 1H), 7.81 (s, 1H), 7.76 (dd, J = 8.6, 1.7 Hz, 1H), 7.59 (d, J = 8.6
Hz, 1H), 5.56 (t, J= 9.1 Hz, 1H), 5.11-5.05 (m, 2H), 4.38-4.29 (m, 2H), 4.26-4.17 (m, 2H), 4.12-4.06 (m, 1H), 3.81-3.77 (m, 2H), 3.58 (s, 2H), 3.54-3.48 (m, 3H), 3.28-3.24 (m, SH), 3.18-3.12 (m, 1H), 3.00- 2.95 (m, 1H), 2.79-2.72 (m, 1H), 2.45-2.40 (m, 1H), 2.28 (s, 3H), 2.11-2.06 (m, 1H), 1.82-1.77 (m, 2H), 1.53-1.47 (m, 2H), 1.37 (d, J= 6.0
Hz, 3H), 1.09-1.05 (m, 4H), 0.92-0.84 (m, 7H), 0.57-0.53 (m, 1H), 0.34 (s, 3H).
Compound 2’
ESI-MS (m/z): 837.5 [M+H]'; LC-MS retention time RT=1.66 min. HPLC retention time RT= 11.98 min. 52
BL-5785 'H NMR (500 MHz, DMSO-d) 5 8.99 (d, J = 2.2 Hz, 1H), 8.57-8.50 (m, 2H), | LUV505464 8.14 (d, J= 2.2 Hz, 1H), 7.81 (s, 1H), 7.75 (dd, J = 8.7, 1.6 Hz, 1H), 7.55 (d, J = 8.6
Hz, 1H), 5.55 (t, J= 9.2 Hz, 1H), 5.07-5.03 (m, 1H), 4.27-4.18 (m, 2H), 4.03-3.93 (m, 2H), 3.86-3.77 (m, 2H), 3.73-3.65 (m, 2H), 3.58-3.47 (m, 3H), 3.28-3.23 (m, 2H), 3.19- 3.13 (m, 1H), 3.09 (s, 3H), 3.09-3.03 (m, 1H), 2.81-2.73 (m, 1H), 2.35-2.26 (m, 4H), 2.16-2.08 (m, 1H), 1.85-1.75 (m, 2H), 1.56-1.48 (m, 2H), 1.24 (d, J= 6.3 Hz, 3H), 1.13- 1.04 (m, 7H), 0.92 (s, 3H), 0.90-0.86 (m, 1H), 0.59-0.53 (m, 1H), 0.49 (s, 3H).
Example 3 (1S,25)-N-((63S,4S,Z))-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(8-(oxetan-3- yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)pyridin-3-yl)-10,10-dimethyl-5,7- dioxo-61,62,63,64,65,66-hexahydro-11 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola- 6(1,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamide
Oy LN o Tel Me
J N 7 (S) N=
S
N N
NO] — N \ —
N
O
N
ST
Example 3 was prepared by the following steps: 53
BL-5785 © LU505464
HN—N
Oo ©) ° 79 NX HNL =
US NE
Jodo) MN 7 >= 7 HN-N — N ° (SZ Q N — —A N= HN (S) Yo N o , oS Ne) O 7 . a "a — N cOH, rt
A >e
HN o 1c fe] ©) 9 79 N= HN 5 av 5 a oN 3
I
Step 1: Compound 1c (40 mg, 0.047 mmol) was dissolved in 1,2-dichloroethane (2 mL), at room temperature 3-oxetanone (6.8 mg, 0.094 mmol), acetic acid (0.3 mg, 0.0047 mmol) and triacetyl sodium oxyborohydride (30 mg, 0.141 mmol) were added to the reaction solution. The reaction solution was continued at room temperature and stirred for 16 hours. LCMS detected that the reaction was complete. The reaction system was added with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined and concentrated. The residue was purified by preparative liquid phase to obtain a white solid compound 3 (3 mg, yield 7%) and epimer 3° (4 mg, yield 9.3%). The absolute configurations drawn by the two compounds are based on empirical assumptions, compound 3 is an isomer with relatively long retention time in LC-MS and HPLC, and 3’ is an isomer with relatively short retention time in LC-MS and HPLC.
Compound 3
ESI-MS (m/z): 907.9 [M+H]'; LC-MS retention time RT=1.66 min. HPLC retention time RT= 12.10 min. 'H NMR (500 MHz, DMSO-de) & 8.98 (d, J = 2.2 Hz, 1H), 8.57-8.48 (m, 2H), 7.98 (d, J= 2.2 Hz, 1H), 7.81 (s, 1H), 7.76 (dd, J = 8.7, 1.6 Hz, 1H), 7.59 (d, J = 8.6
Hz, 1H), 5.56 (t, J= 9.1 Hz, 1H), 5.10-5.05 (m, 1H), 4.54 (t, J = 6.5 Hz, 2H), 4.43 (t, J = 6.1 Hz, 2H), 4.38-4.29 (m, 2H), 4.28-4.16 (m, 2H), 4.14-4.06 (m, 1H), 3.58 (s, 2H), 3.45-3.39 (m, 1H), 3.27 (s, 3H), 3.17-3.12 (m, 1H), 3.00-2.95 (m, 1H), 2.80-2.72 (m, 1H), 2.45-2.33 (m, 3H), 2.26 (s, 2H), 2.13-2.04 (m, 1H), 1.86-1.74 (m, 6H), 1.54-1.45 (m, 2H), 1.38 (d, J = 6.0 Hz, 3H), 1.10-1.03 (m, 4H), 0.93-0.84 (m, 7H), 0.59-0.52 (m, 54
BL-5785 1H), 0.35 (s, 3H). LU505464
Compound 3’
ESI-MS (m/z): 907.6 [M+H]". LC-MS retention time RT=1.65 min. HPLC retention time RT= 12.08 min. 'H NMR (500 MHz, DMSO-ds) 6 8.99 (d, J = 2.1 Hz, 1H), 8.60-8.45 (m, 2H), 8.13 (d, J= 2.3 Hz, 1H), 7.82 (s, 1H), 7.75 (d, J= 8.6 Hz, 1H), 7.55 (d, J= 8.6 Hz, 1H), 5.55 (t, J= 9.2 Hz, 1H), 5.09-5.05 (m, 1H), 4.54 (t, J = 6.5 Hz, 2H), 4.44 (t, J= 6.1 Hz, 2H), 4.29-4.17 (m, 2H), 4.04-3.92 (m, 2H), 3.89-3.78 (m, 1H), 3.70-3.65 (m, 1H), 3.58- 3.53 (m, 1H), 3.47-3.39 (m, 1H), 3.25-3.12 (m, 2H), 3.10 (s, 3H), 3.08-3.04 (m, 1H), 2.82-2.70 (m, 1H), 2.46-2.19 (m, SH), 2.16-2.06 (m, 1H), 1.90-1.72 (m, 6H), 1.58-1.46 (m, 2H), 1.24 (d, J = 6.4 Hz, 3H), 1.15-1.01 (m, 7H), 0.97-0.85 (m, 4H), 0.60-0.53 (m, 1H), 0.49 (s, 3H).
