WO2023020521A1 - Pyridine fused pyrimidine derivatives and use thereof - Google Patents
Pyridine fused pyrimidine derivatives and use thereof Download PDFInfo
- Publication number
- WO2023020521A1 WO2023020521A1 PCT/CN2022/112927 CN2022112927W WO2023020521A1 WO 2023020521 A1 WO2023020521 A1 WO 2023020521A1 CN 2022112927 W CN2022112927 W CN 2022112927W WO 2023020521 A1 WO2023020521 A1 WO 2023020521A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- membered
- haloc
- stereoisomer
- pharmaceutically acceptable
- Prior art date
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title description 2
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 2
- 150000003230 pyrimidines Chemical class 0.000 title 1
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- 125000002098 pyridazinyl group Chemical group 0.000 description 1
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- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
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- 238000003908 quality control method Methods 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
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Classifications
-
- 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
- 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
Definitions
- the invention relates to compounds that inhibit the activity of multiple forms of K-Ras protein including K-Ras wild type and K-Ras mutant types, compositions comprising the same, and the methods of using the same.
- K-Ras Kirsten Rat Sarcoma 2 Viral Oncogene Homolog
- GDP-bound inactive
- GTP-bound active
- Aberrant expression of K-Ras accounts for up to ⁇ 20%of all cancers and oncogenic K-Ras mutations that stabilize GTP binding and lead to constitutive activation of K-Ras.
- K-Ras mutations at codons 12, 13, 61 and other positions of the K-Ras primary amino acid sequence are present in 88%of all pancreatic adenocarcinoma patients, 50%of all colorectal adenocarcinoma patients, and 32%lung adenocarcinoma patients.
- a recent publication also suggested wild type K-Ras inhibition could be a viable therapeutic strategy to treat K-Ras wild type dependent cancers.
- Allele-specific K-Ras G12C inhibitors such as sotorasib (AMG510) or adagrasib (MRTX849) , are currently changing the treatment paradigm for patients with K-Ras G12C mutated non-small cell lung cancer and colorectal cancer.
- sotorasib AMG510
- MRTX849 adagrasib
- K-Ras inhibitors have the potential to address broad patient populations, including K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutant and K-Ras wild type amplified cancers.
- a compound of formula (I) a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof:
- composition comprising a therapeutically effective amount of a compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof as defined herein; and a pharmaceutically acceptable excipient.
- Also provided herein is a method for treating cancer in a subject comprising administering a therapeutically effective amount of a compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein to a subject in need thereof.
- Also provided herein is a process for preparing a compound of formula (I) as defined herein.
- a compound of formula (I) a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof:
- R 1a is selected from hydrogen, deuterium, -C 1-10 alkyl, haloC 1-10 alkyl, haloC 1-10 alkoxy, -C 2-10 alkenyl, haloC 2-10 alkenyl, -C 2-10 alkynyl, haloC 2-10 alkynyl, -N (R 1b ) 2 , -OR 1b , -SR 1b , 3-10 membered cycloalkyl, 3-10 membered hetrocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-10 alkyl, haloC 1-10 alkyl, haloC 1-10 alkoxy, -C 2-10 alkenyl, -C 2-10 alkynyl, 3-10 membered cycloal
- L 1 is selected from a bond or C 1-10 alkylene optionally substituted with one or more R Z11 ;
- two R S1 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 membered carbocylic ring or 3-10 heterocyclic ring is optionally substituted with one or more R Z12 ;
- R S1 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently optionally substituted with one or more R Z13 ;
- R 2 is selected from -L 20 - (3-12 membered heterocyclyl) , -L 20 - (3-12 membered cycloalkyl) , -L 20 - (6-12 membered aryl) , -L 20 - (5-12 membered heteroaryl) , -L 20 -N (R 2b ) 2 ,
- Each of L 20 at each occurrence is independently selected from a bond or C 1-10 alkylene optionally substituted with one or more R Z21 ;
- Said 3-12 membered heterocyclyl in -L 20 - (3-12 membered heterocyclyl) is optionally substituted with one or more R Z22 ;
- Said 3-12 membered cycloalkyl in -L 20 - (3-12 membered cycloalkyl) is optionally substituted with one or more R Z22 ;
- Said 6-12 membered aryl in -L 20 - (6-12 membered aryl) is optionally substituted with one or more R Z22 ;
- Said 5-12 membered heteroaryl in -L 20 - (5-12 membered heteroaryl) is optionally substituted with one or more R Z22 ;
- L 21 is selected from a bond or C 1-10 alkylene optionally substituted with one or more R Z23 ;
- Ring B or ring C is a 3-10 membered heterocyclic ring optionally further containing 1, 2, or 3 heteroatoms selected from N, O or S;
- two R S21 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 membered carbocylic ring or 3-10 heterocyclic ring is optionally substituted with one or more R Z24 ;
- R S21 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently optionally substituted with one or more R Z25 ;
- q 21 is selected from 0, 1, 2, 3, 4, 5 or 6;
- L 22 is selected from a bond or C 1-10 alkylene optionally substituted with one or more R Z27 ;
- Ring D is selected from a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein the moiety of -L 22 -and -L 23 -X 2 are attached to the same atom or different atoms of the ring D;
- L 23 is selected from a bond or C 1-10 alkylene optionally substituted with one or more R Z28 ;
- X 2 is selected from -N (R 25 ) 2 , -OR 25 , -SR 25 , 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein said 3-10 membered heterocyclyl or 5-10 membered heteroaryl is optionally independently substituted with one or more R Z29 ;
- q 22 is selected from 0, 1, 2, 3, 4, 5 or 6;
- R 4 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, wherein said 6-10 membered aryl, 5-10 membered heteroaryl, is optionally independently substituted with one or more R S4 ;
- Z at each occurrence is independently selected from C or N;
- Ring E at each occurrence is independently selected from a 6 membered aryl ring or a 5-6 membered heteroaryl ring and ring F at each occurrence is a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring when Z is selected from C;
- Ring E at each occurrence is selected from a 5-6 membered heteroaryl ring and ring F at each occurrence is a 3-10 membered heterocyclic ring when Z is selected from N;
- each of (two R 11 , two R 13 , two R 15 , two R 21 , two R 23 , two R 25 , two R 26 , two R 28 , two R 31 , two R 33 , two R 41 , two R 43 , two R 51 , and two R 53 ) independently together with the nitrogen atom to which they are both attached forms a 3-20 membered heterocyclic ring or a 5-10 membered heteroaryl ring, wherein, said 3-20 membered heterocyclic ring or 5-10 membered heteroaryl ring is optionally independently substituted with one or more R Za ;
- Each of (R 12 , R 14 , R 16 , R 22 , R 24 , R 27 , R 29 , R 32 , R 34 , R 42 , R 44 , R 52 and R 54 ) at each occurrence is independently selected from hydrogen, deuterium, -C 1-10 alkyl, haloC 1-10 alkyl, haloC 1-10 alkoxy, -C 2-10 alkenyl, haloC 2-10 alkenyl, -C 2-10 alkynyl, haloC 2-10 alkynyl, -N (R b ) 2 , -OR b , -SR b , 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-10 alkyl, haloC 1-10 alky
- Each of (R a , R b , R c , R d , R 1b , R 1c , R 1d , R 2a and R 2b ) at each occurrence is independently selected from hydrogen, deuterium, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -C 2- 6 alkenyl, -C 2-6 alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkeny
- each of (two R a , two R b , two R c , two R 1b , two R 1c , two R 2a and two R 2b ) independently together with the atom to which they are both attached forms a 3-6 membered heterocyclic ring, wherein said 3-6 membered heterocyclic ring is independently optionally substituted with one or more R Zc ;
- Y 1 is selected from a bond, O, or NR 1a ;
- R 1a is selected from hydrogen, deuterium, or -C 1-3 alkyl
- L 1 is selected from a bond or C 1-3 alkylene; said C 1-3 alkylene is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C 1-3 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;
- q 1 is selected from 0, 1, 2 or 3.
- L 1 is selected from a bond or C 1-3 alkylene; said C 1-3 alkylene is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C 1-3 alkyl;
- Y 2 is O
- R 2 is selected from
- L 21 is selected from a bond or C 1-3 alkylene
- L 22 is selected from a bond or C 1-3 alkylene
- L 23 is selected from a bond or C 1-3 alkylene
- Ring B or ring C is a 5-6 membered heterocyclic ring optionally further containing 1 or 2 heteroatoms selected from N or O;
- Ring D is a 3 membered carbocyclic ring; wherein the moiety of -L 22 -and -L 23 -X 2 are attached to the same atom or different atoms of the ring E;
- X 2 is a 6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl is optionally independently substituted with 1, 2 or 3 R Z29 .
- two R 21 or two R 23 together with the carbon atom to which they are both attached form a 3-6 membered heterocyclic ring;
- two R 21 or two R 23 together with the nitrogen atom to which they are both attached form a 3-6 membered heterocyclic ring;
- q 21 is selected from 0, 1 or 2.
- q 21 is selected from 0 or 1.
- Each of R 4b is independently selected from -F; -C 1-3 alkyl; haloC 1-3 alkyl; -CN; -OH; -NH 2 ; -NH (C 1-3 alkyl) ; -NH (C 1-3 alkyl) 2 ; -OC 1-3 alkyl; or -C 1-3 alkyl substituted with 1, 2 or 3 substituents selected form -F, haloC 1- 3 alkyl, -CN, -OH, -NH 2 , -NH (C 1-3 alkyl) , -NH (C 1-3 alkyl) 2 , -OC 1-3 alkyl or cyclopropyl.
- the prodrug moiety is -OR 4a , and R 4a is selected from
- R 4c is selected from hydrogen, -C 1-30 alkyl, -C 2-30 alkenyl, -C 2-30 alkynyl, -C 0-6 alkylene- (3-20 membered carbocyclyl) , -C 0-6 alkylene- (3-20 membered heterocyclyl) , -C 0-6 alkylene- (6-10 membered aryl) or -C 0- 6 alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R 4j ;
- R 5 is selected from hydrogen, deuterium, -F, -Cl, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , -CN, -COOH, -CH 2 OH, -OH, -OCH 3 , -OCH 2 CH 3 , -CF 3 , -CHF 2 , -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 OH, -CH 2 CH 2 OH, -SH, -S-CH 3 , -S
- a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [29] , and at least one pharmaceutically acceptable excipient.
- a method for treating cancer in a subject comprising administering a therapeutically effective amount of the compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [29] , or the pharmaceutical composition of [30] to a subject in need thereof.
- a method for treating cancer in a subject in need thereof comprising:
- the cancer is associated with at least one of K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutation and/or K-Ras wild type amplification.
- halogen or “halo” , as used interchangeably herein, unless otherwise indicated, refers to fluoro, chloro, bromo or iodo.
- the preferred halogen groups include -F, -Cl and -Br.
- alkyl refers to saturated monovalent hydrocarbon radicals having straight or branched arrangement.
- C 1-10 in -C 1-10 alkyl is defined to identify the group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in a linear or branched arrangement.
- Non-limiting alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl.
- haloalkyl refers to the above-mentioned alkyl substituted with one or more (for example 1, 2, 3, 4, 5, or 6) halogen (such as -F, -Cl or -Br) .
- the haloalkyl is interchangeable -C 1-10 haloalkyl or haloC 1-10 alkyl, wherein, C 1-10 in the -C 1- 10 haloaklyl or haloC 1-10 alkyl indicates that the total carbon atoms of the alkyl are 1 to 10.
- the -C 1-10 haloalkyl is the -C 1-6 haloalkyl.
- the -C 1-6 haloalkyl is the -C 1- 3 haloalkyl.
- the -C 1-3 haloalkyl is (methyl, ethyl, propyl or isopropyl) substituted with 1, 2, 3, 4, 5, or 6 -F; preferably, the -C 1-3 haloalkyl is -CF 3 .
- alkylene refers to a divalent group obtained by removal of an additional hydrogen atom from an alkyl group defined above.
- the alkylene is C 0-6 alkylene.
- the C 0-6 alkylene is C 0-3 alkylene. The C 0-6 in the front of the alkylene indicates the total carbon atoms in the alkylene are 0 to 6 and C 0 indicates the two ends of the alkylene are connected directly.
- Non-limiting alkylene includes methylene (i.e., -CH 2 -) , ethylene (i.e., -CH 2 -CH 2 -or -CH (CH 3 ) -) and propylene (i.e., -CH 2 -CH 2 -CH 2 -, -CH (-CH 2 -CH 3 ) -or -CH 2 -CH (CH 3 ) -) .
- alkenyl refers to a straight or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length.
- the alkenyl is -C 2-10 alkenyl.
- the -C 2-10 alkenyl is -C 2-6 alkenyl which contains from 2 to 6 carbon atoms.
- Non-limiting alkenyl includes ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.
- haloalkenyl refers to the above-mentioned alkenyl substituted with one or more (for example 1, 2, 3, 4, 5, or 6) halogen (such as -F, -Cl or -Br) .
- the haloalkenyl is interchangeable -C 2-10 haloalkenyl or haloC 2-10 alkenyl, wherein, C 2-10 in the -C 2-10 haloaklenyl or haloC 2-10 alkenyl indicates that the total carbon atoms of the alkenyl are 2 to 10.
- the -C 2-10 haloalkenyl is the -C 2-6 haloalkenyl. In some embodiments, the -C 2-6 haloalkenyl is the -C 2-3 haloalkenyl. In some embodiments, the -C 2-3 haloalkenyl is (ethenyl or propenyl) substituted with 1, 2, 3, 4, 5, or 6 -F.
- alkynyl refers to a straight or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length.
- the alkynyl is -C 2-10 alkynyl.
- the -C 2-10 alkynyl is -C 2-6 alkynyl which contains from 2 to 6 carbon atoms.
- Non-limiting alkynyl includes ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
- haloalkynyl refers to the above-mentioned alkynyl substituted with one or more (for example 1, 2, 3, 4, 5, or 6) halogen (such as -F, -Cl or -Br) .
- the haloalkynyl is interchangeable -C 2-10 haloalkynyl or haloC 2-10 alkynyl, wherein, C 2-10 in the -C 2-10 haloaklynyl or haloC 2-10 alkynyl indicates that the total carbon atoms of the alkynyl are 2 to 10.
- the -C 2-10 haloalkynyl is the -C 2-6 haloalkynyl. In some embodiments, the -C 2-6 haloalkynyl is the -C 2-3 haloalkynyl. In some embodiments, the -C 2-3 haloalkynyl is (ethynyl or propynyl) substituted with 1, 2, 3, 4, 5, or 6 -F.
- alkoxy refers to oxygen ethers formed from the previously described alkyl groups.
- haloalkoxy refers to the above-mentioned alkoxy substituted with one or more (for 1, 2, 3, 4, 5, or 6) halogen (-F, -Cl or -Br) .
- the haloalkoxy is interchangeable -C 1-10 haloalkoxy or haloC 1-10 alkoxy.
- the haloalkoxy is interchangeable -C 1-6 haloalkoxy or haloC 1-6 alkoxy, wherein, C 1-6 in the -C 1-6 haloakloxy or haloC 1-6 alkoxy indicates that the total carbon atoms of the alkoxy are 1 to 6.
- the -C 1-6 haloalkoxy is the -C 1-3 haloalkoxy. In some embodiments, the -C 1-3 haloalkoxy is (methoxy, ethoxy, propoxy or isopropoxy) substituted with 1, 2, 3, 4, 5, or 6 -F; preferably, the -C 1-3 haloalkoxy is -OCF 3 .
- carrier refers to a totally saturated or partially saturated monocyclic, bicyclic, bridged, fused, or spiro non-aromatic ring only containing carbon atoms as ring members.
- carrier as used herein, unless otherwise indicated, means a monovalent group obtained by removal of a hydrogen atom on the ring carbon atom from the carbocyclic ring defined in the present invention.
- the carbocyclic ring is interchangeable with the carbocyclyl ring in the present invention.
- the carbocyclic ring is a three to twenty membered (such as 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-or 20-membered) carbocyclic ring and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, for example, one, two, three, four, five or six, are included within the present definition.
- the carbocyclic ring includes a cycloalkyl ring in which all ring carbon atoms are saturated, a cycloalkenyl ring which contains at least one double bond (preferred contain one double bond) , and a cycloalkynyl ring which contains at least one triple bond (preferred contain one triple bond) .
- Cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
- Cycloalkenyl includes but not limited to cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like.
- the carbocyclyl ring includes a monocyclic carbocyclyl ring, and a bicyclic or polycyclic carbocyclyl ring in which one, two or three or more atoms are shared between the rings.
- the term “spirocyclic carbocyclic ring” refers to a carbocyclic ring in which each of the rings only shares one ring atom with the other ring.
- the spirocyclic ring is bicyclic spirocyclic ring.
- the spirocyclic carbocyclic ring includes a spirocyclic cycloalkyl ring and a spirocyclic cycloalkenyl ring and a spirocyclic cycloalkynyl ring.
- the term “fused carbocyclic ring” refers to a carbocyclic ring in which each of the rings shares two adjacent ring atoms with the other ring.
- the fused ring is a bicyclic fused ring.
- the fused carbocyclic ring includes a fused cycloalkyl ring and a fused cycloalkenyl ring and a fused cycloalkynyl ring.
- a monocyclic carbocyclic ring fused with an aromatic ring (such as phenyl) is included in the definition of the fused carbocyclic ring.
- the term “bridged carbocyclic ring” refers to a carbocyclic ring that includes at least two bridgehead carbon ring atoms and at least one bridging carbon atom. In some embodiments, the bridged ring is bicyclic bridged ring.
- the bridged carbocyclic ring includes a bicyclic bridged carbocyclic ring which includes two bridgehead carbon atoms and a polycyclic bridged carbocyclic ring which includes more than two bridgehead carbon atoms.
- the bridged carbocyclic ring includes a bridged cycloalkyl ring, a bridged cycloalkenyl ring and a bridged cycloalkynyl ring.
- Examples of monocyclic carbocyclyl and bicyclic carbocyclyl include but not limit to cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.
- heterocyclic ring refers to a totally saturated or partially saturated monocyclic, bicyclic, bridged, fused, or spiro non-aromatic ring containing not only carbon atoms as ring members and but also containing one or more (such as 1, 2, 3, 4, 5, or 6) heteroatoms as ring members.
- Preferred heteroatoms include N, O, S, N-oxides, sulfur oxides, and sulfur dioxides.
- heterocyclyl as used herein, unless otherwise indicated, means a monovalent group obtained by removal of a hydrogen atom on the ring carbon atom or the ring heteroatom from the heterocyclic ring defined in the present invention.
- the heterocyclic ring is interchangeable with the heterocyclyl ring in the present invention.
- the heterocyclic ring is a three to twenty membered (such as 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-or 20-membered) heterocyclic ring and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, for example, one, two, three, four, five or six, are included within the present definition.
- the heterocyclic ring includes a heterocycloalkyl ring in which all ring carbon atoms are saturated, a heterocycloalkenyl ring which contains at least one double bond (preferred contain one double bond) , and a heterocycloalkynyl ring which contains at least one triple bond (preferred contain one triple bond) .
- the heterocyclyl ring includes a monocyclic heterocyclyl ring, and a bicyclic or polycyclic heterocyclyl ring in which one, two or three or more atoms are shared between the rings.
- the term “spirocyclic heterocyclic ring” refers to a heterocyclic ring in which each of the rings only shares one ring atom with the other ring.
- the spirocyclic ring is bicyclic spirocyclic ring.
- the spirocyclic heterocyclic ring includes a spirocyclic heterocycloalkyl ring and a spirocyclic heterocycloalkenyl ring and a spirocyclic heterocycloalkynyl ring.
- the term “fused heterocyclic ring” refers to a heterocyclic ring in which each of the rings shares two adjacent ring atoms with the other ring.
- the fused ring is a bicyclic fused ring.
- the fused heterocyclic ring includes a fused heterocycloalkyl ring and a fused heterocycloalkenyl ring and a fused heterocycloalkynyl ring.
- a monocyclic heterocyclic ring fused with an aromatic ring (such as phenyl) is included in the definition of the fused heterocyclic ring.
- the term “bridged heterocyclic ring” refers to a heterocyclic ring that includes at least two bridgehead ring atoms and at least one bridging atom. In some embodiments, the bridged ring is bicyclic bridged ring.
- the bridged heterocyclic ring includes a bicyclic bridged heterocyclic ring which includes two bridgehead atoms and a polycyclic bridged heterocyclic ring which includes more than two bridgehead atoms.
- the bridged heterocyclic ring includes a bridged heterocycloalkyl ring, a bridged heterocycloalkenyl ring and a bridged heterocycloalkynyl ring.
- heterocyclyl examples include but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
- aryl refers to a mono or polycyclic aromatic ring system only containing carbon ring atoms.
- the preferred aryls are monocyclic or bicyclic 6-10 membered aromatic rings. Phenyl and naphthyl are preferred aryls.
- heteroaryl refers to an aromatic ring containing carbons and one or more (such as 1, 2, 3 or 4) heteroatoms selected from N, O or S.
- the heteroaryl may be monocyclic or polycyclic.
- a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 heteroatoms.
- a polycyclic heteroaryl ring may contain fused ring junction, for example, bicyclic heteroaryl is a polycyclic heteroaryl.
- Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
- Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms) , preferred monocyclic heteroaryl is 5 membered heteroaryl including 1, 2, 3 or 4 heteratomes selected from N, O or S, or 6 membered heteroaryl including 1 or 2 heteroatoms selected from N.
- heteroaryl groups include, but not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladeninyl, quinolinyl or isoquinolinyl.
- one or more refers to one or more than one. In some embodiments, “one or more” refers to 1, 2, 3, 4, 5 or 6. In some embodiments, “one or more” refers to 1, 2, 3 or 4. In some embodiments, “one or more” refers to 1, 2, or 3. In some embodiments, “one or more” refers to 1 or 2. In some embodiments, “one or more” refers to 1. In some embodiments, “one or more” refers to 2. In some embodiments, “one or more” refers to 3. In some embodiments, “one or more” refers to 4. In some embodiments, “one or more” refers to 5. In some embodiments, “one or more” refers to 6.
- substituted refers to a hydrogen atom on the carbon atom or a hydrogen atom on the nitrogen atom is replaced by a substituent.
- substituents When one or more substituents are substituted on a ring in the present invention, it means that each of substituents may be respectively independently substituted on every ring atom of the ring including but not limited to a ring carbon atom or a ring nitrogen atom.
- a ploycyclic ring such as a fused ring, a bridged ring or a sprio ring, each of substituents may be respectively independently substituted on every ring atom of the ploycyclic ring.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.
- pharmaceutically acceptable salt refers to a salt prepared from pharmaceutically acceptable non-toxic bases or acids.
- pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
- compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds in the present invention are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60%pure, more suitably at least 75%pure, especially at least 98%pure (%are on a weight for weight basis) .
- the present invention includes within its scope the prodrug of the compounds of this invention.
- such prodrug will be functional derivatives of the compounds that are readily converted in vivo into the required compound.
- the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.
- Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs” , ed. H. Bundgaard, Elsevier, 1985.
- the present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
- stereoisomer refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and configuration isomers.
- the configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers.
- the invention includes all possible stereoisomers of the compound.
- the present invention is intended to include all isotopes of atoms occurring in the present compounds.
- Isotopes include those atoms having the same atomic number but different mass numbers.
- isotopes of hydrogen include deuterium and tritium.
- the isotopes of hydrogen can be denoted as 1 H (hydrogen) , 2 H (deuterium) and 3 H (tritium) . They are also commonly denoted as D for deuterium and T for tritium.
- CD 3 denotes a methyl group wherein all of the hydrogen atoms are deuterium.
- Isotopes of carbon include 13 C and 14 C.
- Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.
- deuterated derivative refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom ( “D” ) . It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending on the origin of chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation is small and immaterial as compared to the degree of stable isotopic substitution of deuterated derivative described herein.
- the deuterated derivative of the disclosure have an isotopic enrichment factor for each deuterium atom, of at least 3500 (52.5%deuterium incorporation at each designated deuterium) at least 4500, (67.5 %deuterium incorporation) , at least 5000 (75%deuterium incorporation) at least 5500 (82.5%deuterium incorporation) , at least 6000 (90%deuterium incorporation) , at lease 6333.3 (95%deuterium incorporation, at least 6466.7 (97%deuterium incorporation, or at least 6600 (99%deuterium incorporation) .
- the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
- conjugated form refers to herein that the compound described herein is conjugated to another agent through a linker or not through a linker, wherein, the compound functions as a binder or a inhibitor of K-Ras protein (including K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutant protein and K-Ras wild type protein)
- the conjugated form is a PROTAC molecule, e.g. the compound is incorporated into proteolysis targeting chimeras (PROTACs) .
- a PROTAC is a bifunctional molecule, with one portion capable of engaging an E3 ubiquitin ligase, and the other portion having the ability to bind to a target protein meant for degradation by the cellular protein quality control machinery. Recruitment of the target protein to the specific E3 ligase results in its tagging for destruction (i.e., ubiquitination) and subsequent degradation by the proteasome. Any E3 ligase can be used.
- the portion of the PROTAC that engages the E3 ligase is connected to the portion of the PROTAC that engages the target protein via a linker which consists of a variable chain of atoms.
- variable chain of atoms can include, for example, rings, heteroatoms, and/or repeating polymeric units. It can be rigid or flexible. It can be attached to the two portions described above using standard techniques in the art of organic synthesis.
- compositions of the present invention comprise a compound in present invention (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
- the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
- the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
- a compound of Formula (I) a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof as defined herein can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
- the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous) .
- the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
- compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as oil-in-water emulsion or as a water-in-oil liquid emulsion.
- the compound in the present invention or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices.
- the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
- the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
- compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt.
- the compounds of the present invention or pharmaceutically acceptable salts thereof can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
- the pharmaceutical carrier employed can be, for example, a solid, liquid or gas.
- solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
- liquid carriers are sugar syrup, peanut oil, olive oil, and water.
- gaseous carriers include carbon dioxide and nitrogen.
- oral liquid preparations such as suspensions, elixirs and solutions
- carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
- oral solid preparations such as powders, capsules and tablets.
- tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
- tablets may be coated by standard aqueous or nonaqueous techniques.
- a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
- Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
- compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
- a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
- Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
- compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
- the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid.
- the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
- compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound in the present invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
- compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
- the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
- subject refers to an animal.
- the animal is a mammal.
- a subject also refers to for example, primates (e.g., humans) , cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
- the subject is a human.
- a “patient” as used herein refers to a human subject.
- a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
- the subject has experienced and/or exhibited at least one symptom of cancer to be treated and/or prevented.
- the subject has been identified or diagnosed as having a cancer having wild type K-Ras or a K-Ras G12A, K-Ras G12C, K-Ras G12D, K-Ras G12R, K-Ras G12S, K-Ras G12V, K-Ras G13D and/or K-Ras Q61H mutation
- inhibitors refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
- treat refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) .
- “treat” , “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
- “treat” , “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both.
- “treat” , “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
- K-Ras G12A refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an alanine for a glycine at amino acid position 12.
- a “K-Ras G12A inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12A.
- a “K-Ras G12A associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12A mutation.
- K-Ras G12C refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12.
- a “K-Ras G12C inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12C.
- a “K-Ras G12C associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12C mutation.
- K-Ras G12D refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12.
- a “K-Ras G12D inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12D.
- a “K-Ras G12D associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12D mutation.
- K-Ras G12R refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an arginine for a glycine at amino acid position 12.
- a “K-Ras G12R inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12R.
- a “K-Ras G12R associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12R mutation.
- K-Ras G12S refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of a serine for a glycine at amino acid position 12.
- a “K-Ras G12S inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12S.
- a “K-Ras G12S associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12S mutation.
- K-Ras G12V refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of a valine for a glycine at amino acid position 12.
- a “K-Ras G12V inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12V.
- a “K-Ras G12V associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12V mutation.
- K-Ras G13D refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 13.
- a “K-Ras G13D inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G13D.
- a “K-Ras G13D associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G13D mutation.
- K-Ras Q61H refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of a histidine for a glutamine at amino acid position 61.
- a “K-Ras Q61H inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras Q61H.
- a “K-Ras Q61H associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras Q61H mutation.
- the intermediates were synthesized using conventional preparation method.
- N-methyl-2- (methylthio) ethanamine hydrochloride (117 mg, 825.9078 ⁇ mol) in several batches was added into the solution of INT 1 (194 mg, 768.4377 ⁇ mol) , DIEA (309 mg, 2.3909 mmol) in DCM (10 mL) was stirred at 0 °C for 2 h. The solution was diluted with 10%NaHCO 3 solution, the organic layer was washed with sat. NaCl, dried over anhydrous Na 2 SO 4 and concentrated in vacuum to give Compound 16-1 (270 mg, 840.5957 ⁇ mol, 109.3902%yield) . MS m/z: 321 [M+H] + .
- Compound 23-1 was synthesized based on the same method as Compound 1-3 in Example 1, except that “2-methoxy-1, 1-dimethylethylamine hydrochloride” in Example 1 is replaced with “2, 2-difluoroethan-1-amine” .
- K-Ras G12D K-Ras G12V, K-Ras G12C, K-Ras G13D, K-Ras G12A, K-Ras G12R, K-Ras Q61H and K-Ras WT proteins were used in this assay.
- K-Ras His tag, aa 1-169 pre-loaded with GDP was pre-incubated with each of compounds in the presence of 10 nM GDP in a 384-well plate (Greiner) for 15-60 mins, then purified SOS1 ExD (Flag tag, aa 564-1049) , BODIPY TM FL GTP (Invitrogen) and monoclonal antibody anti 6HIS-Tb cryptate Gold (Cisbio) were added to the assay wells and incubated for 4 hours at 25 °C (Specially, we did not add SOS1 in the K-Ras G13D assay) .
- GppNp is an analog of GTP.
- K-Ras G12D, K-Ras G12V, K-Ras G12C, K-Ras G13D, K-Ras G12A, K-Ras G12R, K-Ras Q61H and K-Ras WT proteins were used in this assay.
- K-Ras His tag, aa 1-169 pre-loaded with GppNp was pre-incubated with each of compounds in the presence of 200 ⁇ M GTP in a 384-well plate (Greiner) for 15-60 mins, then cRAF RBD (GST tag, aa 50-132, CreativeBioMart) , monoclonal antibody anti GST-d2 (Cisbio) and monoclonal antibody anti 6HIS-Tb cryptate Gold (Cisbio) were added to the assay wells and incubated for 2 hours at 25 °C. Wells containing same percent of DMSO served as vehicle control, and wells without K-Ras served as low control.
- MKN-1 with K-Ras WT amplification is also a K-Ras dependent cell line.
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Abstract
The invention relates to a compound of Formula (I), stereoisomer thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt of the stereoisomer thereof, prodrug thereof, deuterated molecule thereof or conjugated form thereof; composition containing the same and the use thereof.
Description
Cross-References to Related Applications
This application claims the benefit of priority to PCT/CN2021/113365, filed on August 18, 2021; PCT/C N2021/123604, filed on October 13, 2021; PCT/CN2021/124118, filed on October 15, 2021; PCT/CN2021/132066, filed on November 22, 2021; PCT/CN2021/132636, filed on November 24, 2021; PCT/CN2022/074165, filed on January 27, 2022; PCT/CN2022/087377, filed on April 18, 2022, all of which are hereby incorporated herein by reference in their entireties.
The invention relates to compounds that inhibit the activity of multiple forms of K-Ras protein including K-Ras wild type and K-Ras mutant types, compositions comprising the same, and the methods of using the same.
Background Art
Kirsten Rat Sarcoma 2 Viral Oncogene Homolog ( “K-Ras” ) is a small GTPase and a member of the RAS family of oncogenes. K-Ras serves as a molecular switch cycling between inactive (GDP-bound) and active (GTP-bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes, including cellular proliferation. Aberrant expression of K-Ras accounts for up to ~20%of all cancers and oncogenic K-Ras mutations that stabilize GTP binding and lead to constitutive activation of K-Ras. K-Ras mutations at codons 12, 13, 61 and other positions of the K-Ras primary amino acid sequence are present in 88%of all pancreatic adenocarcinoma patients, 50%of all colorectal adenocarcinoma patients, and 32%lung adenocarcinoma patients. A recent publication also suggested wild type K-Ras inhibition could be a viable therapeutic strategy to treat K-Ras wild type dependent cancers.
Allele-specific K-Ras G12C inhibitors, such as sotorasib (AMG510) or adagrasib (MRTX849) , are currently changing the treatment paradigm for patients with K-Ras G12C mutated non-small cell lung cancer and colorectal cancer. The success of addressing a previously elusive K-Ras allele has fueled drug discovery efforts for all K-Ras mutants. Multiple K-Ras inhibitors have the potential to address broad patient populations, including K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutant and K-Ras wild type amplified cancers.
Therefore, there are unmet needs to develop new multiple K-Ras inhibitors for treating K-Ras mediated cancers.
Summary of Invention
Provided herein is a compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof:
Wherein, the definition of each of variables is as below.
Also provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof as defined herein; and a pharmaceutically acceptable excipient.
Also provided herein is a method for treating cancer in a subject comprising administering a therapeutically effective amount of a compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein to a subject in need thereof.
Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining whether the cancer is associated with K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutation and/or K-Ras wild type amplification; and (b) if so, administering a therapeutically effective amount of a compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein to the subject in need thereof.
Also provided herein is a compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein for use in therapy.
Also provided herein is a compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein for use as a medicament.
Also provided herein is a compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein for use in a method for the treatment of cancer.
Also provided herein is a use of a compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein for the treatment of cancer.
Also provided herein is a use of a compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugated form thereof, or a pharmaceutical composition as defined herein for the manufacture of a medicament for the treatment of cancer.
Also provided herein is a process for preparing a compound of formula (I) as defined herein.
Also provided herein is an intermediate for preparing a compound of formula (I) as defined herein.
