WO2024008068A1 - K-ras mutant protein inhibitors - Google Patents
K-ras mutant protein inhibitors Download PDFInfo
- Publication number
- WO2024008068A1 WO2024008068A1 PCT/CN2023/105682 CN2023105682W WO2024008068A1 WO 2024008068 A1 WO2024008068 A1 WO 2024008068A1 CN 2023105682 W CN2023105682 W CN 2023105682W WO 2024008068 A1 WO2024008068 A1 WO 2024008068A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- membered
- haloc
- stereoisomer
- pharmaceutically acceptable
- Prior art date
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- 238000012986 modification Methods 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 235000014483 powder concentrate Nutrition 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 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
- 150000003254 radicals Chemical class 0.000 description 1
- 102000016914 ras Proteins Human genes 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 102000030938 small GTPase Human genes 0.000 description 1
- 108060007624 small GTPase Proteins 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 229940073531 sotorasib Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229910052815 sulfur oxide Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 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
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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 PROTAC molecule 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 PROTAC molecule thereof, or a pharmaceutical composition as defined herein to a subject in need thereof.
- Acompound of formula (I) a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof:
- X 2 at each occurrence is independently selected from N or CR 1 ;
- Ring A 2 is selected from a 3-10 membered carbocyclic ring, 3-10 membered heterocarbocyclic ring, 6-10 membered aryl or 5-10 membered heteroaryl;
- 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 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S11 ;
- R S1 together with the 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 unsubstituted or substituted with one or more R S12 ;
- n 1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
- two R S2 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 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S21 ;
- R S2 together with the 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 unsubstituted or substituted with one or more R S22 ;
- n 2 is selected from 0, 1, 2, 3, 4 or 5;
- R 3 is selected from
- R 31 and R 32 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 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S33 ;
- R 33 and R 34 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 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S34 ;
- R 35 and R 36 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 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S35 ;
- R 38 and R 39 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 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S310 ;
- R 310 and R 311 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 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S316 ;
- n 2 is selected from 0, 1, 2, 3, 4, 5 or 6;
- n 3 is selected from 0, 1, 2, 3, 4, 5 or 6;
- n 4 is selected from 0, 1, 2, 3, 4, 5 or 6;
- n 5 is selected from 0, 1, 2, 3, 4, 5 or 6;
- n 6 is selected from 0, 1, 2, 3, 4, 5 or 6;
- Ring D is selected from a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring;
- two R S31 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S311 ;
- R S31 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 unsubstituted or substituted with one or more R S312 ;
- m 3 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
- two R S32 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 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S321 ;
- R S32 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 unsubstituted or substituted with one or more R S322 ;
- n 4 is selected from 0, 1, 2, 3, 4, 5 or 6;
- R 37 is selected from -N (R 37A ) 2 or 3-10 membered heterocyclyl, wherein said 3-10 membered heterocyclyl is optionally independently substituted with one or more R S37 ;
- two R S38 together with the carbon atom to which they are both attached form a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein, said 3-10 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S381 ;
- R S38 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 unsubstituted or substituted with one or more R S382 ;
- n 8 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
- two R S39 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 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S391 ;
- R S39 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 unsubstituted or substituted with one or more R S392 ;
- n 9 is selected from 0, 1, 2, 3, 4, 5 or 6;
- two R S315 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 discharged carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more R S3151 ;
- R S315 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 unsubstituted or substituted with one or more R S3152 ;
- n 10 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 independently unsubstituted or 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 1B , R 1D , R S1B , R S1D , R S2B , R S2D , R S31B , R S31D , R S32B , R S32D , R S38B , R S38D , R S39B , R S315B , R S315D , R S39D , R S4B , R S4D , R 5B , R 5D , R 6B and R 6D is independently selected from hydrogen, deuterium, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -C 2-6 alkenyl, haloC 2-6 alkenyl, -C 2-6 alkynyl, haloC 2-6 alkynyl, -N (R A ) 2 , -OR A , -SR A , 3-10 membered cycloalkyl, 3-10 membered cycloalken
- Each of (R A , R B , R C and R D ) 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, 3-10 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 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered ary
- R S11 , R S12 , R S13 , R S21 , R S22 , R S23 , R S33 , R S34 , R S35 , R S311 , R S312 , R S313 , R S321 , R S322 , R S323 , R S37 , R S310 , R S316 , R S381 , R S382 , R S383 , R S391 , R S392 , R S393 , R S3151 , R S3152 , R S3153 , R SS and R SA is independently selected from deuterium, halogen, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, -NO 2 , -N 3 , oxo, -NH 2 , -NH (C 1-6 al
- Each of heteroaryl at each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S.
- R 1 is selected from hydrogen, halogen, -CN, -OC 1-6 alkyl, -O-haloC 1-6 alkyl, -S-haloC 1-6 alkyl, -C 1-6 alkyl or 3-6 membered cycloalkyl; said -OC 1-6 alkyl, -C 1-6 alkyl or 3-6 membered cycloalkyl is unsubsituted or substituted with 1, 2 or 3 substituents slected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl
- Ring I is a 4-6 membered cycloalkyl ring.
- Ring J is a 4-6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O or S.
- the moiety of is selected from:
- R S381 is selected from hydrogen or R S38 ;
- m 81 is selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8.
- R S381 is selected from hydrogen, deuterium, -C 1-6 alkyl or 3-6 membered cycloalkyl wherein, said -C 1-6 alkyl or 3-6 membered cycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly.
- n 9 is selected from 0, 1 or 2.
- n 1
- n 1
- the moiety of is selected from:
- R S394 is selected from hydrogen or R S391 .
- R S39 is selected from halogen
- R S39 is selected from -F.
- R S391 is selected from hydrogen, deuterium, halogen, or -C 1-6 alkyl; wherein, said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly;
- R S391 is selected from hydrogen, deuterium, -F, or -CH 3 .
- the moiety of is selected from:
- the moiety of is selected from:
- Ring B is a 4-6 membered heterocyclic ring containing the fused N atom.
- Ring C is a 4-6 membered heterocyclic ring containing the fused N atom.
- the moiety of is selected from:
- two R S31 together with the carbon atom to which they are both attached form or cyclopropyl; wherein, said or cyclopropyl is independently unsubstituted or substituted with 1, 2 or 3 R S311 ; or
- two adjacent R S31 together with the carbon atoms to which they are respectively attached form a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, a phenyl ring or a 5-10 membered heteroaryl ring containing 1 or 2 heteroatoms selected from N, O or S, wherein, each of rings is independently unsubstituted or substituted with 1, 2 or 3 R S312 .
- the moiety of is selected from:
- Ring G is selected from a 5-6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, a phenyl ring, a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, or S;
- Ring H is selected from a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, a phenyl ring, a 5-10 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, or S;
- R S36 is same as R S31 ;
- R S314 is selected from hydrogen or R S311 ;
- n 31 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
- n 32 is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
- m 33 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
- m 34 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
- n 5 is selected from 0, 1, 2, 3, 4, 5, or 6;
- n 6 is selected from 0, 1, 2, 3, 4, 5, or 6.
- the moiety of is selected from:
- n 31 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
- n 32 is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
- m 33 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
- m 34 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
- n 5 is selected from 0, 1, 2, 3, 4, 5, or 6;
- n 6 is selected from 0, 1, 2, 3, 4, 5, or 6.
- R S311 is independently selected from deuterium, halogen, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -OH, -OC 1-6 alkyl, -CN, -NH 2 , -NH (C 1-6 alkyl) or -N (C 1-6 alkyl) 2 ; wherein, said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly;
- R S312 is independently selected from deuterium, halogen, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -OH, -OC 1-6 alkyl, -CN, -NH 2 , -NH (C 1-6 alkyl) or -N (C 1-6 alkyl) 2 ; wherein, said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly;
- R S314 is independently selected from hydrogen, deuterium, halogen, -C 1-6 alkyl, wherein, said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly.
- R S311 is independently selected from deuterium, -F or -OCH 3 ;
- R S312 is independently selected from deuterium, -F, -OCH 3 , or -CH 2 OCH 3 ;
- R S314 is independently selected from hydrogen, deuterium, -F, -CH 3 , -CH 2 OCH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CHF 2 , -CH 2 CH (CH 3 ) 2 .
- R S36 is selected from deuterium or -F.
- n 31 is selected from 0 or 1;
- n 32 is selected from 0 or 1;
- m 33 is selected from 0 or 1;
- n 34 is selected from 0 or 1;
- m 5 is selected from 0 or 1;
- n 6 is selected from 0 or 1.
- the moiety of is selected from:
- the moiety of is selected from:
- Ring K is a 4-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O atom.
- the moiety of is selected from:
- ring L is selected from a 4-6 membered heterocyclic ring optionally further comtaining 1 or 2 heteroatoms selected from N or O.
- the moiety of is selected from:
- R S315 is independently selected from deuterium, halogen, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -OH, -OC 1-6 alkyl, -CN, -NH 2 , -NH (C 1-6 alkyl) or -N (C 1-6 alkyl) 2 ; wherein, said -C 1-6 alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -OH or -OC 1-6 alkly.
- the moiety of is selected from:
- the moiety of is selected from:
- R 4 is selected from phenyl, pyridyl, naphthyl, quinolyl, isoquinolyl, indazolyl, benzothiaphenyl or benzothiozolyl, said phenyl, pyridyl, naphthyl, quinolyl, isoquinolyl, indazolyl, benzothiaphenyl or benzothiozolyl is unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 R S4 .
- n 7 is selected from 0, 1, 2 or, 3;
- R S4a is selected from -OH or -NH 2 ;
- R S4b is selected from hydrogen, deuterium, halogen
- R S4c is selected from hydrogen, deuterium, -C 1-3 alkyl, -C 2-3 alkenyl or -C 2-3 alkynyl;
- R S4d is selected from hydrogen, deuterium or halogen
- R S4e is selected from hydrogen, deuterium, halogen, -C 1-3 alkyl or haloC 1-3 alkyl;
- R S4f is selected from -OH or -NH 2 ;
- R S4g is selected from hydrogen, deuterium, halogen, -C 1-3 alkyl or haloC 1-3 alkyl;
- R S4h is selected from hydrogen, deuterium, halogen, -C 1-3 alkyl or haloC 1-3 alkyl;
- R S4i is selected from hydrogen, deuterium, halogen, -C 1-3 alkyl or haloC 1-3 alkyl;
- R S4j is selected from hydrogen, deuterium, halogen, -CN, -C 1-3 alkyl, halogC 1-3 alkyl or -OhaloC 1-3 alkyl;
- R S4k is selected from hydrogen, deuterium, halogen, -CN, -C 1-3 alkyl, halogC 1-3 alkyl or -OhaloC 1-3 alkyl;
- R S4l is selected from hydrogen, deuterium, halogen, -CN, -C 1-3 alkyl, halogC 1-3 alkyl or -OhaloC 1-3 alkyl;
- R S4m is selected from hydrogen, deuterium, halogen, -CN, -C 1-3 alkyl, halogC 1-3 alkyl or -OhaloC 1-3 alkyl;
- R S4n is selected from hydrogen, deuterium, halogen, -CN, -C 1-3 alkyl, halogC 1-3 alkyl or -OhaloC 1-3 alkyl;
- R S4o is selected from hydrogen, deuterium, halogen, -CN, -C 1-3 alkyl, halogC 1-3 alkyl or -OhaloC 1-3 alky;
- R S4p is selected from hydrogen, deuterium, halogen, -CN, -C 1-3 alkyl, halogC 1-3 alkyl or -OhaloC 1-3 alky.
- n 7 is selected from 0;
- R S4a is selected from -OH or -NH 2 ;
- R S4b is selected from -F
- R S4c is selected from ethyl, ethenyl or ethynyl
- R S4d is selected from hydrogen, or -F;
- R S4e is selected from -F
- R S4f is selected from -NH 2 ;
- R S4g is selected from hydrogen, -F, or methyl
- R S4h is selected from hydrogen, -F or methyl
- R S4i is selected from -I or -CF 3 ;
- R S4j is selected from -CN
- R S4k is selected from hydrogen
- R S4l is selected from methyl
- R S4m is selected from -CF 3 , -OCF 2 Cl, -OCF 3 or -CF 2 H;
- R S4n is selected from hydrogen, -F, -Cl, -CH 3 or -CF 3 ;
- R S4o is selected from hydrogen, -F, -Cl, -CH 3 or -CF 3 ;
- R S4p is selected from hydrogen, -F, -Cl, -CH 3 or -CF 3 .
- R 4 is selected from
- R 5 is selected from -F.
- R 6 is selected from hydrogen, -F, -OCH 3 , -OCH 2 CH 3 , or -NHCH 3 ;
- R 6 is selected from hydrogen.
- R 3 , R 5 , R 6 , X 2 , Y 1 , R S1 , R S2 , m 1 , m 2 , ring A 1 , and ring A 2 have the same definitions as above;
- R 41 at each occurrence is independently 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 ;
- -OR 41 is selected from:
- the moiety of is selected from:
- the moiety of is selected from: and
- R 4 is selected from: R 4 is selected from:
- -OR 41 is selected from:
- a pharmaceutical composition comprising a therapeutically effective amount 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 PROTAC molecule thereof of any one of [1] to [68] , and a pharmaceutically acceptable excipient.
- 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 or a PROTAC molecule thereof of any one of [1] to [68] , or the pharmaceutical composition of [69] 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 herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo.
- the preferred halogen groups include -F, -Cl and -Br.
- alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched.
- -C 1-6 alkyl radicals include 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.
- C 1-3 as in C 1-3 alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
- haloalkyl such as -C 1-6 haloalkyl, -C 1-4 haloalkyl or -C 1-3 haloalkyl
- an alkyl chain such as -C 1-6 alkyl, -C 1-4 alkyl or -C 1-3 alkyl
- examples include trifluoromethyl, difluoromethyl and fluoromethyl.
- alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group defined above.
- methylene i.e., -CH 2 -
- ethylene i.e., -CH 2 -CH 2 -or -CH (CH 3 ) -
- propylene i.e., -CH 2 -CH 2 -CH 2 -, -CH (-CH 2 -CH 3 ) -or -CH 2 -CH (CH 3 ) -
- alkenyl means a straight or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length.
- C 2-6 alkenyl contains from 2 to 6 carbon atoms.
- Alkenyl group include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.
- alkynyl contains a straight or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length.
- C 2-6 alkynyl contains from 2 to 6 carbon atoms.
- Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
- alkoxy radicals are oxygen ethers formed from the previously described alkyl groups.
- aryl refers to an unsubstituted or substituted mono or polycyclic aromatic ring system containing carbon ring atoms.
- the preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
- heterocyclic refers to unsubstituted and substituted mono or polycyclic non-aromatic ring system containing one or more heteroatoms, which comprising moncyclic heterocyclic ring, bicyclic heterocyclic ring, bridged heterocyclic ring, fused heterocyclic ring or sipro heterocyclic ring.
- Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides.
- the ring is three to ten membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition.
- heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone and oxadiazolyl.
- heteroaryl represents an aromatic ring system containing carbon (s) and at least one heteroatom.
- Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.
- a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms.
- a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclicheteroaryl 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) .
- heteroaryl groups include, but are 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.
- cycloalkyl refers to a substituted or unsubstituted monocyclic ring, bicyclic ring, bridged ring, fused ring, sipiro ring non-aromatic ring system only containing carbon atoms.
- Examplary “cycloalkyl” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
- 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 instan
- pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
- 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.
- 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 prodrugs of the compounds of this invention.
- such prodrugs 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 compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
- the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
- 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 conformational 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.
- Certain of the compounds provided herein may exist as atropisomers, which are conformational stereoisomers that occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule.
- the compounds provided herein include all atropisomers, both as pure individual atropisomer preparations, enriched preparations of each, or a non-specific mixture of each. Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be permitted.
- 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 prcesses analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.
- the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
- the present invention includes any possible solvates and polymorphic forms.
- a type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
- 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.
- the compounds in present invention or a prodrug or a metabolite or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier of 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 an oil-in-water emulsion or as a water-in-oil liquid emulsion.
- the compound represented by Formula I 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 Formula I 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.
- Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
- a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 0.05 to about 95 percent of the total composition.
- Unit dosage forms will generally contain between from about 0.0lmg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, l000mg, 1500mg or 2000mg.
- 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.
- the final injectable form must be sterile and must be effectively fluid for easy syringability.
- 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 represented by Formula I of this 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.
- dosage levels on the order of from about 0.001mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions or alternatively about 0.05mg to about 7g per patient per day.
- inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) may be effectively treated by the administration of from about 0.001 to 50mg of the compound per kilogram of body weight per day or alternatively about 0.05mg to about 3.5g per patient per day.
- the compound in the present invention could be synthesized and the activity could be tested according to the pharmacological experiments.
- the intermediates were synthesized using conventional preparation method.
- the Compound 1 was separated by Prep-HPLC-Gilson with the following conditions: Column, CHIRAL ART Cellulose-SA column (2cm ⁇ 25cm, 5um) ; Mobile phase, Hex/EtOH (60: 40) ; Flowing rate, 20ml/min. This results in Compound 1A (the first eluting isomer, Retention Time 4.535 min) and Compound 1B (the second eluting isomer, Retention Time 5.347 min) MS: m/z: 602 [M+1] + .
- Trifluoromethanesulfonic anhydride (125 mg, 443.0443 ⁇ mol) was dropped in to a solution of Compound 1-9 (199 mg, 262.5479 ⁇ mol) , pyridine (46 mg, 581.5446 ⁇ mol) in DCM (10 mL) at 0 °C, then the system was stirred at room temperature for 12 hours. The solution was diluted with water (10 mL) , the organic layer was washed with sat. NaCl, dried over Na 2 SO 4 and concentrated in vacuum . The residue was purified by Pre-TLC to give Compound 2-1 (264 mg, 296.6230 ⁇ mol) . MS: m/z: 890 [M+1]
- Compound 2 was separated by Prep-HPLC-Gilson with the following conditions: Column, CHIRAL ART Cellulose-SA column (2cm ⁇ 25cm, 5um) ; mobile phase, Hex (0.1%diethylamine) /EtOH (65: 35) ; Flowing rate: 20ml/min. This results in Compound 2A (the first eluting isomer, 49 mg, 81.5807 ⁇ mol) , Ret Time 8.406 min) and Compound 2B (the second eluting isomer, 51 mg, 84.9105 ⁇ mol) , Ret Time 10.304 min) .
- Compound 6-1 is synthesized in the same method as Compound 4-9, with the difference that INT 5 is replaced by INT 2.
- Trifluoromethanesulfonic anhydride (178 mg, 630.8951 ⁇ mol) was dropped into a solution of Compound 6-3 (0.301g, 387.9131 ⁇ mol) , pyridine (193 mg, 2.4400 mmol) in DCM (50 mL) at 0 °C, the system was stirred at room temperature for 12 hours. The solution was diluted with 10%NaHCO 3 (10 mL) , the organic layer was washed with sat. NaCl, dried over Na 2 SO 4 and concentrated in vacuum . The residue was purified by Pre-TLC to give Compound 6-4 (222 mg, 244.4909 ⁇ mol) . MS: m/z: 908 [M+H] + .