Example 4 (1S,2S)-N-((63S,4$,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(8-(2- methoxyethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)SSyridine-3-yl)-10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11 H-8-oxa-2(4,2)-thiazola- 1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1- carboxamide
O
1 {(S) )
HN—N
O (S) 9 79 n= HN
S “Ls
N ~ > 7 NI — N \ — „N
N O
CS
Example 4 was prepared by the following steps:
BL-5785
LU505464
HN—N
O ©) 9 © —Q N= HN 5
SS NE
ER Sd =
O 9/70 79 ASE N - 4
JS N MEN So
CA Dan
HN o 1c 0 © ° 79 N= HN 5 hoy = — N oF „N
Don O 4
Step 1: Compound 1c (40 mg, 0.047 mmol) was dissolved in acetonitrile (2 mL), at room temperature potassium carbonate (6.5 mg, 0.047 mmol), potassium iodide (7.8 mg, 0.047 mmol) and 2-bromoethyl methyl ether (7.8 mg, 0.056 mmol) were added.
The reaction solution was continued to stir at room temperature for 16 hours. LCMS detected that the reaction was complete. The reaction system was added with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined and concentrated. The residue was purified by preparative liquid phase to obtain a white solid compound 4 (4 mg, yield 9.4%) and epimer 4’ (9 mg, yield 21.2%). The absolute configurations drawn by the two compounds are based on empirical assumptions, compound 4 is an isomer with relatively long retention time in
LC-MS and HPLC, and 4’ is an isomer with relatively short retention time in LC-MS and HPLC.
Compound 4
ESI-MS (m/z): 909.7 [M+H]'; LC-MS retention time RT=1.74 min. HPLC retention time RT=12.79 min. 'H NMR (500 MHz, DMSO-ds) 8 8.98 (d, J = 2.2 Hz, 1H), 8.55 - 8.48 (m, 2H), 7.98 (d, J= 23 Hz, 1H), 7.81 (s, 1H), 7.76 (dd, J = 8.7, 1.6 Hz, 1H), 7.59 (d, J = 8.7
Hz, 1H), 5.56 (t, J=9.1 Hz, 1H), 5.09 - 5.04 (m, 1H), 4.39-4.29 (m, 2H), 4.27-4.15 (m, 2H), 4.14-4.04 (m, 1H), 3.58 (s, 2H), 3.45-3.42 (m, 2H), 3.32-3.29 (m, 4H), 3.27 (s, 3H), 3.23 (s, 3H), 3.18-3.12 (m, 1H), 3.00-2.95 (m, 1H), 2.80-2.72 (m, 1H), 2.65-2.57 (m, 2H), 2.44-2.36 (m, 3H), 2.11-2.05 (m, 1H), 1.84-1.72 (m, 6H), 1.54-1.48 (m, 2H), 1.38 (d, J= 6.1 Hz, 3H), 1.10-1.03 (m, 4H), 0.94-0.85 (m, 7H), 0.58-0.53 (m, 1H), 0.35 (s, 3H). 56
BL-5785
Compound 4° LU505464
ESI-MS (m/z): 909.7 [M+H]'; LC-MS retention time RT=1.72 min. HPLC retention time RT=12.66 min. "H NMR (500 MHz, DMSO-ds) 8 9.00 (d, J = 2.1 Hz, 1H), 8.56-8.49 (m, 2H), 8.14 (d, /J=2.2 Hz, 1H), 7.81 (s, 1H), 7.75 (dd, J = 8.7, 1.7 Hz, 1H), 7.55 (d, J = 8.7
Hz, 1H), 5.55 (t, J= 9.2 Hz, 1H), 5.08-5.03 (m, 1H), 4.29-4.18 (m, 2H), 4.04-3.93 (m, 2H), 3.88-3.80 (m, 1H), 3.71-3.65 (m, 1H), 3.58-3.52 (m, 1H), 3.44 (t, J = 5.8 Hz, 2H), 3.25-3.23 (m, 4H), 3.22-3.18 (m, 1H), 3.16-3.11 (m, 1H), 3.10 (s, 3H), 3.09-3.03 (m, 1H), 2.80-2.73 (m, 1H), 2.67-2.59 (m, 2H), 2.45-2.38 (m, 2H), 2.38-2.30 (m, 1H), 2.16- 2.08 (m, 1H), 1.82-1.70 (m, 7H), 1.54-1.48 (m, 2H), 1.42-1.36 (m, 1H), 1.28-1.23 (m, 3H), 1.13-1.03 (m, 8H), 0.92 (s, 3H), 0.90-0.86 (m, 1H), 0.59-0.54 (m, 1H), 0.49 (s, 3H).