Provided herein are the following disclosures:
[1] . A compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof:
Wherein,
Y
1 is selected from a bond, O, NR
1a, S, S (=O) or S (=O)
2;
R
1a is selected from hydrogen, deuterium, -C
1-10alkyl, haloC
1-10alkyl, haloC
1-10alkoxy, -C
2-10alkenyl, haloC
2-10alkenyl, -C
2-10alkynyl, haloC
2-10alkynyl, -N (R
1b)
2, -OR
1b, -SR
1b, 3-10 membered cycloalkyl, 3-10 membered hetrocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C
1-10alkyl, haloC
1-10alkyl, haloC
1-10alkoxy, -C
2-10alkenyl, -C
2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered hetrocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -N (R
1c)
2, -OR
1c, -SR
1c, -S (=O) R
1d, -S (=O)
2R
1d, -C (=O) R
1d, -C (=O) OR
1c, -OC (=O) R
1d, -C (=O) N (R
1c)
2, -NR
1cC (=O) R
1d, -OC (=O) OR
1c, -NR
1cC (=O) OR
1d, -OC (=O) N (R
1c)
2, -NR
1cC (=O) N (R
1c)
2, -S (=O) OR
1c, -OS (=O) R
1d, -S (=O) N (R
1c)
2, -NR
1cS (=O) R
1d, -S (=O)
2OR
1c, -OS (=O)
2R
1d, -S (=O)
2N (R
1c)
2, -NR
1cS (=O)
2R
1d, -OS (=O)
2OR
1c, -NR
1cS (=O)
2OR
1c, -OS (=O)
2NR
1c, -NR
1cS (=O)
2N (R
1c)
2, -P (R
1c)
2, -P (=O) (R
1d)
2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
L
1 is selected from a bond or C
1-10 alkylene optionally substituted with one or more R
Z11;
X
1 is selected from hydrogen, deuterium, -C
1-10alkyl, halogen, -OR
11, -N (R
11)
2, -SR
11, -CN, -S (=O) R
12, -C (=O) R
12, -S (=O)
2R
12, -C (=O) OR
11, -OC (=O) R
12, -NR
11C (=O) R
12, -C (=O) N (R
11)
2, -NR
11S (=O) R
12, -S (=O)
2N (R
11)
2, -NR
11S (=O)
2R
12, -S (=O)
2N (R
11)
2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, said -C
1-10 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with one or more R
S1;
R
S1 at each occurrence is independently selected from deuterium, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, haloC
2-6alkenyl, -C
2-6alkynyl, haloC
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -N (R
13)
2, -OR
13, -SR
13, -S (=O) R
14, -S (=O)
2R
14, -C (=O) R
14, -C (=O) OR
13, -OC (=O) R
14, -C (=O) N (R
13)
2, -NR
13C (=O) R
14, -OC (=O) OR
13, -NR
13C (=O) OR
13, -NR
13C (=S) OR
13, -OC (=O) N (R
13)
2, -NR
13C (=O) N (R
13)
2, -S (=O) OR
13, -OS (=O) R
14, -S (=O) N (R
13)
2, -NR
13S (=O) R
14, -S (=O)
2OR
13, -OS (=O)
2R
14, -S (=O)
2N (R
13)
2, -NR
13S (=O)
2R
14, -OS (=O)
2OR
13, -NR
13S (=O)
2OR
13, -OS (=O)
2N (R
13)
2, -NR
13S (=O)
2N (R
13)
2, -P (R
13)
2, -P (=O) (R
14)
2,
3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein said -C
1-6alkyl, haloC
1-
6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, haloC
2-6alkenyl, -C
2-6alkynyl, haloC
2-6alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 3-8 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, haloC
2-6alkenyl, -C
2-6alkynyl, haloC
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -N (R
15)
2, -OR
15, -SR
15, -S (=O) R
16, -S (=O)
2R
16, -C (=O) R
16, -C (=O) OR
15, -OC (=O) R
16, -C (=O) N (R
15)
2, -NR
15C (=O) R
16, -OC (=O) OR
15, -NR
15C (=O) OR
15, -NR
15C (=S) OR
15, -OC (=O) N (R
15)
2, -NR
15C (=O) N (R
15)
2, -S (=O) OR
15, -OS (=O) R
16, -S (=O) N (R
15)
2, -NR
15S (=O) R
16, -S (=O)
2OR
15, -OS (=O)
2R
16, -S (=O)
2N (R
16)
2, -NR
15S (=O)
2R
16, -OS (=O)
2OR
15, -NR
15S (=O)
2OR
15, -OS (=O)
2N (R
15)
2, -NR
15S (=O)
2N (R
15)
2, -P (R
15)
2, -P (=O) (R
16)
2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Optionally, two R
S1 together with the carbon atom to which they are both attached form
a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said
3-10 membered carbocylic ring or 3-10 heterocyclic ring is optionally substituted with one or more R
Z12;
Optionally, two adjacent R
S1 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently optionally substituted with one or more R
Z13;
Optionally, two nonadjacent R
S1 are connected together to form a bridge containing 0, 1, 2, 3, 4, 5 or 6 carbon atoms, wherein, each of the carbon atoms in the bridge is optionally replaced by 1 or 2 heteroatoms selected from N, O, S, S=O or S (=O)
2; the hydrogen on the each of carbon atoms or N atoms is optionally independently substituted with R
Z14;
Y
2 is a bond, O, S, S (=O) , S (=O)
2 or NR
2a;
R
2 is selected from -L
20- (3-12 membered heterocyclyl) , -L
20- (3-12 membered cycloalkyl) , -L
20- (6-12 membered aryl) , -L
20- (5-12 membered heteroaryl) , -L
20-N (R
2b)
2,
Each of L
20 at each occurrence is independently selected from a bond or C
1-10 alkylene optionally substituted with one or more R
Z21;
Said 3-12 membered heterocyclyl in -L
20- (3-12 membered heterocyclyl) is optionally substituted with one or more R
Z22;
Said 3-12 membered cycloalkyl in -L
20- (3-12 membered cycloalkyl) is optionally substituted with one or more R
Z22;
Said 6-12 membered aryl in -L
20- (6-12 membered aryl) is optionally substituted with one or more R
Z22;
Said 5-12 membered heteroaryl in -L
20- (5-12 membered heteroaryl) is optionally substituted with one or more R
Z22;
L
21 is selected from a bond or C
1-10 alkylene optionally substituted with one or more R
Z23;
Ring B or ring C is a 3-10 membered heterocyclic ring optionally further containing 1, 2, or 3 heteroatoms selected from N, O or S;
R
S21 at each occurrence is independently selected from deuterium, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, haloC
2-6alkenyl, -C
2-6alkynyl, haloC
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -N (R
21)
2, -OR
21, -SR
21, -S (=O) R
22, -S (=O)
2R
22, -C (=O) R
22, -C (=O) OR
21, -OC (=O) R
22, -C (=O) N (R
21)
2, -NR
21C (=O) R
22, -OC (=O) OR
21, -NR
21C (=O) OR
21, -NR
21C (=S) OR
21, -OC (=O) N (R
21)
2, -NR
21C (=O) N (R
21)
2, -S (=O) OR
21, -OS (=O) R
22, -S (=O) N (R
21)
2, -NR
21S (=O) R
22, -S (=O)
2OR
21, -OS (=O)
2R
22, -S (=O)
2N (R
21)
2, -NR
21S (=O)
2R
22, - OS (=O)
2OR
21, -NR
21S (=O)
2OR
21, -OS (=O)
2N (R
21)
2, -NR
21S (=O)
2N (R
21)
2, -P (R
21)
2, -P (=O) (R
22)
2,
3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein said -C
1-6alkyl, haloC
1-
6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, haloC
2-6alkenyl, -C
2-6alkynyl, haloC
2-6alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 3-8 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, haloC
2-6alkenyl, -C
2-6alkynyl, haloC
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -N (R
23)
2, -OR
23, -SR
23, -S (=O) R
24, -S (=O)
2R
24, -C (=O) R
24, -C (=O) OR
23, -OC (=O) R
24, -C (=O) N (R
23)
2, -NR
23C (=O) R
24, -OC (=O) OR
23, -NR
23C (=O) OR
24, -NR
23C (=S) OR
23, -OC (=O) N (R
23)
2, -NR
23C (=O) N (R
23)
2, -S (=O) OR
23, -OS (=O) R
24, -S (=O) N (R
23)
2, -NR
23S (=O) R
24, -S (=O)
2OR
23, -OS (=O)
2R
24, -S (=O)
2N (R
23)
2, -NR
23S (=O)
2R
24, -OS (=O)
2OR
23, -NR
23S (=O)
2OR
23, -OS (=O)
2N (R
23)
2, -NR
23S (=O)
2N (R
23)
2, -P (R
23)
2, -P (=O) (R
24)
2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Optionally, two R
S21 together with the carbon atom to which they are both attached form
a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said
3-10 membered carbocylic ring or 3-10 heterocyclic ring is optionally substituted with one or more R
Z24;
Optionally, two adjacent R
S21 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently optionally substituted with one or more R
Z25;
Optionally, two nonadjacent R
S21 are connected together to form a bridge containing 0, 1, 2, 3, 4, 5 or 6 carbon atoms, wherein, each of the carbon atoms in the bridge is optionally replaced by 1 or 2 heteroatoms selected from N, O, S, S=O or S (=O)
2; the hydrogen on the each of carbon atoms or N atoms is optionally independently substituted with R
Z26;
q
21 is selected from 0, 1, 2, 3, 4, 5 or 6;
L
22 is selected from a bond or C
1-10 alkylene optionally substituted with one or more R
Z27;
Ring D is selected from a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein the moiety of -L
22-and -L
23-X
2 are attached to the same atom or different atoms of the ring D;
L
23 is selected from a bond or C
1-10 alkylene optionally substituted with one or more R
Z28;
X
2 is selected from -N (R
25)
2, -OR
25, -SR
25, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein said 3-10 membered heterocyclyl or 5-10 membered heteroaryl is optionally independently substituted with one or more R
Z29;
Each of R
S22 at each occurrence is independently selected from deuterium, halogen, -C
1-6alkyl, haloC
1-
6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, haloC
2-6alkenyl, -C
2-6alkynyl, haloC
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -N (R
26)
2, -OR
26, -SR
26, -S (=O) R
27, -S (=O)
2R
27, -C (=O) R
27, -C (=O) OR
26, -OC (=O) R
27, -C (=O) N (R
26)
2, -NR
26C (=O) R
27, -OC (=O) OR
26, -NR
26C (=O) OR
26, -OC (=O) N (R
26)
2, -NR
26C (=O) N (R
26)
2, -S (=O) OR
26, -OS (=O) R
27, -S (=O) N (R
26)
2, -NR
26S (=O) R
27, -S (=O)
2OR
26, -OS (=O)
2R
27, -S (=O)
2N (R
26)
2, -NR
26S (=O)
2R
27, -OS (=O)
2OR
26, -NR
26S (=O)
2OR
26, -OS (=O)
2N (R
26)
2, -NR
26S (=O)
2N (R
26)
2, -P (R
26)
2, -P (=O) (R
26)
2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-
6alkenyl, haloC
2-6alkenyl, -C
2-6alkynyl, haloC
2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, haloC
2-6alkenyl, -C
2-6alkynyl, haloC
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -N (R
28)
2, -OR
28, -SR
28, -S (=O) R
29, -S (=O)
2R
29, -C (=O) R
29, -C (=O) OR
28, -OC (=O) R
29, -C (=O) N (R
28)
2, -NR
28C (=O) R
29, -OC (=O) OR
28, -NR
28C (=O) OR
28, -OC (=O) N (R
28)
2, -NR
28C (=O) N (R
28)
2, -S (=O) OR
28, -OS (=O) R
29, -S (=O) N (R
28)
2, -NR
28S (=O) R
29, -S (=O)
2OR
28, -OS (=O)
2R
29, -S (=O)
2N (R
28)
2, -NR
28S (=O)
2R
29, -OS (=O)
2OR
28, -NR
28S (=O)
2OR
28, -OS (=O)
2N (R
28)
2, -NR
28S (=O)
2N (R
28)
2, -P (R
28)
2, -P (=O) (R
29)
2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
q
22 is selected from 0, 1, 2, 3, 4, 5 or 6;
R
3 is independently selected from hydrogen, deuterium, halogen, -C
1-10alkyl, haloC
1-10alkyl, haloC
1-
10alkoxy, -C
2-10alkenyl, haloC
2-10alkenyl, -C
2-10alkynyl, haloC
2-10alkynyl, -CN, -NO
2, -N
3, oxo, -N (R
31)
2, -OR
31, -SR
31, -S (=O) R
32, -S (=O)
2R
32, -C (=O) R
32, -C (=O) OR
31, -OC (=O) R
32, -C (=O) N (R
31)
2, -NR
31C (=O) R
32, -OC (=O) OR
31, -NR
31C (=O) OR
31, -OC (=O) N (R
31)
2, -NR
31C (=O) N (R
31)
2, -S (=O) OR
31, -OS (=O) R
32, - S (=O) N (R
31)
2, -NR
31S (=O) R
32, -S (=O)
2OR
31, -OS (=O)
2R
32, -S (=O)
2N (R
31)
2, -NR
31S (=O)
2R
32, -OS (=O)
2OR
31, -NR
31S (=O)
2OR
31, -OS (=O)
2N (R
31)
2, -NR
31S (=O)
2N (R
31)
2, -P (R
31)
2, -P (=O) (R
32)
2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C
1-10alkyl, haloC
1-10alkyl, haloC
1-10alkoxy, -C
2-10alkenyl, haloC
2-
10alkenyl, -C
2-10alkynyl, haloC
2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C
1-
6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, haloC
2-6alkenyl, -C
2-6alkynyl, haloC
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -N (R
33)
2, -OR
33, -SR
33, -S (=O) R
34, -S (=O)
2R
34, -C (=O) R
34, -C (=O) OR
33, -OC (=O) R
34, -C (=O) N (R
33)
2, -NR
33C (=O) R
34, -OC (=O) OR
33, -NR
33C (=O) OR
33, -OC (=O) N (R
33)
2, -NR
33C (=O) N (R
33)
2, -S (=O) OR
33, -OS (=O) R
34, -S (=O) N (R
33)
2, -NR
33S (=O) R
34, -S (=O)
2OR
33, -OS (=O)
2R
34, -S (=O)
2N (R
33)
2, -NR
33S (=O)
2R
34, -OS (=O)
2OR
33, -NR
33S (=O)
2OR
33, -OS (=O)
2N (R
33)
2, -NR
33S (=O)
2N (R
33)
2, -P (R
33)
2, -P (=O) (R
34)
2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
R
4 is selected from 6-10 membered aryl, 5-10 membered heteroaryl,
wherein said 6-10 membered aryl, 5-10 membered heteroaryl,
is optionally independently substituted with one or more R
S4;
Z at each occurrence is independently selected from C or N;
Ring E at each occurrence is independently selected from a 6 membered aryl ring or a 5-6 membered heteroaryl ring and ring F at each occurrence is a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring when Z is selected from C;
Ring E at each occurrence is selected from a 5-6 membered heteroaryl ring and ring F at each occurrence is a 3-10 membered heterocyclic ring when Z is selected from N;
R
S4 at each occurrence is independently selected from deuterium, halogen, -C
1-10alkyl, haloC
1-10alkyl, haloC
1-10alkoxy, -C
2-10alkenyl, haloC
2-10alkenyl, -C
2-10alkynyl, haloC
2-10alkynyl, -CN, -NO
2, -N
3, oxo, -N (R
41)
2, -OR
41, -SR
41, -S (=O) R
42, -S (=O)
2R
42, -C (=O) R
42, -C (=O) OR
41, -OC (=O) R
42, -C (=O) N (R
41)
2, -NR
41C (=O) R
42, -OC (=O) OR
41, -NR
41C (=O) OR
41, -OC (=O) N (R
41)
2, -NR
41C (=O) N (R
41)
2, -S (=O) OR
41, -OS (=O) R
42, -S (=O) N (R
41)
2, -NR
41S (=O) R
42, -S (=O)
2OR
41, -OS (=O)
2R
42, -S (=O)
2N (R
41)
2, -NR
41S (=O)
2R
42, -OS (=O)
2OR
41, -NR
41S (=O)
2OR
41, -OS (=O)
2N (R
41)
2, -NR
41S (=O)
2N (R
41)
2, -P (R
41)
2, -P (=O) (R
42)
2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, wherein said -C
1-10alkyl, haloC
1-10alkyl, haloC
1-
10alkoxy, -C
2-10alkenyl, haloC
2-10alkenyl, -C
2-10alkynyl, haloC
2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more R
4b;
R
4b at each occurrence is independently selected from deuterium, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, haloC
2-6alkenyl, -C
2-6alkynyl, haloC
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -N (R
43)
2, -OR
43, -SR
43, -S (=O) R
44, -S (=O)
2R
44, -C (=O) R
44, -C (=O) OR
43, -OC (=O) R
44, -C (=O) N (R
43)
2, -NR
43C (=O) R
44, -OC (=O) OR
43, -NR
43C (=O) OR
43, -OC (=O) N (R
43)
2, -NR
43C (=O) N (R
43)
2, -S (=O) OR
43, -OS (=O) R
44, -S (=O) N (R
43)
2, -NR
43S (=O) R
44, -S (=O)
2OR
43, -OS (=O)
2R
44, -S (=O)
2N (R
43)
2, -NR
43S (=O)
2R
44, -OS (=O)
2OR
43, -NR
43S (=O)
2OR
43, -OS (=O)
2N (R
43)
2, -NR
43S (=O)
2N (R
43)
2, -P (R
43)
2, -P (=O) (R
44)
2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
R
5 is independently selected from hydrogen, deuterium, halogen, -C
1-10alkyl, haloC
1-10alkyl, haloC
1-
10alkoxy, -C
2-10alkenyl, haloC
2-10alkenyl, -C
2-10alkynyl, haloC
2-10alkynyl, -CN, -NO
2, -N
3, oxo, -N (R
51)
2, -OR
51, -SR
51, -S (=O) R
52, -S (=O)
2R
52, -C (=O) R
52, -C (=O) OR
51, -OC (=O) R
52, -C (=O) N (R
51)
2, -NR
81C (=O) R
52, -OC (=O) OR
51, -NR
81C (=O) OR
51, -OC (=O) N (R
51)
2, -NR
51C (=O) N (R
51)
2, -S (=O) OR
51, -OS (=O) R
52, -S (=O) N (R
51)
2, -NR
51S (=O) R
52, -S (=O)
2OR
51, -OS (=O)
2R
52, -S (=O)
2N (R
51)
2, -NR
51S (=O)
2R
52, -OS (=O)
2OR
51, -NR
51S (=O)
2OR
51, -OS (=O)
2N (R
51)
2, -NR
51S (=O)
2N (R
51)
2, -P (R
51)
2, -P (=O) (R
52)
2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C
1-10alkyl, haloC
1-10alkyl, haloC
1-10alkoxy, -C
2-10alkenyl, haloC
2-
10alkenyl, -C
2-10alkynyl, haloC
2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C
1-
6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, haloC
2-6alkenyl, -C
2-6alkynyl, haloC
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -N (R
53)
2, -OR
53, -SR
53, -S (=O) R
54, -S (=O)
2R
54, -C (=O) R
54, -C (=O) OR
53, -OC (=O) R
54, -C (=O) N (R
53)
2, -NR
53C (=O) R
54, -OC (=O) OR
53, -NR
53C (=O) OR
53, -OC (=O) N (R
53)
2, -NR
53C (=O) N (R
53)
2, -S (=O) OR
53, -OS (=O) R
54, -S (=O) N (R
53)
2, -NR
53S (=O) R
54, -S (=O)
2OR
53, -OS (=O)
2R
54, -S (=O)
2N (R
53)
2, - NR
53S (=O)
2R
54, -OS (=O)
2OR
53, -NR
53S (=O)
2OR
53, -OS (=O)
2N (R
53)
2, -NR
53S (=O)
2N (R
53)
2, -P (R
53)
2, -P (=O) (R
54)
2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Each of (R
11, R
13, R
15, R
21, R
23, R
25, R
26, R
28, R
31, R
33, R
41, R
43, R
51 and R
53) at each occurrence is independently selected from hydrogen, deuterium, halogen, -C
1-10alkyl, haloC
1-10alkyl, -C
2-10alkenyl, -C
2-
10alkynyl, -S (=O) R
a, -S (=O)
2R
a, -C (=O) R
a, -C (=O) OR
a, -C (=O) N (R
a)
2, -S (=O) OR
a, -S (=O) N (R
a)
2, -S (=O)
2OR
a, -S (=O)
2N (R
a)
2, -P (=O) (R
a)
2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C
1-10alkyl, haloC
1-10alkyl, -C
2-10alkenyl, -C
2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -N (R
c)
2, -OR
c, -SR
c, -S (=O) R
d, -S (=O)
2R
d, -C (=O) R
d, -C (=O) OR
c, -OC (=O) R
d, -C (=O) N (R
c)
2, -NR
cC (=O) R
d, -OC (=O) OR
c, -NR
cC (=O) OR
d, -OC (=O) N (R
c)
2, -NR
cC (=O) N (R
c)
2, -S (=O) OR
c, -OS (=O) R
d, -S (=O) N (R
c)
2, -NR
cS (=O) R
d, -S (=O)
2OR
c, -OS (=O)
2R
d, -S (=O)
2N (R
c)
2, -NR
cS (=O)
2R
d, -OS (=O)
2OR
c, -NR
cS (=O)
2OR
c, -OS (=O)
2NR
c, -NR
cS (=O)
2N (R
c)
2, -P (R
c)
2, -P (=O) (R
d)
2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Optionally, each of (two R
11, two R
13, two R
15, two R
21, two R
23, two R
25, two R
26, two R
28, two R
31, two R
33, two R
41, two R
43, two R
51, and two R
53) independently together with the nitrogen atom to which they are both attached forms a 3-20 membered heterocyclic ring or a 5-10 membered heteroaryl ring, wherein, said 3-20 membered heterocyclic ring or 5-10 membered heteroaryl ring is optionally independently substituted with one or more R
Za;
Each of (R
12, R
14, R
16, R
22, R
24, R
27, R
29, R
32, R
34, R
42, R
44, R
52 and R
54) at each occurrence is independently selected from hydrogen, deuterium, -C
1-10alkyl, haloC
1-10alkyl, haloC
1-10alkoxy, -C
2-10alkenyl, haloC
2-10alkenyl, -C
2-10alkynyl, haloC
2-10alkynyl, -N (R
b)
2, -OR
b, -SR
b, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C
1-10alkyl, haloC
1-10alkyl, haloC
1-10alkoxy, -C
2-10alkenyl, -C
2-
10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-
6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -N (R
c)
2, -OR
c, -SR
c, -S (=O) R
d, -S (=O)
2R
d, -C (=O) R
d, -C (=O) OR
c, -OC (=O) R
d, -C (=O) N (R
c)
2, -NR
cC (=O) R
d, -OC (=O) OR
c, -NR
cC (=O) OR
d, -OC (=O) N (R
c)
2, -NR
cC (=O) N (R
c)
2, -S (=O) OR
c, -OS (=O) R
d, -S (=O) N (R
c)
2, -NR
cS (=O) R
d, -S (=O)
2OR
c, -OS (=O)
2R
d, -S (=O)
2N (R
c)
2, -NR
cS (=O)
2R
d, -OS (=O)
2OR
c, -NR
cS (=O)
2OR
c, -OS (=O)
2NR
c, -NR
cS (=O)
2N (R
c)
2, -P (R
c)
2, -P (=O) (R
d)
2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Each of (R
a, R
b, R
c, R
d, R
1b, R
1c, R
1d, R
2a and R
2b) at each occurrence is independently selected from hydrogen, deuterium, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-
6alkenyl, -C
2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more R
Zb;
Optionally, each of (two R
a, two R
b, two R
c, two R
1b, two R
1c, two R
2a and two R
2b) independently together with the atom to which they are both attached forms a 3-6 membered heterocyclic ring, wherein said 3-6 membered heterocyclic ring is independently optionally substituted with one or more R
Zc;
Each of (R
Z11, R
Z12, R
Z13, R
Z14, R
Z21, R
Z22, R
Z23, R
Z24, R
Z25, R
Z26, R
Z27, R
Z28, R
Z29, R
Za, R
Zb and R
Zc) at each occurrence is independently selected from deuterium, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-
6alkyl) C (=O) (C
1-6alkyl) , -OC (=O) O (C
1-6alkyl) , -NHC (=O) (OC
1-6alkyl) , -N (C
1-6alkyl) C (=O) (OC
1-6alkyl) , -OC (=O) NH (C
1-6alkyl) , -OC (=O) N (C
1-6alkyl)
2, -NHC (=O) NH
2, -NHC (=O) NH (C
1-6alkyl) , -NHC (=O) N (C
1-
6alkyl)
2, -N (C
1-6alkyl) C (=O) NH
2, -N (C
1-6alkyl) C (=O) NH (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) N (C
1-6alkyl)
2, -S (=O) (OC
1-6alkyl) , -OS (=O) (C
1-6alkyl) , -S (=O) NH
2, -S (=O) NH (C
1-6alkyl) , -S (=O) N (C
1-6alkyl)
2, -NHS (=O) (C
1-6alkyl) , -N (C
1-6alkyl) S (=O) (C
1-6alkyl) , -S (=O)
2 (OC
1-6alkyl) , -OS (=O)
2 (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , -OS (=O)
2O (C
1-6alkyl) , -NHS (=O)
2O (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2O (C
1-6alkyl) , -OS (=O)
2NH
2, -OS (=O)
2NH (C
1-6alkyl) , -OS (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2NH
2, -NHS (=O)
2NH (C
1-6alkyl) , -NHS (=O)
2N (C
1-
6alkyl)
2, -N (C
1-6alkyl) S (=O)
2NH
2, -N (C
1-6alkyl) S (=O)
2NH (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2N (C
1-6alkyl)
2, -PH (C
1-6alkyl) , -P (C
1-6alkyl)
2, -P (=O) H (C
1-6alkyl) , -P (=O) (C
1-6alkyl)
2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from deuterium, halogen, -C
1-3alkyl, haloC
1-3alkyl, haloC
1-3alkoxy, -C
2-3alkenyl, -C
2-3alkynyl, -CN, -NO
2, -N
3, oxo, -NH
2, -NH (C
1-3alkyl) , -N (C
1-3alkyl)
2, -OH, -O (C
1-3alkyl) , -SH, -S (C
1-3alkyl) , -S (=O) (C
1-3alkyl) , -S (=O)
2 (C
1-3alkyl) , -C (=O) (C
1-3alkyl) , -C (=O) OH, -C (=O) (OC
1-3alkyl) , -OC (=O) (C
1-3alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-3alkyl) , -C (=O) N (C
1-3alkyl)
2, -NHC (=O) (C
1-3alkyl) , -N (C
1-3alkyl) C (=O) (C
1-3alkyl) , -OC (=O) O (C
1-3alkyl) , -NHC (=O) (OC
1-3alkyl) , -N (C
1-3alkyl) C (=O) (OC
1-3alkyl) , -OC (=O) NH (C
1-3alkyl) , -OC (=O) N (C
1-3alkyl)
2, -NHC (=O) NH
2, -NHC (=O) NH (C
1-3alkyl) , -NHC (=O) N (C
1-3alkyl)
2, -N (C
1-
3alkyl) C (=O) NH
2, -N (C
1-3alkyl) C (=O) NH (C
1-3alkyl) , -N (C
1-3alkyl) C (=O) N (C
1-3alkyl)
2, -S (=O) (OC
1-3alkyl) , -OS (=O) (C
1-3alkyl) , -S (=O) NH
2, -S (=O) NH (C
1-3alkyl) , -S (=O) N (C
1-3alkyl)
2, -NHS (=O) (C
1-3alkyl) , -N (C
1-
3alkyl) S (=O) (C
1-3alkyl) , -S (=O)
2 (OC
1-3alkyl) , -OS (=O)
2 (C
1-3alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-3alkyl) , -S (=O)
2N (C
1-3alkyl)
2, -NHS (=O)
2 (C
1-3alkyl) , -N (C
1-3alkyl) S (=O)
2 (C
1-3alkyl) , -OS (=O)
2O (C
1-3alkyl) , -NHS (=O)
2O (C
1-3alkyl) , -N (C
1-3alkyl) S (=O)
2O (C
1-3alkyl) , -OS (=O)
2NH
2, -OS (=O)
2NH (C
1-3alkyl) , -OS (=O)
2N (C
1-3alkyl)
2, -NHS (=O)
2NH
2, -NHS (=O)
2NH (C
1-3alkyl) , -NHS (=O)
2N (C
1-3alkyl)
2, -N (C
1-
3alkyl) S (=O)
2NH
2, -N (C
1-3alkyl) S (=O)
2NH (C
1-3alkyl) , -N (C
1-3alkyl) S (=O)
2N (C
1-3alkyl)
2, -PH (C
1-3alkyl) , -P (C
1-3alkyl)
2, -P (=O) H (C
1-3alkyl) , -P (=O) (C
1-3alkyl)
2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6 membered aryl or 5-6 membered heteroaryl;
Each of (heterocyclyl and heteroaryl) at each occurrence is independently contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, S (=O) or S (=O)
2.
[2] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of [1] , wherein,
Y
1 is selected from a bond, O, or NR
1a;
R
1a is selected from hydrogen, deuterium, or -C
1-3alkyl;
L
1 is selected from a bond or C
1-3 alkylene; said C
1-3alkylene is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C
1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;
X
1 is selected from -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkyl, -C
2-6alkenyl, -C
2-6alkynyl, 3-8 membered cycloalkyl, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, -OH, -OC
1-6alkyl, -SH, -SC
1-6alkyl, -C (=O) C
1-6alkyl, -S (=O) H, -S (=O) C
1-6alkyl, -S (=O)
2H, -S (=O)
2C
1-6alkyl, -C (=O) OH, -C (=O) OC
1-6alkyl, -OC (=O) C
1-6alkyl, 3-8 membered cycloalkenyl, phenyl, or 5-6 membered heteroaryl; wherein said -C
1-6alkyl, haloC
1-6alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted with one or more R
S1;
R
S1 at each occurrence is independently selected from deuterium, halogen, -C
1-6alkyl, haloC
1-6alkyl, -C
2-
6alkenyl, -CN, -NH
2, -NH (C
1-3alkyl) , -N (C
1-3alkyl)
2, -OH, -OC
1-3alkyl, -SH, -SC
1-3alkyl, -C (=O) C
1-3alkyl, -S (=O) H, -S (=O) C
1-6alkyl, -S (=O)
2H, -S (=O)
2C
1-6alkyl, -C (=O) OH, -C (=O) OC
1-3alkyl, -OC (=O) C
1-3alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl; wherein said -C
1-6alkyl, haloC
1-6alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C
1-6alkyl, haloC
1-
6alkyl, -CN, -NH
2, -NH (C
1-3alkyl) , -N (C
1-3alkyl)
2, -OH, -OC
1-3alkyl, -SH, -SC
1-3alkyl, -C (=O) C
1-3alkyl, -C (=O) OH, -C (=O) OC
1-3alkyl, -OC (=O) C
1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;
Optionally, two R
S1 together with the carbon atom to which they are both attached form
a3-6 membered carbocyclic ring or a 3-6 heterocyclic ring; wherein, said
3-10 membered carbocylic ring or 3-10 heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, -C
1-6alkyl, haloC
1-6alkyl, -CN, -NH
2, -NH (C
1-3alkyl) , -N (C
1-3alkyl)
2, -OH, -OC
1-3alkyl, -SH, -SC
1-
3alkyl, -C (=O) C
1-3alkyl, -C (=O) OH, -C (=O) OC
1-3alkyl, -OC (=O) C
1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;
Optionally, two adjacent R
S1 together with the carbon atoms to which they are respectively attached form a 3-6 membered carbocyclic ring, or a 3-6 membered heterocyclic ring, wherein, each of rings is independently optionally substituted with one or more substituents selected from deuterium, halogen, -C
1-6alkyl, haloC
1-
6alkyl, -CN, -NH
2, -NH (C
1-3alkyl) , -N (C
1-3alkyl)
2, -OH, -OC
1-3alkyl, -SH, -SC
1-3alkyl, -C (=O) C
1-3alkyl, -C (=O) OH, -C (=O) OC
1-3alkyl, -OC (=O) C
1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;
q
1 is selected from 0, 1, 2 or 3.
[3] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of [1] or [2] , wherein, the compound is selected from Formula (II-1) to Formula (II-3) :
[4] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [3] , wherein, the compound is selected from the following formulas:
L
1 is selected from a bond or C
1-3alkylene; said C
1-3alkylene is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C
1-3alkyl;
R
1 is selected from -C
1-3alkyl, haloC
1-3alkyl, -C
2-3alkenyl, -OH, -OC
1-3alkyl, -SH, -SC
1-3alkyl, -C (=O) C
1-
3alkyl, -S (=O) H, -S (=O) C
1-3alkyl, -S (=O)
2H, -S (=O)
2C
1-3alkyl, -C (=O) OH, -C (=O) OC
1-3alkyl, -OC (=O) C
1-
3alkyl; wherein said -C
1-3alkyl, haloC
1-3alkyl is optionally independently substituted with one or more substituents selected from -C
1-3alkyl, haloC
1-3alkyl, -C
2-3alkenyl, -OH, -OC
1-3alkyl, -SH, -SC
1-3alkyl, -C (=O) C
1-3alkyl, -S (=O) H, -S (=O) C
1-3alkyl, -S (=O)
2H, -S (=O)
2C
1-3alkyl, -C (=O) OH, -C (=O) OC
1-3alkyl, -OC (=O) C
1-3alkyl;
X
1 is selected from -C
1-3alkyl, haloC
1-3alkyl, -C
2-3alkenyl, 3-8 membered cycloalkyl, 3-8 membered hetrocycloalkyl, phenyl, or 5-6 membered heteroaryl; wherein said -C
1-3alkyl, haloC
1-3alkyl, -C
2-3alkenyl, 3-8 membered cycloalkyl, 3-8 membered hetrocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted with one or more -C
1-3alkyl, haloC
1-3alkyl, -C
2-3alkenyl, -OH, -OC
1-3alkyl, -SH, -SC
1-3alkyl, -C (=O) C
1-3alkyl, -S (=O) H, -S (=O) C
1-3alkyl, -S (=O)
2H, -S (=O)
2C
1-3alkyl, -C (=O) OH, -C (=O) OC
1-
3alkyl, -OC (=O) C
1-3alkyl, 3-8 membered cycloalkyl, 3-8 membered hetrocycloalkyl;
Ring A is selected from 4-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; wherein said ring A is optionally independently substituted with one or more -C
1-3alkyl, haloC
1-
3alkyl, -C
2-3alkenyl, -OH, -OC
1-3alkyl, -SH, -SC
1-3alkyl, -C (=O) C
1-3alkyl, -S (=O) H, -S (=O) C
1-3alkyl, -S (=O)
2H, -S (=O)
2C
1-3alkyl, -C (=O) OH, -C (=O) OC
1-3alkyl, -OC (=O) C
1-3alkyl, 3-8 membered cycloalkyl, 3-8 membered hetrocycloalkyl.
[5] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [4] , wherein, the moiety of
is selected from any one moiety in the Table A
Table A
[6] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [5] , wherein,
Y
2 is O;
L
21 is selected from a bond or C
1-3 alkylene;
L
22 is selected from a bond or C
1-3 alkylene;
L
23 is selected from a bond or C
1-3 alkylene;
Ring B or ring C is a 5-6 membered heterocyclic ring optionally further containing 1 or 2 heteroatoms selected from N or O;
Ring D is a 3 membered carbocyclic ring; wherein the moiety of -L
22-and -L
23-X
2 are attached to the same atom or different atoms of the ring E;
X
2 is a 6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl is optionally independently substituted with 1, 2 or 3 R
Z29.
[7] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [6] , wherein, the moiety of
is
[8] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [7] , wherein, the compound is selected from Formula (III-1) or Formula (III-2) :
[9] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [8] , wherein, each of R
S21 at each occurrence is independently selected from deuterium, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-3alkenyl, -CN, -N (R
21)
2, -OR
21, -SR
21, -C (=O) R
22, -C (=O) OR
21, -OC (=O) R
22, -C (=O) N (R
21)
2, -NR
21C (=O) R
22, -OC (=O) OR
21, -NR
21C (=O) OR
21, -OC (=O) N (R
21)
2, -NR
21C (=O) N (R
21)
2, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein, said -C
1-6alkyl is substituted with 1, 2 or 3 substituents selected from deuterium, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -CN, oxo, -N (R
23)
2, -OR
23, -C (=O) R
23, -C (=O) OR
23, -OC (=O) R
23, -C (=O) N (R
23)
2, -NR
23C (=O) R
24, -OC (=O) OR
23, -NR
23C (=O) OR
24, -OC (=O) N (R
23)
2, -OC (=S) N (R
23)
2, -NR
23C (=O) N (R
23)
2, -NR
23S (=O)
2R
24, 3-6 membered cycloalkyl or 4-6 membered heterocyclyl; said 4-8 membered heterocyclyl is substituted with 1, 2 or 3 substituents selected from deuterium or -OR
21; said haloC
1-6alkyl is substituted with 1, 2 or 3 substituents selected from deuterium, -OR
21 or -C (=O) OR
21; said -C
2-3alkenyl is substituted with 1 substituents selected from deuterium or -C (=O) NR
21R
22;
Each of (R
21, R
22, R
23 or R
24) is independently selected from hydrogen; deuterium; -C
1-6alkyl; haloC
1-
6alkyl; 5 membered heteroaryl; cyclopropyl; cyclopentyl; cyclohexyl; 5 membered heterocyclyl; 6 membered heterocyclyl; 5-membered heteroaryl; 6 membered heteroaryl; or -C
1-6alkyl substituted with 1, or 2 substituents selected from deuterium, -OC
1-6alkyl, -NHC
1-6alkyl, -N (C
1-6alkyl)
2 or -C (=O) N (C
1-6alkyl)
2; wherein said 5 membered heteroaryl, cyclopropyl, cyclopentyl, cyclohexyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 5-membered heteroaryl or 6 membered heteroaryl is optionally substituted with 1 or 2 subsitutents selected from deuterium, -C
1-3alkyl, -OH, -CN, -NH
2, -NH (C
1-3alkyl) , -N (C
1-3alkyl)
2, -OC
1-3alkyl or cyclopropyl;
Optionally, two R
21 or two R
23 together with the carbon atom to which they are both attached form a 3-6 membered heterocyclic ring;
Optionally, two R
21 or two R
23 together with the nitrogen atom to which they are both attached form a 3-6 membered heterocyclic ring;
q
21 is selected from 0, 1 or 2.
[10] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [9] , wherein, each of R
S21 at each occurrence is independently selected from deuterium, -F, -Cl, -CH
3, -CH
2CH
3, -CH
2CH
2CH
3, -CH (CH
3)
2, -CH (CH
3) CH
2CH
3, -CH=CH
2, -C≡CH, -C≡CCH
3, -C≡CD, -CH
2C≡CH, -CHF
2, -CF
3, -CH
2CF
3, -CH
2CHF
2, -CH
2CH
2F, -CH
2CH
2CH
2F, -OH, -CH
2OH, -CH
2CH
2OH, -OCH
3, -OC (CH
3)
2, -OCH
2CH
3, -OCH (CH
3)
2, -OCF
3, -SH, -SCH
3, -SCF
3, -C (=O) CF
3, -C (=O) OCH
2CH
2N (CH
3) , -C (=O) NHCH
2CH
2N (CH
3) , -CN, -NH
2, -N (CH
3)
2, -NHCH
2CH
3, -CH
2-N (CH
3)
2, -N (CH
3) CH
2CH
2OCH
3, -NHC (=O) CH
3, -NHC (=O) OCH
3, -SCH
2C (=O) N (CH
3)
2, -OC (=O) N (CH
3)
2, -NHC (=O) N (CH
3)
2, -CH
2CH
2CN, -CH
2CH (CH
3)
2, -CH
2OCH
3, -OCHF
2, -CH (CF
3) OCH
3, -C (CH
3)
2OH, -CF (CH
3)
2 or cyclopropyl;
q
21 is selected from 0 or 1.
[11] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [10] , wherein, the moiety of
is selected from:
[12] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [11] , wherein, the moiety of
is selected from
[13] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [11] , wherein, the moiety of
is
[14] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [13] , wherein, the compound is selected from Formula (III-1A) or Formula (III-2A) :
[15] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [14] , wherein, R
4 is selected from any one moiety in the Table B:
Table B
[16] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [15] , wherein,
Each of R
S4 is independently selected from -F, -Cl, -C
1-3alkyl, haloC
1-3alkyl, haloC
1-3alkoxy, -C
2-3alkenyl, -C
2-3alkynyl, -CN, -NH
2, -NO
2, -NH (C
1-3alkyl) , -N (C
1-3alkyl)
2, -OH, -O (C
1-3alkyl) , -SH, -S (C
1-3alkyl) , -C (=O) H, -C (=O) (C
1-3alkyl) , -C (=O) OH, -C (=O) O (C
1-3alkyl) , 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl, wherein said -C
1-3alkyl, haloC
1-3alkyl, haloC
1-3alkoxy, -C
2-3alkenyl, -C
2-6alkynyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl is independently optionally substituted with 1, 2 or 3 R
4b;
Each of R
4b is independently selected from -F; -C
1-3alkyl; haloC
1-3alkyl; -CN; -OH; -NH
2; -NH (C
1-3alkyl) ; -NH (C
1-3alkyl)
2; -OC
1-3alkyl; or -C
1-3alkyl substituted with 1, 2 or 3 substituents selected form -F, haloC
1-
3alkyl, -CN, -OH, -NH
2, -NH (C
1-3alkyl) , -NH (C
1-3alkyl)
2, -OC
1-3alkyl or cyclopropyl.