- GDP-loaded HIS-KRAS (G12V, aa 1-169) was pre-incubated with a compound in the presence of 10nM GDP in a 384-well plate (Greiner) for 15 min, then purified SOS1 ExD (Flag tag, aa 564-1049) , BODIPY TM FL GTP (Invitrogen) and MAb (monoclonal antibody) Anti 6HIS-Tb cryptate Gold (Cisbio) were added to the assay wells (Final concentration: 10-15nM GDP-loaded HIS-KRAS (G12V) , 5 nM GDP, 0.5 ⁇ M SOS1 ExD, 80 nM BODIPY TM FL GTP, 52.5 ng/mL MAb Anti 6HIS-Tb cryptate Gold) and incubated for 4 hours at 25 °C.
Abstract
Provided herein are KRAS mutant protein inhibitors of formula (I), a composition containing the same and the use thereof.
Description
Cross-References to Related Applications
This application claims the benefit of priority to PCT/CN2022/103723, filed on July 4, 2022; PCT/CN2022/103727, filed on July 4, 2022; PCT/CN2022/113760, filed on August 19, 2022; PCT/CN2022/113825, filed on August 22, 2022; PCT/CN2022/113826, filed on August 22, 2022; PCT/CN2022/121011, filed on September 23, 2022; PCT/CN2022/121515, filed on September 27, 2022; PCT/CN2022/121635, filed on September 27, 2022; PCT/CN2022/123336, filed on September 30, 2022; PCT/CN2022/125526, filed on October 14, 2022; PCT/CN2022/125647, filed on October 17, 2022; PCT/CN2022/126756, filed on October 21, 2022; PCT/CN2022/127360, filed on October 25, 2022; PCT/CN2023/070967, filed on January 6, 2023; PCT/CN2023/071315, filed on January 9, 2023; PCT/CN2023/072558, filed on January 17, 2023 and PCT/CN2023/094458, filed on May 16, 2023, 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.
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.
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 PROTAC molecule 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 PROTAC molecule 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 PROTAC molecule 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 PROTAC molecule 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 PROTAC molecule 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 PROTAC molecule 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 PROTAC molecule 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 PROTAC molecule thereof, or a pharmaceutical composition as defined herein for the manufacture of a medicament for the treatment of cancer.
Provided herein are the following disclosures:
[1] . Acompound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof:
Wherein,
X2 at each occurrence is independently selected from N or CR1;
R1 is selected from hydrogen, deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (R1A) 2, -OR1A, -SR1A, -S (=O) R1B, -S (=O) 2R1B, -C (=O) R1B, -C (=O) OR1A, -OC (=O) R1B, -C (=O) N (R1A) 2, -NR1AC (=O) R1B, -OC (=O) OR1A, -NR1AC (=O) OR1A, -NR1AC (=S) OR1A, -OC (=O) N (R1A) 2, -NR1AC (=O) N (R1A) 2, -S (=O) OR1A, -OS (=O) R1B, -S (=O) N (R1A) 2, -NR1AS (=O) R1B, -S (=O) 2OR1A, -OS (=O) 2R1B, -S (=O) 2N (R1A) 2, -NR1AS (=O) 2R1B, -OS (=O) 2OR1A, -NR1AS (=O) 2OR1A, -OS (=O) 2N (R1A) 2, -NR1AS (=O) 2N (R1A) 2, -P (R1A) 2, -P (=O) (R1B) 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 -C1-6alkyl, haloC1-6alkyl,
haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (R1C) 2, -OR1C, -SR1C, -S (=O) R1D, -S (=O) 2R1D, -C (=O) R1D, -C (=O) OR1D, -OC (=O) R1D, -C (=O) N (R1C) 2, -NR1CC (=O) R1D, -OC (=O) OR1C, -NR1CC (=O) OR1C, -NR1CC (=S) OR1C, -OC (=O) N (R1C) 2, -NR1CC (=O) N (R1C) 2, -S (=O) OR1C, -OS (=O) R1D, -S (=O) N (R1C) 2, -NR1CS (=O) R1D, -S (=O) 2OR1C, -OS (=O) 2R1D, -S (=O) 2N (R1C) 2, -NR1CS (=O) 2R1D, -OS (=O) 2OR1C, -NR1CS (=O) 2OR1C, -OS (=O) 2N (R1C) 2, -NR1CS (=O) 2N (R1C) 2, -P (R1C) 2, -P (=O) (R1D) 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;
Ring A1 is selected from a 3-10 membered heterocyclic ring optionally further comprising 1, 2 or 3 heteroatoms selected from N, O, S, S=O or S (=O) 2;
Ring A2 is selected from a 3-10 membered carbocyclic ring, 3-10 membered heterocarbocyclic ring, 6-10 membered aryl or 5-10 membered heteroaryl;
RS1 is independently selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS1A) 2, -ORS1A, -SRS1A, -S (=O) RS1B, -S (=O) 2RS1B, -C (=O) RS1B, -C (=O) ORS1A, -OC (=O) RS1B, -C (=O) N (RS1A) 2, -NS1AC (=O) RS1B, -OC (=O) ORS1A, -NS1AC (=O) ORS1A, -NRS1AC (=S) OS1A, -OC (=O) N (RS1A) 2, -NRS1AC (=O) N (RS1A) 2, -S (=O) ORS1A, -OS (=O) RS1B, -S (=O) N (RS1A) 2, -NRS1AS (=O) RS1B, -S (=O) 2ORS1A, -OS (=O) 2RS1B, -S (=O) 2N (RS1A) 2, -NRS1AS (=O) 2RS1B, -OS (=O) 2ORS1A, -NRS1AS (=O) 2ORS1A, -OS (=O) 2N (RS1A) 2, -NRS1AS (=O) 2N (RS1A) 2, -P (RS1A) 2, -P (=O) (RS1B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS1C) 2, -ORS1C, -SRS1C, -S (=O) RS1D, -S (=O) 2RS1D, -C (=O) RS1D, -C (=O) ORS1C, -OC (=O) RS1D, -C (=O) N (RS1C) 2, -NRS1CC (=O) RS1D, -OC (=O) ORS1C, -NRS1CC (=O) ORS1C, -NRS1CC (=S) ORS1C, -OC (=O) N (RS1C) 2, -NRS1CC (=O) N (RS1C) 2, -S (=O) ORS1C, -OS (=O) RS1D, -S (=O) N (RS1C) 2, -NRS1CS (=O) RS1D, -S (=O) 2ORS1C, -OS (=O) 2RS1D, -S (=O) 2N (RS1C) 2, -NRS1CS (=O) 2RS1D, -OS (=O) 2ORS1C, -NRS1CS (=O) 2ORS1C, -OS (=O) 2N (RS1C) 2, -NRS1CS (=O) 2N (RS1C) 2, -P (RS1C) 2, -P (=O) (RS1D) 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;
Optionally, two RS1 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS11;
Optionally, two adjacent RS1 together with the 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 unsubstituted or substituted with one or more RS12;
Optionally, two nonadjacent RS1 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 independently not replaced or 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 independently unsubstituted or substituted with RS13;
m1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
RS2 is independently selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS2A) 2, -ORS2A, -SRS2A, -S (=O) RS2B, -S (=O) 2RS2B, -C (=O) RS2B, -C (=O) ORS2A, -OC (=O) RS2B, -C (=O) N (RS2A) 2, -NRS2AC (=O) RS2B, -OC (=O) ORS2A, -NRS2AC (=O) ORS2A, -NRS2AC (=S) ORS2A, -OC (=O) N (RS2A) 2, -NRS2AC (=O) N (RS2A) 2, -S (=O) ORS2A, -OS (=O) RS2B, -S (=O) N (RS2A) 2, -NRS2AS (=O) RS2B, -S (=O) 2ORS2A, -OS (=O) 2RS2B, -S (=O) 2N (RS2A) 2, -NRS2AS (=O) 2RS2B, -OS (=O) 2ORS2A, -NRS2AS (=O) 2ORS2A, -OS (=O) 2N (RS2A) 2, -NRS2AS (=O) 2N (RS2A) 2, -P (RS2A) 2, -P (=O) (RS2B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS2C) 2, -ORS2C, -SRS2C, -S (=O) RS2D, -S (=O) 2RS2D, -C (=O) RS2D, -C (=O) ORS2D, -OC (=O) RS2D, -C (=O) N (RS2C) 2, -NRS2CC (=O) RS2D, -OC (=O) ORS2C, -NRS2CC (=O) ORS2C, -NRS2CC (=S) ORS2C, -OC (=O) N (RS2C) 2, -NRS2CC (=O) N (RS2C) 2, -S (=O) ORS2C, -OS (=O) RS2D, -S (=O) N (RS2C) 2, -NRS2CS (=O) RS2D, -S (=O) 2ORS2C, -OS (=O) 2RS2D, -S (=O) 2N (RS2C) 2, -NRS2CS (=O) 2RS2D, -OS (=O) 2ORS2C, -NRS2CS (=O) 2ORS2C, -OS (=O) 2N (RS2C) 2, -NRS2CS (=O) 2N (RS2C) 2, -P (RS2C) 2, -P (=O) (RS2D) 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;
Optionally, two RS2 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS21;
Optionally, two adjacent RS2 together with the 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 unsubstituted or substituted with one or more RS22;
Optionally, two nonadjacent RS2 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 independently not replaced or 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 independently unsubstituted or substituted with RS23;
m2 is selected from 0, 1, 2, 3, 4 or 5;
Y1 is a bond, O, S, S (=O) , S (=O) 2 or NRY11;
RY11 is selected from hydrogen, deuterium, -C1-6alkyl, haloC1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -S (=O) RB, -S (=O) 2RB, -C (=O) RB, -C (=O) ORB, -C (=O) N (RB) 2, -S (=O) ORB, -S (=O) N (RB) 2, -S (=O) 2ORB, -S (=O) 2N (RB) 2, -P (=O) (RB) 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 -C1-6alkyl, haloC1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RC) 2, -ORC, -SRC, -S (=O) RD, -S (=O) 2RD, -C (=O) RD, -C (=O) ORC, -OC (=O) RD, -C (=O) N (RC) 2, -NRCC (=O) RD, -OC (=O) ORC, -NRCC (=O) ORD, -OC (=O) N (RC) 2, -NRCC (=O) N (RC) 2, -S (=O) ORC, -OS (=O) RD, -S (=O) N (RC) 2, -NRCS (=O) RD, -S (=O) 2ORC, -OS (=O) 2RD, -S (=O) 2N (RC) 2, -NRCS (=O) 2RD, -OS (=O) 2ORC, -NRCS (=O) 2ORC, -OS (=O) 2NRC, -NRCS (=O) 2N (RC) 2, -P (RC) 2, -P (=O) (RD) 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;
R3 is selected from
Each of R31, R32, R33, R34, R35, R36, R38, R39, R310 and R311 is independently selected form hydrogen, deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -N (RA) 2, -ORA, -SRA, -S (=O) RB, -S (=O) 2RB, -C (=O) RB, -C (=O) ORB, -C (=O) N (RB) 2, -S (=O) ORB, -S (=O) N (RB) 2, -S (=O) 2ORB, -S (=O) 2N (RB) 2, -P (=O) (RB) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RC) 2, -ORC, -SRC, -S (=O) RD, -S (=O) 2RD, -C (=O) RD, -C (=O) ORC, -OC (=O) RD, -C (=O) N (RC) 2, -NRCC (=O) RD, -OC (=O) ORC, -NRCC (=O) ORD, -OC (=O) N (RC) 2,
-NRCC (=O) N (RC) 2, -S (=O) ORC, -OS (=O) RD, -S (=O) N (RC) 2, -NRCS (=O) RD, -S (=O) 2ORC, -OS (=O) 2RD, -S (=O) 2N (RC) 2, -NRCS (=O) 2RD, -OS (=O) 2ORC, -NRCS (=O) 2ORC, -OS (=O) 2NRC, -NRCS (=O) 2N (RC) 2, -P (RC) 2, -P (=O) (RD) 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;
Optionally, R31 and R32 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS33;
Optionally, R33 and R34 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS34;
Optionally, R35 and R36 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS35;
Optionally, R38 and R39 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS310;
Optionally, R310 and R311 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS316;
n2 is selected from 0, 1, 2, 3, 4, 5 or 6;
n3 is selected from 0, 1, 2, 3, 4, 5 or 6;
n4 is selected from 0, 1, 2, 3, 4, 5 or 6;
n5 is selected from 0, 1, 2, 3, 4, 5 or 6;
n6 is selected from 0, 1, 2, 3, 4, 5 or 6;
Ring B is a 3-10 membered heterocyclic ring optionally further containing 1, 2, or 3 heteroatoms selected from N, O, S, S (=O) or S (=O) 2;
Ring C is a 3-10 membered heterocyclic ring optionally further containing 1, 2, or 3 heteroatoms selected from N, O, S, S (=O) or S (=O) 2;
Ring D is selected from a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring;
Ring I is a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, S, S (=O) or S (=O) 2;
Ring J is a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, S, S (=O) or S (=O) 2;
Ring K is selected from 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, S, S (=O) or S (=O) 2;
RS31 is selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS31A) 2, -ORS31A, -SRS31A, -S (=O) RS31B, -S (=O) 2RS31B, -C (=O) RS31B, -C (=O) ORS31A, -OC (=O) RS31B, -C (=O) N (RS31A) 2, -NRS31AC (=O) RS31B, -OC (=O) ORS31A, -NRS31AC (=O) ORS31A, -NRS31AC (=S) ORS31A, -OC (=O) N (RS31A) 2, -NRS31AC (=O) N (RS31A) 2, -S (=O) ORS31A, -OS (=O) RS31B, -S (=O) N (RS31A) 2, -NRS31AS (=O) RS31B, -S (=O) 2ORS31A, -OS (=O) 2RS31B, -S (=O) 2N (RS31A) 2, -NRS31AS (=O) 2RS31B, -OS (=O) 2ORS31A, -NRS31AS (=O) 2ORS31A, -OS (=O) 2N (RS31A) 2, -NRS31AS (=O) 2N (RS31A) 2, -P (RS31A) 2, -P (=O) (RS31B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS31C) 2, -ORS31C, -SRS31C, -S (=O) RS31D, -S (=O) 2RS31D, -C (=O) RS31D, -C (=O) ORS31C, -OC (=O) RS31D, -C (=O) N (RS31C) 2, -NRS31CC (=O) RS31D, -OC (=O) ORS31C, -NRS31CC (=O) ORS31C, -NRS31CC (=S) ORS31C, -OC (=O) N (RS31C) 2, -NRS31CC (=O) N (RS31C) 2, -S (=O) ORS31C, -OS (=O) RS31D, -S (=O) N (RS31C) 2, -NRS31CS (=O) RS31D, -S (=O) 2ORS31C, -OS (=O) 2RS31D, -S (=O) 2N (RS31C) 2, -NRS31CS (=O) 2RS31D, -OS (=O) 2ORS31C, -NRS31CS (=O) 2ORS31C, -OS (=O) 2N (RS31C) 2, -NRS31CS (=O) 2N (RS31C) 2, -P (RS31C) 2,
-P (=O) (RS31D) 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;
Optionally, two RS31 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS311;
Optionally, two adjacent RS31 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 unsubstituted or substituted with one or more RS312;
Optionally, two nonadjacent RS31 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 independently not replaced or 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 independently unsubstituted or substituted with RS313;
m3 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
RS32 is selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS32A) 2, -ORS32A, -SRS32A, -S (=O) RS32B, -S (=O) 2RS32B, -C (=O) RS32B, -C (=O) ORS32A, -OC (=O) RS32B, -C (=O) N (RS32A) 2, -NRS32AC (=O) RS32B, -OC (=O) ORS32A, -NRS32AC (=O) ORS32A, -NRS32AC (=S) ORS32A, -OC (=O) N (RS32A) 2, -NRS32AC (=O) N (RS32A) 2, -S (=O) ORS32A, -OS (=O) RS32B, -S (=O) N (RS32A) 2, -NRS32AS (=O) RS32B, -S (=O) 2ORS32A, -OS (=O) 2RS32B, -S (=O) 2N (RS32A) 2, -NRS32AS (=O) 2RS32B, -OS (=O) 2ORS32A, -NRS32AS (=O) 2ORS32A, -OS (=O) 2N (RS32A) 2, -NRS32AS (=O) 2N (RS32A) 2, -P (RS32A) 2, -P (=O) (RS32B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS32C) 2, -ORS32C, -SRS32C, -S (=O) RS32C, -S (=O) 2RS32D, -C (=O) RS32D, -C (=O) ORS32C, -OC (=O) RS32D, -C (=O) N (RS32C) 2, -NRS32CC (=O) RS32D, -OC (=O) ORS32C, -NRS32CC (=O) ORS32C, -NRS32CC (=S) ORS32C, -OC (=O) N (RS32C) 2, -NRS32CC (=O) N (RS32C) 2, -S (=O) ORS32C, -OS (=O) RS32C, -S (=O) N (RS32C) 2, -NRS32CS (=O) RS32D, -S (=O) 2ORS32C, -OS (=O) 2RS32D, -S (=O) 2N (RS32C) 2, -NRS32CS (=O) 2RS32D, -OS (=O) 2ORS32C, -NRS32CS (=O) 2ORS32C, -OS (=O) 2N (RS32C) 2, -NRS32CS (=O) 2N (RS32C) 2, -P (RS32C) 2, -P (=O) (RS32D) 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;
Optionally, two RS32 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS321;
Optionally, two adjacent RS32 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 unsubstituted or substituted with one or more RS322;
Optionally, two nonadjacent RS32 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 independently not replaced or 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 independently unsubstituted or substituted with RS323;
m4 is selected from 0, 1, 2, 3, 4, 5 or 6;
R37 is selected from -N (R37A) 2 or 3-10 membered heterocyclyl, wherein said 3-10 membered heterocyclyl is optionally independently substituted with one or more RS37;