Example 5 (1r,2R,3S)-N-((63S,4S,Z)-11-ethyl-12-(5-(8-(2-fluoroethyl)-1-oxa-2,8- diazaspiro[4.5]dec-2-en-3-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11 H-8-oxa-2(4,2)-thiazola- 1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2,3- dimethylcyclopropane-1-carboxamide
O
Su fs) )
HN—N
O s 9 —9 nA HN s = (r)
N = — N \ —
N
N O
G
Example 5 was prepared by the following steps: 57
BL-5785 po LU505464
INT-6 A ] H A 7 H 5 A
Q, N R 7 fo) J PT 0, J 0 © 90 N
N= HN Boc 0 Cs2COs3,Etl ° o VS 0s) Pd(dppf)Clz, (s) DMF, rt 77 N
Xo BED ©)
H
INT4 y sa > so
N N
Boc Bod
Ste Fe PE o N75 o N73 5 M5
TFA FN
DCM K2CO3, +
PS | N DMIF. PS N PS N
N À ) 5c Ny À ) 5 N 2 ) 5
N° > 5 oO O O
H N N
5
F F
Step 1: Intermediate INT-4 (200 mg, 0.29 mmol) and Intermediate INT-6 (120 mg, 0.26 mmol) was dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (0.4 mL), [1,1°-bis(diphenylphosphino)ferrocene]palladium dichloride (38.7 mg, 0.053 mmol) and potassium phosphate (224 mg, 1.06 mmol) were added. The reaction system was replaced with nitrogen and then heated to 70 °C to stir for 12 h. After the reaction solution was cooled to room temperature, The reaction solution was filtered through diatomaceous earth and the filtrate was concentrated. the residue was purified by silica gel column chromatography (dichloromethane/methanol= 20/1) to obtain a light yellow solid compound Sa (161 mg, yield 65.1%). ESI-MS (m/z): 937.5 [M+H]".
Step 2: Compound Sa (161 mg, 0.17 mmol) was dissolved in DMF (4 mL), cesium carbonate (168 mg, 0.52 mmol) was added, and then ethyl iodide (80.4 mg, 0.52 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 6 hours. LCMS detected that the reaction was complete. The reaction 58
BL-5785 system was added with saturated brine, extracted with ethyl acetate, the organic phases 17005606 were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product of compound Sb (166 mg, yield 100%).
ESI-MS (m/z): 965.6 [M+H]".
Step 3: The crude product of compound Sb (166 mg, 0.17 mmol) was dissolved in dichloromethane (3 mL), at 0 °C trifluoroacetic acid (1 mL) was added dropwise to the reaction solution. The reaction solution was stirred at 0 °C for 1 hour. LCMS detected that the reaction was complete. The reaction system was added with saturated sodium bicarbonate to quench to reaction, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a light yellow solid compound Se (132 mg, yield 90%). ESI-MS (m/z): 865.6 [M+H]".
Step 4: Compound Sc (63 mg, 0.073 mmol) was dissolved in N,N- dimethylformamide (2 mL), at room temperature 1-fluoro-2-iodoethane (25 mg, 0.146 mmol) and potassium carbonate (20 mg, 0.146 mmol) were added. The reaction solution was at room temperature stirred for 16 hours. LCMS detected that the reaction was complete. The reaction system was added with water, extracted with dichloromethane, and the organic phases were combined and concentrated. the organic phases were combined and concentrated. The residue was purified by preparative thin layer chromatography to obtain a white solid compound 5 (6 mg, yield 9%) and epimer 5’ (7 mg, yield 10.5%). The absolute configurations drawn by the two compounds are based on empirical assumptions, compound 5 is an isomer with relatively long retention time in LC-MS and HPLC, and 5° is an isomer with relatively short retention time in
LC-MS and HPLC.
Compound 5
ESI-MS (m/z): 912.0 [M+H]'; LC-MS retention time RT=1.81 min. HPLC retention time RT= 13.28 min. 'H NMR (500 MHz, DMSO-de) 8 8.98 (d, J = 2.2 Hz, 1H), 8.51 (s, 1H), 8.40 (d,
J=9.0 Hz, 1H), 7.99 (d, J= 2.2 Hz, 1H), 7.82 (s, 1H), 7.76 (dd, J = 8.7, 1.6 Hz, 1H), 7.59 (d, J= 8.7 Hz, 1H), 5.55 (t, J= 9.1 Hz, 1H), 5.09-5.03 (m, 1H), 4.58-4.51 (m, 2H), 59
BL-5785 4.39-4.05 (m, SH), 3.58 (s, 2H), 3.32-3.30 (m, 2H), 3.27 (s, 3H), 3.17-3.11 (m, 1H), | LU505464 3.00-2.95 (m, 1H), 2.79-2.72 (m, 1H), 2.69-2.60 (m, 4H), 2.48-2.38 (m, 3H), 2.11-2.06 (m, 1H), 1.87-1.73 (m, 7H), 1.56-1.48 (m, 1H), 1.38 (d, J= 6.2 Hz, 3H), 1.20-1.13 (m, 3H), 1.11-1.05 (m, 6H), 0.93-0.85 (m, 6H), 0.36 (s, 3H).
Compound 5°
ESI-MS (m/z): 911.9 [M+H]". LC-MS retention time RT=1.80 min. HPLC retention time RT= 13.24 min. "H NMR (500 MHz, DMSO-ds) 8 9.00 (d, J = 2.2 Hz, 1H), 8.54 (d, J = 1.7 Hz, 1H), 8.41 (d, J= 9.0 Hz, 1H), 8.14 (d, J= 2.2 Hz, 1H), 7.83 (s, 1H), 7.75 (dd, J = 8.7, 1.7 Hz, 1H), 7.56 (d, J= 8.6 Hz, 1H), 5.54 (t, J= 9.2 Hz, 1H), 5.07-5.02 (m, 1H), 4.58- 4.52 (m, 2H), 4.28-4.17 (m, 2H), 4.04-3.93 (m, 2H), 3.89-3.79 (m, 1H), 3.70-3.65 (m, 1H), 3.58-3.53 (m, 1H), 3.24-3.13 (m, 2H), 3.10 (s, 3H), 3.08-3.02 (m, 1H), 2.80-2.73 (m, 1H), 2.71-2.59 (m, 4H), 2.49-2 41 (m, 2H), 2.38-2.31 (m, 1H), 2.16-2.08 (m, 1H), 1.89-1.71 (m, 6H), 1.57-1.45 (m, 1H), 1.26-1.23 (m, 4H), 1.23-1.13 (m, 4H), 1.13-1.04 (m, 9H), 0.93 (s, 3H), 0.49 (s, 3H).