[17] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [16] , wherein, each of R
S4 is independently selected from -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH=CH
2, -C≡CH, -C≡CCH
3, -C≡CD, -CH
2C≡CH, -CHF
2, -CHF
2, -CF
3, -CH
2CF
3, -CH
2CHF
2, -CH
2CH
2F, -CH
2CH
2CH
2F, -OCF
3, -CN, -CH
2CN, -CH
2CH
2CN, -NH
2, -N (CH
3)
2, -NHCH
2CH
3, -CH
2-N (CH
3)
2, -C (=O) H, -C (=O) (CH
3) , -OH, -CH
2OH, -CH
2CH
2OH, -CH
2CH
2CH
2OH, -OCH
3, -OC (CH
3)
2, -CH
2CH (CH
3)
2, -CH (CH
3) CH
2CH
3, -CH
2OCH
3, -CH
2CH
2OCH
3, -SH, -SCH
3, -SCF
3, -OCHF
2, -CH (CF
3) OCH
3, -C (CH
3)
2OH, -CF (CH
3)
2, -OCH (CH
3)
2, -C (=O) OH, -NO
2, cyclopropyl,
[18] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [17] , wherein, the prodrug comprises a prodrug moiety which is attached to R
4 and is capable of being converted to -OH;
R
4c is selected from hydrogen, -C
1-30alkyl, -C
2-30alkenyl, -C
2-30alkynyl, -C
0-6alkylene- (3-20 membered carbocyclyl) , -C
0-6alkylene- (3-20 membered heterocyclyl) , -C
0-6alkylene- (6-10 membered aryl) or -C
0-
6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R
4j;
R
4d and R
4e are each selected from hydrogen, -C
1-30alkyl, -C
2-30alkenyl, -C
2-30alkynyl, -C (=O) C
1-6alkyl, -C
0-6alkylene- (3-20 membered carbocyclyl) , -C
0-6alkylene- (3-20 membered heterocyclyl) , -C
0-6alkylene- (6-10 membered aryl) or -C
0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R
4j;
R
4f and R
4g are each selected from hydrogen, -C
1-30alkyl, -C
2-30alkenyl, -C
2-30alkynyl, -C (=O) C
1-6alkyl, -C
0-6alkylene- (3-20 membered carbocyclyl) , -C
0-6alkylene- (3-20 membered heterocyclyl) , -C
0-6alkylene- (6-10 membered aryl) or -C
0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R
4j;
R
4h, R
4i, R
4m, R
4n and R
4p are each selected from hydrogen, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-
6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, oxo, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-
6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C
1-6alkyl, -C
2-6alkenyl, -C
2-
6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, -C
1-6alkyl, haloC
1-
6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, oxo, -OH, -O (C
1-
6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-
6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Optionally, R
4f and R
4g together with the atoms to which they are respectively attached form a 4-10 membered heterocyclyl ring, said 4-10 membered heterocyclyl ring optionally further contains 1 or 2 heteratoms selected from N, O, S, S (=O) or S (=O)
2 and optionally substituted with one or more R
4j;
Optionally, R
4f and R
4h together with the atoms to which they are respectively attached form a 4-10 membered heterocyclyl ring, said 4-10 membered heterocyclyl ring optionally further contains 1 or 2 heteratoms selected from N, O, S, S (=O) or S (=O)
2 and optionally substituted with one or more R
4j;
R
4j at each occurrence is independently selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, oxo, -NO
2, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-
6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein said -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2 or 3 substituents selected from halogen; -C
1-6alkyl; haloC
1-6alkyl; -CN; oxo; -OH; -NH
2; -NH (C
1-6alkyl) ; -N (C
1-6alkyl)
2; -OC
1-
6alkyl; or -C
1-6alkyl substituted with 1, 2 or 3 substituents selected form halogen, haloC
1-6alkyl, -CN, -OH, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2 or -OC
1-6alkyl.
[19] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [18] , wherein, R
4a is selected from any one moiety in the Table C
Table C
[20] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [19] , wherein, R
4 is selected from
[21] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [20] , wherein, the compound is selected from Formula (IV-1) to Formula (IV-4) :
[22] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [21] , wherein, R
4 is selected from
[23] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [22] , wherein, the compound is selected from Formula (IV-1A) or Formula (IV-1B) :
[24] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [23] , wherein, R
3 is selected from halogen.
[25] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [24] , wherein, R
3 is selected from -F.
[26] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [25] , wherein, the compound is selected from Formula (V-1) to Formula (V-4) :
[27] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [26] , wherein, R
5 is selected from hydrogen, deuterium, -F, -Cl, -CH
3, -CH
2CH
3, -CH
2CH
2CH
3, -CH (CH
3)
2, -CN, -COOH, -CH
2OH, -OH, -OCH
3, -OCH
2CH
3, -CF
3, -CHF
2, -NH
2, -NHCH
3, -N (CH
3)
2, -CH
2NH
2, -CH
2CH
2NH
2, -CH
2OH, -CH
2CH
2OH, -SH, -S-CH
3, -S-CHF
2, -S-CF
3, -CH
2SH, -CH
2CH
2SH, -CH=CH
2, -C≡CH, -CHCH=CH
2, -OCF
3, -OCHF
2, -C (=O) NH
2, -C (=O) OCH
3,
Preferably, R
5 is selected from hydrogen, -CH=CH
2, -OCH
3, or -N (CH
3)
2.
[28] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [27] , wherein, the conjugated form is a PROTAC molecule.
[29] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [28] , wherein, the compound is selected from any one in the Table D:
Table D
[30] . A pharmaceutical composition, comprising a therapeutically effective amount of the compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [29] , and at least one pharmaceutically acceptable excipient.
[31] . A method for treating cancer in a subject comprising administering a therapeutically effective amount of the compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [29] , or the pharmaceutical composition of [30] to a subject in need thereof.
[32] . A method for treating cancer in a subject in need thereof, the method comprising:
(a) determining whether the cancer is associated with K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutation and/or K-Ras wild type amplification; and
(b) if so, administering a therapeutically effective amount of the compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [29] , or the pharmaceutical composition of [30] to the subject in need thereof.
[33] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [29] , or the pharmaceutical composition of [30] for use in therapy.
[34] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [29] , or the pharmaceutical composition of [30] for use as a medicament.
[35] . The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of [1] to [29] , or the pharmaceutical composition of [30] for use in a method for the treatment of cancer.
[36] . A use of the compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof of any one of [1] to [29] , or the pharmaceutical composition of [30] for the treatment of cancer.
[37] . A use of the compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof of any one of [1] to [29] , or the pharmaceutical composition of [30] for the manufacture of a medicament for the treatment of cancer.
[38] . The method for treating cancer of [31] , the use in a method for the treatment of cancer of [35] , the use for the treatment of cancer of [36] , or the use for the manufacture of a medicament for the treatment of cancer of [37] , wherein, said cancer is selected from pancreatic carcinoma, colorectal carcinoma, lung carcinoma (such as non-small cell lung cancer) , breast carcinoma, large intestine carcinoma, stomach carcinoma, endometrial carcinoma, esophageal carcinoma or gastroesophageal junction carcinoma.
[39] . The method for treating cancer of [31] or [38] , the use in a method for the treatment of cancer of [35] or [38] , the use for the treatment of cancer of [36] or [38] , or the use for the manufacture of a medicament for the treatment of cancer of [37] or [38] , wherein, the cancer is associated with at least one of K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutation and/or K-Ras wild type amplification.
[40] . The method for treating cancer of [31] , [38] or [39] , the use in a method for the treatment of cancer of [35] , [38] or [39] , the use for the treatment of cancer of [36] , [38] or [39] , or the use for the manufacture of a medicament for the treatment of cancer of [37] , [38] or [39] , wherein, the cancer a K-Ras G12C associated cancer.
[41] . The method for treating cancer of [31] , [38] or [39] , the use in a method for the treatment of cancer of [35] , [38] or [39] , the use for the treatment of cancer of [36] , [38] or [39] , or the use for the manufacture of a medicament for the treatment of cancer of [37] , [38] or [39] , wherein, the cancer a K-Ras G12D associated cancer.
[42] . The method for treating cancer of [31] , [38] or [39] , the use in a method for the treatment of cancer of [35] , [38] or [39] , the use for the treatment of cancer of [36] , [38] or [39] , or the use for the manufacture of a medicament for the treatment of cancer of [37] , [38] or [39] , wherein, the cancer a K-Ras G12V associated cancer.
[43] . The method for treating cancer of [31] , [38] or [39] , the use in a method for the treatment of cancer of [35] , [38] or [39] , the use for the treatment of cancer of [36] , [38] or [39] , or the use for the manufacture of a medicament for the treatment of cancer of [37] , [38] or [39] , wherein, the cancer a K-Ras G13D associated cancer.
[44] . The method for treating cancer of [31] , [38] or [39] , the use in a method for the treatment of cancer of [35] , [38] or [39] , the use for the treatment of cancer of [36] , [38] or [39] , or the use for the manufacture of a medicament for the treatment of cancer of [37] , [38] or [39] , wherein, the cancer a K-Ras G12R associated cancer.
[45] . The method for treating cancer of [31] , [38] or [39] , the use in a method for the treatment of cancer of [35] , [38] or [39] , the use for the treatment of cancer of [36] , [38] or [39] , or the use for the manufacture of a medicament for the treatment of cancer of [37] , [38] or [39] , wherein, the cancer a K-Ras G12S associated cancer.
[46] . The method for treating cancer of [31] , [38] or [39] , the use in a method for the treatment of cancer of [35] , [38] or [39] , the use for the treatment of cancer of [36] , [38] or [39] , or the use for the manufacture of a medicament for the treatment of cancer of [37] , [38] or [39] , wherein, the cancer a K-Ras G12A associated cancer.
[47] . The method for treating cancer of [31] , [38] or [39] , the use in a method for the treatment of cancer of [35] , [38] or [39] , the use for the treatment of cancer of [36] , [38] or [39] , or the use for the manufacture of a medicament for the treatment of cancer of [37] , [38] or [39] , wherein, the cancer a K-Ras Q61H associated cancer.
[48] . The method for treating cancer of [31] , [38] or [39] , the use in a method for the treatment of cancer of [35] , [38] or [39] , the use for the treatment of cancer of [36] , [38] or [39] , or the use for the manufacture of a medicament for the treatment of cancer of [37] , [38] or [39] , wherein, the cancer a K-Ras wild type amplification associated cancer.
Definition
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated by reference.
The term “a” , “an” , “the” and similar terms, as used herein, unless otherwise indicated, are to be construed to cover both the singular and plural.
The term “halogen” or “halo” , as used interchangeably herein, unless otherwise indicated, refers to fluoro, chloro, bromo or iodo. The preferred halogen groups include -F, -Cl and -Br.
The term “alkyl” , as used herein, unless otherwise indicated, refers to saturated monovalent hydrocarbon radicals having straight or branched arrangement. C
1-10 in -C
1-10alkyl is defined to identify the group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in a linear or branched arrangement. Non-limiting alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl.
The term “haloalkyl” , as used herein, unless otherwise indicated, refers to the above-mentioned alkyl substituted with one or more (for example 1, 2, 3, 4, 5, or 6) halogen (such as -F, -Cl or -Br) . In some embodiments, the haloalkyl is interchangeable -C
1-10haloalkyl or haloC
1-10alkyl, wherein, C
1-10 in the -C
1-
10haloaklyl or haloC
1-10alkyl indicates that the total carbon atoms of the alkyl are 1 to 10. In some embodiments, the -C
1-10haloalkyl is the -C
1-6haloalkyl. In some embodiments, the -C
1-6haloalkyl is the -C
1-
3haloalkyl. In some embodiments, the -C
1-3haloalkyl is (methyl, ethyl, propyl or isopropyl) substituted with 1, 2, 3, 4, 5, or 6 -F; preferably, the -C
1-3haloalkyl is -CF
3.
The term “alkylene” , as used herein, unless otherwise indicated, refers to a divalent group obtained by removal of an additional hydrogen atom from an alkyl group defined above. In some embodiments, the alkylene is C
0-6alkylene. In some embodiments, the C
0-6alkylene is C
0-3alkylene. The C
0-6 in the front of the alkylene indicates the total carbon atoms in the alkylene are 0 to 6 and C
0 indicates the two ends of the alkylene are connected directly. Non-limiting alkylene includes methylene (i.e., -CH
2-) , ethylene (i.e., -CH
2-CH
2-or -CH (CH
3) -) and propylene (i.e., -CH
2-CH
2-CH
2-, -CH (-CH
2-CH
3) -or -CH
2-CH (CH
3) -) .
The term “alkenyl” , as used herein, unless otherwise indicated, refers to a straight or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length. In some embodiments, the alkenyl is -C
2-10alkenyl. In some embodiments, the -C
2-10alkenyl is -C
2-6alkenyl which contains from 2 to 6 carbon atoms. Non-limiting alkenyl includes ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.
The term “haloalkenyl” , as used herein, unless otherwise indicated, refers to the above-mentioned alkenyl substituted with one or more (for example 1, 2, 3, 4, 5, or 6) halogen (such as -F, -Cl or -Br) . In some embodiments, the haloalkenyl is interchangeable -C
2-10haloalkenyl or haloC
2-10alkenyl, wherein, C
2-10 in the -C
2-10haloaklenyl or haloC
2-10alkenyl indicates that the total carbon atoms of the alkenyl are 2 to 10. In some embodiments, the -C
2-10haloalkenyl is the -C
2-6haloalkenyl. In some embodiments, the -C
2-6haloalkenyl is the -C
2-3haloalkenyl. In some embodiments, the -C
2-3haloalkenyl is (ethenyl or propenyl) substituted with 1, 2, 3, 4, 5, or 6 -F.
The term “alkynyl” , as used herein, unless otherwise indicated, refers to a straight or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length. In some embodiments, the alkynyl is -C
2-10alkynyl. In some embodiments, the -C
2-10alkynyl is -C
2-6alkynyl which contains from 2 to 6 carbon atoms. Non-limiting alkynyl includes ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
The term “haloalkynyl” , as used herein, unless otherwise indicated, refers to the above-mentioned alkynyl substituted with one or more (for example 1, 2, 3, 4, 5, or 6) halogen (such as -F, -Cl or -Br) . In some embodiments, the haloalkynyl is interchangeable -C
2-10haloalkynyl or haloC
2-10alkynyl, wherein, C
2-10 in the -C
2-10haloaklynyl or haloC
2-10alkynyl indicates that the total carbon atoms of the alkynyl are 2 to 10. In some embodiments, the -C
2-10haloalkynyl is the -C
2-6haloalkynyl. In some embodiments, the -C
2-6haloalkynyl is the -C
2-3haloalkynyl. In some embodiments, the -C
2-3haloalkynyl is (ethynyl or propynyl) substituted with 1, 2, 3, 4, 5, or 6 -F.
The term “alkoxy” , as used herein, unless otherwise indicated, refers to oxygen ethers formed from the previously described alkyl groups.
The term “haloalkoxy” , as used herein, unless otherwise indicated, refers to the above-mentioned alkoxy substituted with one or more (for 1, 2, 3, 4, 5, or 6) halogen (-F, -Cl or -Br) . In some embodiment, the haloalkoxy is interchangeable -C
1-10haloalkoxy or haloC
1-10alkoxy. In some embodiments, the haloalkoxy is interchangeable -C
1-6haloalkoxy or haloC
1-6alkoxy, wherein, C
1-6 in the -C
1-6haloakloxy or haloC
1-6alkoxy indicates that the total carbon atoms of the alkoxy are 1 to 6. In some embodiments, the -C
1-6haloalkoxy is the -C
1-3haloalkoxy. In some embodiments, the -C
1-3haloalkoxy is (methoxy, ethoxy, propoxy or isopropoxy) substituted with 1, 2, 3, 4, 5, or 6 -F; preferably, the -C
1-3haloalkoxy is -OCF
3.
The term “carbocyclic ring” , as used herein, unless otherwise indicated, refers to a totally saturated or partially saturated monocyclic, bicyclic, bridged, fused, or spiro non-aromatic ring only containing carbon atoms as ring members. The term “carbocyclyl” as used herein, unless otherwise indicated, means a monovalent group obtained by removal of a hydrogen atom on the ring carbon atom from the carbocyclic ring defined in the present invention. The carbocyclic ring is interchangeable with the carbocyclyl ring in the present invention. In some embodiments, the carbocyclic ring is a three to twenty membered (such as 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-or 20-membered) carbocyclic ring and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, for example, one, two, three, four, five or six, are included within the present definition. The carbocyclic ring includes a cycloalkyl ring in which all ring carbon atoms are saturated, a cycloalkenyl ring which contains at least one double bond (preferred contain one double bond) , and a cycloalkynyl ring which contains at least one triple bond (preferred contain one triple bond) . Cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. Cycloalkenyl includes but not limited to cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like. The carbocyclyl ring includes a monocyclic carbocyclyl ring, and a bicyclic or polycyclic carbocyclyl ring in which one, two or three or more atoms are shared between the rings. The term “spirocyclic carbocyclic ring” refers to a carbocyclic ring in which each of the rings only shares one ring atom with the other ring. In some embodiments, the spirocyclic ring is bicyclic spirocyclic ring. The spirocyclic carbocyclic ring includes a spirocyclic cycloalkyl ring and a spirocyclic cycloalkenyl ring and a spirocyclic cycloalkynyl ring. The term “fused carbocyclic ring” refers to a carbocyclic ring in which each of the rings shares two adjacent ring atoms with the other ring. In some embodiments, the fused ring is a bicyclic fused ring. The fused carbocyclic ring includes a fused cycloalkyl ring and a fused cycloalkenyl ring and a fused cycloalkynyl ring. A monocyclic carbocyclic ring fused with an aromatic ring (such as phenyl) is included in the definition of the fused carbocyclic ring. The term “bridged carbocyclic ring” refers to a carbocyclic ring that includes at least two bridgehead carbon ring atoms and at least one bridging carbon atom. In some embodiments, the bridged ring is bicyclic bridged ring. The bridged carbocyclic ring includes a bicyclic bridged carbocyclic ring which includes two bridgehead carbon atoms and a polycyclic bridged carbocyclic ring which includes more than two bridgehead carbon atoms. The bridged carbocyclic ring includes a bridged cycloalkyl ring, a bridged cycloalkenyl ring and a bridged cycloalkynyl ring. Examples of monocyclic carbocyclyl and bicyclic carbocyclyl include but not limit to cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.
The term “heterocyclic ring” , as used herein, unless otherwise indicated, refers to a totally saturated or partially saturated monocyclic, bicyclic, bridged, fused, or spiro non-aromatic ring containing not only carbon atoms as ring members and but also containing one or more (such as 1, 2, 3, 4, 5, or 6) heteroatoms as ring members. Preferred heteroatoms include N, O, S, N-oxides, sulfur oxides, and sulfur dioxides. The term “heterocyclyl” as used herein, unless otherwise indicated, means a monovalent group obtained by removal of a hydrogen atom on the ring carbon atom or the ring heteroatom from the heterocyclic ring defined in the present invention. The heterocyclic ring is interchangeable with the heterocyclyl ring in the present invention. In some embodiments, the heterocyclic ring is a three to twenty membered (such as 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-or 20-membered) heterocyclic ring and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, for example, one, two, three, four, five or six, are included within the present definition. The heterocyclic ring includes a heterocycloalkyl ring in which all ring carbon atoms are saturated, a heterocycloalkenyl ring which contains at least one double bond (preferred contain one double bond) , and a heterocycloalkynyl ring which contains at least one triple bond (preferred contain one triple bond) . The heterocyclyl ring includes a monocyclic heterocyclyl ring, and a bicyclic or polycyclic heterocyclyl ring in which one, two or three or more atoms are shared between the rings. The term “spirocyclic heterocyclic ring” refers to a heterocyclic ring in which each of the rings only shares one ring atom with the other ring. In some embodiments, the spirocyclic ring is bicyclic spirocyclic ring. The spirocyclic heterocyclic ring includes a spirocyclic heterocycloalkyl ring and a spirocyclic heterocycloalkenyl ring and a spirocyclic heterocycloalkynyl ring. The term “fused heterocyclic ring” refers to a heterocyclic ring in which each of the rings shares two adjacent ring atoms with the other ring. In some embodiments, the fused ring is a bicyclic fused ring. The fused heterocyclic ring includes a fused heterocycloalkyl ring and a fused heterocycloalkenyl ring and a fused heterocycloalkynyl ring. A monocyclic heterocyclic ring fused with an aromatic ring (such as phenyl) is included in the definition of the fused heterocyclic ring. The term “bridged heterocyclic ring” refers to a heterocyclic ring that includes at least two bridgehead ring atoms and at least one bridging atom. In some embodiments, the bridged ring is bicyclic bridged ring. The bridged heterocyclic ring includes a bicyclic bridged heterocyclic ring which includes two bridgehead atoms and a polycyclic bridged heterocyclic ring which includes more than two bridgehead atoms. The bridged heterocyclic ring includes a bridged heterocycloalkyl ring, a bridged heterocycloalkenyl ring and a bridged heterocycloalkynyl ring. Examples of such heterocyclyl include but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
The term “aryl” , as used herein, unless otherwise indicated, refers to a mono or polycyclic aromatic ring system only containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic rings. Phenyl and naphthyl are preferred aryls.
The term “heteroaryl” , as used herein, unless otherwise indicated, refers to an aromatic ring containing carbons and one or more (such as 1, 2, 3 or 4) heteroatoms selected from N, O or S. The heteroaryl may be monocyclic or polycyclic. A monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 heteroatoms. A polycyclic heteroaryl ring may contain fused ring junction, for example, bicyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 member atoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms) , preferred monocyclic heteroaryl is 5 membered heteroaryl including 1, 2, 3 or 4 heteratomes selected from N, O or S, or 6 membered heteroaryl including 1 or 2 heteroatoms selected from N. Examples of heteroaryl groups include, but not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladeninyl, quinolinyl or isoquinolinyl.
The term “one or more” , as used herein, unless otherwise indicated, refers to one or more than one. In some embodiments, “one or more” refers to 1, 2, 3, 4, 5 or 6. In some embodiments, “one or more” refers to 1, 2, 3 or 4. In some embodiments, “one or more” refers to 1, 2, or 3. In some embodiments, “one or more” refers to 1 or 2. In some embodiments, “one or more” refers to 1. In some embodiments, “one or more” refers to 2. In some embodiments, “one or more” refers to 3. In some embodiments, “one or more” refers to 4. In some embodiments, “one or more” refers to 5. In some embodiments, “one or more” refers to 6.
The term “substituted” , as used herein, unless otherwise indicated, refers to a hydrogen atom on the carbon atom or a hydrogen atom on the nitrogen atom is replaced by a substituent. When one or more substituents are substituted on a ring in the present invention, it means that each of substituents may be respectively independently substituted on every ring atom of the ring including but not limited to a ring carbon atom or a ring nitrogen atom. In addition, when the ring is a ploycyclic ring, such as a fused ring, a bridged ring or a sprio ring, each of substituents may be respectively independently substituted on every ring atom of the ploycyclic ring.
The term “composition” , as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.
The term “pharmaceutically acceptable salt” refers to a salt prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds in the present invention are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60%pure, more suitably at least 75%pure, especially at least 98%pure (%are on a weight for weight basis) .
The present invention includes within its scope the prodrug of the compounds of this invention. In general, such prodrug will be functional derivatives of the compounds that are readily converted in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs” , ed. H. Bundgaard, Elsevier, 1985.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques know in the art as well as those methods set forth herein.
The present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers. The term “stereoisomer” as used in the present invention refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and configuration isomers. The configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers. The invention includes all possible stereoisomers of the compound.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. The isotopes of hydrogen can be denoted as
1H (hydrogen) ,
2H (deuterium) and
3H (tritium) . They are also commonly denoted as D for deuterium and T for tritium. In the application, CD
3 denotes a methyl group wherein all of the hydrogen atoms are deuterium. Isotopes of carbon include
13C and
14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.
The term “deuterated derivative” , used herein, unless otherwise indicated, refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom ( “D” ) . It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending on the origin of chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation is small and immaterial as compared to the degree of stable isotopic substitution of deuterated derivative described herein. Thus, unless otherwise stated, when a reference is made to a “deuterated derivative” of a compound of the disclosure, at least one hydrogen is replaced with deuterium at well above its natural isotopic abundance (which is typically about 0.015%) In some embodiments, the deuterated derivative of the disclosure have an isotopic enrichment factor for each deuterium atom, of at least 3500 (52.5%deuterium incorporation at each designated deuterium) at least 4500, (67.5 %deuterium incorporation) , at least 5000 (75%deuterium incorporation) at least 5500 (82.5%deuterium incorporation) , at least 6000 (90%deuterium incorporation) , at lease 6333.3 (95%deuterium incorporation, at least 6466.7 (97%deuterium incorporation, or at least 6600 (99%deuterium incorporation) .
When a tautomer of the compound in the present invention exists, the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
The “conjugated form” refers to herein that the compound described herein is conjugated to another agent through a linker or not through a linker, wherein, the compound functions as a binder or a inhibitor of K-Ras protein (including K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutant protein and K-Ras wild type protein) For example, the conjugated form is a PROTAC molecule, e.g. the compound is incorporated into proteolysis targeting chimeras (PROTACs) . A PROTAC is a bifunctional molecule, with one portion capable of engaging an E3 ubiquitin ligase, and the other portion having the ability to bind to a target protein meant for degradation by the cellular protein quality control machinery. Recruitment of the target protein to the specific E3 ligase results in its tagging for destruction (i.e., ubiquitination) and subsequent degradation by the proteasome. Any E3 ligase can be used. Preferably, the portion of the PROTAC that engages the E3 ligase is connected to the portion of the PROTAC that engages the target protein via a linker which consists of a variable chain of atoms. Recruitment of K-Ras protein to the E3 ligase will thus result in the destruction of the K-Ras protein. The variable chain of atoms can include, for example, rings, heteroatoms, and/or repeating polymeric units. It can be rigid or flexible. It can be attached to the two portions described above using standard techniques in the art of organic synthesis.
The pharmaceutical compositions of the present invention comprise a compound in present invention (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
In practice, a compound of Formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof as defined herein can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous) . Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound in the present invention or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt. The compounds of the present invention or pharmaceutically acceptable salts thereof can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier employed can be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound in the present invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described herein or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
Unless otherwise apparent from the context, when a value is expressed as “about” X or “approximately” X, the stated value of X will be understood to be accurate to ±10%, preferably, ±5%, ±2%.
The term “subject” refers to an animal. In some embodiments, the animal is a mammal. A subject also refers to for example, primates (e.g., humans) , cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a human. A “patient” as used herein refers to a human subject. As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment. In some embodiments, the subject has experienced and/or exhibited at least one symptom of cancer to be treated and/or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer having wild type K-Ras or a K-Ras G12A, K-Ras G12C, K-Ras G12D, K-Ras G12R, K-Ras G12S, K-Ras G12V, K-Ras G13D and/or K-Ras Q61H mutation
The term “inhibition” , “inhibiting” or “inhibit” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
The term “treat” , “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) . In another embodiment, “treat” , “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat” , “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both. In yet another embodiment, “treat” , “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
As used herein, “K-Ras G12A” refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an alanine for a glycine at amino acid position 12. A “K-Ras G12A inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12A. A “K-Ras G12A associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12A mutation.
As used herein, “K-Ras G12C” refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12. A “K-Ras G12C inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12C. A “K-Ras G12C associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12C mutation.
As used herein, “K-Ras G12D” refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12. A “K-Ras G12D inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12D. A “K-Ras G12D associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12D mutation.
As used herein, “K-Ras G12R” refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an arginine for a glycine at amino acid position 12. A “K-Ras G12R inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12R. A “K-Ras G12R associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12R mutation.
As used herein, “K-Ras G12S” refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of a serine for a glycine at amino acid position 12. A “K-Ras G12S inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12S. A “K-Ras G12S associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12S mutation.
As used herein, “K-Ras G12V” refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of a valine for a glycine at amino acid position 12. A “K-Ras G12V inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G12V. A “K-Ras G12V associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G12V mutation.
As used herein, “K-Ras G13D” refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 13. A “K-Ras G13D inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras G13D. A “K-Ras G13D associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras G13D mutation.
As used herein, “K-Ras Q61H” refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of a histidine for a glutamine at amino acid position 61. A “K-Ras Q61H inhibitor” refers to a compound is capable of negatively modulating or inhibiting all or a portion of the function of K-Ras Q61H. A “K-Ras Q61H associated cancer” as used herein refers to a cancer associated with or mediated by or having a K-Ras Q61H mutation.
All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
These and other aspects will become apparent from the following written description of the invention.
METHODS OF PREPRATION
Compounds of the present invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The examples which outline specific synthetic route, and the generic schemes below are meant to provide guidance to the ordinarily skilled synthetic chemist, who will readily appreciate that the solvent, concentration, reagent, protecting group, order of synthetic steps, time, temperature, and the like can be modified as necessary, well within the skill and judgment of the ordinarily skilled artisan.
Examples
The following examples are provided to better illustrate the present invention. All parts and percentages are by weight and all temperatures are degrees Celsius, unless explicitly stated otherwise. The following abbreviations in the Table 1 have been used in the examples:
Table 1
Preparation of the Intermediates
Example 1
A solution of INT 1 (226 mg, 895.1903 μmol) , 2-methoxy-1, 1-dimethylethylamine hydrochloride (98 mg, 701.8891 μmol) , N, N-diisopropylethylamine (413 mg, 3.1955 mmol) in DCM (5 mL) was stirred at room temperature for 1 hour. The solution was diluted with 10%NaHCO
3 solution (20 mL) , extracted with DCM (2 × 20 mL) , the organic layer was washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 1-1 (184 mg, 576.5103 μmol, 64.4009%yield) . MS: m/z: 319 [M+H]
+.
A solution of Compound 1-1 (184 mg, 576.5097 μmol) , INT 2 (138 mg, 866.8304 μmol) , potassium fluoride (171 mg, 2.9434 mmol) in DMSO (5 mL) was stirred at 90 ℃ for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with sat. NaHCO
3 (20 mL) , extracted with EA (2 × 20 mL) . The organic layer was washed with NaCl (aq. ) then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 1-2 (148 mg, 334.9163 μmol, 58.0938%yield) . MS: m/z: 442 [M+H]
+.
To a solution of Compound 1-2 (148 mg, 334.9166 μmol) in toluene (5 mL) was added INT 3 (268 mg, 522.8915 μmol) , CataCXium A Pd G3 (48 mg, 65.9096 μmol) , cesium carbonate (329 mg, 1.0098 mmol) and water (1 mL) . The reaction mixture was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with sat. NaHCO
3 (10 mL) and extracted with EA (2 × 20 mL) . The organic layer was washed with NaCl (aq. ) , then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 1-3 (209 mg, 263.8841 μmol, 78.7910%yield) . MS: m/z: 792 [M+H]
+.
A solution of Compound 1-3 (53 mg, 66.9180 μmol) , HCl (4 M in dioxane, 0.8 mL) in DCM (5 mL) was stirred at room temperature for 0.5 h. The solution was diluted with 10%NaHCO
3 solution, extracted with DCM (2 × 20 mL) , the organic layer was washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give Compound 1-4 (62 mg, crude) . MS: m/z: 748 [M+H]
+.
To a solution of Compound 1-4 (62 mg, 82.8919 μmol) in DMF (5 mL) was added CsF (136 mg, 895.3058 μmol) . The reaction mixture was stirred for 3 hours at room temperature. The solution was diluted with sat. NaHCO
3 (10 mL) and extracted with EA (2 × 20 mL) . The organic layer was dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1 %TFA in water, B: CH
3CN, Gradient: 15 %B to 45 %B in 47 min at a flow rate of 60 mL/min, 230 nm) , the eluent was adjusted to PH=8, acetonitrile was concentrated, the aqueous phase was extracted with EA, and the organic layer was dried and concentrated and freeze-dried to give Compound 1 (26 mg) . MS: m/z: 592 [M+H]
+.
Example 2
A solution of INT 1 (270 mg, 1.0695 mmol) , 2-fluoro-1, 1-dimethyl-ethrlamine hydrochloride (101 mg, 791.6105 μmol) , DIEA (428 mg, 3.3116 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours. The solution was diluted with 10%NaHCO
3 solution (20 mL) , extracted with DCM (2 × 20 mL) , the organic layer was washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give Compound 2-1 (321 mg, 1.0452 mmol, 97.7276%yield) . MS: m/z: 307 [M+H]
+.
A solution of Compound 2-1 (321 mg, 1.0452 mmol) , INT 2 (187 mg, 1.1746 mmol) , potassium fluoride (249 mg, 4.2860 mmol) in DMSO (8 mL) was stirred at 90 ℃ for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with sat. NaHCO
3 (20 mL) , extracted with EA (2 × 20 mL) . The organic layer was washed with NaCl (aq. ) then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 2-2 (122 mg, 283.8093 μmol, 27.1543%yield) . MS: m/z: 430 [M+H]
+.
To a solution of Compound 2-2 (122 mg, 283.8094 μmol) in toluene (5 mL) was added INT 3 (217 mg, 423.3861 μmol) , CataCXium A Pd G3 (24 mg, 32.9548 μmol) , cesium carbonate (276 mg, 847.0963 μmol) and water (1 mL) . The reaction mixture was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with sat. NaHCO
3 (10 mL) and extracted with EA (2 × 20 mL) . The organic layer was washed with NaCl (aq. ) , then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 2-3 (170 mg, 217.9546 μmol, 76.7961%yield) . MS: m/z: 780 [M+H]
+.
A solution of Compound 2-3 (46 mg, 58.9759 μmol) , HCl (4 M in dioxane, 1 mL) in DCM (5 mL) was stirred at room temperature for 0.5 h. The solution was diluted with 10%NaHCO
3 solution, extracted with DCM (2 × 20 mL) , the organic layer was washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give Compound 2-4 (59 mg, crude) . MS: m/z: 736 [M+H]
+.
To a solution of Compound 2-4 (59 mg, 80.1710 μmol) in DMF (4 mL) was added CsF (57 mg, 375.2385 μmol) . The reaction mixture was stirred for 1 hour at room temperature. The solution was diluted with sat. NaHCO
3 (10 mL) and extracted with EA (2 × 20 mL) . The organic layer was dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1 %TFA in water, B: CH
3CN, Gradient: 15 %B to 46 %B in 42 min at a flow rate of 60 mL/min, 230 nm) , the eluent was adjusted to PH=8, acetonitrile was concentrated, the aqueous phase was extracted with EA, and the organic phase was dried and concentrated and freeze-dried to give Compound 2 (12 mg) . MS: m/z: 580 [M+H]
+.
Example 3
A solution of INT 1 (313 mg, 1.2398 mmol) , 1-cyclopropylethan-1-amine hydrochloride hydrochloride (223 mg, 1.8338 mmol) , DIEA (482 mg, 3.7294 mmol) in DCM (10 mL) was stirred at 0 ℃ for 1 h. The solution was diluted with 10%NaHCO
3 solution (50 mL) , extracted with DCM (50 mL) , the organic layer was washed with NaCl (aq. 50 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was poured into 10 mL hexane/EA = 20/1, stirred for 10 min at room temperature and filtered to give Compound 3-1 (381 mg, 1.2652 mmol, 102.0460%yield) . MS: m/z: 301 [M+H]
+.
A solution of Compound 3-1 (381 mg, 1.2652 mmol) , INT 2 (271 mg, 1.7023 mmol) , KF (232 mg, 3.9933 mmol) in DMSO (10 mL) was stirred at 100 ℃ for 16 h under nitrogen atmosphere. The mixture was allowed to cooled to room temperature and diluted with sat. NaHCO
3 (50 mL) , extracted with EA (30 mL × 2) . The organic layer was washed with aq. NaCl (50 mL × 2) then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 3-2 (254 mg, 599.2173 μmol, 47.3628%yield) . MS: m/z: 424 [M+H]
+.
To a solution of Compound 3-2 (254 mg, 599.2173 μmol) in toluene (10 mL) and water (2 mL) was added INT 3 (374 mg, 729.7068 μmol) , cataCXium A Pd G3 (177 mg, 243.0417 μmol) ) and cesium carbonate (619 mg, 1.8998 mmol) . The reaction mixture was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with sat. NaHCO
3 (50 mL) and extracted with DCM (30 mL × 2) . The combined organic layer was washed with 50 mL aq. NaCl then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 3-3 (234 mg, 302.3259 μmol, 50.4535%yield) . MS: m/z: 774 [M+H]
+.
A solution of Compound 3-3 (230 mg, 297.1580 μmol) , HCl (1 mL, 4 M in dioxane) in DCM (5 mL) was stirred at room temperature for 1 h. The solution was diluted with 10%NaHCO
3 solution (50 mL) and extracted with DCM (30 mL × 2) . The combined organic layer was washed with sat. NaCl (aq. 50 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give crude Compound 3-4 (233 mg, 319.2014 μmol, 107.4181%yield) . MS: m/z: 730 [M+H]
+.
To a solution of Compound 3-4 (233 mg, 319.2014 μmol) in DMF (10 mL) was added CsF (630 mg, 4.1474 mmol) . The reaction mixture was stirred for 16 hours at 35 ℃ under nitrogen atmosphere. The solution was diluted with sat. NaHCO
3 (50 mL) , extracted with EA (30 mL × 2) , washed with sat. NaCl (aq. 50 mL ×2) , dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, phase A: 0.1 %TFA in water, phase B: CH
3CN, Gradient: 15 %B to 45 %B in 40 min at a flow rate of 60 mL/min, 240 nm) to give Compound 3 (TFA salt, 102.4 mg, 178.5195 μmol, 55.9269%yield) . MS: m/z: 574 [M+H]
+.