RS38 is selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS38A) 2, -ORS38A, -SRS38A, -S (=O) RS38B, -S (=O) 2RS38B, -C (=O) RS38B, -C (=O) ORS38A, -OC (=O) RS38B, -C (=O) N (RS38A) 2, -NRS38AC (=O) RS38B, -OC (=O) ORS38A, -NRS38AC (=O) ORS38A, -NRS38AC (=S) ORS38A, -OC (=O) N (RS38A) 2, -NRS38AC (=O) N (RS38A) 2, -S (=O) ORS38A, -OS (=O) RS38B, -S (=O) N (RS38A) 2, -NRS38AS (=O) RS38B, -S (=O) 2ORS38A, -OS (=O) 2RS38B, -S (=O) 2N (RS38A) 2, -NRS38AS (=O) 2RS38B, -OS (=O) 2ORS38A, -NRS38AS (=O) 2ORS38A, -OS (=O) 2N (RS38A) 2, -NRS38AS (=O) 2N (RS38A) 2, -P (RS38A) 2, -P (=O) (RS38B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS38C) 2, -ORS38C, -SRS38C, -S (=O) RS38D, -S (=O) 2RS38D, -C (=O) RS38D, -C (=O) ORS38C, -OC (=O) RS38D, -C (=O) N (RS38C) 2, -NRS38CC (=O) RS38D, -OC (=O) ORS38C, -NRS38CC (=O) ORS38C, -NRS38CC (=S) ORS38C, -OC (=O) N (RS38C) 2, -NRS38CC (=O) N (RS38C) 2, -S (=O) ORS38C, -OS (=O) RS38D, -S (=O) N (RS38C) 2, -NRS38CS (=O) RS38D, -S (=O) 2ORS38C, -OS (=O) 2RS38D, -S (=O) 2N (RS38C) 2, -NRS38CS (=O) 2RS38D, -OS (=O) 2ORS38C, -NRS38CS (=O) 2ORS38C, -OS (=O) 2N (RS38C) 2, -NRS38CS (=O) 2N (RS38C) 2, -P (RS38C) 2, -P (=O) (RS38D) 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;
Optionally, two RS38 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS381;
Optionally, two adjacent RS38 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 unsubstituted or substituted with one or more RS382;
Optionally, two nonadjacent RS38 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 independently not replaced or 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 independently unsubstituted or substituted with RS383;
m8 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
RS39 is selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS39A) 2, -ORS39A, -SRS39A, -S (=O) RS39B, -S (=O) 2RS39B, -C (=O) RS39B, -C (=O) ORS39A, -OC (=O) RS39B, -C (=O) N (RS39A) 2, -NRS39AC (=O) RS39B, -OC (=O) ORS39A, -NRS39AC (=O) ORS39A, -NRS39AC (=S) ORS39A, -OC (=O) N (RS39A) 2, -NRS39AC (=O) N (RS39A) 2, -S (=O) ORS39A, -OS (=O) RS39B, -S (=O) N (RS39A) 2, -NRS39AS (=O) RS39B, -S (=O) 2ORS39A, -OS (=O) 2RS39B, -S (=O) 2N (RS39A) 2, -NRS39AS (=O) 2RS39B, -OS (=O) 2ORS39A, -NRS39AS (=O) 2ORS39A, -OS (=O) 2N (RS39A) 2, -NRS39AS (=O) 2N (RS39A) 2, -P (RS39A) 2, -P (=O) (RS39B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS39C) 2, -ORS39C, -SRS39C, -S (=O) RS39C, -S (=O) 2RS39D, -C (=O) RS39D, -C (=O) ORS39C, -OC (=O) RS39D, -C (=O) N (RS39C) 2, -NRS39CC (=O) RS39D, -OC (=O) ORS39C, -NRS39CC (=O) ORS39C, -NRS39CC (=S) ORS39C, -OC (=O) N (RS39C) 2, -NRS39CC (=O) N (RS39C) 2, -S (=O) ORS39C, -OS (=O) RS39C, -S (=O) N (RS39C) 2, -NRS39CS (=O) RS39D, -S (=O) 2ORS39C, -OS (=O) 2RS39D, -S (=O) 2N (RS39C) 2, -NRS39CS (=O) 2RS39D, -OS (=O) 2ORS39C, -NRS39CS (=O) 2ORS39C, -OS (=O) 2N (RS39C) 2, -NRS39CS (=O) 2N (RS39C) 2, -P (RS39C) 2, -P (=O) (RS39D) 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;
Optionally, two RS39 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS391;
Optionally, two adjacent RS39 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 unsubstituted or substituted with one or more RS392;
Optionally, two nonadjacent RS39 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 independently not replaced or 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 independently unsubstituted or substituted with RS393;
m9 is selected from 0, 1, 2, 3, 4, 5 or 6;
RS315 is selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS315A) 2, -ORS315A, -SRS315A, -S (=O) RS315B, -S (=O) 2RS315B, -C (=O) RS315B, -C (=O) ORS315A, -OC (=O) RS315B, -C (=O) N (RS315A) 2, -NRS315AC (=O) RS315B, -OC (=O) ORS315A, -NRS315AC (=O) ORS315A, -NRS315AC (=S) ORS315A, -OC (=O) N (RS315A) 2, -NRS315AC (=O) N (RS315A) 2, -S (=O) ORS315A, -OS (=O) RS315B, -S (=O) N (RS315A) 2, -NRS315AS (=O) RS315B, -S (=O) 2ORS315A, -OS (=O) 2RS315B, -S (=O) 2N (RS315A) 2, -NRS315AS (=O) 2RS315B, -OS (=O) 2ORS315A, -NRS315AS (=O) 2ORS315A, -OS (=O) 2N (RS315A) 2, -NRS315AS (=O) 2N (RS315A) 2, -P (RS315A) 2, -P (=O) (RS315B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS315C) 2, -ORS315C, -SRS315C, -S (=O) RS315C, -S (=O) 2RS315D, -C (=O) RS315D, -C (=O) ORS315C, -OC (=O) RS315D, -C (=O) N (RS315C) 2, -NRS315CC (=O) RS315D, -OC (=O) ORS315C, -NRS315CC (=O) ORS315C, -NRS315CC (=S) ORS315C, -OC (=O) N (RS315C) 2, -NRS315CC (=O) N (RS315C) 2, -S (=O) ORS315C, -OS (=O) RS315C, -S (=O) N (RS315C) 2, -NRS315CS (=O) RS315D, -S (=O) 2ORS315C, -OS (=O) 2RS315D, -S (=O) 2N (RS315C) 2, -NRS315CS (=O) 2RS315D, -OS (=O) 2ORS315C, -NRS315CS (=O) 2ORS315C, -OS (=O) 2N (RS315C) 2, -NRS315CS (=O) 2N (RS315C) 2, -P (RS315C) 2, -P (=O) (RS315D) 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;
Optionally, two RS315 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS3151;
Optionally, two adjacent RS315 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 unsubstituted or substituted with one or more RS3152;
Optionally, two nonadjacent RS315 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 independently not replaced or 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 independently unsubstituted or substituted with RS3153;
m10 is selected from 0, 1, 2, 3, 4, 5 or 6;
R4 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, wherein said 6-10 membered aryl, 5-10 membered heteroaryl, is independently unsubstituted or substituted with one or more RS4;
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;
RS4 is independently selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS4A) 2, -ORS4A, -SRS4A, -S (=O) RS4B, -S (=O) 2RS4B, -C (=O) RS4B, -C (=O) ORS4A, -OC (=O) RS4B, -C (=O) N (RS4A) 2, -NRS4AC (=O) RS4B, -OC (=O) ORS4A, -NRS4AC (=O) ORS4A, -NRS4AC (=S) ORS4A, -OC (=O) N (RS4A) 2, -NRS4AC (=O) N (RS4A) 2, -S (=O) ORS4A, -OS (=O) RS4B, -S (=O) N (RS4A) 2, -NRS4AS (=O) RS4B, -S (=O) 2ORS4A, -OS (=O) 2RS4B, -S (=O) 2N (RS4A) 2, -NRS4AS (=O) 2RS4B, -OS (=O) 2ORS4A, -NRS4AS (=O) 2ORS4A, -OS (=O) 2N (RS4A) 2, -NRS4AS (=O) 2N (RS4A) 2, -P (RS4A) 2, -P (=O) (RS4B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl,
haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS4C) 2, -ORS4C, -SRS4C, -S (=O) RS4D, -S (=O) 2RS4D, -C (=O) RS4D, -C (=O) ORS4D, -OC (=O) RS4D, -C (=O) N (RS4C) 2, -NRS4CC (=O) RS4D, -OC (=O) ORS4C, -NRS4CC (=O) ORS4C, -NRS4CC (=S) ORS4C, -OC (=O) N (RS4C) 2, -NRS4CC (=O) N (RS4C) 2, -S (=O) ORS4C, -OS (=O) RS4D, -S (=O) N (RS4C) 2, -NRS4CS (=O) RS4D, -S (=O) 2ORS4C, -OS (=O) 2RS4D, -S (=O) 2N (RS4C) 2, -NRS4CS (=O) 2RS4D, -OS (=O) 2ORS4C, -NRS4CS (=O) 2ORS4C, -OS (=O) 2N (RS4C) 2, -NRS4CS (=O) 2N (RS4C) 2, -P (RS4C) 2, -P (=O) (RS4D) 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;
R5 is selected from hydrogen, deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (R5A) 2, -OR5A, -SR5A, -S (=O) R5B, -S (=O) 2R5B, -C (=O) R5B, -C (=O) OR5A, -OC (=O) R5B, -C (=O) N (R5A) 2, -NR5AC (=O) R5B, -OC (=O) OR5A, -NR5AC (=O) OR5A, -NR5AC (=S) OR5A, -OC (=O) N (R5A) 2, -NR5AC (=O) N (R5A) 2, -S (=O) OR5A, -OS (=O) R5B, -S (=O) N (R5A) 2, -NR5AS (=O) R5B, -S (=O) 2OR5A, -OS (=O) 2R5B, -S (=O) 2N (R5A) 2, -NR5AS (=O) 2R5B, -OS (=O) 2OR5A, -NR5AS (=O) 2OR5A, -OS (=O) 2N (R5A) 2, -NR5AS (=O) 2N (R5A) 2, -P (R5A) 2, -P (=O) (R5B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (R5C) 2, -OR5C, -SR5C, -S (=O) R5D, -S (=O) 2R5D, -C (=O) R5D, -C (=O) OR5D, -OC (=O) R5D, -C (=O) N (R5C) 2, -NR5CC (=O) R5D, -OC (=O) OR5C, -NR5CC (=O) OR5C, -NR5CC (=S) OR5C, -OC (=O) N (R5C) 2, -NR5CC (=O) N (R5C) 2, -S (=O) OR5C, -OS (=O) R5D, -S (=O) N (R5C) 2, -NR5CS (=O) R5D, -S (=O) 2OR5C, -OS (=O) 2R5D, -S (=O) 2N (R5C) 2, -NR5CS (=O) 2R5D, -OS (=O) 2OR5C, -NR5CS (=O) 2OR5C, -OS (=O) 2N (R5C) 2, -NR5CS (=O) 2N (R5C) 2, -P (R5C) 2, -P (=O) (R5D) 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;
R6 is selected from hydrogen, deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (R5A) 2, -OR6A, -SR6A, -S (=O) R6B, -S (=O) 2R6B, -C (=O) R6B, -C (=O) OR6A, -OC (=O) R6B, -C (=O) N (R6A) 2, -NR6AC (=O) R6B, -OC (=O) OR6A, -NR6AC (=O) OR6A, -NR6AC (=S) OR6A, -OC (=O) N (R6A) 2, -NR6AC (=O) N (R6A) 2, -S (=O) OR6A, -OS (=O) R6B, -S (=O) N (R6A) 2, -NR6AS (=O) R6B, -S (=O) 2OR6A, -OS (=O) 2R6B, -S (=O) 2N (R6A) 2, -NR6AS (=O) 2R6B, -OS (=O) 2OR6A, -NR6AS (=O) 2OR6A, -OS (=O) 2N (R6A) 2, -NR6AS (=O) 2N (R6A) 2, -P (R6A) 2, -P (=O) (R6B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (R6C) 2, -OR6C, -SR6C, -S (=O) R6D, -S (=O) 2R6D, -C (=O) R6D, -C (=O) OR6D, -OC (=O) R6D, -C (=O) N (R6C) 2, -NR6CC (=O) R6D, -OC (=O) OR6C, -NR6CC (=O) OR6C, -NR6CC (=S) OR6C, -OC (=O) N (R6C) 2, -NR6CC (=O) N (R6C) 2, -S (=O) OR6C, -OS (=O) R6D, -S (=O) N (R6C) 2, -NR6CS (=O) R6D, -S (=O) 2OR6C, -OS (=O) 2R6D, -S (=O) 2N (R6C) 2, -NR6CS (=O) 2R6D, -OS (=O) 2OR6C, -NR6CS (=O) 2OR6C, -OS (=O) 2N (R6C) 2, -NR6CS (=O) 2N (R6C) 2, -P (R6C) 2, -P (=O) (R6D) 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;
Each of R1A, R1C, RS1A, RS1C, RS2A, RS2C, RS31A, RS31C, RS32A, RS32C, R37A, RS38A, RS38C, RS39A, RS39C, RS315A, RS315C, RS4A, RS4C, R5A, R5C, R6A and R6C is independently selected from hydrogen, deuterium, -C1-6alkyl, haloC1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -S (=O) RB, -S (=O) 2RB, -C (=O) RB, -C (=O) ORB, -C (=O) N (RB) 2, -S (=O) ORB, -S (=O) N (RB) 2, -S (=O) 2ORB, -S (=O) 2N (RB) 2, -P (=O) (RB) 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 -C1-6alkyl, haloC1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RC) 2, -ORC, -SRC, -S (=O) RD, -S (=O) 2RD, -C (=O) RD, -C (=O) ORC, -OC (=O) RD, -C (=O) N (RC) 2, -NRCC (=O) RD, -OC (=O) ORC, -NRCC (=O) ORD, -OC (=O) N (RC) 2, -NRCC (=O) N (RC) 2, -S (=O) ORC, -OS (=O) RD, -S (=O) N (RC) 2, -NRCS (=O) RD, -S (=O) 2ORC, -OS (=O) 2RD, -S (=O) 2N (RC) 2, -NRCS (=O) 2RD, -OS (=O) 2ORC, -NRCS (=O) 2ORC, -OS (=O) 2NRC, -NRCS (=O) 2N (RC) 2, -P (RC) 2,
-P (=O) (RD) 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;
Optionally, (two R1A, two R1C, two RS1A, two RS1C, two RS2A, two RS2C, two RS31A, two RS31C, two RS32A, two RS32C, two R37A, two RS38A, two RS38C, two RS39A, two RS315A, two RS315C, two RS39C, two RS4A, two RS4C, two R5A, two R5C, two R6A and two R6C) together with the nitrogen atom to which they are both attached forms a 3-10 membered heterocyclic ring or a 5-10 membered heteroaryl ring, wherein, said 3-10 membered heterocyclic ring or 5-10 membered heteroaryl ring is independently unsubstituted or substituted with one or more RSS;
Each of R1B, R1D, RS1B, RS1D, RS2B, RS2D, RS31B, RS31D, RS32B, RS32D, RS38B, RS38D, RS39B, RS315B, RS315D, RS39D, RS4B, RS4D, R5B, R5D, R6B and R6D is independently selected from hydrogen, deuterium, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -N (RA) 2, -ORA, -SRA, 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RC) 2, -ORC, -SRC, -S (=O) RD, -S (=O) 2RD, -C (=O) RD, -C (=O) ORC, -OC (=O) RD, -C (=O) N (RC) 2, -NRCC (=O) RD, -OC (=O) ORC, -NRCC (=O) ORD, -OC (=O) N (RC) 2, -NRCC (=O) N (RC) 2, -S (=O) ORC, -OS (=O) RD, -S (=O) N (RC) 2, -NRCS (=O) RD, -S (=O) 2ORC, -OS (=O) 2RD, -S (=O) 2N (RC) 2, -NRCS (=O) 2RD, -OS (=O) 2ORC, -NRCS (=O) 2ORC, -OS (=O) 2NRC, -NRCS (=O) 2N (RC) 2, -P (RC) 2, -P (=O) (RD) 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;
Each of (RA, RB, RC and RD) is independently selected from hydrogen, deuterium, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, 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 unsubsituted or substituted with one or more RSA;
Each of RS11, RS12, RS13, RS21, RS22, RS23, RS33, RS34, RS35, RS311, RS312, RS313, RS321, RS322, RS323, RS37, RS310, RS316, RS381, RS382, RS383, RS391, RS392, RS393, RS3151, RS3152, RS3153, RSS and RSA is independently selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -CN, -NO2, -N3, oxo, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH, -O (C1-6alkyl) , -SH, -S (C1-6alkyl) , -S (=O) (C1-6alkyl) , -S (=O) 2 (C1-6alkyl) , -C (=O) (C1-6alkyl) , -C (=O) OH, -C (=O) (OC1-6alkyl) , -OC (=O) (C1-6alkyl) , -C (=O) NH2, -C (=O) NH (C1-6alkyl) , -C (=O) N (C1-6alkyl) 2, -NHC (=O) (C1-6alkyl) , -N (C1-6alkyl) C (=O) (C1-6alkyl) , -OC (=O) O (C1-6alkyl) , -NHC (=O) (OC1-6alkyl) , -N (C1-6alkyl) C (=O) (OC1-6alkyl) , -OC (=O) NH (C1-6alkyl) , -OC (=O) N (C1-6alkyl) 2, -NHC (=O) NH2, -NHC (=O) NH (C1-6alkyl) , -NHC (=O) N (C1-6alkyl) 2, -N (C1-6alkyl) C (=O) NH2, -N (C1-6alkyl) C (=O) NH (C1-6alkyl) , -N (C1-6alkyl) C (=O) N (C1-6alkyl) 2, -S (=O) (OC1-6alkyl) , -OS (=O) (C1-6alkyl) , -S (=O) NH2, -S (=O) NH (C1-6alkyl) , -S (=O) N (C1-6alkyl) 2, -NHS (=O) (C1-6alkyl) , -N (C1-6alkyl) S (=O) (C1-6alkyl) , -S (=O) 2 (OC1-6alkyl) , -OS (=O) 2 (C1-6alkyl) , -S (=O) 2NH2, -S (=O) 2NH (C1-6alkyl) , -S (=O) 2N (C1-6alkyl) 2, -NHS (=O) 2 (C1-6alkyl) , -N (C1-6alkyl) S (=O) 2 (C1-6alkyl) , -OS (=O) 2O (C1-6alkyl) , -NHS (=O) 2O (C1-6alkyl) , -N (C1-6alkyl) S (=O) 2O (C1-6alkyl) , -OS (=O) 2NH2, -OS (=O) 2NH (C1-6alkyl) , -OS (=O) 2N (C1-6alkyl) 2, -NHS (=O) 2NH2, -NHS (=O) 2NH (C1-6alkyl) , -NHS (=O) 2N (C1-6alkyl) 2, -N (C1-6alkyl) S (=O) 2NH2, -N (C1-6alkyl) S (=O) 2NH (C1-6alkyl) , -N (C1-6alkyl) S (=O) 2N (C1-6alkyl) 2, -PH (C1-6alkyl) , -P (C1-6alkyl) 2, -P (=O) H (C1-6alkyl) , -P (=O) (C1-6alkyl) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-3alkyl, haloC1-3alkyl, haloC1-3alkoxy, -C2-3alkenyl, -C2-3alkynyl, -CN, -NO2, -N3, oxo, -NH2, -NH(C1-3alkyl) , -N (C1-3alkyl) 2, -OH, -O (C1-3alkyl) , -SH, -S (C1-3alkyl) , -S (=O) (C1-3alkyl) , -S (=O) 2 (C1-3alkyl) , -C (=O) (C1-3alkyl) , -C (=O) OH, -C (=O) (OC1-3alkyl) , -OC (=O) (C1-3alkyl) , -C (=O) NH2, -C (=O) NH (C1-3alkyl) , -C (=O) N (C1-3alkyl) 2, -NHC (=O) (C1-3alkyl) , -N (C1-3alkyl) C (=O) (C1-3alkyl) , -OC (=O) O (C1-3alkyl) , -NHC (=O) (OC1-3alkyl) , -N (C1-3alkyl) C (=O) (OC1-3alkyl) , -OC (=O) NH (C1-3alkyl) , -OC (=O) N (C1-3alkyl) 2, -NHC (=O) NH2, -NHC (=O) NH (C1-3alkyl) , -NHC (=O) N (C1-3alkyl) 2, -N (C1-3alkyl) C (=O) NH2, -N (C1-3alkyl) C (=O) NH (C1-3alkyl) , -N (C1-3alkyl) C (=O) N (C1-3alkyl) 2, -S (=O) (OC1-3alkyl) , -OS (=O) (C1-3alkyl) , -S (=O) NH2, -S (=O) NH (C1-3alkyl) , -S (=O) N (C1-3alkyl) 2, -NHS (=O) (C1-3alkyl) , -N (C1-3alkyl) S (=O) (C1-3alkyl) ,
-S (=O) 2 (OC1-3alkyl) , -OS (=O) 2 (C1-3alkyl) , -S (=O) 2NH2, -S (=O) 2NH (C1-3alkyl) , -S (=O) 2N (C1-3alkyl) 2, -NHS (=O) 2 (C1-3alkyl) , -N (C1-3alkyl) S (=O) 2 (C1-3alkyl) , -OS (=O) 2O (C1-3alkyl) , -NHS (=O) 2O (C1-3alkyl) , -N (C1-3alkyl) S (=O) 2O (C1-3alkyl) , -OS (=O) 2NH2, -OS (=O) 2NH (C1-3alkyl) , -OS (=O) 2N (C1-3alkyl) 2, -NHS (=O) 2NH2, -NHS (=O) 2NH (C1-3alkyl) , -NHS (=O) 2N (C1-3alkyl) 2, -N (C1-3alkyl) S (=O) 2NH2, -N (C1-3alkyl) S (=O) 2NH (C1-3alkyl) , -N (C1-3alkyl) S (=O) 2N (C1-3alkyl) 2, -PH (C1-3alkyl) , -P (C1-3alkyl) 2, -P (=O) H (C1-3alkyl) , -P (=O) (C1-3alkyl) 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;
Each of heterocyclyl or heterocyclic at each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, S (=O) or S (=O) 2;
Each of heteroaryl at each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S.