Example 6 (1r,2R,3S)-N-((63S,4S,Z)-11-ethyl-12-(5-(8-(2-hydroxyethyl)-1-oxa-2,8- diazaspiro[4.5]dec-2-en-3-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10- dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11 H-8-oxa-2(4,2)-thiazola- 1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2,3- dimethylcyclopropane-1-carboxamide
O
Nis) >
HN—N © (S) 9 79 n= HN
Ss = (r)
N = 2 — N \ — „N od
OH
Example 6 was prepared by the following steps: 60
BL-5785
LU505464
HN—N
Oo ©) 90 79 uk HN 0
SS NE
© AG
DEN = N
HN—N =,
O sf © x — oO HON 6
O Res Os) Ho” Er
Mo J Ton HE WA / Due. as
N 0 ©) °
HN 9 5c —Q N= HN, gy: TS) » \¢ P
À J
N ;
HO" NN © 6
Step 1: Compound 5e (63 mg, 0.073 mmol) was dissolved in N, N- dimethylformamide (2 mL), at room temperature 2-bromoethanol (18 mg, 0.146 mmol), potassium carbonate (20 mg, 0.146 mmol) and potassium iodide (12 mg, 0.073 mmol) were added. The reaction solution was at room temperature stirred for 16 hours. LCMS detected that the reaction was complete. The reaction system was added with water, extracted with dichloromethane, the organic phases were combined and concentrated.
The residue was purified by preparative thin layer chromatography to obtain a white solid compound 6 (6 mg, yield 9%) and epimer 6’ (6 mg, yield 9%). The absolute configurations drawn for the two compounds are based on empirical assumptions.
Compound 6 is the less polar isomer in forward TLC (dichloromethane/methanol = 10/1), while 6' is the less polar isomer in forward TLC (dichloromethane/methanol = 10/1). Dichloromethane/methanol = 10/1) The more polar isomer.
Compound 6
ESI-MS (m/z): 910.0 [M+H]'; LC-MS retention time RT=1.65 min. HPLC retention time retention time RT= 11.82 min. 'H NMR (500 MHz, DMSO-d) 8 8.98 (d, J = 2.2 Hz, 1H), 8.51 (d, J = 1.7 Hz, 1H), 8.40 (d, J = 8.9 Hz, 1H), 7.99 (d, J = 2.2 Hz, 1H), 7.82 (s, 1H), 7.76 (dd, J = 8.6, 1.7 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 5.55 (t, J = 9.2 Hz, 1H), 5.09-5.04 (m, 1H), 4.40 (t, J = 5.4 Hz, 1H), 4.38-4.29 (m, 2H), 4.27-4.16 (m, 2H), 4.13-4.04 (m, 1H), 3.58 (s, 2H), 3.52-3.49 (m, 2H), 3.30 (d, J = 5.0 Hz, 2H), 3.27 (s, 3H), 3.18-3.12 (m, 1H), 3.00- 2.95 (m, 1H), 2.79-2.72 (m, 1H), 2.67-2.58 (m, 2H), 2.47-2.35 (m, 5H), 2.11-2.04 (m, 1H), 1.88-1.70 (m, 7H), 1.55-1.47 (m, 1H), 1.38 (d, J = 6.0 Hz, 3H), 1.20-1.13 (m, 3H), 1.11-1.04 (m, 6H), 0.94-0.85 (m, 6H), 0.36 (s, 3H). 61
BL-5785
Compound 6° LU505464
ESI-MS (m/z): 910.0 [M+H]". LC-MS retention time RT=1.66 min. HPLC retention time RT= 11.88 min. "H NMR (500 MHz, DMSO-ds) 8 9.00 (d, J = 2.2 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.41 (d, J = 8.9 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.83 (s, 1H), 7.75 (dd, J = 8.7, 1.7 Hz, 1H), 7.55 (d, J= 8.7 Hz, 1H), 5.53 (t, J= 9.2 Hz, 1H), 5.08-5.02 (m, 1H), 4.40 (t, J= 5.2 Hz, 1H), 4.31-4.16 (m, 2H), 4.07-3.94 (m, 2H), 3.90-3.79 (m, 1H), 3.70-3.62 (m, 1H), 3.57-3.49 (m, 3H), 3.22-3.12 (m, 2H), 3.10 (s, 3H), 3.09-3.04 (m, 1H), 2.79- 2.72 (m, 1H), 2.67-2.58 (m, 2H), 2.46-2.37 (m, 4H), 2.38-2.31 (m, 1H), 2.16-2.09 (m, 1H), 1.85-1.71 (m, 6H), 1.57-1.45 (m, 1H), 1.26-1.23 (m, 4H), 1.23-1.14 (m, 4H), 1.14- 1.05 (m, 9H), 0.92 (s, 3H), 0.49 (s, 3H).
Example 7 (1,2R,3S)-N-((63S,4S,Z))-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(2-methyl-5- oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-11 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)- pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide
O
Moods)
HN—N © (S) >. —Q n= HN 7 (A)
S Da
N Is — N \ —
JN
ZN ©
Example 7 was prepared by the following steps: 62
BL-5785
Lo LU505464
N N Br
A X Do X Oo
Q INTT AN OTN glo, A (5) ON shy He 5
DEN Ö ] N ®) ] H ®
HN-N N 0 GS 0 7S 0 ©) > _ Bod Cs,CO3, Et No ne HN Pd(dpphCla, DMF, rt n° NS 3PO4, dioxane,
By. 7 Jo i sone A | A dN CH SCN
H INT4 PZ 7a Lz ) 7b
EN N
O O
N N
Boc Boc a Oo \e NP 0 © NP 0 7 N A 7“ I + ie
H ®) H (R) H ®) 0 N 3 HcHo 0 N CS 0 N C5
TFA NaBH(OAG), +
DCM DCE, rt “af L, “af L, ne L,
NJ ) 7c NJ ) 7 N A ) 7
O O O
HN N N
/ /
Use INT-4 to replace INT-3 in the synthesis step of compound 2, and use similar methods and reaction steps to obtain compound 7 and epimer 7’. The absolute configurations drawn by the two compounds are based on empirical assumptions, and compound 7 is an isomer with relatively long retention time in LC-MS and HPLC, and 7’ is an isomer with relatively short retention time in LC-MS and HPLC.