Example 4
INT 1 (0.70 g, 2.7727 mmol) was dissolved in DCM (20 mL) , cooled to 0~5 ℃, and then DIEA (0.99 g, 7.6600 mmol) and 2, 2-dimethylpropan-1-amine (0.20 g, 2.2946 mmol) were added. The reaction mixture was stirred for 1 h at 0~5 ℃. The solution was diluted with 10%NaHCO
3 solution (10 mL) , extracted with DCM (30 mL × 2) . The organic layers were combined, washed with NaCl (aq. 10 mL) , dried over anhydrous Na
2SO
4, filtrated, and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 4-1 (0.50 g, 1.6493 mmol, 59.4826%yield) . MS: m/z: 303 [M+H]
+.
A solution of Compound 4-1 (0.48 g, 1.5833 mmol) , INT 2 (0.34 g, 2.1357 mmol) , KF (0.61 g, 10.4997 mmol) in DMSO (15 mL) was stirred at 95 ℃ for 20 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with sat. NaHCO
3 (10 mL) , extracted with EA (30 mL × 2) . The organic layers were combined, washed with NaCl (aq. 10 mL) , dried over anhydrous Na
2SO
4, filtered, and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 4-2 (0.22 g, 0.5165 mmol, 32.6247%yield) . MS: m/z: 426 [M+H]
+.
To a solution of Compound 4-2 (212 mg, 0.4977 mmol) in toluene (15 mL) and water (3 mL) was added INT 3 (404 mg, 0.7882 mmol) , cataCXium A Pd G3 (50 mg, 68.6559 μmol) and cesium carbonate (574 mg, 1.7617 mmol) . The reaction mixture was stirred at 100 ℃ for 18 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with sat. NaHCO
3 (10 mL) and extracted with EA (30 mL × 2) . The organic layers were combined, washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4, filtrated, and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 4-3 (0.23 g, 0.2963 mmol, 59.5431%yield) . MS: m/z: 776 [M+H]
+.
A solution of Compound 4-4 (0.22 g, 283.4997 μmol) , HCl (1 mL, 4 M in dioxane) in DCM (5 mL) was stirred at room temperature for 1 h. The solution was diluted with 10%NaHCO
3 solution (8 mL) , extracted with DCM (20 mL ×2) . The organic layers were combined, washed with NaCl (aq. 10 mL) , dried over anhydrous Na
2SO
4, filtrated, and concentrated in vacuum to give crude Compound 4-4 (114 mg, 155.7457 μmol, 54.9368%yield) . MS: m/z: 732 [M+H]
+.
To a solution of Compound 4-4 (98 mg, 133.8865 μmol) in DMF (5 mL) was added CsF (111 mg, 730.7276 μmol) . The reaction mixture was stirred for 20 hours at room temperature under nitrogen atmosphere. The solution was diluted with sat. NaHCO
3 (5 mL) and extracted with EA (20 mL ×2) . The organic layers were combined, washed with NaCl (aq. 10 mL) , dried over anhydrous Na
2SO
4, filtrated, and concentrated in vacuum. The residue was purified by Prep-HPLC (C18 column, phase A: 0.05 %NH
3. H
2O in water, phase B: CH
3CN, Gradient: 30 %B to 75 %B in 36 min at a flow rate of 70 mL/min, 230 nm) to give Compound 4 (TFA salt, 37.9 mg) . MS: m/z: 576 [M+H]
+.
Example 5
To a solution of INT 1 (204 mg, 0.81 mmol) in DCM (5 mL) was added DIEA (319 mg, 2.46 mmol) , then propan-1-amine hydrochloride (60 mg, 0.69 mmol) was added in dropwise at 0 ℃. The resulting solution was stirred at 0 ℃ for 10 minutes. The reaction was diluted with H
2O (30 mL) , extracted with DCM (2 × 20 mL) , the organic layers were dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC with to give crude Compound 5-1 (249 mg, 0.82 mmol) . MS: m/z: 275 [M+H]
+.
A solution of Compound 5-1 (249 mg, 0.82 mmol) , INT 2 (201 mg, 1.26 mmol) , KF (147 mg, 2.53 mmol) in DMSO (5 mL) was stirred at 90 ℃ for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with H
2O (30 mL) , extracted with EA (2 × 20 mL) . The organic layer was dried over anhydrous Na
2SO
4 and then concentrated in vacuum. The residue was purified by Pre-TLC with to give Compound 5-2 (221 mg, 0.52 mmol, 63.17%yield) . MS: m/z: 398 [M+H]
+.
A mixture of Compound 5-2 (221 mg, 518.8986 μmol) , INT 3 (338 mg, 659.4677 μmol) , cataCXium A Pd G3 (48 mg, 65.9096 μmol) , cesium carbonate (506 mg, 1.5530 mmol) in toluene (5 mL) and water (2 mL) was stirred at 100 ℃ for 18 hours under nitrogen atmosphere. The reaction was allowed to cool to room temperature and then concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 5-3 (86 mg, 0.11 mmol, 21.35%yield) . MS: m/z: 748 [M+H]
+.
To a solution of Compound 5-3 (86 mg, 0.11 mmol) in DCM (4 mL) was added HCl (4 M in dioxane, 2 mL) . The solution was stirred at room temperature for 1 h. The reaction was adjusted pH to 8~9 with saturated NaHCO
3 (aq. ) (20 mL) . The solution was then extracted with DCM (2 × 20 mL) , the organic layer was dried over anhydrous Na
2SO
4 and concentrated in vacuum to give crude Compound 5-4 (86 mg, 0.12 mmol) . MS: m/z: 704 [M+H]
+.
A solution of Compound 5-4 (86 mg, 0.12 mmol) in DMF (5 mL) was added CsF (80 mg, 0.53 mmol) was stirred for 3 h at room temperature. The solution was diluted with H
2O (30 mL) , extracted with EA (2 × 20 mL) . The organic layers were dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: (C18 column, A: 0.1 %TFA in water, B: CH
3CN, Gradient: 15 %B to 50 %B in 45 min at a flow rate of 60 mL/min, 230 nm) , freeze-dried to give Compound 5 (TFA salt, 38 mg, 66.01 μmol, 56.18%yield) . MS: m/z: 548 [M+H]
+.
Example 6
A solution of INT 1 (248 mg, 982.3327 μmol) , methylamine alcohol solution (102 mg, 33%) , DIEA (294 mg, 2.2748 mmol) in DCM (5 mL) was stirred at room temperature for 1 h. The solution was extracted with DCM (2 × 30 mL) , the organic layer was washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 6-1 (149 mg, 603.1014 μmol, 61.3948 %yield) . MS: m/z: 247 [M+H]
+.
A solution of Compound 6-1 (147 mg, 595.0061 μmol) , INT 2 (137 mg, 860.5490 μmol) , KF (282 mg, 4.8540 mmol) in DMSO (5 mL) was stirred at 80 ℃ for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with sat. NaHCO
3 (20 mL) , extracted with EA (2 × 30 mL) . The organic layer was washed with NaCl (aq. ) then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 6-2 (81mg, 219.0396 μmol, 36.8130 %yield) . MS: m/z: 370 [M+H]
+.
A solution of Compound 6-2 (80 mg, 216.3354 μmol) , toluene (5 mL) , INT 3 (151 mg, 294.6143 μmol) , cataCXium A Pd G3 (20mg, 27.4623 μmol) , potassium phosphate (190 mg, 895.1020 μmol) and water (1 mL) was stirred at 100 ℃ for 18 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (30 mL) and extracted with EA (2 × 30 mL) . The organic layer was washed with NaCl (aq. ) then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 6-3 (96mg, 133.3502 μmol, 61.6405 %yield) . MS: m/z: 720 [M+H]
+.
A solution of Compound 6-3 (96 mg, 133.3502 μmol) , HCl (1 mL, 4 M in dioxane) in DCM (5 mL) was stirred at room temperature for 0.5 h. The solution was diluted with 10%NaHCO
3 solution (20 mL) , extracted with DCM (2 × 40 mL) , the organic layer was washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give crude Compound 6-4 (90 mg, 133.1644 μmol, 99.8606 %yield) . MS: m/z: 676 [M+H]
+.
A solution of Compound 6-4 (90 mg, 133.1644 μmol) , CsF (157 mg, 1.0336mmol) in DMF (4 mL) was stirred for 14 hours at 35 ℃ under nitrogen atmosphere. The solution was diluted with water (30 mL) and extracted with EA (2 × 30 mL) . The organic layers dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1 %TFA in water, B: CH
3CN, Gradient: 15%B to 45 %B in 37 min at a flow rate of 60 mL/min, 240 nm) and freeze-dried to give Compound 6 (TFA salt, 38 mg) . MS: m/z: 520 [M+H]
+.
Example 7
A solution of INT 1 (247 mg, 978.3716 μmol) , dimethylamine (0.5 mL, 2 M in THF, 1 mmol) , DIEA (293 mg, 2.2671 mmol) in DCM (5 mL) was stirred at room temperature for 1 h. The solution was diluted with water (30 mL) , extracted with DCM (2 × 30 mL) , the organic layer was washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 7-1 (297 mg, 1.1376mmol) . MS: m/z: 261 [M+H]
+.
A solution of Compound 7-1 (292 mg, 1.1184 mmol) , INT 2 (196 mg, 1.2312 mmol) , KF (540 mg, 9.2948 mmol) in DMSO (5 mL) was stirred at 80 ℃ for 20 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with sat. NaHCO
3 (30 mL) , extracted with EA (2 × 30 mL) . The organic layer was washed with NaCl (aq. ) then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 7-2 (231mg, 601.8405 μmol, 53.8117 %yield) . MS: m/z: 384 [M+H]
+.
A solution of Compound 7-2 (228 mg, 594.0244 μmol) , toluene (5 mL) , INT 3 (278 mg, 542.4024 μmol) , cataCXium A Pd G3 (42mg, 57.6709 μmol) , potassium phosphate (510 mg, 2.4026 mmol) and water (1 mL) was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (30 mL) and extracted with EA (2 × 30 mL) . The organic layer was washed with NaCl (aq. ) then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 7-3 (171 mg, 232.9905 μmol, 39.2224 %yield) . MS: m/z: 734 [M+H]
+.
A solution of Compound 7-3 (171 mg, 232.9905 μmol) , HCl (1 mL, 4 M in dioxane) in DCM (5 mL) was stirred at room temperature for 2 h. The solution was diluted with 10%NaHCO
3 solution (20 mL) , extracted with DCM (2 × 40 mL) , the organic layer was washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give crude Compound 7-4 (163 mg, 236.2719 μmol, 101.4083%yield) . MS: m/z: 690 [M+H]
+.
A solution of Compound 7-4 (163 mg, 236.2719 μmol) , CsF (261 mg, 1.7182 mmol) in DMF (5 mL) was stirred for 16 hours at 35 ℃ under nitrogen atmosphere. The solution was diluted with water (30 mL) and extracted with EA (2 × 30 mL) . The organic layers were dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1 %TFA in water, B: CH
3CN, Gradient: 25 %B to 45 %B in 32 min at a flow rate of 200 mL/min, 236 nm) and freeze-dried to give Compound 7 (TFA salt, 63 mg) . MS: m/z: 534 [M+H]
+.
Example 8
To a solution of INT 1 (300 mg, 1.2 mmol) and DIEA (1.01 g, 8.04 mmol) in DCM (2 mL) was added 2- (methylthio) ethan-1-amine (109.4 mg, 1.2 mmol) at -40 ℃. The reaction mixture was stirred at -40 ℃ for 40 min. Upon completion, H
2O (4 mL) was added to the reaction mixture, extracted with DCM (4 mL × 3) . The combined organic phases were dried over anhydrous Na
2SO
4 and concentrated to give a residue, purified by pre-TLC (dichloromethane/methanol = 10: 1) to give Compound 8-1 (220 mg, 0.7 mmol, 44.7%yield) . MS: m/z: 307 [M+H]
+.
A solution of Compound 8-1 (320 mg, 1.04 mmol) and INT 2 (231.8 mg, 1.46 mmol) in DMSO (4.8 mL) was added KF (332.3 mg, 5.7 mmol) . The mixture was stirred at 80 ℃ overnight under N
2 atmosphere. Upon completion, water (8 mL) was added, then extracted with EtOAc (8 mL × 3) . The combined organic phases were dried over anhydrous Na
2SO
4. The solution was concentrated to give a residue, purified by pre-TLC (dichloromethane/methanol = 10: 1) to give Compound 8-2 (270 mg, 0.63 mmol, 60.4%yield) . MS: m/z: 430 [M+H]
+.
Compound 8-2 (140 mg, 0.33 mmol) , INT 3 (203.0 mg, 0.4 mmol) , Cs
2CO
3 (322.6 mg, 0.99 mmol) and cataCxium A Pd G3 (48.1 mg, 0.066 mmol) were placed in the reaction bottle. A solution of toluene/H
2O (5/1, 8.4 mL) was added at room temperature. The mixture was stirred at 100 ℃ under microwave condition for 5 h. Upon completion, water (20 mL) was added to the reaction mixture, the mixture was extracted with EtOAc (20 mL × 3) , and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solution was concentrated to give a crude residue, which was purified by pre-TLC to give Compound 8-3 (84 mg, 0.11 mmol, 32.6%yield) . MS: m/z: 780 [M+H]
+.
To a solution of Compound 8-3 (84 mg, 0.1 mmol) in ACN (3.8 mL) was added HCl (4M in dioxane, 0.88 mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2 h. Then the reaction mixture was concentrated in vacuum to give crude Compound 8-4 which was used directly for the next step without any further purification. MS: m/z: 736 [M+H]
+.
To a solution of Compound 8-4 (crude) in DMF (3.7 mL) was added CsF (250.6 mg, 1.65 mmol) . The reaction mixture was stirred at 40 ℃ for 5 h. Then the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC to give Compound 8 (28.4 mg, 0.049 mmol) . MS: m/z: 580 [M+H]
+.
1H NMR (300 MHz, DMSO-d
6) : δ 10.14 (s, 1H) , 9.23 (s, 1H) , 9.11 (t, J = 5.4 Hz, 1H) , 7.97 (dd, J = 9.2, 6.0 Hz, 1H) , 7.53 –7.33 (m, 2H) , 7.15 (d, J = 2.4 Hz, 1H) , 5.43 –5.15 (m, 1H) , 4.20-4.00 (m, 2H) , 3.95 (s, 1H) , 3.85 (td, J = 13.3, 7.1 Hz, 1H) , 3.69 (td, J = 12.6, 6.8 Hz, 1H) , 3.15-3.05 (m, 2H) , 3.02 (s, 1H) , 2.90-2.70 (m, 2H) , 2.16 (d, J = 9.3 Hz, 4H) , 2.10-1.90 (m, 3H) , 1.90 –1.72 (m, 3H) .
Example 9
To a solution of INT 1 (300 mg, 1.19 mmol) and DIEA (1.03 g, 7.97 mmol) in DCM (1.5 mL) was added (R) -2-methoxypropan-1-amine hydrochloride (150 mg, 1.19 mmol) at -40 ℃. The reaction mixture was stirred at -40 ℃ for 1 h. Upon completion, H
2O (10 mL) was added to the reaction mixture, extracted with DCM (20 mL × 3) . The combined organic phases were dried over anhydrous Na
2SO
4 and concentrated to give a residue, purified by column chromatography (petroleum ether/ethyl acetate = 3: 1) to give Compound 9-1 (380 mg, 1.24 mmol, 99%yield) . MS: m/z: 305 [M+H]
+.
To a solution of Compound 9-1 (330 mg, 1.08 mmol) and INT 2 (240 mg, 1.51 mmol) in DMSO (5.0 mL) was added KF (345 mg, 5.94 mmol) . The mixture was stirred at 80 ℃ overnight under N
2 atmosphere. Upon completion, water (30 mL) was added, then extracted with EtOAc (30 mL × 3) . The combined organic phases were dried over anhydrous Na
2SO
4. The solution was concentrated to give a residue, purified by pre-TLC (DCM/MeOH=10: 1) to give Compound 9-2 (300 mg, 0.70 mmol, 64.9%yield) . MS: m/z: 428 [M+H]
+.
Compound 9-2 (130 mg, 0.304 mmol) , INT 3 (187 mg, 0.365 mmol) , Cs
2CO
3 (297 mg, 0.912 mmol) and cataCxium A Pd G3 (44 mg, 0.0608 mmol) were placed in the reaction bottle. A solution of toluene/H
2O (5/1, 7.8 mL) was added at room temperature. The mixture was stirred at 100 ℃ under microwave condition for 3.5 h. Upon completion, water (10 mL) was added to the reaction mixture, extracted with EtOAc (10 mL × 3) , and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solution was concentrated to give a crude residue, which was purified by pre-TLC to give Compound 9-3 (90 mg, 0.12 mmol, 38%yield) . MS: m/z: 778 [M+H]
+.
To a solution of Compound 9-3 (75 mg, 0.096 mmol) in ACN (4.24 mL) was added HCl (4M in dioxane, 0.77 mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 3 h. Then the reaction mixture was concentrated in vacuum to give crude Compound 9-4 which was used directly for the next step without any further purification. MS: m/z: 734 [M+H]
+.
To a solution of Compound 9-4 (crude) in DMF (3.3 mL) was added CsF (219 mg, 1.44 mmol) . The reaction mixture was stirred at 40 ℃ for 2.5 h. Then the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC to give Compound 9 (40.6 mg, 0.07 mmol) . MS: m/z: 578 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 10.13 (s, 1H) , 9.30 (s, 1H) , 9.01 (s, 1H) , 7.97 (dd, J = 9.1, 6.2 Hz, 1H) , 7.46 (t, J = 9.0 Hz, 1H) , 7.38 (d, J = 2.4 Hz, 1H) , 7.14 (d, J = 2.2 Hz, 1H) , 5.40-5.20 (m, 1H) , 4.09 (d, J = 23.9 Hz, 2H) , 3.95 -3.45 (m, 5H) , 3.20-3.00 (m, 4H) , 2.90-2.80 (m, 1H) , 2.20-1.80 (m, 6H) , 1.18 (d, J = 5.3 Hz, 3H) .
Example 10
To a solution of INT 1 (200 mg, 0.79 mmol) in DCM (2 mL) was added DIEA (686 mg, 5.3 mmol) at room temperature. Then the mixture was cooled to -20 ℃ under argon and added furan-3-ylmethanamine (77 mg, 0.79 mmol) in DCM (0.5 mL) drop wise. After that the reaction mixture was stirred for 30 min at -20 ℃. Then the reaction mixture was quenched with water (2 mL) and extracted with DCM (5 mL) . The organic layer was washed with brine (5 mL) , dried over anhydrous Na
2SO
4, filtered, and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with petroleum ether/EtOAc = 1: 1) to give Compound 10-1 (104 mg, yield 42.0%) . MS: m/z: 313/315 [M+H]
+.
To a solution of Compound 10-1 (100 mg, 0.32 mmol) and INT 2 (71 mg, 0.45 mmol) in DMSO (2 mL) was added KF (102 mg, 1.8 mmol) at room temperature. Then the reaction mixture was heated to 90 ℃ and stirred for 4 h. After that the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL × 3) . The combined organic layers were washed with water (5 mL) , brine (5 mL) , dried over anhydrous Na
2SO
4, filtered, and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with petroleum ether/EtOAc = 1: 1) to give Compound 10-2 (75 mg, yield 53.9%) . MS: m/z: 436 [M+H]
+.
Compound 10-2 (70 mg, 0.16 mmol) , INT 3 (123 mg, 0.24 mmol) , Cs
2CO
3 (156 mg, 0.48 mmol) , cataCxiumA-Pd G3 (23 mg, 0.03 mmol) were added successively into toluene/water = 5: 1 (1.2 mL) , degassing the reaction with argon for 10 min. The mixture was heated to 100 ℃ under argon by microwave and stirred for 1 h. After that the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL × 3) . The combined organic layers were washed with water (5 mL) , brine (5 mL) , dried with anhydrous Na
2SO
4, filtered, and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH = 10: 1) to give Compound 10-3 (53 mg, yield 42.1%) . MS: m/z: 786 [M+H]
+.
To a solution of Compound 10-3 (50 mg, 0.064 mmol) in DCM (0.5 mL) was added HCl (4 M in dioxane, 0.1 mL) at room temperature and stirred for 1 h. Then the reaction mixture was concentrated to give crude Compound 10-4 (35 mg) . MS: m/z: 742 [M+H]
+.
To a solution of Compound 10-4 (35 mg crude, 0.047 mmol) in DMF (1 mL) was added CsF (72 mg, 0.47 mmol) at room temperature. The reaction mixture was heated to 40 ℃ and stirred for 1 h. Then the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC to give Compound 10 (HCOOH salt, 2.5 mg, yield 5.2%for two steps) . MS: m/z: 586 [M+H]
+.
1H NMR (400 MHz, CD
3OD-d
4) : δ 9.16 (s, 1H) , 8.45 (s, 1H) , 7.87-7.83 (m, 1H) , 7.62 (s, 1H) , 7.49 (s, 1H) , 7.36-7.32 (m, 2H) , 7.19 (d, J = 2.4 Hz, 1H) , 6.55 (s, 1H) , 5.55-5.42 (m, 1H) , 4.82-4.69 (m, 4H) , 4.64-4.53 (m, 2H) , 3.81-3.66 (m, 2H) , 3.35 (s, 1H) , 2.63-2.42 (m, 2H) , 2.35-2.32 (m, 1H) , 2.25-2.17 (m, 2H) , 2.07-2.05 (m, 1H) .
Example 11
INT 1 (0.61 g, 2.4162 mmol) was dissolved in DCM (10 mL) , cooled to 0~5 ℃, and then DIEA (0.86 g, 6.6542 mmol) and thiophen-3-amine oxalate (0.39 g, 2.0614 mmol) were added. The reaction mixture was stirred for 1 h at 0~5 ℃. The solution was diluted with 10%NaHCO
3 solution (10 mL) , extracted with DCM (2 × 30 mL) . The organic layers were combined, washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4, filtrated, and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 11-1 (250 mg, 0.7933 mmol, 32.8307 %yield) . MS: m/z: 315 [M+H]
+.
A solution of Compound 11-1 (231 mg, 0.7330 mmol) , INT 2 (180 mg, 1.1306 mmol) , KF (262 mg, 4.5097 mmol) in DMSO (8 mL) was stirred at 95 ℃ for 20 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with sat. NaHCO
3 (10 mL) , extracted with EA (2 × 30 mL) . The organic layers were combined, washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4, filtrated, and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 11-2 (170 mg, 0.3882 mmol, 52.9651%yield) . MS: m/z: 438 [M+H]
+.
A solution of Compound 11-2 (169 mg, 0.3859 mmol) , toluene (10 mL) , INT-3 (309 mg, 0.6029 mmol) , cataCXium A Pd G3 (41 mg, 56.2978 μmol) , cesium carbonate (402 mg, 1.2338 mmol) and water (2 mL) was stirred at 100 ℃ for 18 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with sat. NaHCO
3 (10 mL) and extracted with EA (2 × 30 mL) . The organic layers were combined, washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4, filtrated, and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 11-3 (170 mg, 0.2157 mmol, 55.8986 %yield) . MS: m/z: 788 [M+H]
+.
A solution of Compound 11-3 (170 mg, 0.2157mmol) , HCl (4M solution in dioxane, 1 mL) in DCM (5 mL) was stirred at room temperature for 1 h. The solution was diluted with 10%NaHCO
3 solution (8 mL) , extracted with DCM (2 × 20 mL) . The organic layers were combined, washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4, filtrated, and concentrated in vacuum to give crude Compound 11-4 (150 mg, 0.2016 mmol, 93.4601 %yield) . MS: m/z: 744 [M+H]
+.
A solution of Compound 11-4 (146 mg, 0.1962 mmol) , CsF (190 mg, 1.2508 mmol) in DMF (5 mL) was stirred for 20 hours at 35 ℃ under nitrogen atmosphere. The solution was diluted with sat. NaHCO
3 (5 mL) and extracted with EA (2 × 20 mL) . The organic layers were combined, washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4, filtrated, and concentrated in vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.05 %TFA in water, B: CH
3CN, Gradient: 15 %B to 45 %B in 44 min at a flow rate of 70 mL/min, 232 nm) to give Compound 11 (TFA salt, 15.8 mg) . MS: m/z: 588 [M+H]
+.
Example 12
A solution of INT 1 (173 mg, 2.4325 mmol) , cyclobutanamine (308 mg, 1.2200 mmol) and DIEA (511 mg, 3.9538 mmol) in DCM (10 mL) was stirred at 0 ℃ for 1 h. The solution was diluted with 10%NaHCO
3 solution (50 mL) , extracted with DCM (50 mL) , washed with NaCl (aq. 50 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was poured into 10 mL hexane/EA=20/1, stirred for 10 min at room temperature and filtered to give crude Compound 12-1 (416 mg, 1.4489 mmol) . MS: m/z: 287 [M+H]
+.
A solution of Compound 12-1 (416 mg, 1.4489 mmol) , INT 2 (280 mg, 1.7588 mmol) , KF (300 mg, 5.1638 mmol) in DMSO (10 mL) was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The mixture was cooled to room temperature and diluted with sat. NaHCO
3 (50 mL) , extracted with EA (30 mL × 2) . The organic layer was washed with aq. NaCl (50 mL × 2) then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 12-2 (206 mg, 502.6109 μmol, 34.6898%yield) . MS: m/z: 410 [M+H]
+.
A solution of Compound 12-2 (202 mg, 492.8515 μmol) in toluene (10 mL) and water (2 mL) , INT 3 (325 mg, 634.1035 μmol) , cataCXium A Pd G3 (154 mg, 211.4600 μmol) and cesium carbonate (521 mg, 1.5990 mmol) was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with sat. NaHCO
3 (50 mL) and extracted with DCM (30 mL × 2) . The combined organic layer was washed with 50 mL aq. NaCl, dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 12-3 (304 mg, 400.0144 μmol, 81.1633%yield) . MS: m/z: 760 [M+H]
+.
A solution of Compound 12-3 (304 mg, 400.0144 μmol) , HCl (1 mL, 4M in dioxane) in DCM (5 mL) was stirred at room temperature for 1 h. The solution was diluted with 10%NaHCO
3 solution (50 mL) , extracted with DCM (30 mL × 2) . The combined organic layer was washed with sat. NaCl (aq. 50 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give crude Compound 12-4 (309 mg, 431.6124 μmol) . MS: m/z: 716 [M+H]
+.
A solution of Compound 12-4 (309 mg, 431.6124 μmol) , CsF (938 mg, 6.1750 mmol) in DMF (10 mL) was stirred for 16 hours at 35 ℃ under nitrogen atmosphere. The solution was diluted with sat. NaHCO
3 (50 mL) , extracted with EA (30 mL × 2) . The combined organic layer was washed with sat. NaCl (aq. 50 mL × 2) , dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C
18 column, phase A: 0.1 %TFA in water, phase B: CH
3CN, Gradient: 15 %B to 45 %B in 40 min at a flow rate of 60 mL/min, 240nm) and freeze-dried to give Compound 12 (121.9 mg, 217.8418 μmol, 50.4716%yield) . MS: m/z: 560 [M+H]
+.
Example 13
To a solution of INT 1 (452 mg, 1.7904 mmol) in DCM (10 mL) was added DIEA (644 mg, 4.9829 mmol) , then 2-methylbutan-2-amine hydrochloride (95 mg, 1.6072 mmol) was added in dropwise at 0 ℃. The resulting solution was stirred at 0 ℃ for 10 minutes. The reaction was diluted with H
2O (20 mL) , extracted with DCM (2 × 30 mL) , the organic layers were dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC with to give crude Compound 13-1 (480 mg, 1.7448 mmol, 97.4519%yield) . MS: m/z: 303 [M+H]
+.
A solution of Compound 13-1 (207 mg, 0.75 mmol) , INT 2 (84 mg, 0.53 mmol) , KF (63 mg, 1.08 mmol) in DMSO (5 mL) was stirred at 90 ℃ for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with H
2O (30 mL) , extracted with EA (2 × 20 mL) . The organic layer was dried over anhydrous Na
2SO
4 and then concentrated in vacuum. The residue was purified by Pre-TLC with to give Compound 13-2 (266 mg, 0.67 mmol, 88.85%yield) . MS: m/z: 426 [M+H]
+.
A mixture of Compound 13-2 (260 mg, 0.65 mmol) , INT 3 (411 mg, 0.80 mmol) , cataCXium A Pd G3 (44 mg, 60.41 μmol) , cesium carbonate (672 mg, 2.06 mmol) in toluene (10 mL) and water (3 mL) was stirred at 100 ℃ for 18 hours under nitrogen atmosphere. The reaction was allowed to cool to room temperature and diluted with H
2O (30 mL) , extracted with EA (2 × 20 mL) . The organic layer was dried over anhydrous Na
2SO
4 and then then concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 13-3 (152 mg, 23.21 μmol, 31.09%yield) . MS: m/z: 776 [M+H]
+.
To a solution of Compound 13-3 (152 mg, 0.20 mmol) in DCM (3 mL) was added HCl (4 M in dioxane, 2 mL) . The solution was stirred at room temperature for 1 h. The reaction was adjusted pH to 8~9 with saturated NaHCO
3 (aq. ) (20 mL) . The solution was then extracted with DCM (2 × 20 mL) , the organic layer was dried over anhydrous Na
2SO
4 and concentrated in vacuum to give Compound 13-4 (179 mg, 0.25 mmol, crude) . MS: m/z: 732 [M+H]
+.
To a solution of Compound 13-4 (179 mg, 0.25 mmol) in DMF (5 mL) was added CsF (109 mg, 0.72 mmol) . The reaction mixture was stirred for 3 h at room temperature. The solution was diluted with H
2O (30 mL) , extracted with EA (2 × 20 mL) . The organic layers were dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: (C18 column, A: 0.1 %TFA in water, B: CH
3CN, Gradient: 15 %B to 46 %B in 40 min at a flow rate of 60 mL/min, 230 nm) , the eluent was adjusted to PH=8, acetonitrile was concentrated, the aqueous phase was extracted with EA, and the organic phase was dried and concentrated and freeze-dried to give Compound 13 (55 mg, 0.10 mmol, 39.49%yield) . MS: m/z: 576 [M+H]
+.
Example 14
A solution of INT 1 (208 mg, 823.8919 μmol) , N-ethylmethylamine (87 mg, 1.4718 mmol) , DIEA (351 mg, 2.7158 mmol) in DCM (6 mL) was stirred at room temperature for 1 h. The solution was extracted with DCM (2 × 30 mL) , the organic layer was washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 14-1 (132 mg, 479.8093 μmol, 58.2369%yield) . MS: m/z: 275 [M+H]
+.
A solution of Compound 14-1 (132 mg, 479.8093 μmol) , INT 2 (108 mg, 678.3890 μmol) , KF (102 mg, 1.7557 mmol) in DMSO (8 mL) was stirred at 80 ℃ for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with sat. NaHCO
3 (20 mL) , extracted with EA (2 × 30 mL) . The organic layer was washed with NaCl (aq. ) then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 14-2 (41 mg, 103.0541 μmol, 21.4781%yield) . MS: m/z: 398 [M+H]
+.
A solution of Compound 14-2 (41 mg, 103.0541 μmol) , toluene (10 mL) , INT 3 (66 mg, 128.7718 μmol) , cataCXium A Pd G3 (34 mg, 46.6860 μmol) , cesium carbonate (115 mg, 352.9568 μmol) and water (2 mL) was stirred at 100 ℃ for 18 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (30 mL) and extracted with EA (2 × 30 mL) . The organic layer was washed with NaCl (aq. ) then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 14-3 (55 mg, 73.5332 μmol, 71.3539%yield) . MS: m/z: 748 [M+H]
+.
A solution of Compound 14-3 (55 mg, 73.5332 μmol) , HCl in dioxane (1 mL) in DCM (5 mL) was stirred at room temperature for 0.5 h. The solution was diluted with 10%NaHCO
3 solution (20 mL) , extracted with DCM (2 × 40 mL) , the organic layer was washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give crude Compound 14-4 (65 mg, 92.3414 μmol) . MS: m/z: 704 [M+H]
+.
A solution of Compound 14-4 (65 mg, 92.3414 μmol) , CsF (57 mg, 375.2385 μmol) in DMF (5 mL) was stirred for 3 hours at 35 ℃ under nitrogen atmosphere. The solution was diluted with water (30 mL) and extracted with EA (2 × 30 mL) . The organic layers were dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1 %TFA in water, B: CH
3CN, Gradient: 15%B to 40 %B in 32 min at a flow rate of 60 mL/min, 230 nm) , the eluent was adjusted to PH=8, acetonitrile was concentrated, the aqueous phase was extracted with EA, and the organic phase was dried and concentrated and freeze-dried to give Compound 14 (22 mg) . MS: m/z: 548 [M+H]
+.
Example 15
A solution of INT 1 (202 mg, 800.1268 μmol) , 2-methoxyethylamine (71 mg, 945.2891 μmol) , DIEA (324 mg, 2.5069 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 h. The solution was extracted with DCM (2 × 30 mL) , the organic layer was washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 15-1 (233 mg, 800.3883 μmol, 100.0327%yield) . MS: m/z: 291 [M+H]
+.
A solution of Compound 15-1 (231 mg, 793.5180 μmol) , INT 2 (146 mg, 917.0814 μmol) , KF (314 mg, 5.4048 mmol) in DMSO (5 mL) was stirred at 80 ℃ for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with sat. NaHCO
3 (30 mL) , extracted with EA (2 × 30 mL) . The organic layer was washed with NaCl (aq. ) then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 15-2 (215 mg, 519.5138 μmol, 65.4697%yield) . MS: m/z: 414 [M+H]
+.
A solution of Compound 15-2 (215 mg, 519.5132 μmol) , toluene (5 mL) , INT 3 (258 mg, 503.3803 μmol) , cataCXium A Pd G3 (43 mg, 59.0440 μmol) , potassium phosphate (425 mg, 2.0022 mmol) and water (1 mL) was stirred at 110 ℃ for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (30 mL) and extracted with EA (2 × 30 mL) . The organic layer was washed with NaCl (aq. ) then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 15-3 (93 mg, 121.7339 μmol, 23.4323%yield) . MS: m/z: 764 [M+H]
+.
A solution of Compound 15-3 (93 mg, 121.7339 μmol) , HCl (1 mL, 4 M in dioxane) in DCM (5 mL) was stirred at room temperature for 1 h. The solution was diluted with 10%NaHCO
3 solution (20 mL) , extracted with DCM (2 × 40 mL) , the organic layer was washed with NaCl (aq. ) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give crude Compound 15-4 (140 mg, 194.4691 μmol) . MS: m/z: 720 [M+H]
+.
A solution of Compound 15-4 (140 mg, 194.4691 μmol) , CsF (248 mg, 1.6326 mmol) in DMF (5 mL) was stirred for 16 hours at 35 ℃ under nitrogen atmosphere. The solution was diluted with water (30 mL) and extracted with EA (2 × 30 mL) . The organic layers dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1 %TFA in water, B: CH
3CN, Gradient: 15%B to 45 %B in 42 min at a flow rate of 60 mL/min, 230 nm) and freeze-dried to give Compound 15 (TFA salt, 38 mg) . MS: m/z: 564 [M+H]
+.
Example 16
N-methyl-2- (methylthio) ethanamine hydrochloride (117 mg, 825.9078 μmol) in several batches was added into the solution of INT 1 (194 mg, 768.4377 μmol) , DIEA (309 mg, 2.3909 mmol) in DCM (10 mL) was stirred at 0 ℃ for 2 h. The solution was diluted with 10%NaHCO
3 solution, the organic layer was washed with sat. NaCl, dried over anhydrous Na
2SO
4 and concentrated in vacuum to give Compound 16-1 (270 mg, 840.5957 μmol, 109.3902%yield) . MS m/z: 321 [M+H]
+.
A solution of Compound 16-1 (0.27 g, 840.5957 μmol) , INT 2 (150 mg, 942.2069 μmol) , potassium fluoride (159 mg, 2.7368 mmol) in DMSO (10 mL) was stirred at 100 ℃ for 18 h under nitrogen atmosphere. The mixture was diluted with sat. NaHCO
3 (15 mL) and extracted with EA (15 mL) . The organic layer was washed with sat. NaCl then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 16-2 (241 mg, 542.8654 μmol, 64.5810%yield) . MS m/z: 444 [M+H]
+.
A solution of Compound 16-2 (0.241 g, 542.8649 μmol) , INT 3 (376 mg, 733.6090 μmol) , cataCXium A Pd G3 (47 mg, 64.5365 μmol) , potassium phosphate (565 mg, 1.7341 mmol) in toluene (10 mL) and water (2 mL) was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (15 mL) and extracted with EA (15 mL) . The organic layer was washed with 10 mL sat. NaCl then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 16-3 (290 mg, 365.2147 μmol, 67.2754%yield) . MS m/z: 794 [M+H]
+.
A solution of Compound 16-3 (0.29 g, 365.2147 μmol) , HCl (4 M in dioxane, 1 mL) in DCM (9 mL) was stirred at RT for 1 h. The solution was diluted with 10%NaHCO
3 solution (10 mL) , the organic layer was washed with sat. NaCl, dried over anhydrous Na
2SO
4 and concentrated in vacuum to give Compound 16-4 (0.342 g, 455.9994 μmol) . MS m/z: 750 [M+H]
+.