[2] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of [1] , wherein, ring A1 is selected from 7 membered heterocyclic ring optionally further comprising 1 heteroatom selected from O.
[3] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of [1] or [2] , wherein, ring A1 is a 1, 4-oxazepane ring.
[4] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [3] , wherein, the compound is selected from any one of the following formulas:
[5] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [4] , wherein, ring A2 is selected from a 3-6 membered carbocyclic ring.
[6] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [5] , wherein, ring A2 is selected from a cyclopropyl ring.
[7] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [6] , wherein, the compound is selected from any one of the following formulas:
[8] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [7] , wherein, m1 is selected from 0, 1 or 2.
[9] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [8] , wherein, RS1 is selectd from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -OH, -OC1-6alkyl, -CN, -NH2, -NH (C1-6alkyl) or -N (C1-6alkyl) 2; wherein, said -C1-6alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly.
[10] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [9] , wherein, RS1 is selectd from methyl, -F or -OH.
[11] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [10] , wherein, RS1 is selectd from methyl or -F.
[12] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [11] , wherein, m2 is selected from 0, 1 or 2.
[13] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [12] , wherein, RS2 is selectd from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -OH, -OC1-6alkyl, -CN, -NH2, -NH (C1-6alkyl) or -N (C1-6alkyl) 2; wherein, said -C1-6alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly.
[14] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [13] , wherein, RS2 is selectd from deuterium, methyl, -F or -OH.
[15] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [14] , wherein, RS2 is selectd from deuterium, methyl or -F.
[16] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [15] , wherein, the compound is selected from any one of following formulas:
[17] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [16] , wherein, R1 is selected from hydrogen, halogen, -CN, -OC1-6alkyl, -O-haloC1-6alkyl, -S-haloC1-6alkyl, -C1-6alkyl or 3-6 membered cycloalkyl; said -OC1-6alkyl, -C1-6alkyl or 3-6 membered cycloalkyl is unsubsituted or substituted with 1, 2 or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly.
[18] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [15] , wherein, R1 is selected from hydrogen, -F, -Cl, -CH2CF3, -CH2CH2CN, -SCF3, -CF3, -Br, -CN, -OCH3, methyl, ethyl, or cyclopropyl.
[19] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a
PROTAC molecule thereof of any one of [1] to [18] , wherein, Y1 is selected from O.
[20] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [19] , wherein, each of R38 and R39 is independently selected form hydrogen or deuterium.
[21] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [20] , wherein, n5 is selected from 1.
[22] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] , wherein,
Ring I is a 4-6 membered cycloalkyl ring.
[23] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [22] , wherein:
Ring J is a 4-6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O or S.
[24] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [23] , wherein:
The moiety ofis selected from
Wherein, RS381 is selected from hydrogen or RS38;
m81 is selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8.
[25] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [24] , wherein:
RS381 is selected from hydrogen, deuterium, -C1-6alkyl or 3-6 membered cycloalkyl wherein, said -C1-6alkyl or 3-6 membered cycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly.
[26] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [25] , wherein, RS381 is selected from hydrogen, deuterium, -CH3, -CH2CH3 or cyclopropyl.
[27] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [26] , wherein, m81 is selected from 0.
[28] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [27] , wherein:
m9 is selected from 0, 1 or 2.
[29] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [28] , wherein:
m9 is selected from 0.
[30] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [29] , wherein:
m9 is selected from 1.
[31] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [30] , wherein:
The moiety ofis selected from
Wherein, RS394 is selected from hydrogen or RS391.
[32] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [31] , wherein:
RS39 is selected from halogen;
Preferably, RS39 is selected from -F.
[33] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [32] , wherein:
RS391 is selected from hydrogen, deuterium, halogen, or -C1-6alkyl; wherein, said -C1-6alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly;
Preferably, RS391 is selected from hydrogen, deuterium, -F, or -CH3.
[34] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [33] , wherein:
The moiety ofis selected from
[35] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [34] , wherein:
The moiety ofis selected from
[36] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] , wherein:
Ring B is a 4-6 membered heterocyclic ring containing the fused N atom.
[37] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] and [36] , wherein:
Ring C is a 4-6 membered heterocyclic ring containing the fused N atom.
[38] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] and [36] to [37] , wherein:
The moiety ofis selected from
[39] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] and [36] to [38] , wherein, m3 is selected from 0, 1, 2, 3, or 4.
[40] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] and [31] to [39] , wherein, RS31 is selected from deuterium or -F;
Optionally, two RS31 together with the carbon atom to which they are both attached formor cyclopropyl; wherein, saidor cyclopropyl is independently unsubstituted or substituted with 1, 2 or 3 RS311; or
Optionally, two adjacent RS31 together with the carbon atoms to which they are respectively attached form a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, a phenyl ring or a 5-10 membered heteroaryl ring containing 1 or 2 heteroatoms selected from N, O or S, wherein, each of rings is independently unsubstituted or substituted with 1, 2 or 3 RS312.
[41] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] and [36] to [40] , wherein:
The moiety ofis selected from
Wherein,
Ring G is selected from a 5-6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, a phenyl ring, a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, or S;
Ring H is selected from a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, a phenyl ring, a 5-10 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, or S;
The definition of RS36 is same as RS31;
RS314 is selected from hydrogen or RS311;
m31 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
m32 is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
m33 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
m34 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
m5 is selected from 0, 1, 2, 3, 4, 5, or 6;
m6 is selected from 0, 1, 2, 3, 4, 5, or 6.
[42] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] and [36] to [41] , wherein:
The moiety ofis selected from
Wherein,
m31 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
m32 is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
m33 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
m34 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
m5 is selected from 0, 1, 2, 3, 4, 5, or 6;
m6 is selected from 0, 1, 2, 3, 4, 5, or 6.
[43] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] and [36] to [42] , wherein:
RS311 is independently selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -OH, -OC1-6alkyl, -CN, -NH2, -NH (C1-6alkyl) or -N (C1-6alkyl) 2; wherein, said -C1-6alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly;
RS312 is independently selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -OH, -OC1-6alkyl, -CN, -NH2, -NH (C1-6alkyl) or -N (C1-6alkyl) 2; wherein, said -C1-6alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly;
RS314 is independently selected from hydrogen, deuterium, halogen, -C1-6alkyl, wherein, said -C1-6alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly.
[44] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] and [36] to [43] , wherein:
RS311 is independently selected from deuterium, -F or -OCH3;
RS312 is independently selected from deuterium, -F, -OCH3, or -CH2OCH3;
RS314 is independently selected from hydrogen, deuterium, -F, -CH3, -CH2OCH3, -CH2CH2CH3, -CH(CH3) 2, -CHF2, -CH2CH (CH3) 2.
[45] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] and [36] to [44] , wherein:
RS36 is selected from deuterium or -F.
[46] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] and [36] to [45] , wherein:
m31 is selected from 0 or 1;
m32 is selected from 0 or 1;
m33 is selected from 0 or 1;
m34 is selected from 0 or 1;
m5 is selected from 0 or 1;
m6 is selected from 0 or 1.
[47] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] and [36] to [46] , wherein:
The moiety ofis selected from
[48] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] and [36] to [47] , wherein:
The moiety ofis selected from
[49] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] , wherein, each of R310 and R311 is independently selected form hydrogen or deuterium.
[50] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] , or [49 [wherein, n6 is selected from 1 or 2.
[51] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] , [49] or [50] , wherein:
Ring K is a 4-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O atom.
[52] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] , [49] to [51] , wherein:
The moiety ofis selected from
Wherein, ring L is selected from a 4-6 membered heterocyclic ring optionally further comtaining 1 or 2 heteroatoms selected from N or O.
[53] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] , [49] to [52] , wherein:
The moiety ofis selected from
[54] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] , [49] to [53] , wherein:
RS315 is independently selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -OH, -OC1-6alkyl, -CN, -NH2, -NH (C1-6alkyl) or -N (C1-6alkyl) 2; wherein, said -C1-6alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly.
[55] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] , [49] to [54] , wherein, RS315 is independently selected from -F or -CH3.
[56] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] , [49] to [55] , wherein, m10 is selected from 0, 1, 2, or 3.
[57] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] , [49] to [56] , wherein:
The moiety ofis selected from
[58] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] , [49] to [57] , wherein:
The moiety ofis selected from
[59] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [21] , wherein, is selected from:
[60] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [59] , wherein, R4 is selected from phenyl, pyridyl, naphthyl,
quinolyl, isoquinolyl, indazolyl, benzothiaphenyl or benzothiozolyl, said phenyl, pyridyl, naphthyl, quinolyl, isoquinolyl, indazolyl, benzothiaphenyl or benzothiozolyl is unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 RS4.
[61] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [60] , wherein, R4 is selected from
m7 is selected from 0, 1, 2 or, 3;
RS4a is selected from -OH or -NH2;
RS4b is selected from hydrogen, deuterium, halogen;
RS4c is selected from hydrogen, deuterium, -C1-3alkyl, -C2-3alkenyl or -C2-3alkynyl;
RS4d is selected from hydrogen, deuterium or halogen;
RS4e is selected from hydrogen, deuterium, halogen, -C1-3alkyl or haloC1-3alkyl;
RS4f is selected from -OH or -NH2;
RS4g is selected from hydrogen, deuterium, halogen, -C1-3alkyl or haloC1-3alkyl;
RS4h is selected from hydrogen, deuterium, halogen, -C1-3alkyl or haloC1-3alkyl;
RS4i is selected from hydrogen, deuterium, halogen, -C1-3alkyl or haloC1-3alkyl;
RS4j is selected from hydrogen, deuterium, halogen, -CN, -C1-3alkyl, halogC1-3alkyl or -OhaloC1-3alkyl;
RS4k is selected from hydrogen, deuterium, halogen, -CN, -C1-3alkyl, halogC1-3alkyl or -OhaloC1-3alkyl;
RS4l is selected from hydrogen, deuterium, halogen, -CN, -C1-3alkyl, halogC1-3alkyl or -OhaloC1-3alkyl;
RS4m is selected from hydrogen, deuterium, halogen, -CN, -C1-3alkyl, halogC1-3alkyl or -OhaloC1-3alkyl;
RS4n is selected from hydrogen, deuterium, halogen, -CN, -C1-3alkyl, halogC1-3alkyl or -OhaloC1-3alkyl;
RS4o is selected from hydrogen, deuterium, halogen, -CN, -C1-3alkyl, halogC1-3alkyl or -OhaloC1-3alky;
RS4p is selected from hydrogen, deuterium, halogen, -CN, -C1-3alkyl, halogC1-3alkyl or -OhaloC1-3alky.
[62] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [61] , wherein:
m7 is selected from 0;
RS4a is selected from -OH or -NH2;
RS4b is selected from -F;
RS4c is selected from ethyl, ethenyl or ethynyl;
RS4d is selected from hydrogen, or -F;
RS4e is selected from -F;
RS4f is selected from -NH2;
RS4g is selected from hydrogen, -F, or methyl;
RS4h is selected from hydrogen, -F or methyl;
RS4i is selected from -I or -CF3;
RS4j is selected from -CN;
RS4k is selected from hydrogen;
RS4l is selected from methyl;
RS4m is selected from -CF3, -OCF2Cl, -OCF3 or -CF2H;
RS4n is selected from hydrogen, -F, -Cl, -CH3 or -CF3;
RS4o is selected from hydrogen, -F, -Cl, -CH3 or -CF3;
RS4p is selected from hydrogen, -F, -Cl, -CH3 or -CF3.
[63] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [62] , wherein:
R4 is selected from
[64] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [63] , wherein, R5 is selected from halogen;
Preferably, R5 is selected from -F.
[65] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [64] , wherein, R6 is selected from hydrogen, deuterium, halogen, -OH, -OC1-6alkyl, -NH2, -NHC1-6alkyl or -N (C1-6alkyl) 2;
Preferably, R6 is selected from hydrogen, -F, -OCH3, -OCH2CH3, or -NHCH3;
More preferably, R6 is selected from hydrogen.
[66] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [65] , wherein, the prodrug is selected from the following formula:
R3, R5, R6, X2, Y1, RS1, RS2, m1, m2, ring A1, and ring A2 have the same definitions as above;
R41 at each occurrence is independently selected from
R4c is selected from hydrogen, -C1-30alkyl, -C2-30alkenyl, -C2-30alkynyl, -C0-6alkylene- (3-20 membered carbocyclyl) , -C0-6alkylene- (3-20 membered heterocyclyl) , -C0-6alkylene- (6-10 membered aryl) or -C0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R4j;
R4d and R4e are each selected from hydrogen, -C1-30alkyl, -C2-30alkenyl, -C2-30alkynyl, -C (=O) C1-6alkyl, -C0-6alkylene- (3-20 membered carbocyclyl) , -C0-6alkylene- (3-20 membered heterocyclyl) , -C0-6alkylene- (6-10 membered aryl) or -C0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R4j;
R4f and R4g are each selected from hydrogen, -C1-30alkyl, -C2-30alkenyl, -C2-30alkynyl, -C (=O) C1-6alkyl, -C0-6alkylene- (3-20 membered carbocyclyl) , -C0-6alkylene- (3-20 membered heterocyclyl) , -C0-6alkylene- (6-10 membered aryl) or -C0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R4j;
R4h, R4i, R4m, R4n and R4p are each selected from hydrogen, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, oxo, -OH, -O (C1-6alkyl) , -SH, -S (C1-6alkyl) , -S (haloC1-6alkyl) , -S (=O) (C1-6alkyl) , -S (=O) 2 (C1-6alkyl) , -C (=O) (C1-6alkyl) , -C (=O) OH, -C (=O) (OC1-6alkyl) , -OC (=O) (C1-6alkyl) , -C (=O) NH2, -C (=O) NH (C1-6alkyl) , -C (=O) N (C1-6alkyl) 2, -NHC (=O) (C1-6alkyl) , -N (C1-6alkyl) C (=O) (C1-6alkyl) , -S (=O) 2NH2, -S (=O) 2NH (C1-6alkyl) , -S (=O) 2N (C1-6alkyl) 2, -NHS (=O) 2 (C1-6alkyl) , -N (C1-6alkyl) S (=O) 2 (C1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, 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, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, oxo, -OH, -O (C1-6alkyl) , -SH, -S (C1-6alkyl) , -S (haloC1-6alkyl) , -S (=O) (C1-6alkyl) , -S (=O) 2 (C1-6alkyl) , -C (=O) (C1-6alkyl) , -C (=O) OH, -C (=O) (OC1-6alkyl) , -OC (=O) (C1-6alkyl) , -C (=O) NH2, -C (=O) NH (C1-6alkyl) , -C (=O) N (C1-6alkyl) 2, -NHC (=O) (C1-6alkyl) , -N (C1-6alkyl) C (=O) (C1-6alkyl) , -S (=O) 2NH2, -S (=O) 2NH (C1-6alkyl) , -S (=O) 2N (C1-6alkyl) 2, -NHS (=O) 2 (C1-6alkyl) , -N (C1-6alkyl) S (=O) 2 (C1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Optionally, R4f and R4g 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 R4j;
Optionally, R4f and R4h 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 R4j;
R4j at each occurrence is independently selected from halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -CN, oxo, -NO2, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH, -O (C1-6alkyl) , -SH, -S (C1-6alkyl) , -S (haloC1-6alkyl) , -S (=O) (C1-6alkyl) , -S (=O) 2 (C1-6alkyl) , -C (=O) (C1-6alkyl) , -C (=O) OH, -C (=O) (OC1-6alkyl) , -OC (=O) (C1-6alkyl) , -C (=O) NH2, -C (=O) NH (C1-6alkyl) , -C (=O) N (C1-6alkyl) 2, -NHC (=O) (C1-6alkyl) , -N (C1-6alkyl) C (=O) (C1-6alkyl) , -S (=O) 2NH2, -S (=O) 2NH (C1-6alkyl) , -S (=O) 2N (C1-6alkyl) 2, -NHS (=O) 2 (C1-6alkyl) , -N (C1-6alkyl) S (=O) 2 (C1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein said -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, 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; -C1-6alkyl; haloC1-6alkyl; -CN; oxo; -OH; -NH2; -NH (C1-6alkyl) ; -N (C1-6alkyl) 2; -OC1-6alkyl; or -C1-6alkyl substituted with 1, 2 or 3 substituents selected from halogen, haloC1-6alkyl, -CN, -OH, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2 or -OC1-6alkyl;
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;
Preferably, -OR41 is selected from:
[67] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [66] , wherein,
the compound is selected from the following formula:
Wherein,
The moiety ofis selected from:
The moiety ofis selected from:
and
R4 is selected from: R4 is selected from
-OR41 is selected from:
[68] . The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of [1] to [67] , wherein, the compound is selected from the following Table A:
Table A
[69] . A pharmaceutical composition, comprising a therapeutically effective amount 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 PROTAC molecule thereof of any one of [1] to [68] , and a pharmaceutically acceptable excipient.