Compound 7
ESI-MS (m/z): 851.9 [M+H]'; LC-MS retention time RT=1.74 min. HPLC retention time retention time RT= 12.65 min. 'H NMR (500 MHz, DMSO-d) 8 8.98 (d, J = 2.2 Hz, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 7.98 (d, J= 2.2 Hz, 1H), 7.82 (s, 1H), 7.76 (dd, J = 8.6, 1.6 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 5.55 (t, J = 9.2 Hz, 1H), 5.09-5.04 (m, 1H), 4.38- 4.08 (m, SH), 3.82-3.76 (m, 2H), 3.58 (s, 2H), 3.54-3.49 (m, 2H), 3.31-3.26 (m, SH), 3.18-3.12 (m, 1H), 3.00-2.95 (m, 1H), 2.79-2.72 (m, 1H), 2.45-2.40 (m, 1H), 2.29 (s, 3H), 2.11-2.05 (m, 1H), 1.83-1.73 (m, 2H), 1.54-1.45 (m, 1H), 1.38 (d, J= 6.1 Hz, 3H), 1.27 - 1.21 (m, 4H), 1.11-1.04 (m, 6H), 0.93-0.84 (m, 6H), 0.35 (s, 3H).
Compound 7’
ESI-MS (m/z): 851.9 [M+H]". LC-MS retention time RT=1.72 min. HPLC 63
BL-5785 retention time RT= 12.59 min. LU505464 "H NMR (500 MHz, DMSO-ds) 8 8.99 (d, J = 2.1 Hz, 1H), 8.53 (d, J = 1.7 Hz, 1H), 8.41 (d, J = 9.0 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.83 (s, 1H), 7.75 (dd, J = 8.7, 1.6 Hz, 1H), 7.55 (d, J= 8.6 Hz, 1H), 5.53 (t, J= 9.2 Hz, 1H), 5.07-5.01 (m, 1H), 4.24- 4.18 (m, 2H), 4.00-3.95 (m, 1H), 3.87-3.78 (m, 1H), 3.72-3.64 (m, 2H), 3.58-3.49 (m, 3H), 3.29-3.23 (m, 2H), 3.18-3.13 (m, 1H), 3.10 (s, 3H), 3.06 (d, J = 14.5 Hz, 1H), 2.80-2.71 (m, 1H), 2.35-2.29 (m, 1H), 2.28 (s, 3H), 2.16-2.08 (m, 1H), 1.84-1.74 (m, 2H), 1.55-1.50 (m, 1H), 1.24 (d, J= 6.2 Hz, 3H), 1.23-1.14 (m, 4H), 1.11-1.06 (m, 9H), 0.92 (s, 3H), 0.49 (s, 3H).
Example 8 (1,2R,3S)-N-((63S,4S,Z))-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(7-methyl-1- oxa-2,7-diazaspiro|4.4]non-2-en-3-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-11 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)- pyridazinacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide
O
Mods)
HN—N 9 (S) 9
IX n= HN—Z (S) s Ds)
N Is >— — N \ — „N
O
N
/
Example 8 was prepared by the following steps: 64
BL-5785
Lo LU505464 = Br \ pe oli ° 9 0 J lh ° 9.0
INT-9 | HO N © @ | "ZN ®
O > R) oe + oO NS 5 NS 0 © © N > LP Boc Cs2CO3,Etl ° Ng s “29 Pd(dpphCla 7% | N ove tO | N \ } K3PO,, dioxane, = =
D ¢ ® H20, 90°C N py ) NO )
H
INT4 N sa N 8b
N N
Boc Boc
Os N © ve (s) os N ©) A (s) Os N (s) Me (s)
H Li | N ® | N ® o N° o N°5 5 NS
HCHO,
TFA NaBH(OAc)4
DCM DCE, rt +
AS | N AS | N Pa N
N, 0 ) 8c N. > ) 8 N. 3 ) 8
N N 3 oO O oO
N
Use INT-4 and INT-9 to replace repectively INT-3 and INT-7 in the synthesis step of compound 2, and use similar methods and reaction steps to obtain compound 8 and epimer 8’. The absolute configurations drawn by the two compounds are based on empirical assumptions, and compound 8 is an isomer with relatively long retention time in LC-MS and HPLC, and 8’ is an isomer with relatively short retention time in LC-
MS and HPLC.