A solution of Compound 16-4 (0.342 g, 455.9994 μmol) , CsF (401 mg, 2.6398 mmol) in DMF (10 mL) was stirred for 20 hours at 40 ℃ under nitrogen atmosphere. The solution was diluted with water (10 mL) and extracted with EA (10 mL) . The organic layers were dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1%TFA in water, B: CH
3CN, Gradient: 15%B to 45%B in 55 min at a flow rate of 60 mL/min, 226 nm) and freeze-dried to give Compound 16 (TFA salt, 90 mg, 151.6016 μmol, 33.2460%yield) . MS m/z: 594 [M+H]
+.
Example 17
A solution of INT 1 (206 mg, 815.9699 μmol) , 3-amino-tetrahydrofuran (77 mg, 883.8384 μmol) , DIEA (309 mg, 2.3909 mmol) in DCM (8 mL) was stirred 16 h at room temperature. The solution was diluted with NaHCO
3 (10 mL) , the organic layer was washed with sat. NaCl, dried over anhydrous Na
2SO
4 and concentrated in vacuum to give Compound 17-1 (235 mg, 775.2721 μmol, 95.0123%yield) . MS m/z: 303 [M+H]
+.
A solution of Compound 17-1 (0.235 g, 775.2731 μmol) , INT 2 (140 mg, 879.3931μmol) , potassium fluoride (142 mg, 2.4442 mmol) in DMSO (8 mL) was stirred at 85 ℃ for 20 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (10 mL) and extracted with EA (10 mL) . The organic layer was washed with 10 mL sat. NaCl, dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 17-2 (212 mg, 497.8171 μmol, 64.2118%yield) . MS m/z: 426 [M+H]
+.
A solution of Compound 17-2 (0.212 g, 497.8171 μmol) , INT 3 (282 mg, 550.2063 μmol) , cataCXium A Pd G3 (36 mg, 49.4322 μmol) , potassium phosphate (319 mg, 1.5028 mmol) in toluene (5 mL) and water (1 mL) was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with sat. NaHCO
3 (10 mL) and extracted with EA (10 mL) . The organic layer was washed with 10 mL sat. NaCl then dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 17-3 (285 mg, 367.2813 μmol, 73.7784%yield) . MS m/z: 776 [M+H]
+.
A solution of Compound 17-3 (0.285 g, 367.2813 μmol) , HCl (4 M in 1, 4-dioxane, 1 mL) in DCM (4 mL) was stirred at RT for 1 h. The solution was diluted with DCM (20 mL) and 10%NaHCO
3 solution (20 mL) , the organic layer washed with sat. NaCl, dried over anhydrous Na
2SO
4 and concentrated in vacuum to give Compound 17-4 (208 mg, 284.1842 μmol, 77.3751%yield) . MS m/z: 732 [M+H]
+.
A solution of Compound 17-4 (0.208 g, 284.1842 μmol) , CsF (215.8427 mg, 1.4209 mmol) in DMF (8 mL) was stirred for 20 hours at 40 ℃ under nitrogen atmosphere. The solution was diluted with water (10 mL) and extracted with EA (10 mL) . The organic layers dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1%TFA in water, B: CH
3CN, Gradient: 10%B to 43%B in 35 min at a flow rate of 60 mL/min, 240 nm) The eluent was adjusted to PH=8, acetonitrile was concentrated, aqueous phase was extracted with DCM, and the organic phase was dried and concentrated then and freeze-dried to give Compound 17 (TFA salt, 88 mg, 152.8893 μmol, 53.7994%yield) . MS m/z: 576 [M+H]
+.
Example 18
A solution of INT 1 (204 mg, 808.0488 μmol) , (R) - (tetrahydrofuran-3-yl) methanamine (76 mg, 751.3817 μmol) , DIEA (189 mg, 1.4624 mmol) in DCM (5 mL) was stirred at 0 ℃ for 1 h. The solution was diluted with water (50 mL) , extracted with DCM (2 × 30 mL) , the organic layer was dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was poured into 10 mL hexane/EA = 20/1, stirred for 10 min at room temperature and filtered to give Compound 18-1 (212 mg, 668.4621 μmol, 82.7255 %yield) . MS: m/z: 317 [M+H]
+.
A solution of Compound 18-1 (212 mg, 668.4621 μmol) , INT 2 (156 mg, 979.8933 μmol) , KF (409 mg, 7.0400 mmol) in DMSO (10 mL) was stirred at 100 ℃ for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with EA (30 mL) , washed with aq. NaCl (20 mL × 3) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH=15: 1) to give Compound 18-2 (178 mg, 404.6506 μmol, 60.5346 %yield) . MS: m/z: 440 [M+H]
+.
To a solution of Compound 18-2 (178 mg, 404.6506 μmol) , toluene (10 mL) , was added INT 3 (351 mg, 684.8313 μmol) , cataCXium A Pd G3 (59 mg, 81.0139 μmol) , cesium carbonate (455 mg, 1.3965 mmol) and water (2 mL) . The reaction mixture was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (50 mL) , extracted with DCM (2 × 30 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH=15: 1) to give Compound 18-3 (260 mg, 329.1145 μmol, 81.3330 %yield) . MS: m/z: 790 [M+H]
+.
To a solution of Compound 18-3 (260 mg, 329.1145 μmol) , HCl (1 mL, 4 M in dioxane) in DCM (5 mL) was added, and the mixture was stirred at room temperature for 1 h. The solution was diluted with 10%Na
2CO
3 solution (50 mL) , extracted with DCM (2 × 30 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give crude Compound 18-4 (266 mg, 356.5941 μmol, 108.3495 %yield) . MS: m/z: 746 [M+H]
+.
A solution of Compound 18-4 (266 mg, 356.5941 μmol) , CsF (1517 mg, 9.9866 mmol) in DMF (10 mL) was stirred for 16 hours at 35 ℃ under nitrogen atmosphere. The solution was diluted with EA (50 mL) , washed with sat. NaCl (aq. 50 mL × 3) , dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1 %TFA in water, B: CH
3CN, Gradient: 15 %B to 45 %B in 40 min at a flow rate of 60 mL/min, 240 nm) , the eluent was added NaHCO
3 to adjust to PH=8, acetonitrile was concentrated, aqueous phase was extracted with EA (2 × 100 mL) , and organic phase was dried and concentrated then and freeze-dried to give Compound 18 (113 mg, 191.6533 μmol, 53.7455 %yield) . MS: m/z: 590 [M+H]
+.
Example 19
A solution of INT 1 (208 mg, 823.8929 μmol) , (S) - (tetrahydrofuran-3-yl) methanamine (77 mg, 761.2683 μmol) , DIEA (183 mg, 1.4159 mmol) in DCM (10 mL) was stirred at 0 ℃ for 1 h. The solution was diluted with water (50 mL) , extracted with DCM (2 × 30 mL) , the organic layer was dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was poured into 10 mL hexane/EA=20/1, stirred for 10 min at room temperature and filtered to give Compound 19-1 (222 mg, 699.9933 μmol, 84.9617 %yield) . MS: m/z: 317 [M+H]
+.
A solution of Compound 19-1 (222 mg, 699.9933 μmol) , INT 2 (211 mg, 1.3254 mmol) , KF (199 mg, 3.4253 mmol) in DMSO (10 mL) was stirred at 100 ℃ for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with EA (30 mL) , washed with NaCl (aq. 20 mL × 3) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH = 15: 1) to give Compound 19-2 (213 mg, 484.2167 μmol, 69.1745 %yield) . MS: m/z: 440 [M+H]
+.
A solution of Compound 19-2 (213 mg, 484.2167 μmol) , toluene (15 mL) , INT 3 (379 mg, 739.4617 μmol) , cataCXium A Pd G3 (63 mg, 86.5064 μmol) , cesium carbonate (577 mg, 1.7709 mmol) and water (3 mL) was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (50 mL) , extracted with DCM (2 × 30 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH=15: 1) to give Compound 19-3 (270 mg, 341.7728 μmol, 70.5827 %yield) . MS: m/z: 790 [M+H]
+.
To a solution of Compound 19-3 (270 mg, 341.7728 μmol) , HCl (1 mL, 4 M in dioxane) in DCM (5 mL) was added, and the mixture was stirred at room temperature for 1 h. The solution was diluted with 10%Na
2CO
3 solution (50 mL) , extracted with DCM (2 × 30 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give crude Compound 19-4 (272 mg, 364.6376 μmol, 106.6901 %yield) . MS: m/z: 746 [M+H]
+.
A solution of Compound 19-4 (272 mg, 364.6376 μmol) , CsF (1516 mg, 9.9800 mmol) in DMF (10 mL) was stirred for 16 hours at 35 ℃ under nitrogen atmosphere. The solution was diluted with EA (50 mL) , washed with sat. NaCl (aq. 50 mL × 3) , dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1 %TFA in water, B: CH
3CN, Gradient: 15 %B to 45 %B in 40 min at a flow rate of 60 mL/min, 240 nm) , the eluent was added NaHCO
3 to adjust to PH=8, acetonitrile was concentrated, aqueous phase was extracted with EA (2 × 100 mL) , and organic phase was dried and concentrated then and freeze-dried to give Compound 19 (123 mg, 208.6138 μmol, 57.2113 %yield) . MS: m/z: 590 [M+H]
+.
Example 20
A solution of INT 1 (209 mg, 827.8539 μmol) , 2-methoxy-2-methylpropan-1-amine hydrochloride (113 mg, 809.3211 μmol) , DIEA (345 mg, 2.6694 mmol) in DCM (10 mL) was stirred at 0 ℃ for 1 h. The solution was concentrated in vacuum to give Compound 20-1 (247 mg, 773.9024 μmol, 93.4830 %yield) . MS: m/z: 319 [M+H]
+.
A solution of Compound 20-1 (247 mg, 773.9024 μmol) , INT 2 (232 mg, 1.4573 mmol) , KF (248 mg, 4.2687 mmol) in DMSO (10 mL) was stirred at 90 ℃ for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with EA (30 mL) , washed with NaCl (aq. 20 mL × 3) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH=15: 1) to give Compound 20-2 (208 mg, 470.6931 μmol, 60.8208 %yield) . MS: m/z: 442 [M+H]
+.
A solution of Compound 20-2 (208 mg, 470.6931 μmol) , toluene (10 mL) , INT 3 (351 mg, 684.8318 μmol) , cataCXium A Pd G3 (72 mg, 98.8644 μmol) , cesium carbonate (494 mg, 1.5162 mmol) and water (2 mL) was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (50 mL) , extracted with DCM (2 × 30 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH =15: 1) to give Compound 20-3 (246 mg, 310.6005 μmol, 65.9879 %yield) . MS: m/z: 792 [M+H]
+.
A solution of Compound 20-3 (246 mg, 310.6005 μmol) , HCl (1 mL, 4M in dioxane) in DCM (5 mL) was stirred at room temperature for 1 h. The solution was diluted with 10%Na
2CO
3 solution (50 mL) , extracted with DCM (2 × 30 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give crude Compound 20-4 (284 mg, 379.6985 μmol, 122.2466 %yield) . MS: m/z: 748 [M+H]
+.
A solution of Compound 20-4 (284 mg, 379.6985 μmol) , CsF (1.12 g, 7.3731 mmol) in DMF (10 mL) was stirred for 16 hours at 35 ℃ under nitrogen atmosphere. The solution was diluted with EA (50 mL) , washed with sat. NaCl (aq. 50 mL × 3) , dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.05 %NH
3H
2O in water, B: CH
3CN, Gradient: 35 %B to 75 %B in 31 min at a flow rate of 70 mL/min, 230 nm) , the acetonitrile was concentrated, aqueous phase was extracted with EA (2 × 30 mL) , and organic phase was dried and concentrated then and freeze-dried to give Compound 20 (125 mg, 211.2835 μmol, 55.6451 %yield) . MS: m/z: 592 [M+H]
+.
Example 21
A solution of Compound 21-1 (257 mg, 957.3131 μmol) and sodium methoxide (171 mg, 3.1653 mmol) in DMF (5 mL) was stirred at room temperature for 6 h. The solution was diluted with water (50 mL) , adjusted to PH=6, extracted with EA (3 × 30 mL) , washed with sat. NaCl (aq. 50 mL × 3) , dried over anhydrous Na
2SO
4 and concentrated under vacuum to give Compound 21-2 (226 mg, 855.9293 μmol, 89.4095 %yield) . MS: m/z: 264 [M+H]
+.
A solution of Compound 21-2 (226 mg, 855.9293 μmol) , phosphorus oxychloride (0.5 mL) , DIEA (0.25 mL) in toluene (10 mL) was stirred at 100 ℃ for 3 h. The solution was concentrated in vacuum. The residue was diluted with DCM (10 mL) , added methanamine (81 mg, 860.6783 μmol, 33%) and DIEA (0.25 mL) , stirred at 0 ℃ for 1 h. The solution was diluted with water (50 mL) , extracted with DCM (2 × 30 mL) , the organic layer was dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was poured into 10 mL hexane/EA=15/1, stirred for 10 min at room temperature and filtered to give Compound 21-3 (294 mg, 1.0611 mmol, 123.9655 %yield) . MS: m/z: 277 [M+H]
+.
A solution of Compound 21-3 (294 mg, 1.0611 mmol) , INT 2 (284 mg, 1.7839 mmol) , KF (342 mg, 5.8867 mmol) in DMSO (10 mL) was stirred at 100 ℃ for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with EA (30 mL) , washed with NaCl (aq. 20 mL × 3) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH=15: 1) to give Compound 21-4 (67 mg, 167.5746 μmol, 15.7932 %yield) . MS: m/z: 400 [M+H]
+.
A solution of Compound 21-4 (67 mg, 167.5746 μmol) , toluene (10 mL) , INT-3 (118 mg, 230.2284 μmol) , cataCXium A Pd G3 (35 mg, 48.0591 μmol) , cesium carbonate (197 mg, 604.6304 μmol) and water (2 mL) was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (50 mL) , extracted with DCM (2 × 30 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH=15: 1) to give Compound 21-5 (116 mg, 154.6801 μmol, 92.3052 %yield) . MS: m/z: 750 [M+H]
+.
A solution of Compound 21-5 (116 mg, 154.6801 μmol) , HCl (1 mL, 4 M in dioxane) in DCM (5 mL) was stirred at room temperature for 1 h. The solution was diluted with 10%Na
2CO
3 solution (50 mL) , extracted with DCM (2 × 30 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give crude Compound 21-6 (116 mg, 164.3333 μmol, 106.2408 %yield) . MS: m/z: 706 [M+H]
+.
A solution of Compound 21-6 (116 mg, 164.3333 μmol) , CsF (631 mg, 4.1540 mmol) in DMF (5 mL) was stirred for 16 hours at 35 ℃ under nitrogen atmosphere. The solution was diluted with EA (50 mL) , washed with sat. NaCl (aq. 50 mL × 3) , dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1 %TFA in water, B: CH
3CN, Gradient: 15 %B to 45 %B in 40 min at a flow rate of 60 mL/min, 240 nm) , the eluent was added NaHCO
3 to adjust to PH=8, acetonitrile was concentrated, aqueous phase was extracted with EA (2 × 20 mL) , and organic phase was dried and concentrated then and freeze-dried to give Compound 21 (38 mg, 69.1484 μmol, 42.0781%yield) . MS: m/z: 550 [M+H]
+.
Example 22
A solution of INT 1 (211 mg, 835.7760 μmol) , diethylamine (56 mg, 765.6926 μmol) , DIEA (166 mg, 1.2844 mmol) in DCM (10 mL) was stirred at 0 ℃ for 1 h. The solution was diluted with water (50 mL) , extracted with DCM (2 × 30 mL) , the organic layer dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was poured into 10 mL hexane/EA=10/1, stirred for 10 min at room temperature and filtered to give Compound 22-1 (190 mg, 657.1307 μmol, 78.6252 %yield) . MS: m/z: 289 [M+H]
+.
A solution of Compound 22-1 (190 mg, 657.1307 μmol) , INT 2 (171 mg, 1.0741 mmol) , KF (571 mg, 9.8284 mmol) in DMSO (10 mL) was stirred at 100 ℃ for 20 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with EA (30 mL) , washed with NaCl (aq. 20 mL ×3) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH=15: 1) to give Compound 22-2 (200 mg, 485.5835 μmol, 73.8945 %yield) . MS: m/z: 412 [M+H]
+.
A solution of Compound 22-2 (200 mg, 485.5835 μmol) , toluene (10 mL) , INT-3 (397 mg, 774.5812 μmol) , cataCXium A Pd G3 (79 mg, 108.4763 μmol) , cesium carbonate (544 mg, 1.6696 mmol) and water (2 mL) was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (50 mL) , extracted with DCM (2 × 30 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH=20: 1) to give Compound 22-3 (285 mg, 374.0214 μmol, 77.0252 %yield) . MS: m/z: 762 [M+H]
+.
A solution of Compound 22-3 (285 mg, 374.0214 μmol) , HCl (1 mL, 4 M in dioxane) in DCM (5 mL) was stirred at room temperature for 1 h. The solution was diluted with 10%Na
2CO
3 solution (50 mL) , extracted with DCM (2 × 30 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give crude Compound 22-4 (309 mg, 430.4005 μmol, 115.0737 %yield) . MS: m/z: 718 [M+H]
+.
A solution of Compound 22-4 (309 mg, 430.4005 μmol) , CsF (1419 mg, 9.3415 mmol) in DMF (10 mL) was stirred for 16 hours at 35 ℃ under nitrogen atmosphere. The solution was diluted with EA (50 mL) , washed with sat. NaCl (aq. 50 mL × 3) , dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1 %TFA in water, B: CH
3CN, Gradient: 15 %B to 45 %B in 40 min at a flow rate of 60 mL/min, 240 nm) , the eluent was added NaHCO
3 to adjust to PH=8, acetonitrile was concentrated, aqueous phase was extracted with EA (2 × 100 mL) , and organic phase was dried and concentrated then and freeze-dried to give Compound 22 (84 mg, 149.5737 μmol, 34.7522 %yield) . MS: m/z: 562 [M+H]
+.
Example 23
Compound 23-1 was synthesized based on the same method as Compound 1-3 in Example 1, except that “2-methoxy-1, 1-dimethylethylamine hydrochloride” in Example 1 is replaced with “2, 2-difluoroethan-1-amine” .
A solution of Compound 23-1 (52 mg, 67.5398 μmol) , HCl (1 mL, 4 M in dioxane) in DCM (5 mL) was stirred at room temperature for 2 h. The solution was diluted with 10%Na
2CO
3 solution (50 mL) , extracted with DCM (2 × 30 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give crude Compound 23-2 (82 mg, 112.9688 μmol, 167.2626 %yield) . MS: m/z: 726 [M+H]
+.
A solution of Compound 23-2 (82 mg, 112.9688 μmol) , CsF (484 mg, 3.1862 mmol) in DMF (5 mL) was stirred for 16 hours at 35 ℃ under nitrogen atmosphere. The solution was diluted with EA (50 mL) , washed with sat. NaCl (aq. 50 mL × 3) , dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1 %TFA in water, B: CH
3CN, Gradient: 15 %B to 45 %B in 40 min at a flow rate of 60 mL/min, 240 nm) , the eluent was added NaHCO
3 to adjust to PH=8, acetonitrile was concentrated, aqueous phase was extracted with EA (2 × 100 mL) , and organic phase was dried and concentrated then and freeze-dried to give Compound 23 (31 mg, 54.4314 μmol, 48.1827 %yield) . MS: m/z: 570 [M+H]
+.
Example 24
To a 0 ℃ solution of INT 1 (203 mg, 804.0878 μmol) and DIEA (312 mg, 2.4141 mmol) in DCM (10 mL) was added 5-amino-piperidin-2-one hydrochloride (99 mg, 657.3435 μmol) . The mixture was stirred at 0 ℃for 1 h. The mixture was concentrated and purified by pre-HPLC to give Compound 24-1 (351 mg, 1.0632 mmol, 132.2207%yield) . MS: m/z 330 (M+H)
+.
A solution of INT 2 (296 mg, 1.8593 mmol) , Compound 24-1 (309 mg, 935.9532 μmol) and potassium fluoride (303 mg, 5.2154 mmol) in DMSO (5 mL) was stirred at 100 ℃ overnight. The mixture was concentrated and purified by pre-TLC to give Compound 24-2 (111 mg, 245.0956 μmol, 26.1867%yield) . MS: m/z 453 (M+H)
+.
A solution of INT 3 (107 mg, 208.7662 μmol) , Compound 24-2 (45 mg, 99.3632 μmol) , cataCXium A Pd G3 (28 mg, 38.4473 μmol) and Cs
2CO
3 (114 mg, 349.8876 μmol) in toluene (12 mL) and water (2 mL) was stirred at 100 ℃ overnight under nitrogen atmosphere. The mixture was concentrated and purified by pre-HPLC to give Compound 24-3 (47 mg, 58.5307 μmol, 58.9058%yield) . MS: m/z 803 (M+H)
+.
To a solution of Compound 24-3 (47 mg, 58.5307 μmol) in MeCN (5 mL) was added hydrochloric acid solutions (1 mL) . The mixture was stirred at RT for 2 h. The residue was added TEA to adjust PH=8. The mixture was filtered and collected the organic phase. The organic phase was concentrated under reduced pressure to give a mixture. To a solution of the mixture in DMF (5 mL) was added CsF (191 mg, 1.2574 mmol) . The reaction mixture was stirred at 45 ℃ for 2 h. The mixture was filtered and collected the organic phase. The residue was purified by pre-HPLC (C18 column, phase A: 0.1 %TFA in water, phase B: CH
3CN, Gradient: 15 %B to 30%B in 40 min at a flow rate of 60 mL/min, 230 nm) and lyophilized to give Compound 24 (TFA salt, 0.0161 g, 26.7173 μmol, 45.6467%yield) . MS: m/z 603 (M+H)
+.
Example 25
To a solution of INT 1 (1049 mg, 4.1551 mmol) and DIEA (1094 mg, 8.4647 mmol) in 1, 4-dioxane (3 mL) was added 2, 2, 2-trifluoroethanol (449 mg, 4.4882 mmol) . The mixture was stirred at 45 ℃ for 4 h. The mixture was concentrated and purified by pre-HPLC to give Compound 25-1 (900 mg, 2.8477 mmol, 68.5361%yield) . MS: m/z 316 (M+H)
+.
To a solution of INT 2 (2701 mg, 16.9660 mmol) , Compound 25-1 (5 g, 15.8208 mmol) , DIEA (6179 mg, 47.8094 mmol) in 1, 4-dioxane (30 mL) was added of some molecular sieve 4A. The mixture was stirred at 30 ℃ overnight under nitrogen atmosphere. The mixture was filtrated and collected the filtrate, purified by pre-HPLC to Compound 25-2 (2545 mg, 5.8002 mmol, 36.6617%yield) . MS: m/z 439 (M+H)
+.
A solution of Compound 25-2 (191 mg, 435.2989 μmol) , INT 3 (460 mg, 897.5004 μmol) , cataCXium A Pd G3 (129 mg, 199.4992 μmol) and Cs
2CO
3 (451 mg, 1.3842 mmol) in toluene (6 mL) and water (1.2 mL) was stirred at 100 ℃ overnight under Nitrogen protected. The mixture was added water (10 mL) , extracted with EA (10 mL × 3) , and combined organic phase. The organic phase was washed with saturated sodium chloride (10 mL × 3) , dry with sodium sulfate. The organic phase was filtrated and concentrated, purified by pre-TLC to Compound 25-3 (267 mg, 338.4495 μmol, 77.7511%yield) . MS: m/z 789 (M+H)
+.
A solution of Compound 25-3 (100 mg, 126.7601 μmol) , 3, 3, 3-trifluoropropylamine hydrochloride (31 mg, 207.2996 μmol) , DIEA (60 mg, 464.2439 mmol) and some 4A molecular sieve in DMF (1 mL) was stirred at 40 ℃ overnight. The mixture was quenched with water (10 mL) and extracted with EA (5 ×10 mL) . The organic extracts were concentrated, purified by pre-TLC to give Compound 25-4 (64 mg, 79.8071 μmol, 62.9592%yield) . MS: m/z 802 (M+H)
+.
A solution of Compound 25-4 (64 mg, 79.8071 μmol) , HCl (4 M in dioxane, 0.5 mL) in MeCN (2 mL) was stirred for 1 h. The reaction was concentrated under reduced pressure to give a mixture. To a solution of the mixture in DMF (2 mL) was added CsF (2.03 g, 13.3638 mmol) . The reaction mixture was stirred overnight. The mixture was quenched with water (20 mL) , extracted with EA (5 ×10 mL) and collected the organic phase. The organic phase was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18 column, phase A: 0.1 %TFA in water, phase B: CH
3CN, Gradient: 15 %B to 30%B in 40 min at a flow rate of 60 mL/min, 230 nm) and freeze-dried to give Compound 25 (TFA salt, 27.3 mg, 45.3834 μmol, 56.8664%yield) . MS: m/z 602 (M+H)
+.
1H NMR (400 MHz, DMSO) δ 10.88 (s, 1H) , 10.21 (s, 1H) , 9.36 (t, J = 5.2 Hz, 1H) , 9.29 (s, 1H) , 7.99 (dd, J = 9.0, 6.0 Hz, 1H) , 7.47 (t, J = 8.9 Hz, 1H) , 7.43 –7.38 (m, 1H) , 7.20 –7.14 (m, 1H) , 5.58 (d, J = 52.8 Hz, 1H) , 4.69 –4.53 (m, 2H) , 3.92 –3.83 (m, 4H) , 3.82 –3.68 (m, 3H) , 3.17 (s, 1H) , 2.85 –2.70 (m, 2H) , 2.58 –2.53 (m, 1H) , 2.38 –2.26 (m, 1H) , 2.25 –2.11 (m, 2H) , 2.06 (s, 1H) .
Example 26
A solution of INT 1 (215 mg, 851.6201 μmol) , 1-fluoropropan-2-amine hydrochloride (93 mg, 818.9410 μmol) , DIEA (312 mg, 2.4141 mmol) in DCM (5 mL) was stirred at 0 ℃ for 1 h. The solution was diluted with water (50 mL) , extracted with DCM (2 × 30 mL) , the organic layer was dried over anhydrous Na
2SO
4 and concentrated in vacuum to give Compound 26-1 (258 mg, 880.2463 μmol, 103.3614 %yield) . MS: m/z: 293 [M+H]
+.
A solution of Compound 26-1 (258 mg, 880.2463 μmol) , INT 2 (226 mg, 1.4196 mmol) , KF (220 mg, 3.7868 mmol) in DMSO (10 mL) was stirred at 90 ℃ for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with EA (30 mL) , washed with NaCl (aq. 20 mL × 3) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH=15: 1) to give Compound 26-2 (248 mg, 596.3838 μmol, 67.7520 %yield) . MS: m/z: 416 [M+H]
+.
A solution of Compound 26-2 (248 mg, 596.3838 μmol) , toluene (15 mL) , INT 3 (384 mg, 749.2177 μmol) , cataCXium A Pd G3 (78 mg, 107.1031 μmol) , cesium carbonate (613 mg, 1.8814 mmol) and water (3 mL) . The reaction mixture was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (50 mL) , extracted with DCM (2 × 30 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH=15: 1) to give Compound 26-3 (317 mg, 413.8638 μmol, 69.3956 %yield) . MS: m/z: 766 [M+H]
+.
A solution of Compound 26-3 (317 mg, 413.8638 μmol) , HCl (1 mL, 4 M in dioxane) in DCM (5 mL) was stirred at room temperature for 1 h. The solution was diluted with 10%Na
2CO
3 solution (50 mL) , extracted with DCM (2 × 30 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give crude Compound 26-4 (313 mg, 433.5781 μmol, 104.7634 %yield) . MS: m/z: 722 [M+H]
+.
A solution of Compound 26-4 (313 mg, 433.5781 μmol) , CsF (1674 mg, 11.0202 mmol) in DMF (10 mL) was stirred at 35 ℃ for 16 hours under nitrogen atmosphere. The solution was diluted with EA (50 mL) , washed with sat. NaCl (aq. 50 mL × 3) , dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1 %TFA in water, B: CH
3CN, Gradient: 15 %B to 45 %B in 40 min at a flow rate of 60 mL/min, 240 nm) , the eluent was added NaHCO
3 to adjust to PH=8, acetonitrile was concentrated, aqueous phase was extracted with EA (2 × 30 mL) , and organic phase was dried and concentrated then and freeze-dried to give Compound 26 (143 mg, 252.8466 μmol, 58.3163 %yield) . MS: m/z: 566 [M+H]
+.
Example 27
A solution of INT 1 (217 mg, 859.5411 μmol) , N-methylprop-2-en-1-amine (58 mg, 815.5162 μmol) , DIEA (216 mg, 1.6713 mmol) in DCM (5 mL) was stirred at 0 ℃ for 1 h. The solution was diluted with water (50 mL) , extracted with DCM (2 × 30 mL) , the organic layer was dried over anhydrous Na
2SO
4 and concentrated in vacuum to give Compound 27-1 (258 mg, 898.5790 μmol, 104.5417 %yield) . MS: m/z: 287 [M+H]
+.
A solution of Compound 27-1 (258 mg, 898.5790 μmol) , INT 2 (200 mg, 1.2563 mmol) , KF (160 mg, 2.7540 mmol) in DMSO (10 mL) was stirred at 90 ℃ for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with EA (30 mL) , washed with NaCl (aq. 20 mL × 3) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH=15: 1) to give Compound 27-2 (252 mg, 614.8444 μmol, 68.4241 %yield) . MS: m/z: 410 [M+H]
+.
A solution of Compound 27-2 (252 mg, 614.8444 μmol) , toluene (15 mL) , INT 3 (391 mg, 762.8753 μmol) , cataCXium A Pd G3 (79 mg, 108.4763 μmol) , cesium carbonate (618 mg, 1.8968 mmol) and water (3 mL) was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (50 mL) , extracted with DCM (2 × 30 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH=15: 1) to give Compound 27-3 (218 mg, 286.8524 μmol, 46.6545 %yield) . MS: m/z: 760 [M+H]
+.
A solution of Compound 27-3 (218 mg, 286.8524 μmol) , HCl (1 mL, 4 M in dioxane) in DCM (5 mL) was stirred at room temperature for 1 h. The solution was diluted with 10%Na
2CO
3 solution (50 mL) , extracted with DCM (2 × 30 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum to give crude Compound 27-4 (217 mg, 303.1064 μmol, 105.6664 %yield) . MS: m/z: 716 [M+H]
+
To a solution of Compound 27-4 (217 mg, 303.1064 μmol) , CsF (1092 mg, 7.1888 mmol) in DMF (10 mL) . The reaction mixture was stirred at 35 ℃ for 16 hours under nitrogen atmosphere. The solution was diluted with EA (50 mL) , washed with sat. NaCl (aq. 50 mL × 3) , dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1 %TFA in water, B: CH
3CN, Gradient: 15 %B to 45 %B in 40 min at a flow rate of 60 mL/min, 240 nm) , the eluent was added NaHCO
3 to adjust to PH=8, acetonitrile was concentrated, aqueous phase was extracted with EA (2 × 30 mL) , and organic phase was dried and concentrated then and freeze-dried to give Compound 27 (89 mg, 159.0477 μmol, 52.4726 %yield) . MS: m/z: 560 [M+H]
+.
Example 28
To a solution of Compound 8-3 (30 mg, 0.038 mmol) in DCM (1.2 mL) was added m-CPBA (10.5 mg, 0.06 mmol, in portions until starting materials consumed) at 0 ℃. The reaction mixture was stirred at room temperature overnight. Upon completion, sat. Na
2SO
3 (2 mL) and sat. NaHCO
3 (2 mL) was added to the reaction mixture, the mixture was extracted with DCM (4 mL × 3) . The combined organic phases were dried over anhydrous Na
2SO
4 and concentrated to give Compound 28-1 (crude) . MS: m/z: 796 [M+H]
+.
To a solution of Compound 28-1 (crude) in ACN (2 mL) was added HCl (4M in dioxane, 0.44 mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2.5 h. Then the reaction mixture was concentrated in vacuum to give crude Compound 28-2, which was used directly for the next step without any further purification. MS: m/z: 752 [M+H]
+.
To a solution of Compound 28-2 (crude) in DMF (2 mL) was added CsF (125.3 mg, 0.83 mmol) . The reaction mixture was stirred at 40 ℃ for 3 h. Then the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC to give Compound 28 (2.1 mg, 0.004 mmol) . MS: m/z: 596 [M+H]
+.
Example 29
To a solution of INT 1 (200 mg, 0.80 mmol) in DCM (2 mL) was added DIEA (684 mg, 5.36 mmol) at room temperature. Then the mixture was cooled to -40 ℃ under argon and N-methylpropan-2-amine (60 mg, 0.80 mmol) in DCM (0.5 mL) was added dropwise. After that the reaction mixture was stirred for 1 h at -40 ℃. Then the reaction mixture was quenched with water (2 mL) and extracted with DCM (5 mL) . The organic layer was washed with brine (5 mL) , dried over anhydrous Na
2SO
4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with Petroleum ether/EtOAc=1: 1) to give Compound 29-1 (170 mg, yield 73.5%) . MS: m/z: 289 [M+H]
+.
To a solution of Compound 29-1 (190 mg, 0.657 mmol) and INT 2 (209 mg, 1.31 mmol) in dioxane (2 mL) was added DIEA (255 mg, 1.97 mmol) and 4A MS at room temperature. Then the reaction mixture was heated to 85 ℃ and stirred overnight. After that the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL × 3) . The combined organic layers were washed with water (5 mL) , brine (5 mL) , dried over anhydrous Na
2SO
4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with dichloromethane/methanol=1: 1) to give Compound 29-2 (158 mg, yield 58.5%) . MS: m/z: 412 [M+H]
+.
Compound 29-2 (110 mg, 0.267 mmol) , INT 3 (205 mg, 0.400 mmol) , Cs
2CO
3 (174 mg, 0.534 mmol) , cataCxiumA-Pd G3 (39 mg, 0.053 mmol) were added successively into toluene/water = 5: 1 (4.8 mL) , degassing the reaction with argon for 10 min. The mixture was heated to 115 ℃ under argon by microwave and stirred for 3 h. After that the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL × 3) . The combined organic layers were washed with water (5 mL) , brine (5 mL) , dried with anhydrous Na
2SO
4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with dichloromethane/methanol=10: 1) to give Compound 29-3 (140 mg, 68.9%yield) . MS: m/z: 762 [M+H]
+.
To a solution of Compound 29-3 (140 mg, 0.184 mmol) in DCM (1.5 mL) was added HCl (4 m in dioxane, 0.3 mL) at room temperature and stirred for 2 h. Then the reaction mixture was concentrated to give crude Compound 29-4 (110 mg) . MS: m/z: 718 [M+H]
+.
To a solution of Compound 29-4 (110 mg crude, 0.153 mmol) in DMF (1 mL) was added CsF (232 mg, 1.53 mmol) at room temperature. The reaction mixture was stirred for 3 h at 40 ℃. Then the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC to give Compound 29 (HCOOH salt, 33.0 mg, yield 29.5%for two steps) . MS: m/z: 562 [M+H]
+.
1H NMR (400 MHz, CD
3OD-d
4) : δ 9.18 (s, 1H) , 8.45 (brs, 1H) , 7.89-7.85 (m, 1H) , 7.36-7.22 (m, 2H) , 7.21 (d, J = 2.4 Hz, 1H) , 5.46 (brs, 1H) , 5.24-5.21 (m, 1H) , 4.58-4.57 (m, 1H) , 4.53-4.51 (m, 1H) , 3.84-3.80 (m, 3H) , 3.71-3.70 (m, 4H) , 3.31-3.30 (m, 1H) , 2.52-2.46 (m, 2H) , 2.34-2.32 (m, 3H) , 2.06 (brs, 1H) , 1.42 (d, J = 6.4 Hz, 6H) .
Example 30
To a solution of INT 1 (150 mg, 0.594 mmol) and DIEA (515 mg, 3.98 mmol) in DCM (1.5 mL) was added 2- (methylsulfonyl) ethan-1-amine hydrochloride (95 mg, 0.594 mmol) at -40 ℃. The reaction mixture was stirred at -40 ℃ for 1 h. Upon completion, H
2O (20 mL) was added to the reaction mixture, the reaction mixture was extracted with DCM (30 mL × 3) . The combined organic phases were dried over anhydrous Na
2SO
4 and concentrated to give crude Compound 30-1 which was used directly for the next step without any further purification. MS: m/z: 339 [M+H]
+.
To a solution of Compound 30-1 (crude) and INT 2 (79 mg, 0.496 mmol) in DMSO (1.62 mL) and was added KF (113 mg, 1.947 mmol) . The mixture was stirred at 90 ℃ overnight under N
2 atmosphere. Upon completion, water (20 mL) was added, then the mixture was extracted with EtOAc (20 mL × 3) . The combined organic phases were dried over anhydrous Na
2SO
4. The solution was concentrated to give a residue, which was purified by pre-TLC (Dichloromethane/methanol = 10: 1) to give Compound 30-2 (34 mg, 0.0736 mmol, 20.8%yield) . MS: m/z: 462 [M+H]
+.
Compound 30-2 (23 mg, 0.050 mmol) , INT 3 (30.8 mg, 0.06 mmol) , Cs
2CO
3 (48.9 mg, 0.15 mmol) and cataCxium A Pd G3 (7.3 mg, 0.01 mmol) were placed in the reaction bottle. A solution of toluene/H
2O (5/1, 1.28 mL) was added at room temperature. The mixture was stirred under microwave at 100 ℃ for 3.5 h. Upon completion, water (10 mL) was added to the reaction mixture, the reaction mixture was extracted with EtOAc (10 mL × 3) , and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solution was concentrated to give a crude residue. Purified by pre-TLC (Dichloromethane/methanol = 10: 1) to give Compound 30-3 (25 mg, 0.031 mmol, 61.6%yield) . MS: m/z: 812 [M+H]
+.