[70] . 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 or a PROTAC molecule thereof of any one of [1] to [68] , or the pharmaceutical composition of [69] to a subject in need thereof.
[71] . 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 PROTAC molecule thereof of any one of [1] to [68] , or the pharmaceutical composition of [69] to the subject in need thereof.
[72] . 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 the PROTAC molecule thereof of any one of [1] to [68] , or the pharmaceutical composition of [69] for use in therapy.
[73] . 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 PROTAC molecule thereof of any one of [1] to [68] , or the pharmaceutical composition of [69] for use as a medicament.
[74] . 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 PROTAC molecule thereof of any one of [1] to [68] , or the pharmaceutical composition of [69] for use in a method for the treatment of cancer.
[75] . A use of the compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a 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 [68] , or the pharmaceutical composition of [69] for the treatment of cancer.
[76] . 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 PROTAC molecule thereof of any one of [1] to [68] , or the pharmaceutical composition of [69] for the manufacture of a medicament for the treatment of cancer.
[77] . The method for treating cancer of [70] , the use in a method for the treatment of cancer of [74] , the use for the treatment of cancer of [75] , or the use for the manufacture of a medicament for the treatment of cancer of [76] , 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.
[78] . The method for treating cancer of [70] or [77] , the use in a method for the treatment of cancer of [74] or [77] , the use for the treatment of cancer of [75] or [77] , or the use for the manufacture of a medicament for the treatment of cancer of [76] or [77] , 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.
[79] . The method for treating cancer of [70] , [77] or [78] , the use in a method for the treatment of cancer of [74] , [77] or [78] , the use for the treatment of cancer of [75] , [77] or [78] , or the use for the manufacture of a medicament for the treatment of cancer of [76] , [77] or [78] , wherein, the cancer a K-Ras G12C associated cancer.
[80] . The method for treating cancer of [70] , [77] or [78] , the use in a method for the treatment of cancer of [74] , [77] or [78] , the use for the treatment of cancer of [75] , [77] or [78] , or the use for the manufacture of a medicament for the treatment of cancer of [76] , [77] or [78] , wherein, the cancer a K-Ras G12D associated cancer.
[81] . The method for treating cancer of [70] , [77] or [78] , the use in a method for the treatment of cancer of [74] , [77] or [78] , the use for the treatment of cancer of [75] , [77] or [78] , or the use for the manufacture of a medicament for the treatment of cancer of [76] , [77] or [78] , wherein, the cancer a K-Ras G12V associated cancer.
[82] . The method for treating cancer of [70] , [77] or [78] , the use in a method for the treatment of cancer of [74] , [77] or [78] , the use for the treatment of cancer of [75] , [77] or [78] , or the use for the manufacture of a medicament for the treatment of cancer of [76] , [77] or [78] , wherein, the cancer a K-Ras G13D associated cancer.
[83] . The method for treating cancer of [70] , [77] or [78] , the use in a method for the treatment of cancer of [74] , [77] or [78] , the use for the treatment of cancer of [75] , [77] or [78] , or the use for the manufacture of a medicament for the treatment of cancer of [76] , [77] or [78] , wherein, the cancer a K-Ras G12R associated cancer.
[84] . The method for treating cancer of [70] , [77] or [78] , the use in a method for the treatment of cancer of [74] , [77] or [78] , the use for the treatment of cancer of [75] , [77] or [78] , or the use for the manufacture of a medicament for the treatment of cancer of [76] , [77] or [78] , wherein, the cancer a K-Ras G12S associated cancer.
[85] . The method for treating cancer of [70] , [77] or [78] , the use in a method for the treatment of cancer of [74] , [77] or [78] , the use for the treatment of cancer of [75] , [77] or [78] , or the use for the manufacture of a medicament for the treatment of cancer of [76] , [77] or [78] , wherein, the cancer a K-Ras G12A associated cancer.
[86] . The method for treating cancer of [70] , [77] or [78] , the use in a method for the treatment of cancer of [74] , [77] or [78] , the use for the treatment of cancer of [75] , [77] or [78] , or the use for the manufacture of a medicament for the treatment of cancer of [76] , [77] or [78] , wherein, the cancer a K-Ras Q61H associated cancer.
[87] . The method for treating cancer of [70] , [77] or [78] , the use in a method for the treatment of cancer of [74] , [77] or [78] , the use for the treatment of cancer of [75] , [77] or [78] , or the use for the manufacture of a medicament for the treatment of cancer of [76] , [77] or [78] , 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 “halogen” or “halo” , as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. The preferred halogen groups include -F, -Cl and -Br.
The term “alkyl” , as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched. For example, -C1-6alkyl radicals include 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. Similary, C1-3, as in C1-3alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
The term “haloalkyl” (such as -C1-6haloalkyl, -C1-4haloalkyl or -C1-3haloalkyl) as used herein, unless otherwise indicated, an alkyl chain (such as -C1-6alkyl, -C1-4alkyl or -C1-3alkyl) as defined herein in which one or more (such as one, two or three) hydrogen has been replaced by a halogen. Examples include trifluoromethyl, difluoromethyl and fluoromethyl.
The term “alkylene” means a difunctional group obtained by removal of a hydrogen atom from an alkyl group defined above. For example, methylene (i.e., -CH2-) , ethylene (i.e., -CH2-CH2-or -CH (CH3) -) and propylene (i.e., -CH2-CH2-CH2-, -CH (-CH2-CH3) -or -CH2-CH (CH3) -) .
The term “alkenyl” means a straight or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length. For example, “C2-6alkenyl” contains from 2 to 6 carbon atoms. Alkenyl group include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.
The term “alkynyl” contains a straight or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length. For example, “C2-6alkynyl” contains from 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
The term “alkoxy” radicals are oxygen ethers formed from the previously described alkyl groups.
The term “aryl” , as used herein, unless otherwise indicated, refers to an unsubstituted or substituted mono or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
The term “heterocyclic” , as used herein, unless otherwise indicated, refers to unsubstituted and substituted mono or polycyclic non-aromatic ring system containing one or more heteroatoms, which comprising moncyclic heterocyclic ring, bicyclic heterocyclic ring, bridged heterocyclic ring, fused heterocyclic ring or sipro heterocyclic ring. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably, the ring is three to ten membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition. Examples of such heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone and oxadiazolyl.
The term “heteroaryl” , as used herein, unless otherwise indicated, represents an aromatic ring system containing carbon (s) and at least one heteroatom. Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted. A monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms. A polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclicheteroaryl 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) . Examples of heteroaryl groups include, but are 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 “carbocyclic” refers to a substituted or unsubstituted monocyclic ring, bicyclic ring, bridged ring, fused ring, sipiro ring non-aromatic ring system only containing carbon atoms. Examplary “cycloalkyl” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
The term “oxo” refers to oxygen atom together with the attached carbon atom forms the group
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 instan
The term “pharmaceutically acceptable salts” refers to salts 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 prodrugs of the compounds of this invention. In general, such prodrugs 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 compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
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 conformational 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.
Certain of the compounds provided herein may exist as atropisomers, which are conformational stereoisomers that occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule. The compounds provided herein include all atropisomers, both as pure individual atropisomer preparations, enriched preparations of each, or a non-specific mixture of each. Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be permitted.
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, CD3 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 prcesses analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.
When a tautomer of the compound in the present inventon exists, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
When the compound in present invention and pharmaceutically acceptable salts thereof exist in the form of solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. A type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
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, the compounds in present invention or a prodrug or a metabolite or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier of 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 an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I 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 Formula I 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. Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient. For example, a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 0.05 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 0.0lmg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, l000mg, 1500mg or 2000mg.
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 for easy syringability. 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 represented by Formula I of this 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 by Formula I or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
Generally, dosage levels on the order of from about 0.001mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions or alternatively about 0.05mg to about 7g per patient per day. For example, inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) , may be effectively treated by the administration of from about 0.001 to 50mg of the compound per kilogram of body weight per day or alternatively about 0.05mg to about 3.5g per patient per day.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
These and other aspects will become apparent from the following written description of the invention.
It is to be understood that, if any prior art publication is referred to herein; such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art in any country.
The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and Examples should not be construed as limiting the scope 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 compound in the present invention could be synthesized and the activity could be tested according to the pharmacological experiments.
Preparation of the Intermediates
The intermediates
were synthesized using conventional preparation method.
Example 1
K2CO3 (18.0 g, 130 mmol) was added into THF (40.0 mL) , and then SM (4.40 g, 43.5 mmol) and Cbz-Cl (8.91 g, 52.2 mmol) were added. The mixture was stirred at 20 ℃ for 16 hrs. After that, water (20.0 mL) was added, stirred at 20 ℃ for 1 hr and extracted with EtOAc (30.0 mL × 3) . The organic layer was collected, dried over with anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 30/1 to 2/1) to give Compound 1-1 (7.49 g, 31.8 mmol) .
1H NMR: (400 MHz, CDCl3) δ 7.32-7.37 (m, 5H) , 5.15 (s, 2H) , 3.70-3.75 (m, 4H) , 3.58-3.62 (m, 4H) , 1.87-2.04 (m, 2H) .
Compound 1-1 (2.30 g, 9.78 mmol) was dissolved in a 0.025 M solution of Et4NOTs (1.47 g, 4.89 mmol) in MeOH (40 mL) . The reaction mixture was electrolysis with C (+) | C (-) electrodes at constant current 28 mA (10 F/mol, 10 mA/cm2) . The mixture was stirred at 25 ℃ for 16 h and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 30/1 to 5/1) to give Compound 1-2 (4.01 g, 15.1 mmol) .
Compound 1-2 (2.60 g, 9.80 mmol) was added into DCM (18.0 mL) and then TMSOTf (2.61 g, 11.7 mmol, 2.13 mL) and DIEA (1.52 g, 11.7 mmol, 2.05 mL) were added. The mixture was stirred at 20 ℃ for 2 h. After that, the mixture was washed with NaHCO3 aqueous solution (20.0 mL × 3) and washed with brine (20 mL × 3) . The organic layer was collected, dried over with anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 30/1 to 2/1) to give 1-3 (0.376 g, 1.61 mmol) .
1H NMR: (400 MHz, CDCl3) δ 7.32-7.38 (m, 5H) , 5.75-5.96 (m, 2H) , 5.19 (s, 2H) , 4.08-4.11 (m, 2H) , 3.85-3.88 (m, 2H) , 1.98-2.02 (m, 2H) .
Compound 1-3 (0.376 g, 1.61 mmol) was added in DCM (5.00mL) . ZnEt2 (1 M, 4.03 mL) was added to the solution at 20 ℃ and stirred at 20 ℃ for 0.5 h. A solution of CH2I2 (1.73 g, 6.45 mmol, 520 uL) in DCM (2.00 mL) was added to the mixture dropwise and then stirred at 20 ℃ for 12 h. The reaction mixture was poured into saturated NH4Cl aqueous solution (15.0 mL) . The organic layer was separated, washed with brine (15.0 mL × 3) , dried with anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 30/1 to 2/1) to give Compound 1-4 (0.36 g, 1.45 mmol) . MS: m/z: 248 [M+1] +.
1H NMR: (400 MHz, CDCl3) δ 7.33-7.37 (m, 5H) , 5.11-5.21 (m, 2H) , 3.94-4.19 (m, 2H) , 3.64-3.69 (m, 1H) , 3.42 (s, 1H) , 3.11-3.16 (m, 1H) , 2.44 (s, 1H) , 1.75-1.92 (m, 2H) , 1.14-1.22 (m, 2H) .
A solution of Compound 1-4 (0.315 g, 1.2738 mmol) and Pd/C (101 mg) in MeOH (10 mL) was stirred in H2 at room temperature for 2.5 h. The mixture was filtered and concentrated in vacuum to Compound 1-5 (45 mg, 397.6776 μmol) . MS: m/z: 114 [M+1] +.
Compound 1-5 (0.045g, 397.6776 μmol) was added into a solution of INT 1 (101 mg, 400.0629 mmol) and DIEA (150 mg, 1.1606 mmol) in DCM (10 mL) . The mixture was stirred at rt for 2 h. The solution was diluted with 10%citric solution (10 mL) and extracted with DCM (10 mL) . The organic layer was washed with NaCl aqueous solution, dried over anhydrous Na2SO4 and concentrated in vacuum to give Compound 1-6 (142 mg, 431.4056 μmol) . MS: m/z: 329 [M+1] +.
A solution of Compound 1-6 (0.142g, 431.4056 μmol) , INT 2 (111 mg, 697.2331 μmol) and KF (86 mg, 1.4803 mmol) in DMSO (10 mL) was stirred at 100 ℃ for 20 h under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with saturated NaCl aqueous solution (15 mL) and extracted with EA (15 mL) . The organic layer was washed with NaCl aqueous solution (15 mL) then dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 1-7 (89 mg, 196.9478 μmol) . MS: m/z: 452 [M+1] +.
A solution of Compound 1-7 (0.089 g, 196.9480 μmol) , INT 3 (155 mg, 302.4186 μmol) , cataCXium A Pd G3 (17 mg, 23.3430 μmol) , cesium carbonate, (213 mg, 653.7374 μmol) , toluene (10 mL) and water (2 mL) was stirred at 100 ℃ overnight under nitrogen atmosphere. The mixture was allowed to cool to room temperature, diluted with saturated NaCl aqueous solution (15 mL) and extracted with EA (15 mL) . The organic layer was washed with 15 mL NaCl aqueous solution, then dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 1-8 (146 mg, 182.0428 μmol) . MS: m/z: 802 [M+1] +.
A solution of Compound 1-8 (0.146g, 182.0428 μmol) and HCl (4M in dioxane, 1mL) in DCM (9 mL) was stirred at room temperature for 1 h. The solution was diluted with 10%NaHCO3 aqueous solution (20 mL) . The organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4 and concentrated in vacuum to give crude Compound 1-9 (129 mg, 170.1944 μmol) . MS: m/z: 758 [M+1] +.
A solution of Compound 1-9 (0.129g, 170.1944 μmol) and CsF (130 mg, 855.8070 μmol) in DMF (8 mL) was stirred for 20 hours at 40 ℃ under nitrogen atmosphere. The solution was diluted with H2O (10 mL) and extracted with EA (10 mL × 2) . The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1 %TFA in water, B: CH3CN, Gradient: 15 %B to 35 %B in 34 min at a flow rate of 60mL/min, 235 nm) . The eluent was adjusted to pH 8 and the acetonitrile in the eluent was concentrated. The resulting aqueous phase was extracted with DCM (50 mL) , and the organic phase was dried and concentrated then freeze-dried to afford Compound 1 (36 mg, 59.8387 μmol) .
The Compound 1 was separated by Prep-HPLC-Gilson with the following conditions: Column, CHIRAL ART Cellulose-SA column (2cm × 25cm, 5um) ; Mobile phase, Hex/EtOH (60: 40) ; Flowing rate, 20ml/min. This results in Compound 1A (the first eluting isomer, Retention Time 4.535 min) and Compound 1B (the second eluting isomer, Retention Time 5.347 min) MS: m/z: 602 [M+1] +.
Example 2
Trifluoromethanesulfonic anhydride (125 mg, 443.0443 μmol) was dropped in to a solution of Compound 1-9 (199 mg, 262.5479 μmol) , pyridine (46 mg, 581.5446 μmol) in DCM (10 mL) at 0 ℃, then the system was stirred at room temperature for 12 hours. The solution was diluted with water (10 mL) , the organic layer was washed with sat. NaCl, dried over Na2SO4 and concentrated in vacuum . The residue was purified by Pre-TLC to give Compound 2-1 (264 mg, 296.6230 μmol) . MS: m/z: 890 [M+1]
A solution of Compound 2-1 (0.264g, 296.6230 μmol) , benzophenone imine (135 mg, 744.8975 μmol) ,
cesium carbonate (297 mg, 911.5493 μmol) , Pd2 (dba) 3 (55 mg, 60.0623 μmol) , INT 9 (38 mg, 65.6738 μmol) in toluene (10 mL) . The reaction mixture was stirred for 20 hours at 100 ℃ under nitrogen atmosphere. The solution was diluted with sat. NaCl (20 mL) and extracted with EA (20 mL) . The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by Pre-TLC to give Compound 2-2 (317 mg, 344.1260 μmol) . MS: m/z: 921 [M+1]
A solution of Compound 2-2 (0.317g, 344.1261 μmol) , HCl (4 mol/L in dioxane, 2 mL) in acetonitrile (8 mL) was stirred at room temperature for 1 h. The solution was diluted with 10%NaHCO3 solution (20 mL) , the acetonitrile was evaporated in vacuum, then the layer extracted with EA (20 mL) , the organic layer was washed with sat. NaCl dried over Na2SO4 and concentrated in vacuum to give crude Compound 2-3 (291 mg, 384.4264 μmol) . MS: m/z: 757 [M+1]
A solution of Compound 2-3 (0.302g, 398.9580 μmol) , CsF (168 mg, 1.1060 mmol) in DMF (10 mL) . The reaction mixture 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 layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by TLC to give Compound 2. MS: m/z: 601 [M+1]
Compound 2 was separated by Prep-HPLC-Gilson with the following conditions: Column, CHIRAL ART Cellulose-SA column (2cm × 25cm, 5um) ; mobile phase, Hex (0.1%diethylamine) /EtOH (65: 35) ; Flowing rate: 20ml/min. This results in Compound 2A (the first eluting isomer, 49 mg, 81.5807 μmol) , Ret Time 8.406 min) and Compound 2B (the second eluting isomer, 51 mg, 84.9105 μmol) , Ret Time 10.304 min) .
Example 3
A mixture of 2, 6-dichloropyridin-4-amine (35.7 g, 219.0 mmol) , 1- (chloromethyl) -4-fluoro-1, 4-diazoniabicyclo [2.2.2] octane ditetrafluoroborate (93.1 g, 262.8 mmol) in DMF (357 mL) and CH3CN (357 mL) was stirred at 80 ℃ for 6 hours. The reaction mixture was quenched by water (400 mL) and extracted with DCM (400 mL × 3) . The organic layer was combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (eluting with petroleum ether: EtOAc=30: 1, v/v) to give INT 4-1 (12.6 g, purity: about 50%) . MS (ESI, m/z) : 181 [M+H] +.
A mixture of INT 4-1 (2.0 g, 11.05 mmol) , NIS (2.98 g, 13.26 mmol) and p-toluenesulfonic acid monohydrate (105 mg, 0.55 mmol) in CH3CN (8.4 mL) was stirred at 70 ℃ for 4 hours under nitrogen atmosphere. The reaction mixture was quenched by water (20 mL) and extracted with EtOAc (20 mL × 3) . The organic layer was combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column (eluting with petroleum ether: EtOAc=50: 1~ 20: 1, v/v) to give INT 4-2 (3.6 g) . MS (ESI, m/z) : 307 [M+H] +.