Compound 8
ESI-MS (m/z): 865.5 [M+H]'; LC-MS retention time RT=1.75 min. HPLC retention time retention time RT= 12.86 min. 'H NMR (500 MHz, DMSO-ds) 8 8.97 (d, J = 2.1 Hz, 1H), 8.51 (d, J = 1.0 Hz, 1H), 8.39 (d, J= 8.8 Hz, 1H), 7.97 (d, J= 2.2 Hz, 1H), 7.82 (s, 1H), 7.78-7.74 (m, 1H), 7.59 (d, J = 8.6 Hz, 1H), 5.55 (t, J = 9.3 Hz, 1H), 5.09-5.03 (m, 1H), 4.36-4.30 (m, 2H), 4.26-4.21 (m, 2H), 4.20-4.16 (m, 1H), 4.13-4.05 (m, 1H), 3.61-3.56 (m, 4H), 3.30 (s, 2H), 3.27 (s, 3H), 3.17-3.13 (m, 1H), 2.99-2.95 (m, 1H), 2.86 (d, J = 10.0 Hz, 1H), 2.78-2.70 (m, 3H), 2.47-2.40 (m, 1H), 2.30 (s, 3H), 2.18-2.12 (m, 2H), 2.08-2.05 (m, 1H), 1.81-1.77 (m, 2H), 1.37 (d, J = 6.1 Hz, 3H), 1.23 (s, 1H), 1.18-1.15 (m, 2H), 1.08 (d, J= 5.9 Hz, 3H), 1.06 (d, J= 5.6 Hz, 3H), 0.91 (s, 3H), 0.87 (t, J= 7.1 Hz, 3H), 0.35 (s, 3H). 65
BL-5785
Compound 8° LU505464
ESI-MS (m/z): 865.5 [M+H]+. LC-MS retention time RT=1.74 min. HPLC retention time retention time RT= 12.67 min. 'H NMR (500 MHz, DMSO-d) 8.98 (d, J = 1.0 Hz, 1H), 8.53 (d, J = 1.1 Hz, 1H), 8.41 (d, J = 9.0 Hz, 1H), 8.12 (d, J= 2.1 Hz, 1H), 7.82 (s, 1H), 7.76-7.73 (m, 1H), 7.55 (d, J= 8.6 Hz, 1H), 5.53 (t, J= 9.4 Hz, 1H), 5.07-5.01 (m, 1H), 4.26-4.18 (m, 2H), 4.02-3.94 (m, 2H), 3.85-3.77 (m, 1H), 3.69-3.60 (m, 2H), 3.59-3.43 (m, 3H), 3.30 (s, 2H), 3.18-3.12 (m, 1H), 3.09 (s, 2H), 3.09-3.03 (m, 1H), 2.83-2.78 (m, 1H), 2.77-2.71 (m, 1H), 2.70-2.64 (m, 1H), 2.63-2.57 (m, 1H), 2.48-2.44 (m, 1H), 2.36-2.30 (m, 1H), 2.26 (d, J= 1.6 Hz, 3H), 2.19-2.08 (m, 3H), 1.83-1.75 (m, 2H), 1.57-1.47 (m, 1H), 1.24 (d, J = 6.3 Hz, 3H), 1.22-1.14 (m, 3H), 1.13-1.08 (m, SH), 1.07 (d, J = 5.8 Hz, 3H), 0.92 (s, 3H), 0.50 (s, 3H).
Example 9 (1S,2S)-N-((63S,4$,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-S5-(2-methy1-7- oxa-2,8-diazadispiro[3.1.46.14|undec-8-en-9-yl)pyridin-3-yl)-10,10-dimethyl-5,7- dioxo-61,62,63,64,65,66-hexahydro-11 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola- 6(1,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamide
Oe ZNO 6 o "8, Je d À Vo (S) N=
S
N Us ; NI — N \ — ‚N
O
N
Example 9 was prepared by the following steps: 66
BL-5785 _0 LU505464
N Br 7 (oN Do A 99
INT-8 N 7 N > rod 7 N > AS
O
3 — — o © ° Boc Cs,CO,Etl
N= HN Pd(dppf)Cls, ° DMF, rt 0 = 8 ©] 3PO4, dioxane, 7 7
Ba Ÿ | “ fies N°7 N N°77 ) o N \ Lz
H INT-3 sa Sb oN ON oO O
N N
Boc Boc (a Oo ex 99 (aN Oo
Oo NZ S 0 N° Ss 0 ING Ss = HCHO, = =
TFA NaBH(OAc)z +
DCM DCE, rt
N = N = N
N ) 9c NC ) 9 NC ) 9
O oO O
HN N N
/ /
Use INT-8 to replace INT-6 in the synthesis step of compound 1, and use similar methods and reaction steps to obtain compound 9 and epimer 9’. Compound 9 and its epimer 9’ cannot be separated and purified by reverse preparative liquid chromatography and normal phase column. Both epimers have the same retention time in LC-MS and HPLC.
Compound 9+9°:
ESI-MS (m/z) : 877.9 [M+H]'; LC-MS retention time RT=1.85 min. HPLC retention time RT=11.86 min.
BIOLOGICAL SCREENING AND RESULTS OF RAS INHIBITORS
Test Example 1: In vitro cell proliferation inhibition test
Due to the diversity of RAS mutations and in order to evaluate the activity of compounds in different RAS mutant cell lines, we selected KRASWT, KRASC!2C,
KRASS!P, KRASSY and BRAF mutant cell lines (see the table below) for in vitro activity evaluation and screening of compounds. 67
BL-5785
LU505464
Experimental protocol: CellTiter-Glo® Cell Luminescent Viability Assay (Promega)
According to the doubling time of different cell lines, different numbers of cells (1000-5000 cells/well) were inoculated into 96-well plates containing 180 ul of the corresponding medium, and cultured overnight in a 37°C cell incubator containing 5% CO». On the second day, the compound to be tested was pre-diluted 3-fold with the medium, the highest concentration was 100 uM, and there were 10 concentration gradients in total; then 20 pl of the medium containing different concentrations of the compound was added to the cells in the 96-well plate to ensure the final concentration of the compound to be up to 10 uM, with 10 concentration gradients of 3-fold dilutions. After co-incubating cells and compounds for 72 hours, the 96-well plate was taken out of the incubator, placed at room temperature for 30 minutes, and then 25 ul
CellTiter-Glo® Reagent was added to each well to mix well, and incubated at room temperature for 10 minutes, and then 100 ul of the sample was transferred to a white 96-well plate (OptiPlateTM-96, PerkinElmer), the fluorescent signal value was read using a multi-functional microplate reader (SpectraMax® 13x, Molecular devices).