To a solution of Compound 30-3 (25 mg, 0.031 mmol) in ACN (1.37 mL) was added HCl (4M in dioxane, 0.25 mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2 h. Then the reaction mixture was concentrated in vacuum to give crude Compound 30-4, which was used directly for the next step without any further purification. MS: m/z: 768 [M+H]
+.
To a solution of Compound 30-4 (crude) in DMF (1.1 mL) was added CsF (70.6 mg, 0.465 mmol) . The reaction mixture was stirred at 40 ℃ for 3 h. Then the reaction mixture was filtered and the filtrate was purified by Prep-HPLC to give Compound 30 (3.5 mg, 0.0057 mmol) . MS: m/z: 612 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 10.14 (s, 1H) , 9.26 –9.17 (m, 2H) , 8.15 (s, 1H) , 7.97 (dd, J = 9.2, 6.0 Hz, 1H) , 7.46 (t, J = 9.0 Hz, 1H) , 7.39 (d, J = 2.5 Hz, 1H) , 7.16 (d, J = 2.3 Hz, 1H) , 5.33 -5.22 (m, 1H) , 4.14 (dd, J = 10.5, 3.9 Hz, 1H) , 4.12 –3.91 (m, 3H) , 3.91 (d, J = 9.5 Hz, 1H) , 3.56 (t, J = 6.7 Hz, 2H) , 3.03 (s, 6H) , 2.85-2.75 (m, 1H) , 2.20-1.70 (m, 6H) .
Example 31
INT 1 (200 mg, 0.8 mmol) , DIEA (686 mg, 5.4 mmol) were added successively into DCM (5 mL) under N
2 atmosphere. The mixture was cooled to -40 ℃, then furan-2-ylmethanamine (77 mg, 0.8mmol) was added, which was stirred for 2 h. After that the mixture was poured into water (5 mL) and extracted with DCM (5 mL) . The organic layer was washed with water (5 mL) , brine (5 mL) , dried with anhydrous Na
2SO
4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10: 1) to give Compound 31-1 (150 mg, yield 60.0%) . MS: m/z: 313.0 [M+H]
+.
Compound 31-1 (150 mg, 0.48 mmol) , INT 2 (155 mg, 0.97 mmol) , DIEA (190 mg, 1.47 mmol) , 4A Ms were added successively into dioxane (6 mL) under N
2 atmosphere. The mixture was heated to 85 ℃ and stirred for 8 h. After that the mixture was cooled to room temperature, poured into water (10 mL) and extracted with EtOAc (8 mL × 2) . The organic layers were washed with water (5 mL) , brine (5 mL) , dried with anhydrous Na
2SO
4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with PE/EtOAc=1: 1) to give Compound 31-2 (100 mg, yield 48.1%) . MS: m/z: 436 [M+H]
+.
Compound 31-2 (100 mg, 0.23 mmol) , INT 3 (176 mg, 0.34 mmol) , Cs
2CO
3 (223 mg, 0.68 mmol) , Pd (dppf) Cl
2-DCM (50 mg, 0.06 mmol) were added successively into dioxane/water=5: 1 (2.4 mL) , degassing the reaction with argon for 2 min. The mixture was heated to 105 ℃ under argon and stirred overnight. After that the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL×2) . The organic layers were washed with water (5 mL) , brine (5 mL) , dried with anhydrous Na
2SO
4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10: 1) to give Compound 31-3 (80 mg, yield 44.4%) . MS: m/z: 786 [M+H]
+.
To a solution of Compound 31-3 (80 mg, 0.1 mmol) in DCM (2.0 mL) was added HCl (2.0 mL, 4M in dioxane) at room temperature and stirred for 2 h. Then the reaction mixture was concentrated to give Compound 31-4 (80 mg, crude) . MS: m/z: 742 [M+H]
+.
To a solution of Compound 31-4 (75 mg crude, 0.1 mmol) in DMF (3 mL) was added CsF (328 mg, 2.0 mmol) at room temperature. The reaction mixture was heated to 40 ℃ and stirred for 4 h. Then the reaction mixture was filtered and the filtrate was purified by Prep-HPLC to give Compound 31 (45.8 mg, yield 76.8%for two steps) . MS: m/z: 586 [M+H]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 9.44 (s, 1H) , 9.30 (s, 1H) , 8.14 (s, 1H) , 7.99-7.95 (m, 1H) , 7.65 (s, 1H) , 7.46 (t, J = 8.0 Hz, 1H) , 7.38 (s, 1H) , 6.44 (d, J = 10.8 Hz, 2H) , 5.43-5.22 (m, 1H) , 4.95-4.76 (m, 2H) , 4.20-4.08 (m, 2H) , 4.05 (s, 1H) , 3.22-3.05 (m, 4H) , 2.85 (s, 1H) , 2.20-2.97 (m, 3H) , 1.86-1.78 (m, 4H) .
Example 32
To a solution of INT 1 (250 mg, 0.99 mmol) in DCM (2.0 mL) was added DIEA (767 mg, 5.94 mmol) at room temperature. Then the mixture was cooled to -40 ℃ under argon and added N-methylcyclobutanamine (84 mg, 0.99 mmol) in DCM (0.5 mL) dropwise. After that the reaction mixture was stirred for 1 h at -40 ℃. Then the reaction mixture was quenched with water (2 mL) and extracted with DCM (5 mL) . The organic layer was washed with brine (5 mL) , dried over anhydrous Na
2SO
4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with petroleum ether/EtOAc=1: 1) to give Compound 32-1 (150 mg, yield 50.3%) . MS: m/z: 301 [M+H]
+.
To a solution of Compound 32-1 (150 mg, 0.50 mmol) and INT 2 (159 mg, 0.10 mmol) in dioxane (2 mL) was added DIEA (194 mg, 1.5 mmol) and 4A MS at room temperature. Then the reaction mixture was heated to 80 ℃ and stirred overnight. After that the mixture was cooled to room temperature, poured into water (5 mL) and extracted with DCM (5 mL × 3) . The combined organic layers were washed with water (5 mL) , brine (5 mL) , dried over anhydrous Na
2SO
4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10: 1) to give Compound 32-2 (80 mg, yield 37.9%) . MS: m/z: 424 [M+H]
+.
Compound 32-2 (80 mg, 0.19 mmol) , INT 3 (146 mg, 0.28 mmol) , Cs
2CO
3 (185 mg, 0.57 mmol) , Pd (dppf) Cl
2 (43 mg, 0.057 mmol) were added successively into dioxane/water = 3: 1 (1.6 mL) . The mixture was heated to reflux under argon and stirred overnight. After that the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL × 3) . The combined organic layers were washed with water (5 mL) , brine (5 mL) , dried with anhydrous Na
2SO
4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH = 10: 1) to give Compound 32-3 (30 mg, yield 20.5%) . MS: m/z: 774 [M+H]
+.
To a solution of Compound 32-3 (25 mg, 0.32 mmol) in DCM (0.5 mL) was added HCl (4M in dioxane, 0.1 mL) at room temperature and stirred for 1 h. Then the reaction mixture was concentrated to give Compound 32-4 (25 mg, crude) . MS: m/z: 730 [M+H]
+.
To a solution of Compound 32-4 (20 mg crude, 0.027 mmol) in DMF (0.5 mL) was added CsF (62 mg, 0.41 mmol) at room temperature. The reaction mixture was heated to 40 ℃ and stirred for 4 h. Then the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC to give Compound 32 (HCOOH salt, 3.4 mg, yield 17.0%for two steps) . MS: m/z: 574 [M+H-FA]
+.
1H NMR (400 MHz, CD
3OD-d
4) : δ 9.10 (s, 1H) , 8.39 (brs, 1H) , 7.89-7.86 (m, 1H) , 7.37-7.31 (m, 2H) , 7.23-7.22 (m, 1H) , 5.56-5.43 (m, 1H) , 4.96-4.85 (m, 1H) , 4.62-4.60 (m, 1H) , 4.55-4.54 (m, 1H) , 3.85-3.83 (m, 1H) , 3.74-3.70 (m, 2H) , 3.52-3.42 (m, 3H) , 3.41-3.40 (m, 1H) , 3.14-2.62 (m, 1H) , 2.66-2.56 (m, 1H) , 2.52-2.41 (m, 5H) , 2.39-2.31 (m, 1H) , 2.27-2.26 (m, 2H) , 2.14-2.04 (m, 1H) , 1.95-1.80 (m, 2H) .
Example 33
To a solution of INT 1 (110 mg, 0.44 mmol) in DCM (2 mL) was added DIEA (343 mg, 2.6 mmol) at room temperature. Then the mixture was cooled to -40 ℃ under argon and added thiophen-3-ylmethanamine (50 mg, 0.44 mmol) in DCM (3 mL) dropwise. After that the reaction mixture was stirred for 1 h at -40 ℃. Then the reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL) . The organic layer was washed with brine (10 mL) , dried over anhydrous Na
2SO
4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with petroleum ether/EtOAc=1: 1) to give Compound 33-1 (120 mg, yield 83.6%) . MS: m/z: 329 [M+H]
+.
To a solution of Compound 33-1 (90 mg, 0.27 mmol) and INT 2 (86.5 mg, 0.54 mmol) in dioxane (2 mL) was added DIEA (105.4 mg, 0.82 mmol) and 4A MS at room temperature. Then the reaction mixture was heated to 85 ℃ and stirred overnight. After that the mixture was cooled to room temperature, poured into water (20 mL) and extracted with EtOAc (10 mL × 2) . The combined organic layers were washed with water (10 mL) , brine (20 mL) , dried over anhydrous Na
2SO
4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with EtOAc) to give Compound 33-2 (85 mg, yield 69.7%) . MS: m/z: 452 [M+H]
+.
Compound 33-2 (85 mg, 0.19 mmol) , INT 3 (144.5 mg, 0.28 mmol) , Cs
2CO
3 (183.8 mg, 0.56 mmol) , Pd (dppf) Cl
2 (27.7 mg, 0.038 mmol) were added successively into dioxane/water = 5: 1 (3 mL) , degassing the reaction with argon for 10 min. The mixture was heated to 100 ℃ under argon and stirred overnight. After that the mixture was cooled to room temperature, poured into water (10 mL) and extracted with EtOAc (5 mL × 3) . The combined organic layers were washed with water (5 mL) , brine (5 mL) , dried with anhydrous Na
2SO
4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH = 10: 1) to give Compound 33-3 (50 mg, yield 32.8%) . MS: m/z: 802 [M+H]
+.
To a solution of Compound 33-3 (50 mg, 0.062 mmol) in DCM (1.5 mL) was added 4M HCl (4 M in dioxane, 0.3 mL) at room temperature and stirred for 1 h. Then the reaction mixture was concentrated to give crude Compound 33-4 (60 mg) . MS: m/z: 758 [M+H]
+.
To a solution of Compound 33-4 (60 mg crude, 0.062 mmol) in DMF (2 mL) was added CsF (120 mg, 0.62 mmol) at room temperature. The reaction mixture was stirred at 40 ℃ for 3 h. Then the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC to give Compound 33 (HCOOH salt, 12 mg, yield 30.0 %for two steps) . MS: m/z: 602 [M+H-FA]
+.
1H NMR (400 MHz, CD
3OD-d
4) : δ 9.21 (s, 1H) , 7.88 (m, 1H) , 7.87-7.86 (m, 2H) , 7.42-7.34 (m, 2H) , 7.32-7.21 (m, 2H) , 5.55 (d, J = 52 Hz, 1H) , 4.87 (s, 1H) , 4.67-4.63 (m, 2H) , 3.99-3.86 (m, 4H) , 3.38-3.31 (m, 2H) , 2.67-2.49 (m, 2H) , 2.38-2.02 (m, 4H) , 1.29 (s, 1H) .
Example 34
To a solution of Compound 34-1 (7.6 g, 51.8 mmol) and 2-aminoethane-1-thiol (4.0 g, 51.8 mmol) in toluene (640 mL) was added TEA (25.6 mL) . The reaction mixture was stirred at 130 ℃ overnight and water was removed by Dean-Stark trap. Upon completion, the reaction mixture was concentrated. EtOAc (100 mL) and saturated NaHCO
3 solution (100 mL) was added to the reaction mixture, the reaction mixture was washed with H
2O (100 mL × 2) . The organic phase was dried over anhydrous Na
2SO
4, filtered and concentrated to give a residue, which was purified by column chromatography (Petroleum ether/Ethyl acetate=10: 1) to give Compound 34-2 (7.8 g, 37.6 mmol, 72.7%yield) . MS: m/z: 208 [M+H]
+.
To a solution of Compound 34-2 (1.8 g, 8.7 mmol) and bromocyclopropane (1.1 g, 8.7 mmol) in DMSO (25.2 mL) was added t-BuOK (975 mg, 8.7 mmol) . The mixture was stirred at 80 ℃ for 4 h under N
2 atmosphere. Upon completion, EtOAc (30 mL) and saturated NaHCO
3 solution (20 mL) was added, then the reaction mixture was washed with H
2O (30 mL × 3) . The organic phase was dried over anhydrous Na
2SO
4. The solution was concentrated to give a residue, which was purified by column chromatography (petroleum ether/ethyl acetate = 20: 1) to give Compound 34-3 (480 mg, 1.9 mmol, 22.3%yield) . MS: m/z: 248 [M+H]
+.
To a solution of Compound 34-3 (308 mg, 1.2 mmol) in MeOH (4 mL) was added N
2H
4-H
2O (240 mg, 4.8 mmol) . The mixture was stirred at 75 ℃ for 2 h. Upon completion, the reaction mixture was filtered and the filtrate was concentrated to give a crude residue, which was triturated with ether (4 mL) and the reaction mixture was filtered and the solution was concentrated to give crude Compound 34-4 (90 mg) . MS: m/z: 118 [M+H]
+.
To a solution of INT 1 (143 mg, 0.57 mmol) and DIEA (493 mg, 3.8 mmo) in DCM (1.4 mL) was added Compound 34-4 (67 mg, 0.57 mmol) at -40 ℃ under N
2 atmosphere. The reaction mixture was stirred at -40 ℃ for 1 h. Upon completion, H
2O (4 mL) was added to the reaction mixture, the reaction mixture was extracted with DCM (4 mL × 3) . The combined organic phases were dried over anhydrous Na
2SO
4 and concentrated to give a residue, which was purified by pre-TLC (Petroleum ether/Ethyl acetate = 1: 1) to give Compound 34-5 (100 mg, 0.3 mmol, 52.7%yield) . MS: m/z: 333 [M+H]
+.
To a solution of Compound 34-5 (70 mg, 0.21 mmol) and INT 2 (46 mg, 0.29 mmol) in DMSO (1 mL) was added KF (67 mg, 1.2 mmol) . The mixture was stirred at 80 ℃ overnight under N
2 atmosphere. Upon completion, water (5 mL) was added, then the reaction mixture was extracted with EtOAc (5 mL × 3) . The combined organic phases were dried over anhydrous Na
2SO
4. The solution was concentrated to give a residue, which was purified by pre-TLC (dichloromethane/methanol=10: 1) to give Compound 34-6 (with another 30 mg batch, 100 mg, 0.22 mmol, 73.1%yield) . MS: m/z: 456 [M+H]
+.
A mixture of Compound 34-6 (70 mg, 0.15 mmol) , INT 3 (100.0 mg, 0.2 mmol) , Cs
2CO
3 (147 mg, 0.45 mmol) and Pd (dppf) Cl
2 (22 mg, 0.03 mmol) in 1, 4-dioxane/H
2O (3/1, 4.8 mL) was stirred at 100 ℃ overnight under N
2 atmosphere. Upon completion, water (8 mL) was added to the reaction mixture, the mixture was extracted with EtOAc (8 mL × 3) , and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solution was concentrated to give a crude residue. The residue was purified by pre-TLC (Dichloromethane/methanol=20: 1) to give Compound 34-7 (with another 30 mg batch, 49 mg, 0.06 mmol, 27.6%yield) . MS: m/z: 806 [M+H]
+.
To a solution of Compound 34-7 (20 mg, 0.024 mmol) in ACN (1.2 mL) was added HCl (4M in dioxane, 0.2 mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 3 h. Then the reaction mixture was concentrated in vacuum to give crude Compound 34-8, which was used directly for the next step without any further purification. MS: m/z: 762 [M+H]
+.
To a solution of crude Compound 34-8 in DMF (1 mL) was added CsF (54 mg, 0.36 mmol) . The reaction mixture was stirred at 40 ℃ for 1 h. Then the reaction mixture was filtered and the filtrate was purified by Prep-HPLC to give Compound 34 (1.9 mg, 0.003 mmol) . MS: m/z: 606 [M+H]
+.
1H NMR (300 MHz, DMSO-d
6) : δ 10.76 (s, 1H) , 10.17 (s, 1H) , 9.32 (d, J = 7.4 Hz, 2H) , 7.99 (dd, J = 9.2, 5.9 Hz, 1H) , 7.47 (t, J = 9.0 Hz, 1H) , 7.40 (d, J = 2.5 Hz, 1H) , 7.16 (d, J = 2.5 Hz, 1H) , 5.70-5.40 (m, 1H) , 4.71 –4.52 (m, 2H) , 3.91 (d, J = 11.3 Hz, 2H) , 3.87 –3.67 (m, 3H) , 2.92 (t, J = 7.3 Hz, 3H) , 2.30-1.90 (m, 8H) , 0.87 (dt, J = 13.2, 4.2 Hz, 3H) , 0.59 –0.50 (m, 2H) .
Example 35
To a solution of Compound 35-1 (300 mg, 3.12 mmol) in MeOH (6 mL) was added methylamine (2 N in THF, 9 mL, 18.73 mmol) dropwise under argon at room temperature. The reaction mixture was stirred for 12 h at room temperature. Then NaBH
4 (567 mg, 15.6 mmol) was added to the mixture slowly under argon. After that the reaction mixture was stirred for 1 h at room temperature. Then the reaction mixture was concentrated to dryness to give crude, saturated solution of NaHCO
3 (10 mL) was added, and extracted with DCM (10 mL ×3) . The combined organic layers were washed with water (10 mL) , brine (10 mL × 3) , dried over anhydrous Na
2SO
4 and filtered, the filtrate was concentrated to dryness to give crude Compound 35-2 (100 mg) . MS: m/z: 112 [M+H]
+.
To a solution of INT 1 (159 mg, 0.63 mmol) in THF (1.5 mL) was added DIEA (488 mg, 3.78 mmol) at room temperature. Then Compound 35-2 (100 mg, 0.63 mmol) in THF (0.5 mL) was added dropwise to the mixture under argon. After that the reaction mixture was stirred for 12 h at 40 ℃. Then the reaction mixture was quenched with water (2 mL) and extracted with EtOAc (5 mL × 3) . The organic layers were washed with brine (5 mL) , dried over anhydrous Na
2SO
4 and filtered; the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with petroleum ether/EtOAc=1: 1) to give Compound 35-3 (45 mg, yield 4.4%for two steps) . MS: m/z: 327 [M+H]
+.
To a solution of Compound 35-3 (45 mg, 0.14 mmol) and INT 2 (44 mg, 0.28 mmol) in dioxane (1 mL) was added DIEA (53 mg, 0.41 mmol) and 4A MS at room temperature. Then the reaction mixture was heated to 80 ℃ and stirred overnight. After that the mixture was cooled to room temperature, poured into water (3 mL) and extracted with EtOAc (3 mL × 3) . The combined organic layers were washed with water (3 mL) , brine (3 mL) , dried over anhydrous Na
2SO
4 and filtered, the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with Petroleum ether/EtOAc=1: 1) to give Compound 35-4 (25 mg, yield 40.4%) . MS: m/z: 450 [M+H]
+.
Compound 35-4 (25 mg, 0.06 mmol) , INT 3 (43 mg, 0.084 mmol) , Cs
2CO
3 (54 mg, 0.17 mmol) , Pd (dppf) Cl
2 (13 mg, 0.02 mmol) were added successively into dioxane/water=5: 1 (1.2 mL) , degassing the reaction with argon for 10 min. The mixture was heated to 100 ℃ under argon and stirred for 12 h. After that the mixture was cooled to room temperature, poured into water (3 mL) and extracted with EtOAc (3 mL × 3) . The combined organic layers were washed with water (3 mL) , brine (3 mL) , dried with anhydrous Na
2SO
4 and filtered, the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10: 1) to give Compound 35-5 (12 mg, yield 27.0%) . MS: m/z: 800 [M+H]
+.
To a solution of Compound 35-5 (12 mg, 0.015 mmol) in DCM (0.3 mL) was added HCl (4 M in dioxane, 0.1 mL) at room temperature, the mixture was stirred for 1 h. Then the reaction mixture was concentrated to give crude Compound 35-6 (15 mg) . MS: m/z: 756 [M+H]
+.
To a solution of crude Compound 35-6 (15 mg, 0.015 mmol) in DMF (0.2 mL) was added CsF (30 mg, 0.20 mmol) at room temperature. The reaction mixture was heated to 40 ℃ and stirred for 12 h. Then the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC to give Compound 35 (HCOOH salt, 2.3 mg, yield 24.5%for two steps) . MS: m/z: 600 [M+H]
+.
1H NMR (300 MHz, CD
3OD-d
4) : δ 9.20 (s, 1H) , 8.45 (brs, 1H) , 7.69 (s, 1H) , 7.56 (t, J = 1.5 Hz, 1H) , 7.36-7.21 (m, 2H) , 7.21 (s, 1H) , 6.57 (d, J = 0.9 Hz, 1H) , 5.52-5.38 (m, 1H) , 5.03-5.02 (m, 2H) , 4.58-4.52 (m, 2H) , 3.68-3.30 (m, 8H) , 2.65-2.41 (m, 2H) , 2.40-2.14 (m, 3H) , 2.13-1.98 (m, 1H) .
Example 36
A solution of 1-cyclopropyl-N-methylmethanamine (101.2 mg, 1.18 mmol) and DIEA (1.02 g, 8.0 mmol) in DCM (2 mL) at room temperature was cooled to -40 ℃ under argon and added INT 1 (300 mg, 1.18 mmol) in DCM (0.5 mL) dropwise. After that the reaction mixture was stirred for 1 h at -40 ℃. After that the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL) . The organic layer was washed with brine (10 mL) , dried over anhydrous Na
2SO
4 and filtered; the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with petroleum ether/EtOAc=3: 1) to give Compound 36-1 (255 mg, yield 71.2%) . MS: m/z: 301/303 [M+H]
+.
To a solution of Compound 36-1 (255 mg, 0.85 mmol) and INT 2 (269 mg, 1.7 mmol) in dioxane (2 mL) was added DIEA (328 mg, 2.54 mmol) and 4A MS (300 mg) at room temperature. Then the reaction mixture was heated to 100 ℃ and stirred overnight. After that the mixture was cooled to room temperature, poured into water (20 mL) and extracted with EtOAc (10 mL × 2) . The combined organic layers were washed with water (10 mL) , brine (20 mL) , dried over anhydrous Na
2SO
4 and filtered, the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with EtOAc) to give Compound 36-2 (180 mg, yield 49.9%) . MS: m/z: 424 [M+H]
+.
Compound 36-2 (146 mg, 0.34 mmol) , INT 3 (264.8 mg, 0.516 mmol) , Cs
2CO
3 (336 mg, 1.03 mmol) , Pd (dppf) Cl
2 (48.2 mg, 0.068 mmol) were added successively into dioxane/water=3: 1 (4 mL) , degassing the reaction with argon for 10 min. The mixture was heated to 100 ℃ under argon and stirred overnight. After that the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL × 3) . The combined organic layers were washed with water (5 mL) , brine (5 mL) , dried with anhydrous Na
2SO
4 and filtered, the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10: 1) to give Compound 36-3 (110 mg, yield 41.3%) . MS: m/z: 774 [M+H]
+.
To a solution of Compound 36-3 (110 mg, 0.15 mmol) in DCM (2.0 mL) was added HCl (4M in dioxane, 0.4 mL) at room temperature and stirred for 1 h. Then the reaction mixture was concentrated to give Compound 36-4 (125 mg, crude) . MS: m/z: 730 [M+H]
+.
To a solution of Compound 36-4 (125 mg crude, 0.17 mmol) in DMF (1 mL) was added CsF (410 mg, 2.56 mmol) at room temperature. The reaction mixture was stirred at 40 ℃ for 1 h. Then the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC to give Compound 36 (HCOOH salt, 36.9 mg) . MS: m/z: 574 [M+H]
+.
1H NMR (300 MHz, CD
3OD) : δ 9.26 (s, 1H) , 7.87 (dd, J = 9.3 Hz, 1H) , 7.37-7.30 (m, 2H) , 7.23 (d, J = 2.7 Hz, 1H) , 5.59-5.39 (m, 1H) , 4.66-4.51 (m, 2H) , 3.92-3.87 (m, 2H) , 3.76-3.74 (m, 2H) , 3.69 (s, 3H) , 3.44-3.48 (m, 1H) , 2.50-2.60 (m, 2H) , 2.54-2.23 (m, 3H) , 2.15-2.01 (m, 1H) , 1.40-1.28 (m, 1H) , 0.73-0.66 (m, 2H) , 0.50-0.44 (m, 2H) .
Example 37
To a solution of INT 1 (200 mg, 0.80 mmol) in DCM (4 mL) was added DIEA (672 mg, 5.20 mmol) at room temperature. Then the mixture was cooled to -40 ℃ under argon and 2-methylpropan-1-amine (58 mg, 0.80 mmol) in DCM (0.5 mL) was added drop wise. After that the reaction mixture was stirred for 1 h at -40 ℃. Then the reaction mixture was quenched with water (4 mL) and extracted with DCM (8 mL) . The organic layer was washed with brine (5 mL) , dried over anhydrous Na
2SO
4 and concentrated to give the crude Compound 37-1 (230 mg) and used directly for the next step without further purification. MS: m/z: 289 [M+H]
+.
To a solution of Compound 37-1 (300 mg, crude, 1.04 mmol) and INT 2 (330 mg, 2.08 mmol) in dioxane (5 mL) was added DIEA (402 mg, 3.11 mmol) and 4A MS at room temperature. Then the reaction mixture was heated to 85 ℃ and stirred overnight. After that the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL × 3) . The combined organic layers were washed with water (5 mL) , brine (5 mL) , dried over anhydrous Na
2SO
4 and filtered, the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10: 1) to give Compound 37-2 (350 mg, yield 61.3%for two steps) . MS: m/z: 412 [M+H]
+.
Compound 37-2 (140 mg, 0.34 mmol) , INT 3 (270 mg, 0.53 mmol) , Cs
2CO
3 (342 mg, 1.05 mmol) , cataCxiumA-Pd G3 (51 mg, 0.07 mmol) were added successively into toluene/water=5: 1 (2.4 mL) , degassing the reaction with argon for 10 min. The mixture was heated to 100 ℃ under argon by microwave and stirred for 2 h. After that the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL × 3) . The combined organic layers were washed with water (5 mL) , brine (5 mL) , dried with anhydrous Na
2SO
4 and filtered, the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10: 1) to give Compound 37-3 (130 mg, yield 49.5%) . MS: m/z: 762 [M+H]
+.
To a solution of Compound 37-3 (150 mg, 0.20 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 1 mL) at room temperature and stirred for 1 h. Then the reaction mixture was concentrated to give crude Compound 37-4 (180 mg) . MS: m/z: 718 [M+H]
+.
To a solution of Compound 37-4 (180 mg crude, 0.227 mmol) in DMF (2 mL) was added CsF (350 mg, 2.27 mmol) at room temperature. The reaction mixture was heated to 40 ℃ and stirred for 2 h. Then the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC to give Compound 37 (HCOOH salt, 32.0 mg, yield 26.8%for two steps) . MS: m/z: 562 [M+H]
+.
1H NMR (400 MHz, CD
3OD) : δ 9.18 (s, 1H) , 8.47 (brs, 1H) , 7.87 (t, J = 3.6 Hz, 1H) , 7.36-7.21 (m, 2H) , 7.20 (s, 1H) , 5.52-5.39 (m, 1H) , 4.57 (q, J = 17.2 Hz, 2H) , 3.79-3.76 (m, 1H) , 3.66-3.57 (m, 4H) , 3.49-3.36 (m, 1H) , 3.31 (s, 1H) , 2.60-2.55 (m, 2H) , 2.49-2.43 (m, 1H) , 2.32-2.17 (m, 3H) , 2.17-2.14 (m, 1H) , 1.38-1.29 (m, 2H) , 1.04 (d, J = 6.6 Hz, 6H) .
Example 38
To a solution of INT 1 (200 mg, 0.8 mmol) and DIEA (698 mg, 5.4 mmol) in DCM (2.0 mL) was added 2-methoxy-N-methylethan-1-amine (72 mg, 0.8 mmol) at -40 ℃. The reaction mixture was stirred at -40 ℃for 1.5 h. Upon completion, H
2O (10 mL) was added to the reaction mixture, extracted with DCM (10 mL ×3) . The combined organic phases were dried over anhydrous Na
2SO
4 and concentrated to give a residue, purified by pre-TLC (Petroleum ether/Ethyl acetate = 1: 2) to give Compound 38-1 (170 mg, 0.56 mmol, 70.0%yield) . MS: m/z: 305 [M+H]
+.
To a solution of Compound 38-1 (140 mg, 0.46 mmol) and INT 2 (146 mg, 0.92 mmol) in dioxane (4.0 mL) was added 4A MS (70 mg) and DIEA (178 mg, 1.38 mmol) . The mixture was stirred at 95 ℃ overnight under N
2 atmosphere. Upon completion, water (10 mL) was added, then extracted with DCM (10 mL × 3) . The combined organic phases were dried over anhydrous Na
2SO
4. The solution was concentrated to give a residue, purified by pre-TLC (dichloromethane/methanol = 10: 1) to give Compound 38-2 (130 mg, 0.30 mmol, 65.2%yield) . MS: m/z: 428 [M+H]
+.
Compound 38-2 (130 mg, 0.30 mmol) , INT 3 (184 mg, 0.36 mmol) , Cs
2CO
3 (293 mg, 0.9 mmol) and cataCxium A Pd G3 (36 mg, 0.05 mmol) were placed in the reaction bottle. A solution of Toluene/H
2O (5/1, 5.9 mL) was added at room temperature. The mixture was stirred with microwave reaction at 120 ℃ for 2 h. Upon completion, water (10 mL) was added to the reaction mixture, extracted with EtOAc (10 mL × 3) , and the combined organic layers were washed with saturated brine (10 mL × 1) and dried over anhydrous sodium sulfate. The solution was concentrated to give a residue, purified by pre-TLC (dichloromethane/methanol = 10: 1) to give Compound 38-3 (180 mg, 0.23 mmol, 76.7%yield) . MS: m/z: 778 [M+H]
+.
To a solution of Compound 38-3 (90 mg, 0.12 mmol) in ACN (5.3 mL) was added HCl (4M in dioxane, 1.0 mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 h. Then the reaction mixture was concentrated in vacuum to give crude Compound 38-4, which was used directly for the next step without any further purification. MS: m/z: 734 [M+H]
+.
To a solution of Compound 38-4 (crude) in DMF (4.5 mL) was added CsF (273 mg, 1.8 mmol) . The reaction mixture was stirred at 40 ℃ overnight. Then the reaction mixture was filtered and the filtrate was purified by Prep-HPLC to give Compound 38 (HCOOH salt, 58.8 mg, 0.094 mmol, 78.3%yield for two steps) . MS: m/z: 578 [M+H]
+.
1H NMR (300 MHz, DMSO-d
6) : δ 10.16 (s, 1H) , 9.24 (s, 1H) , 8.14 (s, 0.5H) , 7.97 (t, J = 6.8 Hz, 1H) , 7.44 (dd, J = 18.9, 11.1 Hz, 2H) , 7.18 (s, 1H) , 5.29 (d, J = 54.9 Hz, 1H) , 4.20 –3.88 (m, 5H) , 3.76 (s, 2H) , 3.53 (s, 3H) , 3.33 (s, 3H) , 3.12 (s, 2H) , 3.03 (s, 1H) , 2.85 (s, 1H) , 2.15 (s, 1H) , 2.03 (d, J = 12.4 Hz, 2H) , 1.92 –1.71 (m, 3H) .
Example 39
To a solution of INT 1 (300 mg, 1.189 mmol) in DCM (3 mL) was added DIEA (1.03 g, 7.96 mmol) at room temperature. Then the mixture was cooled to -40 ℃ under argon and added 2-fluoroethan-1-amine hydrochloride (118.3 mg, 1.189 mmol) in DCM (3 mL) dropwise. After that, the reaction mixture was stirred for 1 h at -40 ℃. Then the reaction mixture was quenched with water (20 mL) and extracted with DCM (20 mL × 3) . The organic layers were washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=15: 1) to give Compound 39-1 (290 mg, 1.04 mmol, 87.4%yield) . MS: m/z: 279 [M+H]
+.
To a solution of Compound 39-1 (290 mg, 1.04 mmol) and INT 2 (231.6 mg, 1.45 mmol) in DMSO (3 mL) was added KF (332.1 mg, 5.72 mmol) at room temperature. The reaction mixture was heated to 80 ℃ and stirred overnight. After that, the mixture was cooled to room temperature, poured into water (20 mL) and extracted with EtOAc (20 mL × 2) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous Na
2SO
4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10: 1) to give Compound 39-2 (320 mg, 0.796 mmol, 76.6%yield) . MS: m/z: 402 [M+H]
+.
Compound 39-2 (320 mg, 0.796 mmol) , INT 3 (489.8 mg, 0.956 mmol) , Cs
2CO
3 (778.5 mg, 2.39 mmol) , cataCxiumA-Pd-G
3 (116.0 mg, 0.159 mmol) were added successively into toluene/water = 5: 1 (20 mL) , degassing the reaction with argon for 10 min. The mixture was heated to 110 ℃ under argon and stirred overnight. After that, the mixture was cooled to room temperature, poured into water (30 mL) and extracted with EtOAc (20 mL × 3) . The combined organic layers were washed with brine (40 mL) , dried with anhydrous Na
2SO
4, filtered and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10: 1) to give Compound 39-3 (90 mg, 0.120 mmol, yield 15.0%) . MS: m/z: 752 [M+H]
+.
To a solution of Compound 39-3 (90 mg, 0.120 mmol) in DCM (6 mL) was added 4M HCl (4 M in dioxane, 0.86 mL) at 0 ℃ and stirred for 1 h. Then the reaction mixture was concentrated to give crude Compound 39-4 without any purification. MS: m/z: 708 [M+H]
+.
To a solution of Compound 39-4 (85 mg, 0.120 mmol) in DMF (3 mL) was added CsF (272.7 mg, 1.80 mmol) at room temperature. The reaction mixture was stirred at 40 ℃ for 3 h. Then the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC to give Compound 39 (21.7 mg, yield 32.8%for two steps) . MS: m/z: 552 [M+H]
+.
1H NMR (300 MHz, DMSO-d6) : δ 9.19 (s, 1H) , 8.47 (s, 1H) , 7.89 –7.85 (m, 1H) , 7.36 –7.30 (m, 2H) , 7.20 (s, 1H) , 5.44 (d, J = 53.4 Hz, 1H) , 4.87 –4.82 (m, 1H) , 4.66 (s, 1H) , 4.56 –4.45 (q, 2H) , 5.44 (d, J = 25.2 Hz, 2H) , 3.70 –3.57 (m, 3H) , 3.37 (s, 1H) , 2.55 –2.40 (m, 2H) , 2.30 –2.03 (m, 5H) .
Example 40
To a solution of INT 1 (200 mg, 0.80 mmol) in DCM (4 mL) was added DIEA (686 mg, 5.30 mmol) at room temperature. Then the mixture was cooled to -40 ℃ under argon and N-methylpropan-1-amine (58 mg, 0.80 mmol) in DCM (0.5 mL) was added dropwise. After that, the reaction mixture was stirred for 1 h at -40 ℃. Then the reaction mixture was quenched with water (4 mL) and extracted with DCM (8 mL) . The organic layer was washed with brine (5 mL) , dried over anhydrous Na
2SO
4 and concentrated to give crude Compound 40-1 (233 mg) and used directly for the next step without further purification. MS: m/z: 289 [M+H]
+.
To a solution of Compound 40-1 (300 mg, crude, 1.0 mmol) and INT 2 (330 mg, 2.0 mmol) in dioxane (5 mL) was added DIEA (402 mg, 3.0 mmol) and 4A MS at room temperature. Then the reaction mixture was heated to 85 ℃ and stirred overnight. After that, the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL × 3) . The combined organic layers were washed with water (5 mL) , brine (5 mL) , dried over anhydrous Na
2SO
4 and filtered, the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10: 1) to give Compound 40-2 (257.0 mg, 52.6%yield for two steps) . MS: m/z: 412 [M+H]
+.
Compound 40-2 (250 mg, 0.61 mmol) , INT 3 (467 mg, 0.91 mmol) , Cs
2CO
3 (593 mg, 1.82 mmol) , cataCxiumA-Pd G3 (87 mg, 0.12 mmol) were added successively into toluene/water=5: 1 (6 mL) , degassing the reaction with argon for 10 min. The mixture was heated to 120 ℃ under argon by microwave and stirred for 2.5 h. After that, the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL × 3) . The combined organic layers were washed with water (5 mL) , brine (5 mL) , dried with anhydrous Na
2SO
4 and filtered, the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10: 1) to give Compound 40-3 (292 mg, 63.1%yield) . MS: m/z: 762 [M+H]
+.
To a solution of Compound 40-3 (250 mg, 0.33 mmol) in DCM (2.5 mL) was added HCl (4M in dioxane, 0.5 mL) at room temperature and stirred for 1 h. Then the reaction mixture was concentrated to give crude Compound 40-4 (350 mg) . MS: m/z: 718 [M+H]
+.