A mixture of INT 4-2 (1.0 g, 3.26 mmol) , Pd (PPh3) 2Cl2 (229 mg, 0.33 mmol) and Et3N (1.19 g, 11.77 mmol) in EtOH (17.0 mL) was stirred at 80 ℃ for 20 hours under carbon monoxide atmosphere (1.5 MPa) in a sealed tube. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column to give INT 4-3 (1.2 g) . MS (ESI, m/z) : 253 [M+H] +.
A mixture of INT 4-3 (4.53 g, 17.90 mmol) , NaOH (2.99 g, 74.76 mmol) in EtOH (50 mL) and water (10 mL) was stirred for 4 hours at 50 ℃. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (40 mL) and extracted with EtOAc (2 × 30 mL) . The water phase was adjusted pH to 2 and extracted with EtOAc (2 × 30 mL) . The organic layer was combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give INT 4-4 (2.68 g, 11.91 mmol, 66.54%yield) . MS:m/z 225 (M+H) +.
A mixture of INT 4-4 (2.44 g, 10.84 mmol) and SOCl2 (15 mL) was stirred for 2 hours at 70 ℃. The mixture was concentrated under reduced pressure. A solution of the obtained residue in CH3CN (10 mL) was added dropwise to a mixture of ammonium thiocyanate (2.22 g, 29.16 mmol) in CH3CN (40 mL) , then stirred for 1.5 hours. The reaction mixture was filtered and the filter cake was collected, dried to give INT 4-5 (2.21 g, 8.31 mmol, 76.59%yield) . MS: m/z 264 (M-H) -.
To a mixture of INT 4-5 (2.01 g, 7.55 mmol) , NaOH (aq. 0.1 M, 150 mL) and MeOH (150 mL) was added CH3I (2.22 g, 15.64 mmol) . The mixture was stirred for 0.5 hour at RT. The water phase was adjusted pH to 3 by hydrochloric acid and extracted with EtOAc (1 × 200 mL, 1 × 100 mL) . The organic layer was combined and concentrated under reduced pressure. The residue was triturated with water (20 mL) to give INT 4-6 (1.88 g, 6.71 mmol, 88.85 %yield) . MS: m/z 278 (M-H) -.
To a solution of INT 4-6 (9.01 g, 32.17 mmol) in DMF (100 mL) and MeOH (20 mL) and THF (50 mL) was added NaH (2.79 g, 69.76 mmol, 60%content) in portions at 0 ℃. The mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched by hydrochloric acid (1 N) , then filtered. The collected filter cake was dried in an oven. The crude product INT 4 (10.038 g) was used in the next step directly. MS: m/z 274 [M-H] -.
To a solution of INT 4 (2.85 g, 10.34 mmol) and DIEA (5 mL) in toluene (30 mL) was added phosphorus oxychloride (5 mL) , then stirred at 85 ℃ for 1 hour. Upon completion, the mixture was concentrated under reduced pressure. The residue was diluted with DCM (40 mL) , then DIEA (5 mL) and 2-oxa-6-azabicyclo [5.1.0] octane (1188 mg, 10.50 mmol) were added and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with sat. aq. NH4Cl. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give Compound 3-1 (2.84 g, 74.08%yield) . MS: m/z 371 [M+H] +.
A solution of Compound 3-1 (193 mg, 0.52 mmol) and m-CPBA (226 mg, 1.31 mmol) in DCM (5 mL) was stirred for 0.5 h, and quenched with sat. NaHCO3 (10 mL) . The collected organic layer was concentrated under reduced pressure. The obtained crude Compound 3-2 (297 mg) was used to next step directly. MS m/z: 403 [M+H] +.
To a solution of Compound 3-2 (297 mg, crude) and (2-methylenetetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (155 mg, 1.01 mmol) in THF (10 mL) was added t-BuONa (52 mg, 0.54 mmol) at RT under nitrogen atmosphere. The mixture was stirred for 1 h, quenched with water (10 mL) and extracted with EA (15 mL) . The collected organic layer was concentrated under reduced pressure. The obtained crude Compound 3-3 (280 mg) was used to next step directly. MS m/z: 476 [M+H] +.
To a solution of Compound 3-3 (280 mg, crude) , INT 3 (400 mg, 0.78 mmol) in toluene (5 mL) and water (1 mL) were added Cs2CO3 (395 mg, 1.21 mmol) and cataCXium A Pd G3 (45 mg, 0.06 mmol) . The reaction mixture was stirred at 100 ℃ overnight under nitrogen atmosphere. The mixture was filtered and the filtrate was diluted with water (10 mL) and extracted with EA (10 mL) . The collected organic layer was concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM: MeOH=12/1, v/v) to give Compound 3-4 (59 mg, 0.07 mmol, 12.14%yield for three steps) . MS m/z: 826 [M+H] +.
A solution of Compound 3-4 (59 mg, 0.07 mmol) and HCl (2 mL, 4M in dioxane) in DCM (5 mL) was stirred at RT for 2 h. The mixture was concentrated under reduced pressure and diluted with water (15 mL) and EA (15 mL) . The pH of the solution was adjusted to 9 with K2CO3. The collected organic layer was concentrated under reduced pressure to give Compound 3-5 (crude) . MS m/z: 782 [M+H] +.
A mixture of Compound 3-5 (crude) and CsF (0.28 g, 1.84 mmol) in DMF (5 mL) was stirred at 60 ℃
for 1.5 h under nitrogen atmosphere. The mixture was diluted with water (20 mL) and extracted with EA (20 mL) . The collected organic layer was washed with brine (20 mL) and concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1%TFA in water, B: CH3CN, Gradient: 15%B to 40%B in 35 min at a flow rate of 60 mL/min, 285 nm) to freeze-dried to afford Compound 3 (20.3 mg, TFA salt) . MS m/z: 626 [M+H] +.
Example 4
Compound 1-6 was separated by Prep-HPLC-Gilson with the following conditions: Column, CHIRAL ART Cellulose-IG column (2cm × 25cm, 5um) ; mobile phase, (Hex: DCM=3: 1) : EtOH=70: 30; Flowing rate: 20 ml/min. This results in the first eluting isomer (Ret Time 4.8758 min) and the second eluting isomer (Ret Time 6.02 min) . The first eluting isomer was confirmed to Compound 4-7 and the second eluting isomer was confirmed to Compound 4-8. MS: m/z: 329 [M+1] +.
A solution of Compound 4-8 (329 mg, 0.99 mmol) , INT 5 (162 mg, 1.06 mmol) , t-BuONa (102 mg, 1.06 mmol) in THF (5 mL) was stirred at RT for 40 min. The reaction was diluted with H2O (20 mL) , extracted with EA (2 × 20 mL) . The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC with (DCM/MeOH=10/1) to give Compound 4-9 (172 mg, 0.38 mmol, 38.6%yield) . MS:m/z: 446 [M+H] +.
A mixture of Compound 4-9 (172 mg, 0.38 mmol) , INT 3 (270 mg, 0.53 mmol) , cataCXium A Pd G3 (30 mg, 41.19 μmol) , Cesium carbonate (384 mg, 1.17 mmol) in toluene (4 mL) and water (1 mL) was stirred at 100 ℃ for 18 hours under nitrogen atmosphere. The reaction was allowed to cool to room temperature and then diluted with H2O (20 mL) , extracted with EA (2 × 10 mL) . The organic layer was concentrated in vacuum. The residue was purified by Pre-TLC (DCM/MeOH=12/1) to give Compound 4-10 (152 mg, 0.19 mmol, 49.5%yield) . MS: m/z: 796 [M+H] +.
To a solution of Compound 4-10 (152 mg, 0.19 mmol) in ACN (5 mL) was added HCl (4M in 1, 4-dioxane, 2 mL) . The solution was stirred at room temperature for 2 h. The reaction was concentrated, the residue was dissolved in EA (20 mL) and H2O (20 mL) , the pH value of the reaction was adjusted to 9 with saturated K2CO3 (aq. ) (20 mL) . The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuum to give crude Compound 4-11 (143 mg, 0.19 mmol, 99.6%yield) . MS: m/z: 752 [M+H] +
To a solution of Compound 4-11 (143 mg, 0.19 mmol) in DMF (5 mL) was added CsF (270 mg, 1.77 mmol) . The reaction mixture was stirred for 3 h at 50 ℃. The solution was diluted with H2O (20 mL) , extracted with EA (2 × 20 mL) . The organic layer was concentrated under vacuum. The residue was purified by Prep-HPLC (YMC-Triart Prep C18-S12nm, A: 0.05%NH3·H2O in water, B: CH3CN, Gradient: 30 %B to 85 %B in 50 min at a flow rate of 70 mL/min, 228 nm) , freeze-dried to give Compound 4 (105 mg, 0.17 mmol, 89.47%yield) . MS: m/z: 596 [M+H] +.
Example 5
A solution of INT 6 (16 mg, 93.4517 μmol) , sodium tert-butoxide (161 mg, 494.1395 μmol) in THF (5 mL) was stirred at 5 ℃, and a solution of Compound 4-8 (39 mg, 118.4845 μmol) in THF (1 mL) was added dropwise. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with 10%NaHCO3 solution (10 mL) , extracted with EA (2 × 30 mL) . The organic layer was washed with NaCl (aq. ) , then dried over Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 5-1 (24 mg, 51.7345 μmol, 43.6635%yield) . MS: m/z: 464 [M+H] +.
To a solution of Compound 5-1 (24 mg, 51.7345 μmol) in toluene (3 mL) were added INT 3 (44 mg, 85.8479 μmol) , cataCXium A Pd G3 (12 mg, 16.4774 μmol) , cesium carbonate (55 mg, 168.8054 μmol) and water (0.5 mL) . The mixture was stirred at 110 ℃ for 4 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (20 mL) and extracted with EA (2 × 20 mL) . The organic layer was washed with NaCl (aq. ) , then dried over Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 5-2 (28 mg, 34.3972 μmol, 66.4879%yield) . MS: m/z: 814 [M+H] +.
To a solution of Compound 5-2 (28 mg, 34.3972 μmol) in DCM (3 mL) was added HCl (4M in dioxane, 0.6 mL) . The mixture was stirred at room temperature for 15 min. The solution was diluted with 10%NaHCO3 solution (20 mL) , extracted with DCM (2 × 20 mL) , the organic layer was washed with NaCl (aq. ) , dried over Na2SO4 and concentrated in vacuum to give crude Compound 5-3 (28 mg, 36.3652 μmol, crude) . MS: m/z: 770 [M+H] +.
To a solution of Compound 5-3 (28 mg, 36.3652 μmol) in DMF (3 mL) was added CsF (162 mg, 1.0665 mmol) . The mixture was stirred for 2 hours at room temperature. The solution was diluted with water (20 mL) and extracted with EA (2 × 20mL) . The organic layers were dried over Na2SO4 and concentrated under vacuum . The residue was purified by Prep-HPLC (C18 column, A: 0.05 %NH3·H2O in water, B: CH3CN, Gradient: 0%B to 48%B in 33 min at a flow rate of 40 mL/min, 228 nm) , the eluent was concentrated to freeze-dried to give Compound 5 (10.4 mg, 16.9484 μmol, 46.6061%yield) . MS: m/z: 614 [M+H] +.
Example 6
Compound 6-1 is synthesized in the same method as Compound 4-9, with the difference that INT 5 is replaced by INT 2.
A solution of Compound 6-1 (0.344g, 761.2371 μmol) ,
2- [2, 3-difluoro-6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-naphthyl] ethynyl-triis opropyl-silane (523 mg, 985.8158 μmol) , cataCXium A Pd G3 (66 mg, 90.6257 μmol) , cesium carbonate (761 mg, 2.3357 mmol) in toluene (15 mL) and water (3 mL) . The reaction mixture was stirred at 100 ℃ for 18 hours under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with sat. NaCl (15 mL) and extracted with EA (15 mL) . The organic layer was washed with NaCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 6-2 (296 mg, 360.9757 μmol, 47.4196%yield) . MS: m/z: 820 [M+H] +.
A solution of Compound 6-2 (0.296g, 360.9757 μmol) , HCl in (4M in 1, 4-dioxane, 2 mL) in DCM (10 mL) was stirred at room temperature for 2 h. The solution was diluted with 10%NaHCO3 solution (20 mL) . The organic layer was washed with NaCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give crude Compound 6-3 (301 mg, 387.9129 μmol) . MS: m/z: 776 [M+H] +.
Trifluoromethanesulfonic anhydride (178 mg, 630.8951 μmol) was dropped into a solution of Compound 6-3 (0.301g, 387.9131 μmol) , pyridine (193 mg, 2.4400 mmol) in DCM (50 mL) at 0 ℃, the system was stirred at room temperature for 12 hours. The solution was diluted with 10%NaHCO3 (10 mL) , the organic layer was washed with sat. NaCl, dried over Na2SO4 and concentrated in vacuum . The residue was purified by Pre-TLC to give Compound 6-4 (222 mg, 244.4909 μmol) . MS: m/z: 908 [M+H] +.
A solution of Compound 6-4 (0.222g, 244.4910 μmol) , Benzophenone imine (88 mg, 485.5628 μmol) , Cesium carbonate (173 mg, 530.9698 μmol) , Palladium (II) Acetate (18 mg, 80.1754 μmol) , BINAP (28 mg, 44.9676 μmol) in 1, 4-dioxane (10 mL) . The reaction mixture was stirred for 20 hours at 95 ℃ under nitrogen atmosphere. The solution was diluted with water (10 mL) and extracted with EA (10 mL) , the organic layer was washed with sat. NaCl. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by Pre-TLC to give Compound 6-5 (235 mg, 250.2223 μmol) . MS: m/z: 939 [M+H] +.
A solution of Compound 6-5 (235 mg, 250.2223 μmol) , HCl (4M in 1, 4-dioxane, 0.5 mL) in DCM (8 mL) was stirred at room temperature for 2 h. The solution was diluted with 10%NaHCO3 (20 mL) , the organic layer was washed with sat. NaCl dried over Na2SO4 and concentrated in vacuum to give crude Compound 6-6 (216 mg, 278.7232 μmol) . MS: m/z: 775 [M+H] +.
A solution of Compound 6-6 (216 mg, 278.7232 μmol) , CsF (127 mg, 836.0577 μmol) in DMF (10 mL) . The reaction mixture was stirred for 20 hours at 40 ℃ under nitrogen atmosphere. The solution was diluted with sat. NaCl (10 mL) and extracted with EA (10 mL) . The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by TLC, the eluent was concentrated and freeze-dried to give Compound 6 (93 mg, 150.3340 μmol) . MS: m/z: 619 [M+H] +.
Example 7
To a solution of INT 7 (130 mg, 0.49 mmol) and DIEA (3 mL) in toluene (10 mL) was added phosphorus oxychloride (3 mL) , then stirred at 100 ℃ for 0.5 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was diluted with DCM (20 mL) , then DIEA (2 mL) and Compound 1-5 (158 mg, 1.40 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, the residue was diluted with sat. aq. NaHCO3, extracted with EtOAc (2 × 30 mL) , the organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give Compound 7-1 (72 mg, 40.71%yield) . MS: m/z 359 [M+H] +.
To a solution of Compound 7-1 (72 mg, 0.20 mmol) and INT 2 (52 mg, 0.33 mmol) in DMSO (5 mL) was added KF (108 mg, 1.86 mmol) , then the mixture was stirred at 90 ℃ for 4 hours. After cooled to room temperature, the mixture was diluted with water (20 mL) , extracted with EtOAc (2 × 30 mL) , the organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with DCM: MeOH= 15: 1, v/v) to give Compound 7-2 (62 mg, 64.18%
yield) . MS: m/z 482 [M+H] +.
To a solution of Compound 7-2 (62 mg, 0.13 mmol) , INT 3 (86 mg, 0.17 mmol) and Cs2CO3 (150 mg, 0.46 mmol) in toluene (4 mL) and water (1 mL) was added cataCXium A Pd G3 (20 mg, 0.027 mmol) . The mixture was purged with nitrogen followed by stirring at 100 ℃ for 16 hours. Upon completion, the reaction mixture was diluted with water (20 mL) , extracted with EtOAc (2 × 20 mL) , the organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with DCM: MeOH= 10: 1, v/v) to give Compound 7-3 (20.7 mg, 19.34%yield) . MS: m/z 832 [M+1] +.
To a solution of Compound 7-3 (30 mg, 0.036 mmol) in acetonitrile (5 mL) was added HCl (4M in 1, 4-dioxnae, 1.5 mL) . The reaction mixture was stirred at 0 ℃ for 1 hour. After completion, the mixture was concentrated under reduced pressure. The residue was dissolved in DMF (5 mL) and CsF (284 mg, 1.87 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion, the mixture was concentrated under reduced pressure to obtain Compound 7-4. Compound 7-4 was dissolved in DMF (5 mL) and CsF (284 mg, 1.87 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion, the mixture was diluted with water (30 mL) , extracted with EtOAc (2 × 30 mL) , the organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Pre-HPLC (Agela Durashell C18, 30 mm × 250 mm, 10 um; A: 0.1 %TFA in water, B: CH3CN, Gradient: 15 %B to 50 %B in 33 min at a flow rate of 40 mL/min, 285 nm) and freeze-dried to give Compound 7 (1.1 mg, 4.09 yield, TFA salt) . MS: m/z 632 [M+H] + .
Example 8
To a solution of INT 8 (92 mg, 0.33 mmol) and DIEA (1 mL) in toluene (5 mL) was added phosphorus oxychloride (1 mL) , then stirred at 100 ℃ for 1.5 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was diluted with DCM (10 mL) , then DIEA (2 mL) and Compound 1-5 (119 mg, 1.05 mmol) were added and the reaction mixture was stirred at room temperature for 1 hour. Another batch of Compound 1-5 (42 mg, 0.37 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (30 mL) , extracted with DCM (2 × 30 mL) , the organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC to give Compound 8-1 (39 mg, 31.58 %yield) . MS: m/z 373 [M+H] +.
To a solution of Compound 8-1 (39 mg, 0.10 mmol) and INT 2 (41 mg, 0.26 mmol) in DMSO (5 mL) was added KF (32 mg, 0.55 mmol) , then the mixture was stirred at 90 ℃ for 16 hours. After cooled to room temperature, the mixture was diluted with water (30 mL) , extracted with EtOAc (2 × 30 mL) , the organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Pre-TLC to give Compound 8-2 (69 mg, 133.14%yield, crude) . MS: m/z 496 [M+H] +.
To a solution of Compound 8-2 (69 mg, 0.14 mmol) , INT 3 (97 mg, 0.19 mmol) and Cs2CO3 (144 mg, 0.44 mmol) in toluene (4 mL) and water (1 mL) was added cataCXium A Pd G3 (11 mg, 0.015 mmol) . The mixture was purged with nitrogen followed by stirring at 100 ℃ for 4 hours. The reaction mixture was diluted with water (30 mL) , extracted with EtOAc (2 × 30 mL) , the organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with DCM: MeOH= 10: 1, v/v) to give Compound 8-3 (21 mg, 17.84%yield) . MS: m/z 846 [M+1] +.