Subsequently, the signal value was standardized, and the four-parameter fitting regression equation was used for curve fitting to calculate the half maximal inhibitory concentration (IC50) of the compound on the cell line. 68
BL-5785
LU505464
Table 1: Antiproliferative activity of compounds of the present invention on
KRAS cell mutants
NCI- NCI- | NCI
PaCa- | LS513 | AsPC-1 | HCCI1588 | SW480 HT-29
H358 H727 | H520 2
To [ew me
ERE EE EN ET
EERE EE [re am
Tw [ww [er ow ww [ow [ow
To [ao [on [ome ew [on [ows [so
Tw [ww [on] ow ew [ow [ow * NT MEANS NOT TESTED 69
Claims (1)
1. A compound having the structure: og A °s Oe y" Pa Oy y" °8 Og y" °9 0 © (>) Ö ©) {9 0 © Les 0 ©) Les < NRA J NRA J NRA J NRA q 17s < NT > = > 17 N = N = N = NN A 4 = A NS 4 N N N N X — $ — 4 — x A on oN oN oN N N N. - N ST 7 9 > 9 Q ws } Pr 0 Suds > Donde) / HN-N J He 3 / AN me 0 © = > d, NR” 9 ©" ° © Æ o — n=l _ 0 ) i= —0 wd ht nt HNL N SS @ A / = N ) 5 Os) N SS 9, rN a) — N rN + oN ® N Ne J N N X — ; J { — N 0 $ oO N N N 0 AN 0 C © N OH
0. ° Q, X Wa we) / Ha / ANN 0 0 9 ©" 0 AD T9 NA HN ©) NF HN “0 9 N: 5 a, N= _ y PN J U N fæ N = $ — X N N oO ¢ 9 N I Ea ©) en 0 NL NN 5% 5 FL o Hal Jo à Mel de Ö oN Ao / N / N EF / N © F d HN © o À © o H 9 N= @ 9 NA Q NA, s s N = N ne N N Wi Wi ON N N N À — À — X — N N a _N o _N o AN Os X 0 N Os ex oO N Os ex 0 Oz ©) 0 SON o à SUN og IN 9 0 SON 0 9 © A eo, À ©) A / © ve / © helo / © NN wo / © yh © NS q H q H q H q H 9 N= 9 = 9 N= 9 N= s 5 5 s Mg > NA 9 = IN = Mg > N N N N 4 — + — { — { J N N N N N o N 0 N ° N ° u oO oto 0 alo oO oo oO SON 9. SN o SON 9 SON 0 ©) : ©) H F H / 9 oe / 9 vs / 9 9 het F / © 9 ve, 9 H 9 H 0 H 0 H 9 N= 3 N= @ N= © N= 5 oS s 5 Mg Ng NA 7 > NA 9 = N N N N { { ( { N N N N _N o _N o _N © _N 9
6 ol -~ 6) LU505464 Oy SN 9. Oy SN °° Oy SN °° Op NL à N N , 0 Hg Ah oH , o Ne ol © om , 0 Meg wl of , à Ne © oF q H 7e 0 BH Ve 0 H © q Ve 3 NA, 3 NA, Q NA, 3 NA, = N = N = N x A NS NA NS N N N N À — X — X — x N N N N NL NO NO NO Oy N20 à Oy 2 N20 à oy 2 N20 à 5 N 5 o Mel J à "mek À à MeN Je _ 0 A Ho © J NONE / NON / N vase J N © N= LN Og OL Lo Og n=l Hf 9 NA, ®\_0 Ss s N = = = N = a4 NA Mg rN N N N N a ( ( { N N N N AN ° _N o _N o N ° ; Go © Oy GA oy % DR 9 9 Os A N20 à Oy SP à / H 3 H H A H N (5), (5), (5), . (5), so ope J wd 1 P Tue y ve @ N= 9 N= 18 0 3 N= ox N 3 N= © N = N SS N SS N LS vo Ny rN ÄZ rN rN N N N N 7 4 — € — { N N N N NO NO NJ N° 6) | 6 © Oy GA °° Oy GA °° Oy NN 09 N_ Oy ON EIR / 0 N / 0 N / © AA / 09 VE H H 0 H Og N= Og N= 3 N= (Le Og FE ° 5 5 5 N > N = N > N > A rN rN rN N N N N Lo 4 — 4 (J N N N N N o —N ° N _N o oc lo) Q "ON NS)
0. 6) ole) SN 6 ON 0. 1 M00 IN 90 / o fy N= Ja ir o H / 0 eo, À 0 / 0 ©) / al À ° N N o N 9 NTN 5 y Ne 9 nA ©) H ng n=l "M NY N A Ss ° N Los © 4 78 (À / SS _ 4 rN a —/ =/ _J N — X — N i — ‘N N N. 0 N _Nn fo _N_ or - A ooo) N | 6 oko = y" 0 N Og oto, 8 Oy o_o, > pt 0 0 o 0 hl © J o He I X Ce © A 0 J © 2 Te NN 0 ©) H H 6, H nN LS NT n=l un nz N= X J N = = ff x a; SS AA; > © J > 0” N =/ =/ N i + 4 — wo —N or N oN _n fo _N_ or OWL om I No 4H IN pe 73 NNO N / NN / o Fe à / 0 al À, =, / o He = Og NN 0 ye 9 NON 9 2 vo N= ©) H ) n={ H ©) H N 5 N N= N ; N N= MN 7 47 SS rN = a 5 N ON AN AAN + 4 _J i — i J ‘N N N N N 0 N oO N. o N. o Yoo TN Te IW J © > And J © I el o © 2 a J O02 eg a 5) ©) WY nt TON WY n=l H © WY nd H a NG Nel H NS 5 ARN 5 GNS 2S Ng oS + =/ =/ N — N — N — N — —N o” N. 0° N. 0 —N 0 or le oe) or. le) on a) he NT 99 5 Nt 99 3 y” Oo | , J N ; Pa NY o SAN de o Con Ae o Oo Ay 9 ON = 5 © H © ) © H ° ) oh "OD ©) n=(O H N 6 N= ® N: N= 5 N N= N > oN 2 ARN 5 CA oS «4j = += =/ =/ N i J N — N — N — No Nor N Jo N or