To a solution of Compound 40-4 (350 mg crude, 0.33 mmol) in DMF (2 mL) was added CsF (501 mg, 3.30 mmol) at room temperature. The reaction mixture was heated to 40 ℃ and stirred for 24 h. Then the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC (FA) to give Compound 40 (HCOOH salt, 94.0 mg, 47.3%yield for two steps) . MS: m/z: 562 [M+H]
+.
1H NMR (400 MHz, CD
3OD-d
4) : δ 9.15 (s, 1H) , 8.50 (brs, 1H) , 7.88-7.84 (m, 1H) , 7.36-7.21 (m, 2H) , 7.22 (s, 1H) , 5.50-5.40 (m, 1H) , 4.48-4.42 (m, 2H) , 3.92-3.89 (m, 2H) , 3.61-3.53 (m, 6H) , 3.49-3.42 (m, 1H) , 3.25-3.20 (m, 1H) , 2.55-2.42 (m, 1H) , 2.40-2.37 (m, 1H) , 2.25-2.23 (m, 2H) , 2.17-2.13 (m, 1H) , 1.95-1.89 (m, 2H) , 1.09-1.05 (m, 3H) .
Example 41
To a solution of INT 1 (300 mg, 1.2 mmol) in DCM (4 mL) was added DIEA (1.02 g, 8.0 mmol) at room temperature. Then the mixture was cooled to -40 ℃ under argon and N, 2-dimethylpropan-1-amine (104 mg, 1.2 mmol) in DCM (0.5 mL) was added dropwise. After that, the reaction mixture was stirred for 1 h at -40 ℃. Then the reaction mixture was quenched with water (4 mL) and extracted with DCM (8 mL) . The organic layer was washed with brine (5 mL) , dried over anhydrous Na
2SO
4 and concentrated to give Compound 41-1 (233 mg, 64.0%yield) . MS: m/z: 303 [M+H]
+.
To a solution of Compound 41-1 (232 mg, 0.8 mmol) and INT 2 (255 mg, 1.6 mmol) in dioxane (5 mL) was added DIEA (383 mg, 2.3 mmol) and 4A MS at room temperature. The reaction mixture was heated to 85 ℃ and stirred overnight. After that, the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL × 3) . The combined organic layers were washed with water (5 mL) , brine (5 mL) , dried over anhydrous Na
2SO
4 and filtered, the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10: 1) to give Compound 41-2 (172 mg, yield 52.2%) . MS: m/z: 426 [M+H]
+.
Compound 41-2 (172 mg, 0.41 mmol) , INT 3 (310 mg, 0.61 mmol) , Cs
2CO
3 (394 mg, 1.2 mmol) , cataCxiumA-Pd G3 (59 mg, 0.08 mmol) were added successively into toluene/water = 5: 1 (6 mL) , degassing the reaction with argon for 10 min. The mixture was heated to 120 ℃ under argon by microwave and stirred for 2.5 h. After that, the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL × 3) . The combined organic layers were washed with water (5 mL) , brine (5 mL) , dried with anhydrous Na
2SO
4 and filtered, the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH = 10: 1) to give Compound 41-3 (120 mg, yield 37.8%) . MS: m/z: 776 [M+H]
+.
To a solution of Compound 41-3 (120 mg, 0.15 mmol) in DCM (2.5 mL) was added HCl (4M in dioxane, 0.5 mL) at room temperature and stirred for 1 h. Then the reaction mixture was concentrated to give crude Compound 41-4 (130 mg, ) . MS: m/z: 732 [M+H]
+.
To a solution of Compound 41-4 (130 mg crude, 0.18 mmol) in DMF (2 mL) was added CsF (270 mg, 1.8 mmol) at room temperature. The reaction mixture was heated to 40 ℃ and stirred for 24 h. Then the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC to give Compound 41 (HCOOH salt, 15 mg, yield 16.4%for two steps) . MS: m/z: 576 [M+H]
+.
1H NMR (300 MHz, CD
3OD-d
4) : δ 9.22 (s, 1H) , 7.89-7.84 (m, 1H) , 7.36-7.25 (m, 2H) , 7.22 (s, 1H) , 5.40 (d, J = 68.0 Hz, 1H) , 4.42 (dd, J = 31.2 Hz, 2H) , 4.02-3.94 (m, 1H) , 3.71-3.68 (m, 1H) , 3.66-3.60 (m, 3H) , 3.50-3.48 (m, 4H) , 3.19-3.15 (m, 1H) , 2.60-2.10 (m, 6H) , 2.05-1.98 (m, 1H) , 1.10-1.00 (m, 6H) .
Example 42
To a solution of INT 1 (200 mg, 0.8 mmol) and DIEA (684 mg, 5.3 mmol) in DCM (4.0 mL) was added 3-methoxy-N-methylpropan-1-amine (82 mg, 0.8 mmol) at -40 ℃. The reaction mixture was stirred at -40 ℃for 1 h. Upon completion, H
2O (10 mL) was added to the reaction mixture, extracted with DCM (10 mL × 3) . The combined organic phases were dried over anhydrous Na
2SO
4 and concentrated to give a residue, purified by pre-TLC (petroleum ether/ethyl acetate=1: 2) to give Compound 42-1 (240 mg, 0.75 mmol, 93.75%yield) . MS: m/z: 319 [M+H]
+.
To a solution of Compound 42-1 (190 mg, 0.6 mmol) and INT 2 (191 mg, 1.2 mmol) in dioxane (1.9 mL) was added 4A Ms (95 mg) and DIEA (233 mg, 1.8 mmol) . The mixture was stirred at 85 ℃ overnight under N
2 atmosphere. Upon completion, water (10 mL) was added, then extracted with DCM (10 mL × 3) . The combined organic phases were dried over anhydrous Na
2SO
4. The solution was concentrated to give a residue, purified by pre-TLC (Dichloromethane/methanol = 10: 1) to give Compound 42-2 (250 mg, 0.56 mmol, 93.33%yield) . MS: m/z: 442 [M+H]
+.
Compound 42-2 (200 mg, 0.45 mmol) , INT 3 (277 mg, 0.54 mmol) , Cs
2CO
3 (440 mg, 1.35 mmol) and cataCxium A Pd G3 (66 mg, 0.09 mmol) were placed in the reaction bottle. A solution of toluene/H
2O (5/1, 12.0 mL) was added at room temperature. The mixture was stirred with microwave reaction at 120 ℃ for 2 h. Upon completion, water (10 mL) was added to the reaction mixture, extracted with EtOAc (10 mL × 3) , and the combined organic layers were washed with saturated brine (10 mL × 1) and dried over anhydrous sodium sulfate. The solution was concentrated to give a residue, purified by pre-TLC (dichloromethane/methanol=10: 1) to give Compound 42-3 (280 mg, 0.35 mmol, 77.8%yield) . MS: m/z: 792 [M+H]
+.
To a solution of Compound 42-3 (140 mg, 0.18 mmol) in ACN (8.0 mL) was added HCl (4M in dioxane, 1.5 mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 h. Then the reaction mixture was concentrated in vacuum to give crude Compound 42-4, which was used directly for the next step without any further purification. MS: m/z: 748 [M+H]
+.
To a solution of crude Compound 42-4 in DMF (6.8 mL) was added CsF (410 mg, 2.7 mmol) . The reaction mixture was stirred at 40 ℃ overnight. Then the reaction mixture was filtered and the filtrate was purified by Prep-HPLC to give Compound 42 (HCOOH salt, 102.7 mg, 0.16 mmol, 88.89%yield for two steps) . MS: m/z: 592 [M-FA+H]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 10.17 (s, 1H) , 9.17 (s, 1H) , 8.15 (s, 1H) , 7.97 (dd, J = 9.1, 5.9 Hz, 1H) , 7.55 –7.35 (m, 2H) , 7.17 (d, J = 1.9 Hz, 1H) , 5.28 (d, J = 53.9 Hz, 1H) , 4.23 –3.93 (m, 4H) , 3.81 (d, J = 6.7 Hz, 1H) , 3.55 –3.42 (m, 6H) , 3.26 (s, 3H) , 3.10 (d, J = 7.6 Hz, 2H) , 3.03 (s, 1H) , 2.84 (d, J = 6.1 Hz, 1H) , 2.14 (d, J = 5.0 Hz, 1H) , 2.08 –1.96 (m, 4H) , 1.87 –1.76 (m, 2H) .
Example 43
To a solution of INT 1 (200 mg, 0.71 mmol) in DCM (5 mL) was added DIEA (614 mg, 4.74 mmol) at room temperature. Then the mixture was cooled to -40 ℃ under argon and (1-methoxycyclopropyl) methanamine hydrochloride (98 mg, 0.71 mmol) was added dropwise. After that, the reaction mixture was stirred for 1 h at -40 ℃. Then the reaction mixture was quenched with water (4 mL) and extracted with DCM (8 mL) . The organic layer was washed with brine (5 mL) , dried over anhydrous Na
2SO
4 and concentrated to give crude Compound 43-1 (233 mg) and used directly for the next step without further purification. MS: m/z: 317 [M+H]
+.
To a solution of Compound 43-1 (300 mg, crude, 1.0 mmol) and INT 2 (300 mg, 1.89 mmol) in dioxane (6 mL) was added DIEA (366 mg, 2.83 mmol) and 4A MS at room temperature. Then the reaction mixture was heated to 85 ℃ and stirred overnight. After that, the mixture was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (5 mL × 3) . The combined organic layers were washed with water (5 mL) , brine (5 mL) , dried over anhydrous Na
2SO
4 and filtered, the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10: 1) to give Compound 43-2 (257 mg, 49.1%yield for two steps) . MS: m/z: 440 [M+H]
+.
Compound 43-2 (250 mg, 0.61 mmol) , INT 3 (435 mg, 0.85 mmol) , Cs
2CO
3 (555 mg, 1.71 mmol) , cataCxiumA-Pd G3 (45 mg, 0.057 mmol) were added successively into toluene/water = 5: 1 (10.8 mL) , degassing the reaction with argon for 10 min. The mixture was heated to 120 ℃ under argon by microwave and stirred for 3.5 h. After that, the mixture was cooled to room temperature, poured into water (10 mL) and extracted with EtOAc (10 mL × 3) . The combined organic layers were washed with water (10 mL) , brine (10 mL) , dried with anhydrous Na
2SO
4 and filtered, the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10: 1) to give Compound 43-3 (292 mg, 65.0%yield) . MS: m/z: 790 [M+H]
+.
To a solution of Compound 43-3 (300 mg, 0.38 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 1 mL) at room temperature and stirred for 1 h. Then the reaction mixture was concentrated to give crude Compound 43-4 (350 mg) . MS: m/z: 746 [M+H]
+.
To a solution of Compound 43-4 (350 mg crude, 0.38 mmol) in DMF (4 mL) was added CsF (865 mg, 5.70 mmol) at room temperature. The reaction mixture was heated to 40 ℃ and stirred for 24 h. Then the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC (FA) to give Compound 43 (HCOOH salt, 145 mg, yield 51.8%for two steps) . MS: m/z: 590 [M+H]
+.
1H NMR (400 MHz, CD
3OD-d
4) : δ 9.26 (s, 1H) , 8.50 (s, 1H) , 7.89-7.85 (m, 1H) , 7.36-7.31 (m, 2H) , 7.21-7.20 (m, 1H) , 5.52-5.39 (m, 1H) , 4.57-4.50 (m, 2H) , 3.99-3.93 (m, 2H) , 3.62-3.59 (m, 3H) , 3.44 (s, 3H) , 3.37 (s, 1H) , 3.31-3.29 (m, 1H) , 2.48-2.44 (m, 1H) , 2.42-2.38 (m, 1H) , 2.36-2.35 (m, 1H) , 2.30-2.20 (m, 2H) , 2.20 (s, 1H) , 0.93-0.92 (m, 2H) , 0.84-0.81 (m, 2H) .
Example 44
To a solution of INT 1 (250 mg, 1.0 mmol) in DCM (5 mL) was added DIEA (877 mg, 6.8 mmol) at room temperature. Then the mixture was cooled to -40 ℃ under argon and 2-methoxy-2-methylpropan-1-amine (103 mg, 1.0 mmol) in DCM (5 mL) was added drop wise. After that the reaction mixture was stirred for 1 h at -40 ℃. Then the reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL) . The organic layer was washed with brine (5 mL) , dried over anhydrous Na
2SO
4 and concentrated to give the residue, purified by Pre-TLC (eluted with petroleum ether/EtOAc=3: 1) to give Compound 44-1 (250 mg, 78.8%yield) . MS: m/z: 319 [M+H]
+.
To a solution of Compound 44-1 (200 mg, 0.6 mmol) and INT 2 (287 mg, 1.8 mmol) in dioxane (9.5 mL) was added DIEA (233 mg, 1.8 mmol) and 4A MS at room temperature. Then the reaction mixture was heated to 100 ℃ and stirred overnight under argon. After that the mixture was cooled to room temperature, poured into water (10 mL) and extracted with EtOAc (10 mL × 3) . The combined organic layers were washed with water (10 mL) , brine (10 mL) , dried over anhydrous Na
2SO
4 and filtered, the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10: 1) to give Compound 44-2 (180 mg, 68.3%yield) . MS: m/z: 442 [M+H]
+.
Compound 44-2 (150 mg, 0.34 mmol) , INT 3 (209 mg, 0.41 mmol) , Cs
2CO
3 (331 mg, 1.02 mmol) , cataCxiumA-Pd G3 (50 mg, 0.07 mmol) were added successively into Toluene/water=5: 1 (9 mL) , degassing the reaction with argon for 10 min. The mixture was heated to 120 ℃ under argon by microwave and stirred for 2 h. After that the mixture was cooled to room temperature, poured into water (10 mL) and extracted with EtOAc (10 mL × 3) . The combined organic layers were washed with water (20 mL) , brine (20 mL) , dried with anhydrous Na
2SO
4 and filtered, the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM/MeOH=10: 1) to give Compound 44-3 (130 mg, 48.0%yield) . MS: m/z: 792 [M+H]
+.
To a solution of Compound 44-3 (120 mg, 0.15 mmol) in DCM (4 mL) was added HCl (4 M in dioxane, 0.8 mL) at room temperature and stirred for 1 h. Then the reaction mixture was concentrated to give crude Compound 44-4 (140 mg) . MS: m/z: 748 [M+H]
+.
To a solution of crude Compound 44-4 in DMF (2 mL) was added CsF (343 mg, 2.3 mmol) at room temperature. The reaction mixture was heated to 40 ℃ and stirred for 3 h. Then the reaction mixture was filtered, and the filtrate was purified by Prep-HPLC of FA to give Compound 44 (HCOOH salt, 16 mg, 16.6%yield for two steps) . MS: m/z: 592 [M-FA+H]
+.
1H NMR (400 MHz, DMSO-d
6) : δ 10.25 (s, 1H) , 9.45 (s, 1H) , 8.78 (t, J = 5.9 Hz, 1H) , 8.04 (dd, J = 9.1, 6.0 Hz, 1H) , 7.53 (t, J = 9.0 Hz, 1H) , 7.45 (d, J = 2.2 Hz, 1H) , 7.21 (d, J = 1.7 Hz, 1H) , 5.35 (d, J = 53.9 Hz, 1H) , 4.21 –3.87 (m, 4H) , 3.61 (d, J = 3.3 Hz, 2H) , 3.28 (s, 3H) 3.19 –3.05 (m, 4H) , 2.95 –2.82 (m, 1H) , 2.24 –1.82 (m, 6H) , 1.28 (d, J = 2.7 Hz, 6H) .
Example 45
To a solution of INT 1 (251 mg, 994.21 μmol) and N, N-Diisopropylethylamine (0.4 mL) in DCM (10.0 mL) was added (S) -2-methoxypropan-1-amine hydrochloride (104 mg, 828.04 μmol) at 0 ℃. The reaction mixture was stirred for 1 hour at room temperature. Then the mixture was removed solvent and diluted with EA (30 mL) , washed with water (2 × 20 mL) and brine (20 mL) , the organic layers was dried over anhydrous Na
2SO
4 and concentrated in vacuum to give Compound 45-1 (292 mg, 956.95 μmol, 96.2%yield) . MS (ESI, m/z) : 305 [M+H]
+.
To a solution of Compound 45-1 (292 mg, 956.95 μmol) and INT 2 (325 mg, 2.04 mmol) in DMSO (8 mL) was added KF (174 mg, 2.99 mmol) at room temperature. The reaction mixture was stirred at 100 ℃ for 16 hours. The reaction mixture was quenched by sat. aq. NaHCO
3 (50 mL) and extracted with EA (2 × 50 mL) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (DCM: MeOH = 15: 1, v/v) to give Compound 45-2 (mg, 474.43 μmol, 49.5%yield) . MS (ESI, m/z) : 428 [M + H]
+.
A solution of Compound 45-2 (101 mg, 236.05 μmol) , INT 3 (180 mg, 351.19 μmol) , CataCXium A Pd G3 (20 mg, 27.46 μmol) , Cs
2CO
3 (252 mg, 773.43 μmol) in toluene (6 mL) and water (1.5 mL) was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The reaction was diluted with EA (50 mL) and washed with water (3 × 30 mL) . The organic layer was dried over anhydrous Na
2SO
4 and concentrated under vacuum. The residue was purified by Pre-TLC (DCM: MeOH = 15: 1, v/v) to give Compound 45-3 (157 mg, 201.80 μmol, 85.4%yield) . MS (ESI, m/z) : 778 [M + H]
+.
To a solution of Compound 45-3 (157 mg, 201.80 μmol) in CH
3CN (6 mL) was added HCl (4 M in 1, 4-dioxane, 2 mL) . The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EA (50 mL) , washed with sat. aq. NaHCO
3 (3 × 30 mL) . The organic layer was dried over anhydrous Na
2SO
4 and concentrated under reduced pressure to give Compound 45-4 (154 mg, 209.82 μmol, 103.9%yield) . MS (ESI, m/z) : 734 [M+H]
+.
To a solution of Compound 45-4 (154 mg, 209.82 μmol) in DMF (3 mL) was added CsF (0.53 g, 3.48 mmol) and the reaction mixture was stirred at 40 ℃ for 16 hours. The resulting mixture was concentrated under reduced pressure and the residue was purified by Pre-HPLC (YMC-Triart C18-S12nm column, 50 × 250 mm, 7 μm, A: 0.1%TFA in water, B: CH
3CN, Gradient: 15%B to 60%B in 33 min at a flow rate of 70 mL/min, 240 nm) to give Compound 45 (TFA salt, 94 mg, 135.91 μmol, 64.7%yield) . MS (ESI, m/z) : 578 [M+H]
+.
The following compounds in the Table 2 were synthesized using the above procedures or modification procedures:
Table 2
Pharmacological Experiments
1. SOS1 catalyzed nucleotide exchange assay
The inhibition activity of each of compounds on GDP form K-Ras was evaluated by SOS1 catalyzed nucleotide exchange assays. K-Ras G12D, K-Ras G12V, K-Ras G12C, K-Ras G13D, K-Ras G12A, K-Ras G12R, K-Ras Q61H and K-Ras WT proteins were used in this assay.
Briefly, K-Ras (His tag, aa 1-169) pre-loaded with GDP was pre-incubated with each of compounds in the presence of 10 nM GDP in a 384-well plate (Greiner) for 15-60 mins, then purified SOS1 ExD (Flag tag, aa 564-1049) , BODIPY
TM FL GTP (Invitrogen) and monoclonal antibody anti 6HIS-Tb cryptate Gold (Cisbio) were added to the assay wells and incubated for 4 hours at 25 ℃ (Specially, we did not add SOS1 in the K-Ras G13D assay) . Wells containing same percent of DMSO served as vehicle control, and wells without K-Ras served as low control. TR-FRET signals were read on Tecan Spark multimode microplate reader. The parameters were F486: Excitation 340nm, Emission 486 nm, Lag time 100 μs, Integration time 200 μs; F515: Excitation 340nm, Emission 515nm, Lag time 100 μs, Integration time 200 μs. TR-FRET ratios for each individual wells were calculated by equation: TR-FRET ratio = (Signal F515/Signal F486) *10000. The percent of activation of compounds treated wells were normalized between vehicle control and low control (% Activation = (TR-FRET ratio
Compound treated –TR-FRET ratio
Low control) / (TR-FRET ratio
Vehicle control –TR-FRET ratio
Low control) *100%) . Then the data were analyzed either by fitting a 4-parameter logistic model or by Excel to calculate IC
50 values. The results are shown in the following Table 3.
2. GTP-K-Ras and cRAF interaction assay
The inhibition activity of each of compounds on GTP form K-Ras was evaluated by GppNp-K-Ras and cRAF interaction assays. GppNp is an analog of GTP. K-Ras G12D, K-Ras G12V, K-Ras G12C, K-Ras G13D, K-Ras G12A, K-Ras G12R, K-Ras Q61H and K-Ras WT proteins were used in this assay.
Briefly, K-Ras (His tag, aa 1-169) pre-loaded with GppNp was pre-incubated with each of compounds in the presence of 200 μM GTP in a 384-well plate (Greiner) for 15-60 mins, then cRAF RBD (GST tag, aa 50-132, CreativeBioMart) , monoclonal antibody anti GST-d2 (Cisbio) and monoclonal antibody anti 6HIS-Tb cryptate Gold (Cisbio) were added to the assay wells and incubated for 2 hours at 25 ℃. Wells containing same percent of DMSO served as vehicle control, and wells without K-Ras served as low control. HTRF signals were read on Tecan Spark multimode microplate reader and HTRF ratios were calculated under manufacturer's instructions. The percent of activation of compounds treated wells were normalized between vehicle control and low control (%Activation = (HTRF ratio
Compound treated –HTRF ratio
Low control) / (HTRF ratio
Vehicle control –HTRF ratio
Low control) *100%) . Then the data were analyzed either by fitting a 4-parameter logistic model or by Excel to calculate IC
50 values. The results are shown in the following Table 3.
Table 3
3. Phospho-ERK1/2 (THR202/TYR204) HTRF assay
p-ERK (MAPK pathway) inhibition activity of each of compounds in a varity of K-Ras mutant and K-Ras WT cell lines indicated in Table 4 was evaluated. MKN-1 with K-Ras WT amplification is also a K-Ras dependent cell line.
Table 4
Each of cells in culture medium was seeded in 96-well plates at density indicated in Table 4 and then put in a cell incubator to incubate overnight. The next day, the culture medium was removed and the compound diluted in assay medium was added in each well. After 2 hours incubation in a cell incubator, the assay medium in 96-well plates was removed, then 50 μL of 1X blocking reagent-supplemented lysis buffer (Cisbio) was added and the plates were incubated at 25℃ for 45 min with shaking. 10 μL of cell lysates from the 96-well plates were transferred to a 384-well plate (Greiner) containing 2.5 μL/well
pre-mixed antibodies (Cisbio 64AERPEH) . The plate was incubated 4 hours at 25 ℃ and then read HTRF signals on Tecan Spark multimode microplate reader. The data were analyzed using a 4-parameter logistic model to calculate IC
50 values. The results are shown in the following Table 5:
Table 5
4. Cell growth inhibition assay
The cell growth inhibition activity of each of compounds was tested by performing cell growth inhibition assays on a variety of K-Ras mutant and K-Ras WT cell lines indicated in Table 6.
Table 6
2D cell growth inhibition assays
Each of cells in culture medium was plated in TC-treated 96-well plates at a density indicated in Table 6 and incubated in a cell incubator overnight. The next day, each of compounds was diluted in culture medium and added to the plates. After 6 days incubation in cell incubator, the cell viability was detected by CellTiter-
Cell Viability Assay kit (Promega) . Luminescent signals were read on Tecan Spark multimode microplate reader and analyzed using a 4-parameter logistic model to calculate absolute IC
50 values. The results are shown in the following Table 7.
3D cell growth inhibition assays
Each of cells in culture medium was plated in ultra-low attachment-coated 96-well plates at a density indicated in Table 6 and incubated in a cell incubator overnight. The next day, each of compounds was diluted in culture medium and added to the plates. After 6 days incubation in cell incubator, the cell viability was detected by
3D Cell Viability Assay kit (Promega) . Luminescent signals were read on Tecan Spark multimode microplate reader and analyzed using a 4-parameter logistic model to calculate absolute IC
50 values. The results are shown in the following Table 7.
Table 7
Claims (48)
- A compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof:Wherein,Y 1 is selected from a bond, O, NR 1a, S, S (=O) or S (=O) 2;R 1a is selected from hydrogen, deuterium, -C 1-10alkyl, haloC 1-10alkyl, haloC 1-10alkoxy, -C 2-10alkenyl, haloC 2-10alkenyl, -C 2-10alkynyl, haloC 2-10alkynyl, -N (R 1b) 2, -OR 1b, -SR 1b, 3-10 membered cycloalkyl, 3-10 membered hetrocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-10alkyl, haloC 1-10alkyl, haloC 1-10alkoxy, -C 2-10alkenyl, -C 2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered hetrocycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -N (R 1c) 2, -OR 1c, -SR 1c, -S (=O) R 1d, -S (=O) 2R 1d, -C (=O) R 1d, -C (=O) OR 1c, -OC (=O) R 1d, -C (=O) N (R 1c) 2, -NR 1cC (=O) R 1d, -OC (=O) OR 1c, -NR 1cC (=O) OR 1d, -OC (=O) N (R 1c) 2, -NR 1cC (=O) N (R 1c) 2, -S (=O) OR 1c, -OS (=O) R 1d, -S (=O) N (R 1c) 2, -NR 1cS (=O) R 1d, -S (=O) 2OR 1c, -OS (=O) 2R 1d, -S (=O) 2N (R 1c) 2, -NR 1cS (=O) 2R 1d, -OS (=O) 2OR 1c, -NR 1cS (=O) 2OR 1c, -OS (=O) 2NR 1c, -NR 1cS (=O) 2N (R 1c) 2, -P (R 1c) 2, -P (=O) (R 1d) 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;L 1 is selected from a bond or C 1-10 alkylene optionally substituted with one or more R Z11;X 1 is selected from hydrogen, deuterium, -C 1-10alkyl, halogen, -OR 11, -N (R 11) 2, -SR 11, -CN, -S (=O) R 12, -C (=O) R 12, -S (=O) 2R 12, -C (=O) OR 11, -OC (=O) R 12, -NR 11C (=O) R 12, -C (=O) N (R 11) 2, -NR 11S (=O) R 12, -S (=O) 2N (R 11) 2, -NR 11S (=O) 2R 12, -S (=O) 2N (R 11) 2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, said -C 1-10 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with one or more R S1;R S1 at each occurrence is independently selected from deuterium, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, haloC 2-6alkenyl, -C 2-6alkynyl, haloC 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -N (R 13) 2, -OR 13, -SR 13, -S (=O) R 14, -S (=O) 2R 14, -C (=O) R 14, -C (=O) OR 13, -OC (=O) R 14, -C (=O) N (R 13) 2, -NR 13C (=O) R 14, -OC (=O) OR 13, -NR 13C (=O) OR 13, -NR 13C (=S) OR 13, -OC (=O) N (R 13) 2, -NR 13C (=O) N (R 13) 2, -S (=O) OR 13, -OS (=O) R 14, -S (=O) N (R 13) 2, -NR 13S (=O) R 14, -S (=O) 2OR 13, -OS (=O) 2R 14, -S (=O) 2N (R 13) 2, -NR 13S (=O) 2R 14, -OS (=O) 2OR 13, -NR 13S (=O) 2OR 13, -OS (=O) 2N (R 13) 2, -NR 13S (=O) 2N (R 13) 2, -P (R 13) 2, -P (=O) (R 14) 2, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein said -C 1-6alkyl, haloC 1- 6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, haloC 2-6alkenyl, -C 2-6alkynyl, haloC 2-6alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 3-8 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, haloC 2-6alkenyl, -C 2-6alkynyl, haloC 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -N (R 15) 2, -OR 15, -SR 15, -S (=O) R 16, -S (=O) 2R 16, -C (=O) R 16, -C (=O) OR 15, -OC (=O) R 16, -C (=O) N (R 15) 2, -NR 15C (=O) R 16, -OC (=O) OR 15, -NR 15C (=O) OR 15, -NR 15C (=S) OR 15, -OC (=O) N (R 15) 2, -NR 15C (=O) N (R 15) 2, -S (=O) OR 15, -OS (=O) R 16, -S (=O) N (R 15) 2, -NR 15S (=O) R 16, -S (=O) 2OR 15, -OS (=O) 2R 16, -S (=O) 2N (R 16) 2, -NR 15S (=O) 2R 16, -OS (=O) 2OR 15, -NR 15S (=O) 2OR 15, -OS (=O) 2N (R 15) 2, -NR 15S (=O) 2N (R 15) 2, -P (R 15) 2, -P (=O) (R 16) 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;Optionally, two R S1 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 membered carbocylic ring or 3-10 heterocyclic ring is optionally substituted with one or more R Z12;Optionally, two adjacent R S1 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently optionally substituted with one or more R Z13;Optionally, two nonadjacent R S1 are connected together to form a bridge containing 0, 1, 2, 3, 4, 5 or 6 carbon atoms, wherein, each of the carbon atoms in the bridge is optionally replaced by 1 or 2 heteroatoms selected from N, O, S, S=O or S (=O) 2; the hydrogen on the each of carbon atoms or N atoms is optionally independently substituted with R Z14;Y 2 is a bond, O, S, S (=O) , S (=O) 2 or NR 2a;R 2 is selected from -L 20- (3-12 membered heterocyclyl) , -L 20- (3-12 membered cycloalkyl) , -L 20- (6-12 membered aryl) , -L 20- (5-12 membered heteroaryl) , -L 20-N (R 2b) 2,Each of L 20 at each occurrence is independently selected from a bond or C 1-10 alkylene optionally substituted with one or more R Z21;Said 3-12 membered heterocyclyl in -L 20- (3-12 membered heterocyclyl) is optionally substituted with one or more R Z22;Said 3-12 membered cycloalkyl in -L 20- (3-12 membered cycloalkyl) is optionally substituted with one or more R Z22;Said 6-12 membered aryl in -L 20- (6-12 membered aryl) is optionally substituted with one or more R Z22;Said 5-12 membered heteroaryl in -L 20- (5-12 membered heteroaryl) is optionally substituted with one or more R Z22;L 21 is selected from a bond or C 1-10 alkylene optionally substituted with one or more R Z23;Ring B or ring C is a 3-10 membered heterocyclic ring optionally further containing 1, 2, or 3 heteroatoms selected from N, O or S;R S21 at each occurrence is independently selected from deuterium, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, haloC 2-6alkenyl, -C 2-6alkynyl, haloC 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -N (R 21) 2, -OR 21, -SR 21, -S (=O) R 22, -S (=O) 2R 22, -C (=O) R 22, -C (=O) OR 21, -OC (=O) R 22, -C (=O) N (R 21) 2, -NR 21C (=O) R 22, -OC (=O) OR 21, -NR 21C (=O) OR 21, -NR 21C (=S) OR 21, -OC (=O) N (R 21) 2, -NR 21C (=O) N (R 21) 2, -S (=O) OR 21, -OS (=O) R 22, -S (=O) N (R 21) 2, -NR 21S (=O) R 22, -S (=O) 2OR 21, -OS (=O) 2R 22, -S (=O) 2N (R 21) 2, -NR 21S (=O) 2R 22, -OS (=O) 2OR 21, -NR 21S (=O) 2OR 21, -OS (=O) 2N (R 21) 2, -NR 21S (=O) 2N (R 21) 2, -P (R 21) 2, -P (=O) (R 22) 2, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 4-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl; wherein said -C 1-6alkyl, haloC 1- 6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, haloC 2-6alkenyl, -C 2-6alkynyl, haloC 2-6alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered cycloalkynyl, 3-8 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, haloC 2-6alkenyl, -C 2-6alkynyl, haloC 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -N (R 23) 2, -OR 23, -SR 23, -S (=O) R 24, -S (=O) 2R 24, -C (=O) R 24, -C (=O) OR 23, -OC (=O) R 24, -C (=O) N (R 23) 2, -NR 23C (=O) R 24, -OC (=O) OR 23, -NR 23C (=O) OR 24, -NR 23C (=S) OR 23, -OC (=O) N (R 23) 2, -NR 23C (=O) N (R 23) 2, -S (=O) OR 23, -OS (=O) R 24, -S (=O) N (R 23) 2, -NR 23S (=O) R 24, -S (=O) 2OR 23, -OS (=O) 2R 24, -S (=O) 2N (R 23) 2, -NR 23S (=O) 2R 24, -OS (=O) 2OR 23, -NR 23S (=O) 2OR 23, -OS (=O) 2N (R 23) 2, -NR 23S (=O) 2N (R 23) 2, -P (R 23) 2, -P (=O) (R 24) 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;Optionally, two R S21 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said 3-10 membered carbocylic ring or 3-10 heterocyclic ring is optionally substituted with one or more R Z24;Optionally, two adjacent R S21 together with the carbon atoms to which they are respectively attached form a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, wherein, each of rings is independently optionally substituted with one or more R Z25;Optionally, two nonadjacent R S21 are connected together to form a bridge containing 0, 1, 2, 3, 4, 5 or 6 carbon atoms, wherein, each of the carbon atoms in the bridge is optionally replaced by 1 or 2 heteroatoms selected from N, O, S, S=O or S (=O) 2; the hydrogen on the each of carbon atoms or N atoms is optionally independently substituted with R Z26;q 21 is selected from 0, 1, 2, 3, 4, 5 or 6;L 22 is selected from a bond or C 1-10 alkylene optionally substituted with one or more R Z27;Ring D is selected from a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein the moiety of -L 22-and -L 23-X 2 are attached to the same atom or different atoms of the ring D;L 23 is selected from a bond or C 1-10 alkylene optionally substituted with one or more R Z28;X 2 is selected from -N (R 25) 2, -OR 25, -SR 25, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein said 3-10 membered heterocyclyl or 5-10 membered heteroaryl is optionally independently substituted with one or more R Z29;Each of R S22 at each occurrence is independently selected from deuterium, halogen, -C 1-6alkyl, haloC 1- 6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, haloC 2-6alkenyl, -C 2-6alkynyl, haloC 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -N (R 26) 2, -OR 26, -SR 26, -S (=O) R 27, -S (=O) 2R 27, -C (=O) R 27, -C (=O) OR 26, -OC (=O) R 27, -C (=O) N (R 26) 2, -NR 26C (=O) R 27, -OC (=O) OR 26, -NR 26C (=O) OR 26, -OC (=O) N (R 26) 2, -NR 26C (=O) N (R 26) 2, -S (=O) OR 26, -OS (=O) R 27, -S (=O) N (R 26) 2, -NR 26S (=O) R 27, -S (=O) 2OR 26, -OS (=O) 2R 27, -S (=O) 2N (R 26) 2, -NR 26S (=O) 2R 27, -OS (=O) 2OR 26, -NR 26S (=O) 2OR 26, -OS (=O) 2N (R 26) 2, -NR 26S (=O) 2N (R 26) 2, -P (R 26) 2, -P (=O) (R 26) 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2- 6alkenyl, haloC 2-6alkenyl, -C 2-6alkynyl, haloC 2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, haloC 2-6alkenyl, -C 2-6alkynyl, haloC 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -N (R 28) 2, -OR 28, -SR 28, -S (=O) R 29, -S (=O) 2R 29, -C (=O) R 29, -C (=O) OR 28, -OC (=O) R 29, -C (=O) N (R 28) 2, -NR 28C (=O) R 29, -OC (=O) OR 28, -NR 28C (=O) OR 28, -OC (=O) N (R 28) 2, -NR 28C (=O) N (R 28) 2, -S (=O) OR 28, -OS (=O) R 29, -S (=O) N (R 28) 2, -NR 28S (=O) R 29, -S (=O) 2OR 28, -OS (=O) 2R 29, -S (=O) 2N (R 28) 2, -NR 28S (=O) 2R 29, -OS (=O) 2OR 28, -NR 28S (=O) 2OR 28, -OS (=O) 2N (R 28) 2, -NR 28S (=O) 2N (R 28) 2, -P (R 28) 2, -P (=O) (R 29) 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;q 22 is selected from 0, 1, 2, 3, 4, 5 or 6;R 3 is independently selected from hydrogen, deuterium, halogen, -C 1-10alkyl, haloC 1-10alkyl, haloC 1- 10alkoxy, -C 2-10alkenyl, haloC 2-10alkenyl, -C 2-10alkynyl, haloC 2-10alkynyl, -CN, -NO 2, -N 3, oxo, -N (R 31) 2, -OR 31, -SR 31, -S (=O) R 32, -S (=O) 2R 32, -C (=O) R 32, -C (=O) OR 31, -OC (=O) R 32, -C (=O) N (R 31) 2, -NR 31C (=O) R 32, -OC (=O) OR 31, -NR 31C (=O) OR 31, -OC (=O) N (R 31) 2, -NR 31C (=O) N (R 31) 2, -S (=O) OR 31, -OS (=O) R 32, -S (=O) N (R 31) 2, -NR 31S (=O) R 32, -S (=O) 2OR 31, -OS (=O) 2R 32, -S (=O) 2N (R 31) 2, -NR 31S (=O) 2R 32, -OS (=O) 2OR 31, -NR 31S (=O) 2OR 31, -OS (=O) 2N (R 31) 2, -NR 31S (=O) 2N (R 31) 2, -P (R 31) 2, -P (=O) (R 32) 2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-10alkyl, haloC 1-10alkyl, haloC 1-10alkoxy, -C 2-10alkenyl, haloC 2- 10alkenyl, -C 2-10alkynyl, haloC 2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C 1- 6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, haloC 2-6alkenyl, -C 2-6alkynyl, haloC 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -N (R 33) 2, -OR 33, -SR 33, -S (=O) R 34, -S (=O) 2R 34, -C (=O) R 34, -C (=O) OR 33, -OC (=O) R 34, -C (=O) N (R 33) 2, -NR 33C (=O) R 34, -OC (=O) OR 33, -NR 33C (=O) OR 33, -OC (=O) N (R 33) 2, -NR 33C (=O) N (R 33) 2, -S (=O) OR 33, -OS (=O) R 34, -S (=O) N (R 33) 2, -NR 33S (=O) R 34, -S (=O) 2OR 33, -OS (=O) 2R 34, -S (=O) 2N (R 33) 2, -NR 33S (=O) 2R 34, -OS (=O) 2OR 33, -NR 33S (=O) 2OR 33, -OS (=O) 2N (R 33) 2, -NR 33S (=O) 2N (R 33) 2, -P (R 33) 2, -P (=O) (R 34) 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;R 4 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, wherein said 6-10 membered aryl, 5-10 membered heteroaryl, is optionally independently substituted with one or more R S4;Z at each occurrence is independently selected from C or N;Ring E at each occurrence is