To a solution of Compound 8-3 (30 mg, 0.036 mmol) in acetonitrile (5 mL) was added HCl (4M in 1,
4-dioxnae, 2 mL) . The reaction mixture was stirred at 0 ℃ for 2 hours. After completion, the mixture was concentrated under reduced pressure. The residue was dissolved in DMF (5 mL) and CsF (766 mg, 5.04 mmol) was added. The mixture was stirred at room temperature for 16 hours. After completion, the mixture was diluted with water (20 mL) , extracted with EtOAc (2 × 20 mL) , the organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Pre-HPLC (Agela Durashell C18, 30 mm × 250 mm, 10 um; A: 0.1 %TFA in water, B: CH3CN, Gradient: 20 %B to 59 %B in 39 min at a flow rate of 40 mL/min, 240 nm) and freeze-dried to give Compound 8 (5.5 mg, TFA salt) . MS:m/z 646 [M+H] + .
Example 9
To a mixture of methyltriphenylphosphonium bromide (13.10 g, 36.67 mmol) in THF (60 mL) was added t-BuOK (4.22 g, 37.61 mmol) at 0 ℃. After stirring for 0.75 h, the mixture was added 1- (tert-butyl) 2-methyl 4-oxopyrrolidine-1, 2-dicarboxylate (6.72 g, 27.63 mmol) in THF (20 ml) . The mixture was stirring for 2h at RT, diluted with aq. NH4Cl (50 mL) , extracted with EA (30 mL × 2) . The collected organic layer was washed with brine (50 mL) , dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column to give Compound 9-1 (4.83 g, 20.02 mmol) . MS m/z: 242 [M+H] +.
To a solution of Compound 9-1 (4.52 g, 18.73 mmol) in THF (45 mL) was added LiHMDS (35 ml, 1 mol/L in THF) at -78 ℃. After stirring for 1 h, the mixture was added 3-chloro-2- (chloromethyl) prop-1-ene (5.18 g, 41.44 mmol) in THF (10 ml) at -65 ℃. The mixture was slowly warmed up to RT and stirring for 2 h. The reaction was diluted with water (50 mL) , extracted with EA (40 mL × 2) . The collected organic layer was washed with brine (50 mL) , dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column to give Compound 9-2 (4.26 g, 12.92 mmol) . MS m/z: 330 [M+H] +.
To a solution of Compound 9-2 (4.05 g, 12.28 mmol) in DCM (40 mL) was added TFA (13 ml) . The reaction mixture was stirred at RT for 1.5 h and concentrated under reduced pressure. The residue was dissolved in DCM (30 mL) and the PH adjusted to 9 with NH3 (7 mol/L in MeOH) . The reaction was stirred at RT for 1 h and concentrated under reduced pressure. To the residue was added DCM (40 mL) and filtered, the filtrate concentrated under reduced pressure. The residue was purified by silica gel column to give Compound 9-3 (1.47 g, 7.62 mmol) . MS m/z: 194 [M+H] +.
To a mixture of Compound 9-3 (1.47 g, 7.62 mmol) in THF (15 mL) was added LAH (537 mg, 14.15 mmol) at 0 ℃. The reaction mixture was stirred at RT for 1 h, quenched with water (0.5 ml) , aq. NaOH (0.5 ml, 15 %w/w) , and water (1.5 mL) . The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column to give Compound 9-4 (822 mg, 4.97 mmol) . MS m/z: 166 [M+H] +.
To a solution of Compound 9-4 (169 mg, 1.02 mmol) in THF (5 ml) was added t-BuONa (129 mg, 1.34 mmol) at 0 ℃. After stirring for 10 min, to the mixture was added Compound 4-8 (219 mg, 0.67 mmol) . The mixture was stirred at RT for 1 h, quenched with water (20 mL) and extracted with EA (30 mL) . The organic layer was washed with brine (30 mL) , dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC to give Compound 9-5 (252 mg, 0.55 mol) . MS m/z: 458 [M+H] +.
To a solution of Compound 9-5 (60 mg, 131.03 μmol) , INT 3 (94 mg, 183.40 μmol) in toluene (6 mL) and water (1.5 mL) was added cataCXium A Pd G3 (26 mg, 31.93 μmol) , Cs2CO3 (103 mg, 0.32 mmol) . The reaction mixture was stirred at 100 ℃ for 17 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (40 mL) and extracted with EA (2 × 30mL) . The collected organic layer was washed with aq. NaCl (30 mL) , dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC to give Compound 9-6 (52 mg, 64.35 μmol) . MS: m/z: 808 [M+H] +.
A solution of Compound 9-6 (52 mg, 64.35 μmol) , HCl (4M in dioxane, 1mL) in ACN (3 mL) was stirred at RT for 1 h. The solution was concentrated under reduced pressure, diluted with sat. NaHCO3 solution (20 mL) , extracted with EA (30 mL × 2) . The collected organic layer was washed with brine (30 mL) , dried over Na2SO4 and concentrated under reduced pressure to give Compound 9-7 (64 mg, crude) . MS m/z: 764 [M+H] +.
A mixture of Compound 9-7 (64 mg, crude) , CsF (0.34 g, 2.24 mmol) in DMF (5 mL) was stirred at 45 ℃for 3 h. The mixture was diluted with water (30 mL) and extracted with EA (30 mL) . The collected organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1%TFA in water, B: CH3CN, Gradient: 15%B to 35%B in 29 min at a flow rate of 60 mL/min, 245 nm) to freeze-dried to give Compound 9 (23.8 mg, TFA salt) . MS m/z: 608 [M+H] +.
Example 10
To a solution of Compound 7-4 (645 mg, 0.82 mmol) , pyridine (653 mg, 8.26 mmol) in DCM (10 mL) was added trifluoromethanesulfonic anhydride (1296 mg, 4.59 mmol) at 0 ℃. The mixture was stirred at 0 ℃for 1 hour. The reaction mixture was diluted with EtOAc (50 mL) , washed with water (2 × 30 mL) , the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM: MeOH= 30: 1, v/v) to give Compound 10-1 (654 mg, 86.84%yield) . MS m/z: 920 [M+H] +.
To a solution of Compound 10-1 (504 mg, 0.55 mmol) , benzophenone imine (214 mg, 1.18 mmol) in toluene (10 mL) were added Cs2CO3 (564 mg, 1.73 mmol) , Pd2 (dba) 3 (100 mg, 0.11 mmol) and Xantphos (122 mg, 0.21 mmol) . The reaction mixture was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Pre-TLC (DCM: MeOH=30: 1, v/v) to give Compound 10-2 (720 mg, 138.18%yield) . MS m/z: 951 [M+H] +.
A solution of Compound 10-2 (720 mg, 0.76 mmol) and HCl (4 mL, 4 M in dioxane) in DCM (20 mL) was stirred at room temperature overnight. The solution was concentrated under reduced pressure. The residue was diluted with sat. NaHCO3 solution (30 mL) and extracted with EtOAc (50 mL) . The organic layer was concentrated under reduced pressure to give Compound 10-3 (655 mg, 0.83 mmol, 109.95 %yield) . MS m/z: 787 [M+H] +
To a solution of Compound 10-3 (655 mg, 0.83 mmol) in DMF (5 mL) was added CsF (1.34 g, 8.82 mmol) . The reaction mixture was stirred at 40 ℃ for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1%TFA in water, B: CH3CN, Gradient: 15%B to 40%B in 45 min at a flow rate of 60 mL/min, 240 nm) to freeze-dried to give Compound 10 (78.9 mg, TFA salt) . MS m/z: 631 [M+H] +.
Example 11
To a solution of tert-butyl 2-oxa-6-azabicyclo [5.1.0] octane-6-carboxylate (0.747 g, 3.5026 mmol) in DCM (10 mL) was added TFA (5 mL) . The mixture was stirred at RT for 1 h. The mixture was concentrated. The residue was charged with DCM (20 mL) and then concentrated and repeated the operation for 3 times. The residue was charged with DCM (5 mL) and added DIPEA to adjust PH~7 to give mixture A. To a solution of 7-bromo-2, 4-dichloro-8-fluoro-6-iodoquinazoline (1064 mg, 2.5224 mmol) , DIPEA (928 mg, 7.1803 mmol) in DCM (5 mL) was added the mixture A dropwise. The mixture was stirred at RT for 3 h. The mixture was charged with DCM (50 mL) , washed with brine (3 × 30 mL) and concentrated to give Compound 11-1 (1231 mg, 2.4693 mmol) . MS: m/z 498/500 [M+H] +.
A mixture of Compound 11-1 (1231 mg, 2.4693 mmol) , INT 2 (548 mg, 3.4422 mmol) , DIPEA (886 mg, 6.8553 mmol) in 1, 4-dioxane (10 mL) was stirred at 100 ℃ overnight. Another INT 2 (580 mg, 3.6432 mmol) and DIPEA (945 mg, 7.3118 mmol) were added to the reaction and the reaction was stirred at 100 ℃ overnight. The mixture was concentrated and purified by pre-HPLC to give Compound 11-2 (563 mg, 906.2295 μmol) MS:m/z 621/623 [M+H] +.
A mixture of Compound 11-2 (0.563 g, 906.2301 μmol) , zinc cyanide (162 mg, 1.3796 mmol) , tetrakis (triphenylphosphine) palladium (110 mg, 95.1920 μmol) in DMF (8 mL) was stirred at 100 ℃overnight. The mixture was charged with water (80 mL) and filtered. The filter cake was purified by pre-TLC to give Compound 11-3 (78 mg, 149.8937 μmol) . MS: m/z 520/522 [M+H] +.
A mixture of Compound 11-3 (0.078 g, 149.8937 μmol) , INT 9 (0.40 g, 633.2123 μmol) , cataCXium A Pd G3 (44 mg, 60.4172 μmol) , Cs2CO3 (158 mg, 484.9320 μmol) in toluene (3 mL) and water (0.8 mL) was stirred at 100 ℃ overnight under nitrogen atmosphere. The mixture was charged with DCM/MeOH = 10/1 (30 mL) , washed with brine (30 mL) and concentrated. The mixture was purified by pre-TLC to give Compound 11-4 (67 mg, 70.8848 μmol) . MS: m/z 945 [M+H] +.
To a solution of Compound 11-4 (0.067 g, 70.8848 μmol) in DCM (2 mL) was added HCl (0.3 mL, 4 M in 1, 4-dioxane) . The mixture was stirred at RT for 2h. The mixture was added another HCl (0.3 mL, 4M in 1, 4-dioxane) and stirred at RT overnight. The reaction mixture was concentrated under vacuum to give crude Compound 11-5 which was used in the next step directly without further purification (55 mg, 70.4231 μmol) . MS:781 [M+H] +.
A mixture of Compound 11-5 (0.055 g, 70.4232 μmol) , cesium fluoride (1.37 g, 9.0198 mmol) in DMF (1 mL) was stirred at RT for 3 h. The reaction was purified by pre-HPLC. The product fractions were lyophilized to give Compound 11 (17 mg, 43.9901μmol) . MS: m/z 625 [M+H] +.
Example 12
A mixture of 6-bromo-N, N-bis (4-methoxybenzyl) -4-methylpyridin-2-amine (1000 mg, 2.3401 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (836 mg, 3.32921 mmol) , 1, 1'-Bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (180 mg, 221.51 μmol) , potassium acetate (463 mg, 4.717 mmol) in 1, 4-dioxane (20 ml) was stirred overnight at 90 ℃ under nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered and concentrated under vacuum to give crude (6- (bis (4-methoxybenzyl) amino) -4-methylpyridin-2-yl) boronic acid which was used in the next step directly without further purification. MS: 393 [M+H] +
A mixture of INT 10 (3.05 g, 9.2321 mmol) in DCM (40 mL) was cooled to 0 ℃. 2-oxa-6-azabicyclo [5.1.0] octane was added dropwise over 5 min maintaining the internal temperature below 0 ℃. The reaction was stirred at 0 ℃ for 1 h. The residue was diluted with H2O (10 mL) and extracted with DCM (2 × 20 mL) . The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was pulped with methanol and the mixture was filtered and the solids were washed with Hex to give Compound 12-1 (2.60 g) . MS: m/z 406/408 [M+H] +
A mixture of Compound 12-1 (701 mg, 1.722 mmol) , (6- (bis (4-methoxybenzyl) amino) -4-methylpyridin-2-yl) boronic acid (1124 mg, 1.369 mmol) , potassium phosphate (743 mg, 3.500mmol) , bis (triphenylphosphine) palladium (II) chloridein (128 mg, 181.32 μmol) in 1, 4-dioxane (16 ml) and water (4 ml) was stirred overnight at 60 ℃ under nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered and concentrated under vacuum. The crude product was purified by silica column chromatography using 0%~39.2%EA in Hex to give Compound 12-2 (830 mg) . MS: 674 [M+H] +.
A mixture of Compound 12-2 (326 mg, 483.2565 μmol) in acetic acid (3 mL) was cooled to 0 ℃. NIS (108 mg, 483.2565 μmol) was added batch-wise. The resulting mixture was stirred for 1 h. The residue was diluted with sat. sodium thiosulfate (5 mL) and extracted with DCM (2 × 20 mL) . The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by pre-TLC (Hex: EtOAc = 2: 1, v/v) to give Compound 12-3. MS: m/z 800 [M+H] +.
To a mixture of Compound 12-3 (93 mg, 116.1794 μmol) , CuI (49 mg, 257.2854 μmol) in DMF (2 ml) were added methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (114 mg, 593.3989 μmol) and hexamethylphosphoramide (107 mg, 597.0992 μmol) dropwise maintaining the internal temperature below 0 ℃. The resulting mixture was stirred for 5 h at 90 ℃. The residue was diluted with water (5 mL) and extracted with EA (2 × 20 mL) . The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by pre-TLC (Hex: EtOAc = 3: 1, v/v) to give Compound 12-4 (78 mg) . MS: m/z 742 [M+H] +.
A mixture of INT 2 (31 mg, 194.7224 μmol) in THF (1 mL) was cooled to 0 ℃. NaH (11 mg, 275.0264 μmol) was added batch-wise. The resulting mixture was stirred for 1 h at RT. Compound 12-4 (58 mg, 78.1052 μmol) in THF (1 ml) was added dropwise. The resulting mixture was stirred for 3 h at RT. The residue was diluted with sat. ammonium chloride (4 mL) and extracted with EA (2 × 10 mL) . The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by pre-TLC (Hex: EtOAc = 3: 1, v/v) to give Compound 12-5 (32 mg) . MS: m/z 865 [M+H] +.
A mixture of Compound 12-5 (32 mg) in TFA (1.5 ml) was stirred for 5 h at 50 ℃. The reaction mixture
was concentrated under vacuum. The residue was purified by Prep-HPLC. The product fractions were lyophilized to give Compound 12 (4.2 mg, TFA salt) . MS: m/z 625 [M+H] + .
Example 13
A solution of Compound 12-1 (472 mg, 1.1595 mmol) , INT 11 (703 mg, 4.1054 mmol) and KF (227 mg, 3.9073 mmol) in DMSO (10 mL) was stirred at 135 ℃ for 72 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (20 mL) and extracted with EA (10 mL) . The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 13-2 (232 mg, 428.1708 μmol, 36.9266%yield) . MS: m/z: 541 [M+H] +.
A solution of Compound 13-2 (76 mg, 140.2628 μmol) , toluene (3 mL) , INT 12 (49 mg, 156.9889 μmol) , cataCXium A Pd G3 (12 mg, 16.4774 μmol) , cesium carbonate (148 mg, 454.2401 μmol) and water (1 mL) was stirred at 100 ℃ for 13 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 13-3 (78 mg, 106.9615 μmol, 76.2579%) . MS: m/z: 729 [M+H] +.
A solution of Compound 13-3 (78 mg, 106.9614 μmol) and TFA (1 mL) in DCM (5 mL) was stirred at room temperature for 1 h. The solution was diluted with 10%aqueous NaHCO3 solution and extracted with DCM (10 mL × 2) . The residue was purified by Prep-HPLC (C18 column, A: 0.1 %TFA in water, B: CH3CN, gradient: 15 %B to 44 %B in 35 min at a flow rate of 60 mL/min, 240 nm) . The eluent was adjusted to pH 8 and the acetonitrile in the eluent was concentrated. The resulting aqueous phase was extracted with EA (10 mL) , and the organic phase was dried and concentrated then freeze-dried to give Compound 13 (14 mg, 22.2533 μmol, 20.8050%) . MS: m/z: 629 [M+H] +.
Example 14
A solution of 1- (tert-butyl) 2-methyl (2S, 4R) -4-fluoropyrrolidine-1, 2-dicarboxylate (5.06 g, 20.46 mmol) in THF (40 mL) was cooled to -60 ℃. LiHMDS (1 M in THF, 40 mL) was added dropwise and stirred at -60 ℃for 50 min. Then 3-chloro-2- (chloromethyl) prop-1-ene (5.05 g, 40.40 mmol) was added and stirred for 16 h. Then the mixture was quenched with water (100 mL) , extracted with EA (2 × 50 mL) . The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuum. The crude was purified by silica gel column chromatography, eluted with 0-10%EA in hex to afford Compound 14-1 (4927 mg, 14.67 mmol, 71.6%yield) . MS (ESI, m/z) : 336 [M+H] +.
To a solution of Compound 14-1 (4927 mg, 14.67 mmol) in DCM (45 mL) was added TFA (15 mL) . The solution was stirred for 1.5 h at room temperature. Then the mixture was concentrated under reduced pressure. The residue was dissolved in DCM (15 mL) , added dropwise ammonia (7 M in MeOH, 15 mL) and stirred at room temperature for 1.5 h. Then the mixture was concentrated under reduced pressure. The residue was dissolved in EA (30 mL) , washed with water (30 mL) . The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuum. The crude was purified by silica gel column chromatography, eluted with 0-20%
EA in hex to afford Compound 14-2 (2.52 g, 12.64 mmol, 86.2%yield) . MS (ESI, m/z) : 200 [M+H] +.
To a solution of Compound 14-2 (2.52 g, 12.64 mmol) in THF (20 mL) was added LAH (788 mg, 20.76 mmol) at 0 ℃ and stirred at room temperature for 1 h. Then crystalline sodium sulfate solid was added, filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0 -5%methanol in DCM to afford Compound 14-3 (1537 mg, 8.97 mmol, 70.9%yield) . MS (ESI, m/z) : 172 [M+H] +.
A solution of Compound 14-3 (45 mg, 262.83 μmol) in THF (5 mL) was cooled to 0 ℃. Then t-BuONa (46 mg, 478.65 μmol) was added, followed with N- (4- (4- (2-oxa-6-azabicyclo [5.1.0] octan-6-yl) -8-fluoro-5-methoxy-2- (methylsulfinyl) pyrido [4, 3-d] pyrimidin-7-yl) -6-fluoro-5- ( (triisopropylsilyl) ethynyl) naphthalen-2-yl) -1, 1-diphenylmethanimine (96.8092 mg, 113.08 μmol) . The reaction mixture was stirred for 1 hour. Then the mixture was quenched with water (10 mL) . The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Pre-TLC to afford Compound 14-4 (102 mg, 105.89 μmol, 93.6%yield) . MS (ESI, m/z) : 963 [M+H] +.