Te TNS NG THES / o Hel Le J ° Mol le J J o Ae 4 N © H © © oH 5 © 0. H > © N A ® Wd N= ® N N= ® N N= ® = \ X A SS a =” CN > X AS > NT EN N = N F 5 F N Fe N hod N N _N o —N oO _N oO N oO Ny © 0,66 À Ye he SOS o 0 fg 1e J 0 Mol Le o 0 oh, pis N ® ©) nd F F ©) nd A id Ww n= N ® N N | > (NA 5 A nS 0 vw, oN = o NY AN +; N Lone [A i — N — N N o N 0 9 ON 0 N oto) sr Ng 0: 61 Os ©) Os 6) SN a BU EC Spike TON 99 / °o Ml Le o A / o "el / 9 U, 9 N o 2 he 9 Fae N" ©) N F Ca © À = 19 nd A F 19 nd H w@ 13 y ® N A 5 rN J 8 an; 8 aw, x N — = = N — N N ï — N { — Ÿ — N co = N o N o N ° ° f vr ST o Ï ou fo 6) alo or fe) 0, Ve a 0 A A H J o "we Ao J 9 ok Jo J à Mg ho PA 0 hh “ A Ve vo H 19 nl # & N (3) n={ fH ® N S) n=l H 5 1-9 n= ® (4 SS a, SS AN SS A; = N TON = N N bl — | — 4 — i _J N N N \ rN o N © Jd NA © d WSO 9 — ou lo ou lo oo) 99 ole.) Og y ge °° X NN Oo J o Hg Hh re o Hg ho re oO & he J Qa (3) Ae < 7 7 78 8 Ea Ci N nA C8 N nA ® N- n= HM ® PA 8 4j 8 4 OS CN Ÿ n° =n N N N Ÿ — i — N — N — N N i \ X\ 3 {X 2 o o Ho N— © —N NAO FON \ — —/ ou lo) 61 Oger ex ° Or ©) oO > SE SA 4 H 9 . H 9 / Oo” f / o Hel J 0 ol Je J 0 ©, A J © A o Hono NT © ©) © NAH p 9 nu ee N n= Te 2 n= Ye Mf 5 aa SB C4 Ss FA LS F =/ on = \ N N i — Ÿ — N — w — or N So No No N No N00 TNT 00 A N 9 o 0 & wi © S o Hg A © J 0 & ue J © A A © N &, nd H F 3) Nel F F N ) n={ H F N 5 N= ®) A) OS A 5 a.
LS a.
Ss — == == — N N N N i — 0 i _J CN N — Ÿ — N N - - N © CN 0 LN 0 IN 0 oJ 0,6) ou do) oy GA 99 ole) 99 y ip 99 Ÿ Nt 99 d o Hg y © J o fg wl © o 0 (3) 9h © o 0 (3) y © f pe 78 © 8 nA 0 N= Ea ND IE ® NT nA ® SA 5 AR} 5 MS 5 SA 5 MA =/ =/ N { — i — N — Ÿ — „N N — N 0 HO Lo 9 Wo N 0 / / \
oo) NO oy) JN o 61 Oy GA 9 q N %0 / 0 How de SN 0 à À Î / 0 ol Jy 0 N < o Tg I / ou, Ne o N A ê N 7 J N°24 9 N ©) © wel H 1G N = (3) N= H ® N (3) = ® N {7 = 4) N = N — 4) 5 CA WS om 75 — N 3 ( e4 4 — N 7 oN N or N ” N. oO N. 0 N a 6 yr y" 99
Ow. l® JH Oye bo) ° x NN 09 o ol Jo 6 OO No TON 9 y o fel 9, 8 ONE SONT 9 / O ol de o N < N { / o Hg pi Q N % a N 7s NC) = 0 N°2 © HVS N , 5 N © N N= aly = { WY N= ® MS OS ad 3 N Ss $ N—¢ À 0 > N | 3 NR ; N | — N oN 4 — x oN N N N N —N 0 N 67 Og 61 SNL pa THs 1 LS @ No y 5 ol Ia Jp © N 9 ° N eg Og Qu 09 o 0 ok, de ps x Ne 15 N 7s _ s J Cel F 9 nk N 1 47 3 C4 7 = © N A _ N-Ÿ NH A ® oN yg oS I . 5 oN D CF; > 4 —ö Of TON N No Y X — N o N oO N / 6) oO 6) y @ No 0, fo) Our GA 0 Ÿ NN 04 x N o So SON 9 TN ; Ci, H / 0 Sy Ne / so Ne o N / 0 el JL ; © N N Z 5 vo 5 H 5 ) N H 5 ©) N= As ©) N= H ®) N ©, N= ®) N = N = N 5 VON SS ae, = + © = = Nn N a N J © — ~ | N o N ot 0=s 0 0=$ 0 oO Ss = 05 N — N NT N | !
I
0. 6) ° 6) Si Su ON O1 ou lo) o on fo) 00 s N 09 5 a 0, IN a o Mel } / 0 ol Mm / 0 ol Ju o Hy A / 0 o . . ! 2 3 N © N © N 4 5 H > 5, H ® “) N= ® © N= As ©) — H N= N " : ° C3 =” MY 15 N 5 rN = J / “4% _ = N N N N — { — ; J} N À — N J oh x N N . - NN % | oO _Ng [To
/
0.61
©. 61 Se @ Ng og, 6) SNL og 5 N 3 "pe o H | / of de Sa I / ol Jo o N Z TUNE o © OH 3 N © ) n= H ® oH À, N © 6 N= AS N N a (8) 0) (5) N= ® N , I~ J W a N © N à a = 8 ©) N= ® rN gy ee _ 1 = N — aay SS N (0 ( \ — ° N N o N N N © {J \ o £ N N C Ow N “NON o x ; Tr N h © ! oo 6) 0 61 y ut 99 SON / 0 a À. Os Sn 09 x N 99 o > 0A OS N o H d / o ol Jo 3 Wa 7% Ne 09 J © Te o N Zz N , H ‘ = / 9 [CI Ps nl H y 19 N= ® d 7 Ng q N © N a NE) 5 +< “ N= ® rN = MeO, 5 ; N 5 moo 4, N { , * — N. oO —N 0 N { y A i — _N o —N N —N o oo 0 6) y y" °° © © Sao / 0 og Mo TO o H | 9 N © Os 1O Ng 6 nel 1 J oh de ps nl # ONE SON q J oly N Z | ; 9 "AL H © 6, N= ® AR le / 3) © © N © N ( a N © N x A . Ww N= æ oy 8 3 5 N ( 4} N € 5 N o ES Wo N be — „N 9 o a { < o N N N oO H a h à N ©
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