independently selected from a 6 membered aryl ring or a 5-6 membered heteroaryl ring and ring F at each occurrence is a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring when Z is selected from C;Ring E at each occurrence is selected from a 5-6 membered heteroaryl ring and ring F at each occurrence is a 3-10 membered heterocyclic ring when Z is selected from N;R S4 at each occurrence is independently selected from deuterium, halogen, -C 1-10alkyl, haloC 1-10alkyl, haloC 1-10alkoxy, -C 2-10alkenyl, haloC 2-10alkenyl, -C 2-10alkynyl, haloC 2-10alkynyl, -CN, -NO 2, -N 3, oxo, -N (R 41) 2, -OR 41, -SR 41, -S (=O) R 42, -S (=O) 2R 42, -C (=O) R 42, -C (=O) OR 41, -OC (=O) R 42, -C (=O) N (R 41) 2, -NR 41C (=O) R 42, -OC (=O) OR 41, -NR 41C (=O) OR 41, -OC (=O) N (R 41) 2, -NR 41C (=O) N (R 41) 2, -S (=O) OR 41, -OS (=O) R 42, -S (=O) N (R 41) 2, -NR 41S (=O) R 42, -S (=O) 2OR 41, -OS (=O) 2R 42, -S (=O) 2N (R 41) 2, -NR 41S (=O) 2R 42, -OS (=O) 2OR 41, -NR 41S (=O) 2OR 41, -OS (=O) 2N (R 41) 2, -NR 41S (=O) 2N (R 41) 2, -P (R 41) 2, -P (=O) (R 42) 2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, wherein said -C 1-10alkyl, haloC 1-10alkyl, haloC 1- 10alkoxy, -C 2-10alkenyl, haloC 2-10alkenyl, -C 2-10alkynyl, haloC 2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more R 4b;R 4b at each occurrence is independently selected from deuterium, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, haloC 2-6alkenyl, -C 2-6alkynyl, haloC 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -N (R 43) 2, -OR 43, -SR 43, -S (=O) R 44, -S (=O) 2R 44, -C (=O) R 44, -C (=O) OR 43, -OC (=O) R 44, -C (=O) N (R 43) 2, -NR 43C (=O) R 44, -OC (=O) OR 43, -NR 43C (=O) OR 43, -OC (=O) N (R 43) 2, -NR 43C (=O) N (R 43) 2, -S (=O) OR 43, -OS (=O) R 44, -S (=O) N (R 43) 2, -NR 43S (=O) R 44, -S (=O) 2OR 43, -OS (=O) 2R 44, -S (=O) 2N (R 43) 2, -NR 43S (=O) 2R 44, -OS (=O) 2OR 43, -NR 43S (=O) 2OR 43, -OS (=O) 2N (R 43) 2, -NR 43S (=O) 2N (R 43) 2, -P (R 43) 2, -P (=O) (R 44) 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;R 5 is independently selected from hydrogen, deuterium, halogen, -C 1-10alkyl, haloC 1-10alkyl, haloC 1- 10alkoxy, -C 2-10alkenyl, haloC 2-10alkenyl, -C 2-10alkynyl, haloC 2-10alkynyl, -CN, -NO 2, -N 3, oxo, -N (R 51) 2, -OR 51, -SR 51, -S (=O) R 52, -S (=O) 2R 52, -C (=O) R 52, -C (=O) OR 51, -OC (=O) R 52, -C (=O) N (R 51) 2, -NR 81C (=O) R 52, -OC (=O) OR 51, -NR 81C (=O) OR 51, -OC (=O) N (R 51) 2, -NR 51C (=O) N (R 51) 2, -S (=O) OR 51, -OS (=O) R 52, -S (=O) N (R 51) 2, -NR 51S (=O) R 52, -S (=O) 2OR 51, -OS (=O) 2R 52, -S (=O) 2N (R 51) 2, -NR 51S (=O) 2R 52, -OS (=O) 2OR 51, -NR 51S (=O) 2OR 51, -OS (=O) 2N (R 51) 2, -NR 51S (=O) 2N (R 51) 2, -P (R 51) 2, -P (=O) (R 52) 2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-10alkyl, haloC 1-10alkyl, haloC 1-10alkoxy, -C 2-10alkenyl, haloC 2- 10alkenyl, -C 2-10alkynyl, haloC 2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C 1- 6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, haloC 2-6alkenyl, -C 2-6alkynyl, haloC 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -N (R 53) 2, -OR 53, -SR 53, -S (=O) R 54, -S (=O) 2R 54, -C (=O) R 54, -C (=O) OR 53, -OC (=O) R 54, -C (=O) N (R 53) 2, -NR 53C (=O) R 54, -OC (=O) OR 53, -NR 53C (=O) OR 53, -OC (=O) N (R 53) 2, -NR 53C (=O) N (R 53) 2, -S (=O) OR 53, -OS (=O) R 54, -S (=O) N (R 53) 2, -NR 53S (=O) R 54, -S (=O) 2OR 53, -OS (=O) 2R 54, -S (=O) 2N (R 53) 2, -NR 53S (=O) 2R 54, -OS (=O) 2OR 53, -NR 53S (=O) 2OR 53, -OS (=O) 2N (R 53) 2, -NR 53S (=O) 2N (R 53) 2, -P (R 53) 2, -P (=O) (R 54) 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;Each of (R 11, R 13, R 15, R 21, R 23, R 25, R 26, R 28, R 31, R 33, R 41, R 43, R 51 and R 53) at each occurrence is independently selected from hydrogen, deuterium, halogen, -C 1-10alkyl, haloC 1-10alkyl, -C 2-10alkenyl, -C 2- 10alkynyl, -S (=O) R a, -S (=O) 2R a, -C (=O) R a, -C (=O) OR a, -C (=O) N (R a) 2, -S (=O) OR a, -S (=O) N (R a) 2, -S (=O) 2OR a, -S (=O) 2N (R a) 2, -P (=O) (R a) 2, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-10alkyl, haloC 1-10alkyl, -C 2-10alkenyl, -C 2-10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -N (R c) 2, -OR c, -SR c, -S (=O) R d, -S (=O) 2R d, -C (=O) R d, -C (=O) OR c, -OC (=O) R d, -C (=O) N (R c) 2, -NR cC (=O) R d, -OC (=O) OR c, -NR cC (=O) OR d, -OC (=O) N (R c) 2, -NR cC (=O) N (R c) 2, -S (=O) OR c, -OS (=O) R d, -S (=O) N (R c) 2, -NR cS (=O) R d, -S (=O) 2OR c, -OS (=O) 2R d, -S (=O) 2N (R c) 2, -NR cS (=O) 2R d, -OS (=O) 2OR c, -NR cS (=O) 2OR c, -OS (=O) 2NR c, -NR cS (=O) 2N (R c) 2, -P (R c) 2, -P (=O) (R d) 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;Optionally, each of (two R 11, two R 13, two R 15, two R 21, two R 23, two R 25, two R 26, two R 28, two R 31, two R 33, two R 41, two R 43, two R 51, and two R 53) independently together with the nitrogen atom to which they are both attached forms a 3-20 membered heterocyclic ring or a 5-10 membered heteroaryl ring, wherein, said 3-20 membered heterocyclic ring or 5-10 membered heteroaryl ring is optionally independently substituted with one or more R Za;Each of (R 12, R 14, R 16, R 22, R 24, R 27, R 29, R 32, R 34, R 42, R 44, R 52 and R 54) at each occurrence is independently selected from hydrogen, deuterium, -C 1-10alkyl, haloC 1-10alkyl, haloC 1-10alkoxy, -C 2-10alkenyl, haloC 2-10alkenyl, -C 2-10alkynyl, haloC 2-10alkynyl, -N (R b) 2, -OR b, -SR b, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-10alkyl, haloC 1-10alkyl, haloC 1-10alkoxy, -C 2-10alkenyl, -C 2- 10alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1- 6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -N (R c) 2, -OR c, -SR c, -S (=O) R d, -S (=O) 2R d, -C (=O) R d, -C (=O) OR c, -OC (=O) R d, -C (=O) N (R c) 2, -NR cC (=O) R d, -OC (=O) OR c, -NR cC (=O) OR d, -OC (=O) N (R c) 2, -NR cC (=O) N (R c) 2, -S (=O) OR c, -OS (=O) R d, -S (=O) N (R c) 2, -NR cS (=O) R d, -S (=O) 2OR c, -OS (=O) 2R d, -S (=O) 2N (R c) 2, -NR cS (=O) 2R d, -OS (=O) 2OR c, -NR cS (=O) 2OR c, -OS (=O) 2NR c, -NR cS (=O) 2N (R c) 2, -P (R c) 2, -P (=O) (R d) 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;Each of (R a, R b, R c, R d, R 1b, R 1c, R 1d, R 2a and R 2b) at each occurrence is independently selected from hydrogen, deuterium, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2- 6alkenyl, -C 2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally independently substituted with one or more R Zb;Optionally, each of (two R a, two R b, two R c, two R 1b, two R 1c, two R 2a and two R 2b) independently together with the atom to which they are both attached forms a 3-6 membered heterocyclic ring, wherein said 3-6 membered heterocyclic ring is independently optionally substituted with one or more R Zc;Each of (R Z11, R Z12, R Z13, R Z14, R Z21, R Z22, R Z23, R Z24, R Z25, R Z26, R Z27, R Z28, R Z29, R Za, R Zb and R Zc) at each occurrence is independently selected from deuterium, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1- 6alkyl) C (=O) (C 1-6alkyl) , -OC (=O) O (C 1-6alkyl) , -NHC (=O) (OC 1-6alkyl) , -N (C 1-6alkyl) C (=O) (OC 1-6alkyl) , -OC (=O) NH (C 1-6alkyl) , -OC (=O) N (C 1-6alkyl) 2, -NHC (=O) NH 2, -NHC (=O) NH (C 1-6alkyl) , -NHC (=O) N (C 1- 6alkyl) 2, -N (C 1-6alkyl) C (=O) NH 2, -N (C 1-6alkyl) C (=O) NH (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) N (C 1-6alkyl) 2, -S (=O) (OC 1-6alkyl) , -OS (=O) (C 1-6alkyl) , -S (=O) NH 2, -S (=O) NH (C 1-6alkyl) , -S (=O) N (C 1-6alkyl) 2, -NHS (=O) (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) (C 1-6alkyl) , -S (=O) 2 (OC 1-6alkyl) , -OS (=O) 2 (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , -OS (=O) 2O (C 1-6alkyl) , -NHS (=O) 2O (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2O (C 1-6alkyl) , -OS (=O) 2NH 2, -OS (=O) 2NH (C 1-6alkyl) , -OS (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2NH 2, -NHS (=O) 2NH (C 1-6alkyl) , -NHS (=O) 2N (C 1- 6alkyl) 2, -N (C 1-6alkyl) S (=O) 2NH 2, -N (C 1-6alkyl) S (=O) 2NH (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2N (C 1-6alkyl) 2, -PH (C 1-6alkyl) , -P (C 1-6alkyl) 2, -P (=O) H (C 1-6alkyl) , -P (=O) (C 1-6alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from deuterium, halogen, -C 1-3alkyl, haloC 1-3alkyl, haloC 1-3alkoxy, -C 2-3alkenyl, -C 2-3alkynyl, -CN, -NO 2, -N 3, oxo, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl) 2, -OH, -O (C 1-3alkyl) , -SH, -S (C 1-3alkyl) , -S (=O) (C 1-3alkyl) , -S (=O) 2 (C 1-3alkyl) , -C (=O) (C 1-3alkyl) , -C (=O) OH, -C (=O) (OC 1-3alkyl) , -OC (=O) (C 1-3alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-3alkyl) , -C (=O) N (C 1-3alkyl) 2, -NHC (=O) (C 1-3alkyl) , -N (C 1-3alkyl) C (=O) (C 1-3alkyl) , -OC (=O) O (C 1-3alkyl) , -NHC (=O) (OC 1-3alkyl) , -N (C 1-3alkyl) C (=O) (OC 1-3alkyl) , -OC (=O) NH (C 1-3alkyl) , -OC (=O) N (C 1-3alkyl) 2, -NHC (=O) NH 2, -NHC (=O) NH (C 1-3alkyl) , -NHC (=O) N (C 1-3alkyl) 2, -N (C 1- 3alkyl) C (=O) NH 2, -N (C 1-3alkyl) C (=O) NH (C 1-3alkyl) , -N (C 1-3alkyl) C (=O) N (C 1-3alkyl) 2, -S (=O) (OC 1-3alkyl) , -OS (=O) (C 1-3alkyl) , -S (=O) NH 2, -S (=O) NH (C 1-3alkyl) , -S (=O) N (C 1-3alkyl) 2, -NHS (=O) (C 1-3alkyl) , -N (C 1- 3alkyl) S (=O) (C 1-3alkyl) , -S (=O) 2 (OC 1-3alkyl) , -OS (=O) 2 (C 1-3alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-3alkyl) , -S (=O) 2N (C 1-3alkyl) 2, -NHS (=O) 2 (C 1-3alkyl) , -N (C 1-3alkyl) S (=O) 2 (C 1-3alkyl) , -OS (=O) 2O (C 1-3alkyl) , -NHS (=O) 2O (C 1-3alkyl) , -N (C 1-3alkyl) S (=O) 2O (C 1-3alkyl) , -OS (=O) 2NH 2, -OS (=O) 2NH (C 1-3alkyl) , -OS (=O) 2N (C 1-3alkyl) 2, -NHS (=O) 2NH 2, -NHS (=O) 2NH (C 1-3alkyl) , -NHS (=O) 2N (C 1-3alkyl) 2, -N (C 1- 3alkyl) S (=O) 2NH 2, -N (C 1-3alkyl) S (=O) 2NH (C 1-3alkyl) , -N (C 1-3alkyl) S (=O) 2N (C 1-3alkyl) 2, -PH (C 1-3alkyl) , -P (C 1-3alkyl) 2, -P (=O) H (C 1-3alkyl) , -P (=O) (C 1-3alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6 membered aryl or 5-6 membered heteroaryl;Each of (heterocyclyl and heteroaryl) at each occurrence is independently contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, S (=O) or S (=O) 2.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 1, wherein,Y 1 is selected from a bond, O, or NR 1a;R 1a is selected from hydrogen, deuterium, or -C 1-3alkyl;L 1 is selected from a bond or C 1-3 alkylene; said C 1-3alkylene is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C 1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;X 1 is selected from -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkyl, -C 2-6alkenyl, -C 2-6alkynyl, 3-8 membered cycloalkyl, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, -OH, -OC 1-6alkyl, -SH, -SC 1-6alkyl, -C (=O) C 1-6alkyl, -S (=O) H, -S (=O) C 1-6alkyl, -S (=O) 2H, -S (=O) 2C 1-6alkyl, -C (=O) OH, -C (=O) OC 1-6alkyl, -OC (=O) C 1-6alkyl, 3-8 membered cycloalkenyl, phenyl, or 5-6 membered heteroaryl; wherein said -C 1-6alkyl, haloC 1-6alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted with one or more R S1;R S1 at each occurrence is independently selected from deuterium, halogen, -C 1-6alkyl, haloC 1-6alkyl, -C 2- 6alkenyl, -CN, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl) 2, -OH, -OC 1-3alkyl, -SH, -SC 1-3alkyl, -C (=O) C 1-3alkyl, -S (=O) H, -S (=O) C 1-6alkyl, -S (=O) 2H, -S (=O) 2C 1-6alkyl, -C (=O) OH, -C (=O) OC 1-3alkyl, -OC (=O) C 1-3alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl; wherein said -C 1-6alkyl, haloC 1-6alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C 1-6alkyl, haloC 1- 6alkyl, -CN, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl) 2, -OH, -OC 1-3alkyl, -SH, -SC 1-3alkyl, -C (=O) C 1-3alkyl, -C (=O) OH, -C (=O) OC 1-3alkyl, -OC (=O) C 1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;Optionally, two R S1 together with the carbon atom to which they are both attached form a 3-6 membered carbocyclic ring or a 3-6 heterocyclic ring; wherein, said 3-10 membered carbocylic ring or 3-10 heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, -C 1-6alkyl, haloC 1-6alkyl, -CN, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl) 2, -OH, -OC 1-3alkyl, -SH, -SC 1- 3alkyl, -C (=O) C 1-3alkyl, -C (=O) OH, -C (=O) OC 1-3alkyl, -OC (=O) C 1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;Optionally, two adjacent R S1 together with the carbon atoms to which they are respectively attached form a 3-6 membered carbocyclic ring, or a 3-6 membered heterocyclic ring, wherein, each of rings is independently optionally substituted with one or more substituents selected from deuterium, halogen, -C 1-6alkyl, haloC 1- 6alkyl, -CN, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl) 2, -OH, -OC 1-3alkyl, -SH, -SC 1-3alkyl, -C (=O) C 1-3alkyl, -C (=O) OH, -C (=O) OC 1-3alkyl, -OC (=O) C 1-3alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl;q 1 is selected from 0, 1, 2 or 3.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of claim 1 or 2, wherein, the compound is selected from Formula (II-1) to Formula (II-3) :
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 3, wherein, the compound is selected from the following formulas:L 1 is selected from a bond or C 1-3alkylene; said C 1-3alkylene is optionally independently substituted with one or more substituents selected from deuterium, halogen, -C 1-3alkyl;R 1 is selected from -C 1-3alkyl, haloC 1-3alkyl, -C 2-3alkenyl, -OH, -OC 1-3alkyl, -SH, -SC 1-3alkyl, -C (=O) C 1- 3alkyl, -S (=O) H, -S (=O) C 1-3alkyl, -S (=O) 2H, -S (=O) 2C 1-3alkyl, -C (=O) OH, -C (=O) OC 1-3alkyl, -OC (=O) C 1- 3alkyl; wherein said -C 1-3alkyl, haloC 1-3alkyl is optionally independently substituted with one or more substituents selected from -C 1-3alkyl, haloC 1-3alkyl, -C 2-3alkenyl, -OH, -OC 1-3alkyl, -SH, -SC 1-3alkyl, -C (=O) C 1-3alkyl, -S (=O) H, -S (=O) C 1-3alkyl, -S (=O) 2H, -S (=O) 2C 1-3alkyl, -C (=O) OH, -C (=O) OC 1-3alkyl, -OC (=O) C 1-3alkyl;X 1 is selected from -C 1-3alkyl, haloC 1-3alkyl, -C 2-3alkenyl, 3-8 membered cycloalkyl, 3-8 membered hetrocycloalkyl, phenyl, or 5-6 membered heteroaryl; wherein said -C 1-3alkyl, haloC 1-3alkyl, -C 2-3alkenyl, 3-8 membered cycloalkyl, 3-8 membered hetrocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted with one or more -C 1-3alkyl, haloC 1-3alkyl, -C 2-3alkenyl, -OH, -OC 1-3alkyl, -SH, -SC 1-3alkyl, -C (=O) C 1-3alkyl, -S (=O) H, -S (=O) C 1-3alkyl, -S (=O) 2H, -S (=O) 2C 1-3alkyl, -C (=O) OH, -C (=O) OC 1- 3alkyl, -OC (=O) C 1-3alkyl, 3-8 membered cycloalkyl, 3-8 membered hetrocycloalkyl;Ring A is selected from 4-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; wherein said ring A is optionally independently substituted with one or more -C 1-3alkyl, haloC 1- 3alkyl, -C 2-3alkenyl, -OH, -OC 1-3alkyl, -SH, -SC 1-3alkyl, -C (=O) C 1-3alkyl, -S (=O) H, -S (=O) C 1-3alkyl, -S (=O) 2H, -S (=O) 2C 1-3alkyl, -C (=O) OH, -C (=O) OC 1-3alkyl, -OC (=O) C 1-3alkyl, 3-8 membered cycloalkyl, 3-8 membered hetrocycloalkyl.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 4, wherein, the moiety of is selected from any moiety in the Table A as shown in the description.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 5, wherein,Y 2 is O;L 21 is selected from a bond or C 1-3 alkylene;L 22 is selected from a bond or C 1-3 alkylene;L 23 is selected from a bond or C 1-3 alkylene;Ring B or ring C is a 5-6 membered heterocyclic ring optionally further containing 1 or 2 heteroatoms selected from N or O;Ring D is a 3 membered carbocyclic ring; wherein the moiety of -L 22-and -L 23-X 2 are attached to the same atom or different atoms of the ring E;X 2 is a 6 membered heterocyclyl, wherein said 3-6 membered heterocyclyl is optionally independently substituted with 1, 2 or 3 R Z29.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 6, wherein, the moiety of is
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 7, wherein, the compound is selected from Formula (III-1) or Formula (III-2) :
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 8, wherein, each of R S21 at each occurrence is independently selected from deuterium, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-3alkenyl, -CN, -N (R 21) 2, -OR 21, -SR 21, -C (=O) R 22, -C (=O) OR 21, -OC (=O) R 22, -C (=O) N (R 21) 2, -NR 21C (=O) R 22, -OC (=O) OR 21, -NR 21C (=O) OR 21, -OC (=O) N (R 21) 2, -NR 21C (=O) N (R 21) 2, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S; wherein, said -C 1-6alkyl is substituted with 1, 2 or 3 substituents selected from deuterium, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -CN, oxo, -N (R 23) 2, -OR 23, -C (=O) R 23, -C (=O) OR 23, -OC (=O) R 23, -C (=O) N (R 23) 2, -NR 23C (=O) R 24, -OC (=O) OR 23, -NR 23C (=O) OR 24, -OC (=O) N (R 23) 2, -OC (=S) N (R 23) 2, -NR 23C (=O) N (R 23) 2, -NR 23S (=O) 2R 24, 3-6 membered cycloalkyl or 4-6 membered heterocyclyl; said 4-8 membered heterocyclyl is substituted with 1, 2 or 3 substituents selected from deuterium or -OR 21; said haloC 1-6alkyl is substituted with 1, 2 or 3 substituents selected from deuterium, -OR 21 or -C (=O) OR 21; said -C 2-3alkenyl is substituted with 1 substituents selected from deuterium or -C (=O) NR 21R 22;Each of (R 21, R 22, R 23 or R 24) is independently selected from hydrogen; deuterium; -C 1-6alkyl; haloC 1- 6alkyl; 5 membered heteroaryl; cyclopropyl; cyclopentyl; cyclohexyl; 5 membered heterocyclyl; 6 membered heterocyclyl; 5-membered heteroaryl; 6 membered heteroaryl; or -C 1-6alkyl substituted with 1, or 2 substituents selected from deuterium, -OC 1-6alkyl, -NHC 1-6alkyl, -N (C 1-6alkyl) 2 or -C (=O) N (C 1-6alkyl) 2; wherein said 5 membered heteroaryl, cyclopropyl, cyclopentyl, cyclohexyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 5-membered heteroaryl or 6 membered heteroaryl is optionally substituted with 1 or 2 subsitutents selected from deuterium, -C 1-3alkyl, -OH, -CN, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl) 2, -OC 1-3alkyl or cyclopropyl;Optionally, two R 21 or two R 23 together with the carbon atom to which they are both attached form a 3-6 membered heterocyclic ring;Optionally, two R 21 or two R 23 together with the nitrogen atom to which they are both attached form a 3-6 membered heterocyclic ring;q 21 is selected from 0, 1 or 2.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 9, wherein, each of R S21 at each occurrence is independently selected from deuterium, -F, -Cl, -CH 3, -CH 2CH 3, -CH 2CH 2CH 3, -CH (CH 3) 2, -CH (CH 3) CH 2CH 3, -CH=CH 2, -C≡CH, -C≡CCH 3, -C≡CD, -CH 2C≡CH, -CHF 2, -CF 3, -CH 2CF 3, -CH 2CHF 2, -CH 2CH 2F, -CH 2CH 2CH 2F, -OH, -CH 2OH, -CH 2CH 2OH, -OCH 3, -OC (CH 3) 2, -OCH 2CH 3, -OCH (CH 3) 2, -OCF 3, -SH, -SCH 3, -SCF 3, -C (=O) CF 3, -C (=O) OCH 2CH 2N (CH 3) , -C (=O) NHCH 2CH 2N (CH 3) , -CN, -NH 2, -N (CH 3) 2, -NHCH 2CH 3, -CH 2-N (CH 3) 2, -N (CH 3) CH 2CH 2OCH 3, -NHC (=O) CH 3, -NHC (=O) OCH 3, -SCH 2C (=O) N (CH 3) 2, -OC (=O) N (CH 3) 2, -NHC (=O) N (CH 3) 2, -CH 2CH 2CN, -CH 2CH (CH 3) 2, -CH 2OCH 3, -OCHF 2, -CH (CF 3) OCH 3, -C (CH 3) 2OH, -CF (CH 3) 2 or cyclopropyl;q 21 is selected from 0 or 1.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 10, wherein, the moiety of is selected from:
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 11, wherein, the moiety of is selected from
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 11, wherein, the moiety of is
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 13, wherein, the compound is selected from Formula (III-1A) or Formula (III-2A) :
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 14, wherein, R 4 is selected from any moiety in the Table B as shown in the description.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 15, wherein,Each of R S4 is independently selected from -F, -Cl, -C 1-3alkyl, haloC 1-3alkyl, haloC 1-3alkoxy, -C 2-3alkenyl, -C 2-3alkynyl, -CN, -NH 2, -NO 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl) 2, -OH, -O (C 1-3alkyl) , -SH, -S (C 1-3alkyl) , - C (=O) H, -C (=O) (C 1-3alkyl) , -C (=O) OH, -C (=O) O (C 1-3alkyl) , 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl, wherein said -C 1-3alkyl, haloC 1-3alkyl, haloC 1-3alkoxy, -C 2-3alkenyl, -C 2-6alkynyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl is independently optionally substituted with 1, 2 or 3 R 4b;Each of R 4b is independently selected from -F; -C 1-3alkyl; haloC 1-3alkyl; -CN; -OH; -NH 2; -NH (C 1-3alkyl) ; -NH (C 1-3alkyl) 2; -OC 1-3alkyl; or -C 1-3alkyl substituted with 1, 2 or 3 substituents selected form -F, haloC 1- 3alkyl, -CN, -OH, -NH 2, -NH (C 1-3alkyl) , -NH (C 1-3alkyl) 2, -OC 1-3alkyl or cyclopropyl.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 16, wherein, each of R S4 is independently selected from -F, -Cl, methyl, ethyl, propyl, isopropyl, -CH=CH 2, -C≡CH, -C≡CCH 3, -C≡CD, -CH 2C≡CH, -CHF 2, -CHF 2, -CF 3, -CH 2CF 3, -CH 2CHF 2, -CH 2CH 2F, -CH 2CH 2CH 2F, -OCF 3, -CN, -CH 2CN, -CH 2CH 2CN, -NH 2, -N (CH 3) 2, -NHCH 2CH 3, -CH 2-N (CH 3) 2, -C (=O) H, -C (=O) (CH 3) , -OH, -CH 2OH, -CH 2CH 2OH, -CH 2CH 2CH 2OH, -OCH 3, -OC (CH 3) 2, -CH 2CH (CH 3) 2, -CH (CH 3) CH 2CH 3, -CH 2OCH 3, -CH 2CH 2OCH 3, -SH, -SCH 3, -SCF 3, -OCHF 2, -CH (CF 3) OCH 3, -C (CH 3) 2OH, -CF (CH 3) 2, -OCH (CH 3) 2, -C (=O) OH, -NO 2, cyclopropyl,
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 17, wherein, the prodrug comprises a prodrug moiety which is attached to R 4 and is capable of being converted to -OH;R 4c is selected from hydrogen, -C 1-30alkyl, -C 2-30alkenyl, -C 2-30alkynyl, -C 0-6alkylene- (3-20 membered carbocyclyl) , -C 0-6alkylene- (3-20 membered heterocyclyl) , -C 0-6alkylene- (6-10 membered aryl) or -C 0- 6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R 4j;R 4d and R 4e are each selected from hydrogen, -C 1-30alkyl, -C 2-30alkenyl, -C 2-30alkynyl, -C (=O) C 1-6alkyl, -C 0-6alkylene- (3-20 membered carbocyclyl) , -C 0-6alkylene- (3-20 membered heterocyclyl) , -C 0-6alkylene- (6-10 membered aryl) or -C 0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R 4j;R 4f and R 4g are each selected from hydrogen, -C 1-30alkyl, -C 2-30alkenyl, -C 2-30alkynyl, -C (=O) C 1-6alkyl, -C 0-6alkylene- (3-20 membered carbocyclyl) , -C 0-6alkylene- (3-20 membered heterocyclyl) , -C 0-6alkylene- (6-10 membered aryl) or -C 0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R 4j;R 4h, R 4i, R 4m, R 4n and R 4p are each selected from hydrogen, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1- 6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, oxo, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1- 6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C 1-6alkyl, -C 2-6alkenyl, -C 2- 6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, -C 1-6alkyl, haloC 1- 6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, oxo, -OH, -O (C 1- 6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1- 6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;Optionally, R 4f and R 4g together with the atoms to which they are respectively attached form a 4-10 membered heterocyclyl ring, said 4-10 membered heterocyclyl ring optionally further contains 1 or 2 heteratoms selected from N, O, S, S (=O) or S (=O) 2 and optionally substituted with one or more R 4j;Optionally, R 4f and R 4h together with the atoms to which they are respectively attached form a 4-10 membered heterocyclyl ring, said 4-10 membered heterocyclyl ring optionally further contains 1 or 2 heteratoms selected from N, O, S, S (=O) or S (=O) 2 and optionally substituted with one or more R 4j;R 4j at each occurrence is independently selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, oxo, -NO 2, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1- 6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein said -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2 or 3 substituents selected from halogen; -C 1-6alkyl; haloC 1-6alkyl; -CN; oxo; -OH; -NH 2; -NH (C 1-6alkyl) ; -N (C 1-6alkyl) 2; -OC 1- 6alkyl; or -C 1-6alkyl substituted with 1, 2 or 3 substituents selected form halogen, haloC 1-6alkyl, -CN, -OH, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2 or -OC 1-6alkyl.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 18, wherein, R 4a is selected from any moiety in the Table C as shown in the description.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 19, wherein, R 4 is selected from
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 20, wherein, the compound is selected from Formula (IV-1) to Formula (IV-4) :
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 21, wherein, R 4 is selected from
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 22, wherein, the compound is selected from Formula (IV-1A) or Formula (IV-1B) :
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 23, wherein, R 3 is selected from halogen.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 24, wherein, R 3 is selected from -F.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 25, wherein, the compound is selected from Formula (V-1) to Formula (V-4) :
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 26, wherein, R 5 is selected from hydrogen, deuterium, -F, -Cl, -CH 3, -CH 2CH 3, -CH 2CH 2CH 3, -CH (CH 3) 2, -CN, -COOH, -CH 2OH, -OH, -OCH 3, -OCH 2CH 3, -CF 3, -CHF 2, -NH 2, -NHCH 3, -N (CH 3) 2, -CH 2NH 2, -CH 2CH 2NH 2, -CH 2OH, -CH 2CH 2OH, -SH, -S-CH 3, -S-CHF 2, -S-CF 3, -CH 2SH, -CH 2CH 2SH, -CH=CH 2, -C≡CH, -CHCH=CH 2, -OCF 3, -OCHF 2, - C (=O) NH 2, -C (=O) OCH 3,Preferably, R 5 is selected from hydrogen, -CH=CH 2, -OCH 3, or -N (CH 3) 2.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 27, wherein, the conjugated form is a PROTAC molecule.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 28, wherein, the compound is selected from any one in the Table D as shown in the description.
- A pharmaceutical composition, comprising a therapeutically effective amount of the compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 29, and at least one pharmaceutically acceptable excipient.
- A method for treating cancer in a subject comprising administering a therapeutically effective amount of the compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 29, or the pharmaceutical composition of claim 30 to a subject in need thereof.
- A method for treating cancer in a subject in need thereof, the method comprising:(a) determining whether the cancer is associated with K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutation and/or K-Ras wild type amplification; and(b) if so, administering a therapeutically effective amount of the compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 29, or the pharmaceutical composition of claim 30 to the subject in need thereof.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 29, or the pharmaceutical composition of claim 30 for use in therapy.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 29, or the pharmaceutical composition of claim 30 for use as a medicament.
- The compound of formula (I) , the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt of the stereoisomer thereof, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 29, or the pharmaceutical composition of claim 30 for use in a method for the treatment of cancer.
- A use of the compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof of any one of claims 1 to 29, or the pharmaceutical composition of claim 30 for the treatment of cancer.
- A use of the compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugated form thereof of any one of claims 1 to 29, or the pharmaceutical composition of claim 30 for the manufacture of a medicament for the treatment of cancer.
- The method for treating cancer of claim 31, the use in a method for the treatment of cancer of claim 35, the use for the treatment of cancer of claim 36, or the use for the manufacture of a medicament for the treatment of cancer of claim 37, wherein, said cancer is selected from pancreatic carcinoma, colorectal carcinoma, lung carcinoma (such as non-small cell lung cancer) , breast carcinoma, large intestine carcinoma, stomach carcinoma, endometrial carcinoma, esophageal carcinoma or gastroesophageal junction carcinoma.
- The method for treating cancer of claim 31 or 38, the use in a method for the treatment of cancer of claim 35 or 38, the use for the treatment of cancer of claim 36 or 38, or the use for the manufacture of a medicament for the treatment of cancer of claim 37 or 38, wherein, the cancer is associated with at least one of K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutation and/or K-Ras wild type amplification.
- The method for treating cancer of claim 31, 38 or 39, the use in a method for the treatment of cancer of claim 35, 38 or 39, the use for the treatment of cancer of claim 36, 38 or 39, or the use for the manufacture of a medicament for the treatment of cancer of claim 37, 38 or 39, wherein, the cancer a K-Ras G12C associated cancer.
- The method for treating cancer of claim 31, 38 or 39, the use in a method for the treatment of cancer of claim 35, 38 or 39, the use for the treatment of cancer of claim 36, 38 or 39, or the use for the manufacture of a medicament for the treatment of cancer of claim 37, 38 or 39, wherein, the cancer a K-Ras G12D associated cancer.
- The method for treating cancer of claim 31, 38 or 39, the use in a method for the treatment of cancer of claim 35, 38 or 39, the use for the treatment of cancer of claim 36, 38 or 39, or the use for the manufacture of a medicament for the treatment of cancer of claim 37, 38 or 39, wherein, the cancer a K-Ras G12V associated cancer.
- The method for treating cancer of claim 31, 38 or 39, the use in a method for the treatment of cancer of claim 35, 38 or 39, the use for the treatment of cancer of claim 36, 38 or 39, or the use for the manufacture of a medicament for the treatment of cancer of claim 37, 38 or 39, wherein, the cancer a K-Ras G13D associated cancer.
- The method for treating cancer of claim 31, 38 or 39, the use in a method for the treatment of cancer of claim 35, 38 or 39, the use for the treatment of cancer of claim 36, 38 or 39, or the use for the manufacture of a medicament for the treatment of cancer of claim 37, 38 or 39, wherein, the cancer a K-Ras G12R associated cancer.
- The method for treating cancer of claim 31, 38 or 39, the use in a method for the treatment of cancer of claim 35, 38 or 39, the use for the treatment of cancer of claim 36, 38 or 39, or the use for the manufacture of a medicament for the treatment of cancer of claim 37, 38 or 39, wherein, the cancer a K-Ras G12S associated cancer.
- The method for treating cancer of claim 31, 38 or 39, the use in a method for the treatment of cancer of claim 35, 38 or 39, the use for the treatment of cancer of claim 36, 38 or 39, or the use for the manufacture of a medicament for the treatment of cancer of claim 37, 38 or 39, wherein, the cancer a K-Ras G12A associated cancer.
- The method for treating cancer of claim 31, 38 or 39, the use in a method for the treatment of cancer of claim 35, 38 or 39, the use for the treatment of cancer of claim 36, 38 or 39, or the use for the manufacture of a medicament for the treatment of cancer of claim 37, 38 or 39, wherein, the cancer a K-Ras Q61H associated cancer.
- The method for treating cancer of claim 31, 38 or 39, the use in a method for the treatment of cancer of claim 35, 38 or 39, the use for the treatment of cancer of claim 36, 38 or 39, or the use for the manufacture of a medicament for the treatment of cancer of claim 37, 38 or 39, wherein, the cancer a K-Ras wild type amplification associated cancer.
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CNPCT/CN2021/124118 | 2021-10-15 | ||
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CN2021132066 | 2021-11-22 | ||
CNPCT/CN2021/132066 | 2021-11-22 | ||
CNPCT/CN2021/132636 | 2021-11-24 | ||
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CN2022074165 | 2022-01-27 | ||
CNPCT/CN2022/074165 | 2022-01-27 | ||
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