To a solution of Compound 14-4 (102 mg, 105.89 μmol) in DCM (10 mL) was added HCl (4 M in 1, 4-dioxane, 5 mL) . The reaction mixture was stirred at room temperature for 10 min and concentrated under reduced pressure to afford Compound 14-5 which was used to next step directly without further purification.
To a solution of Compound 14-5 (84.6117 mg, 105.89 μmol) in DMF (5 mL) was added CsF (531 mg, 3.49 mmol) . The reaction mixture was stirred at room temperature for 18 hours. Then the solution was added water (20 mL) , extracted with EA (20 mL) . The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by Prep-HPLC (Daisogel-C18, phase A: 0.1 %TFA in water, phase B: CH3CN, gradient: 15 %B to 40 %B in 41 min at a flow rate of 60 mL/min, 245 nm) and freeze-dried to afford Compound 14 (13.2 mg, TFA salt) . MS (ESI, m/z) : 643 [M+H] +.
Pharmacological Experiments
1. SOS1 catalyzed nucleotide exchange assay
GDP-loaded HIS-KRAS (G12V, aa 1-169) was pre-incubated with a compound in the presence of 10nM GDP in a 384-well plate (Greiner) for 15 min, then purified SOS1 ExD (Flag tag, aa 564-1049) , BODIPYTM FL GTP (Invitrogen) and MAb (monoclonal antibody) Anti 6HIS-Tb cryptate Gold (Cisbio) were added to the assay wells (Final concentration: 10-15nM GDP-loaded HIS-KRAS (G12V) , 5 nM GDP, 0.5μM SOS1 ExD, 80 nM BODIPYTM FL GTP, 52.5 ng/mL MAb Anti 6HIS-Tb cryptate Gold) and incubated for 4 hours at 25 ℃. Wells containing same percent of DMSO served as vehicle control, and wells without KRAS served as low control. TR-FRET signals were read on Tecan Spark multimode microplate reader. The parameters were F486: Excitation 340nm, Emission 486nm, Lag time 100 μs, Integration time 200 μs; F520: Excitation 340nm, Emission 520nm, Lag time 100 μs, Integration time 200 μs. TR-FRET ratios for each individual wells were calculated by equation: TR-FRET ratio = (Signal F520/Signal F486) *10000. The percent of activation of compounds treated wells were normalized between vehicle control and low control (%Activation = (TR-FRET ratioCompound treated –TR-FRET ratioLow control) / (TR-FRET ratioVehicle control –TR-FRET ratioLow control) *100%) . Then the data were analyzed either by fitting a 4-parameter logistic model or by Excel to calculate IC50 values.
Table 1
Claims (87)
- A compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof:
Wherein,X2 at each occurrence is independently selected from N or CR1;R1 is selected from hydrogen, deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (R1A) 2, -OR1A, -SR1A, -S (=O) R1B, -S (=O) 2R1B, -C (=O) R1B, -C (=O) OR1A, -OC (=O) R1B, -C (=O) N (R1A) 2, -NR1AC (=O) R1B, -OC (=O) OR1A, -NR1AC (=O) OR1A, -NR1AC (=S) OR1A, -OC (=O) N (R1A) 2, -NR1AC (=O) N (R1A) 2, -S (=O) OR1A, -OS (=O) R1B, -S (=O) N (R1A) 2, -NR1AS (=O) R1B, -S (=O) 2OR1A, -OS (=O) 2R1B, -S (=O) 2N (R1A) 2, -NR1AS (=O) 2R1B, -OS (=O) 2OR1A, -NR1AS (=O) 2OR1A, -OS (=O) 2N (R1A) 2, -NR1AS (=O) 2N (R1A) 2, -P (R1A) 2, -P (=O) (R1B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (R1C) 2, -OR1C, -SR1C, -S (=O) R1D, -S (=O) 2R1D, -C (=O) R1D, -C (=O) OR1D, -OC (=O) R1D, -C (=O) N (R1C) 2, -NR1CC (=O) R1D, -OC (=O) OR1C, -NR1CC (=O) OR1C, -NR1CC (=S) OR1C, -OC (=O) N (R1C) 2, -NR1CC (=O) N (R1C) 2, -S (=O) OR1C, -OS (=O) R1D, -S (=O) N (R1C) 2, -NR1CS (=O) R1D, -S (=O) 2OR1C, -OS (=O) 2R1D, -S (=O) 2N (R1C) 2, -NR1CS (=O) 2R1D, -OS (=O) 2OR1C, -NR1CS (=O) 2OR1C, -OS (=O) 2N (R1C) 2, -NR1CS (=O) 2N (R1C) 2, -P (R1C) 2, -P (=O) (R1D) 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;Ring A1 is selected from a 3-10 membered heterocyclic ring optionally further comprising 1, 2 or 3 heteroatoms selected from N, O, S, S=O or S (=O) 2;Ring A2 is selected from a 3-10 membered carbocyclic ring, 3-10 membered heterocarbocyclic ring, 6-10 membered aryl or 5-10 membered heteroaryl;RS1 is independently selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS1A) 2, -ORS1A, -SRS1A, -S (=O) RS1B, -S (=O) 2RS1B, -C (=O) RS1B, -C (=O) ORS1A, -OC (=O) RS1B, -C (=O) N (RS1A) 2, -NS1AC (=O) RS1B, -OC (=O) ORS1A, -NS1AC (=O) ORS1A, -NRS1AC (=S) OS1A, -OC (=O) N (RS1A) 2, -NRS1AC (=O) N (RS1A) 2, -S (=O) ORS1A, -OS (=O) RS1B, -S (=O) N (RS1A) 2, -NRS1AS (=O) RS1B, -S (=O) 2ORS1A, -OS (=O) 2RS1B, -S (=O) 2N (RS1A) 2, -NRS1AS (=O) 2RS1B, -OS (=O) 2ORS1A, -NRS1AS (=O) 2ORS1A, -OS (=O) 2N (RS1A) 2, -NRS1AS (=O) 2N (RS1A) 2, -P (RS1A) 2, -P (=O) (RS1B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS1C) 2, -ORS1C, -SRS1C, -S (=O) RS1D, -S (=O) 2RS1D, -C (=O) RS1D, -C (=O) ORS1C, -OC (=O) RS1D, -C (=O) N (RS1C) 2, -NRS1CC (=O) RS1D, -OC (=O) ORS1C, -NRS1CC (=O) ORS1C, -NRS1CC (=S) ORS1C, -OC (=O) N (RS1C) 2, -NRS1CC (=O) N (RS1C) 2, -S (=O) ORS1C, -OS (=O) RS1D, -S (=O) N (RS1C) 2, -NRS1CS (=O) RS1D, -S (=O) 2ORS1C, -OS (=O) 2RS1D, -S (=O) 2N (RS1C) 2, -NRS1CS (=O) 2RS1D, -OS (=O) 2ORS1C, -NRS1CS (=O) 2ORS1C, -OS (=O) 2N (RS1C) 2, -NRS1CS (=O) 2N (RS1C) 2, -P (RS1C) 2, -P (=O) (RS1D) 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;Optionally, two RS1 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS11;Optionally, two adjacent RS1 together with the 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 unsubstituted or substituted with one or more RS12;Optionally, two nonadjacent RS1 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 independently not replaced or 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 independently unsubstituted or substituted with RS13;m1 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;RS2 is independently selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS2A) 2, -ORS2A, -SRS2A, -S (=O) RS2B, -S (=O) 2RS2B, -C (=O) RS2B, -C (=O) ORS2A, -OC (=O) RS2B, -C (=O) N (RS2A) 2, -NRS2AC (=O) RS2B, -OC (=O) ORS2A, -NRS2AC (=O) ORS2A, -NRS2AC (=S) ORS2A, -OC (=O) N (RS2A) 2, -NRS2AC (=O) N (RS2A) 2, -S (=O) ORS2A, -OS (=O) RS2B, -S (=O) N (RS2A) 2, -NRS2AS (=O) RS2B, -S (=O) 2ORS2A, -OS (=O) 2RS2B, -S (=O) 2N (RS2A) 2, -NRS2AS (=O) 2RS2B, -OS (=O) 2ORS2A, -NRS2AS (=O) 2ORS2A, -OS (=O) 2N (RS2A) 2, -NRS2AS (=O) 2N (RS2A) 2, -P (RS2A) 2, -P (=O) (RS2B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS2C) 2, -ORS2C, -SRS2C, -S (=O) RS2D, -S (=O) 2RS2D, -C (=O) RS2D, -C (=O) ORS2D, -OC (=O) RS2D, -C (=O) N (RS2C) 2, -NRS2CC (=O) RS2D, -OC (=O) ORS2C, -NRS2CC (=O) ORS2C, -NRS2CC (=S) ORS2C, -OC (=O) N (RS2C) 2, -NRS2CC (=O) N (RS2C) 2, -S (=O) ORS2C, -OS (=O) RS2D, -S (=O) N (RS2C) 2, -NRS2CS (=O) RS2D, -S (=O) 2ORS2C, -OS (=O) 2RS2D, -S (=O) 2N (RS2C) 2, -NRS2CS (=O) 2RS2D, -OS (=O) 2ORS2C, -NRS2CS (=O) 2ORS2C, -OS (=O) 2N (RS2C) 2, -NRS2CS (=O) 2N (RS2C) 2, -P (RS2C) 2, -P (=O) (RS2D) 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;Optionally, two RS2 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS21;Optionally, two adjacent RS2 together with the 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 unsubstituted or substituted with one or more RS22;Optionally, two nonadjacent RS2 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 independently not replaced or 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 independently unsubstituted or substituted with RS23;m2 is selected from 0, 1, 2, 3, 4 or 5;Y1 is a bond, O, S, S (=O) , S (=O) 2 or NRY11;RY11 is selected from hydrogen, deuterium, -C1-6alkyl, haloC1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -S (=O) RB, -S (=O) 2RB, -C (=O) RB, -C (=O) ORB, -C (=O) N (RB) 2, -S (=O) ORB, -S (=O) N (RB) 2, -S (=O) 2ORB, -S (=O) 2N (RB) 2, -P (=O) (RB) 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 -C1-6alkyl, haloC1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RC) 2, -ORC, -SRC, -S (=O) RD, -S (=O) 2RD, -C (=O) RD, -C (=O) ORC, -OC (=O) RD, -C (=O) N (RC) 2, -NRCC (=O) RD, -OC (=O) ORC, -NRCC (=O) ORD, -OC (=O) N (RC) 2, -NRCC (=O) N (RC) 2, -S (=O) ORC, -OS (=O) RD, -S (=O) N (RC) 2, -NRCS (=O) RD, -S (=O) 2ORC, -OS (=O) 2RD, -S (=O) 2N (RC) 2, -NRCS (=O) 2RD, -OS (=O) 2ORC, -NRCS (=O) 2ORC, -OS (=O) 2NRC, -NRCS (=O) 2N (RC) 2, -P (RC) 2, -P (=O) (RD) 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;R3 is selected fromEach of R31, R32, R33, R34, R35, R36, R38, R39, R310 and R311 is independently selected form hydrogen, deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -N (RA) 2, -ORA, -SRA, -S (=O) RB, -S (=O) 2RB, -C (=O) RB, -C (=O) ORB, -C (=O) N (RB) 2, -S (=O) ORB, -S (=O) N (RB) 2, -S (=O) 2ORB, -S (=O) 2N (RB) 2, -P (=O) (RB) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RC) 2, -ORC, -SRC, -S (=O) RD, -S (=O) 2RD, -C (=O) RD, -C (=O) ORC, -OC (=O) RD, -C (=O) N (RC) 2, -NRCC (=O) RD, -OC (=O) ORC, -NRCC (=O) ORD, -OC (=O) N (RC) 2, -NRCC (=O) N (RC) 2, -S (=O) ORC, -OS (=O) RD, -S (=O) N (RC) 2, -NRCS (=O) RD, -S (=O) 2ORC, -OS (=O) 2RD, -S (=O) 2N (RC) 2, -NRCS (=O) 2RD, -OS (=O) 2ORC, -NRCS (=O) 2ORC, -OS (=O) 2NRC, -NRCS (=O) 2N (RC) 2, -P (RC) 2, -P (=O) (RD) 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;Optionally, R31 and R32 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS33;Optionally, R33 and R34 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS34;Optionally, R35 and R36 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS35;Optionally, R38 and R39 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS310;Optionally, R310 and R311 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS316;n2 is selected from 0, 1, 2, 3, 4, 5 or 6;n3 is selected from 0, 1, 2, 3, 4, 5 or 6;n4 is selected from 0, 1, 2, 3, 4, 5 or 6;n5 is selected from 0, 1, 2, 3, 4, 5 or 6;n6 is selected from 0, 1, 2, 3, 4, 5 or 6;Ring B is a 3-10 membered heterocyclic ring optionally further containing 1, 2, or 3 heteroatoms selected from N, O, S, S (=O) or S (=O) 2;Ring C is a 3-10 membered heterocyclic ring optionally further containing 1, 2, or 3 heteroatoms selected from N, O, S, S (=O) or S (=O) 2;Ring D is selected from a 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring;Ring I is a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, S, S (=O) or S (=O) 2;Ring J is a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, S, S (=O) or S (=O) 2;Ring K is selected from 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, S, S (=O) or S (=O) 2;RS31 is selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS31A) 2, -ORS31A, -SRS31A, -S (=O) RS31B, -S (=O) 2RS31B, -C (=O) RS31B, -C (=O) ORS31A, -OC (=O) RS31B, -C (=O) N (RS31A) 2, -NRS31AC (=O) RS31B, -OC (=O) ORS31A, -NRS31AC (=O) ORS31A, -NRS31AC (=S) ORS31A, -OC (=O) N (RS31A) 2, -NRS31AC (=O) N (RS31A) 2, -S (=O) ORS31A, -OS (=O) RS31B, -S (=O) N (RS31A) 2, -NRS31AS (=O) RS31B, -S (=O) 2ORS31A, -OS (=O) 2RS31B, -S (=O) 2N (RS31A) 2, -NRS31AS (=O) 2RS31B, -OS (=O) 2ORS31A, -NRS31AS (=O) 2ORS31A, -OS (=O) 2N (RS31A) 2, -NRS31AS (=O) 2N (RS31A) 2, -P (RS31A) 2, -P (=O) (RS31B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS31C) 2, -ORS31C, -SRS31C, -S (=O) RS31D, -S (=O) 2RS31D, -C (=O) RS31D, -C (=O) ORS31C, -OC (=O) RS31D, -C (=O) N (RS31C) 2, -NRS31CC (=O) RS31D, -OC (=O) ORS31C, -NRS31CC (=O) ORS31C, -NRS31CC (=S) ORS31C, -OC (=O) N (RS31C) 2, -NRS31CC (=O) N (RS31C) 2, -S (=O) ORS31C, -OS (=O) RS31D, -S (=O) N (RS31C) 2, -NRS31CS (=O) RS31D, -S (=O) 2ORS31C, -OS (=O) 2RS31D, -S (=O) 2N (RS31C) 2, -NRS31CS (=O) 2RS31D, -OS (=O) 2ORS31C, -NRS31CS (=O) 2ORS31C, -OS (=O) 2N (RS31C) 2, -NRS31CS (=O) 2N (RS31C) 2, -P (RS31C) 2, -P (=O) (RS31D) 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;Optionally, two RS31 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS311;Optionally, two adjacent RS31 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 unsubstituted or substituted with one or more RS312;Optionally, two nonadjacent RS31 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 independently not replaced or 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 independently unsubstituted or substituted with RS313;m3 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;RS32 is selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS32A) 2, -ORS32A, -SRS32A, -S (=O) RS32B, -S (=O) 2RS32B, -C (=O) RS32B, -C (=O) ORS32A, -OC (=O) RS32B, -C (=O) N (RS32A) 2, -NRS32AC (=O) RS32B, -OC (=O) ORS32A, -NRS32AC (=O) ORS32A, -NRS32AC (=S) ORS32A, -OC (=O) N (RS32A) 2, -NRS32AC (=O) N (RS32A) 2, -S (=O) ORS32A, -OS (=O) RS32B, -S (=O) N (RS32A) 2, -NRS32AS (=O) RS32B, -S (=O) 2ORS32A, -OS (=O) 2RS32B, -S (=O) 2N (RS32A) 2, -NRS32AS (=O) 2RS32B, -OS (=O) 2ORS32A, -NRS32AS (=O) 2ORS32A, -OS (=O) 2N (RS32A) 2, -NRS32AS (=O) 2N (RS32A) 2, -P (RS32A) 2, -P (=O) (RS32B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS32C) 2, -ORS32C, -SRS32C, -S (=O) RS32C, -S (=O) 2RS32D, -C (=O) RS32D, -C (=O) ORS32C, -OC (=O) RS32D, -C (=O) N (RS32C) 2, -NRS32CC (=O) RS32D, -OC (=O) ORS32C, -NRS32CC (=O) ORS32C, -NRS32CC (=S) ORS32C, -OC (=O) N (RS32C) 2, -NRS32CC (=O) N (RS32C) 2, -S (=O) ORS32C, -OS (=O) RS32C, -S (=O) N (RS32C) 2, -NRS32CS (=O) RS32D, -S (=O) 2ORS32C, -OS (=O) 2RS32D, -S (=O) 2N (RS32C) 2, -NRS32CS (=O) 2RS32D, -OS (=O) 2ORS32C, -NRS32CS (=O) 2ORS32C, -OS (=O) 2N (RS32C) 2, -NRS32CS (=O) 2N (RS32C) 2, -P (RS32C) 2, -P (=O) (RS32D) 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;Optionally, two RS32 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS321;Optionally, two adjacent RS32 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 unsubstituted or substituted with one or more RS322;Optionally, two nonadjacent RS32 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 independently not replaced or 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 independently unsubstituted or substituted with RS323;m4 is selected from 0, 1, 2, 3, 4, 5 or 6;R37 is selected from -N (R37A) 2 or 3-10 membered heterocyclyl, wherein said 3-10 membered heterocyclyl is optionally independently substituted with one or more RS37;RS38 is selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS38A) 2, -ORS38A, -SRS38A, -S (=O) RS38B, -S (=O) 2RS38B, -C (=O) RS38B, -C (=O) ORS38A, -OC (=O) RS38B, -C (=O) N (RS38A) 2, -NRS38AC (=O) RS38B, -OC (=O) ORS38A, -NRS38AC (=O) ORS38A, -NRS38AC (=S) ORS38A, -OC (=O) N (RS38A) 2, -NRS38AC (=O) N (RS38A) 2, -S (=O) ORS38A, -OS (=O) RS38B, -S (=O) N (RS38A) 2, -NRS38AS (=O) RS38B, -S (=O) 2ORS38A, -OS (=O) 2RS38B, -S (=O) 2N (RS38A) 2, -NRS38AS (=O) 2RS38B, -OS (=O) 2ORS38A, -NRS38AS (=O) 2ORS38A, -OS (=O) 2N (RS38A) 2, -NRS38AS (=O) 2N (RS38A) 2, -P (RS38A) 2, -P (=O) (RS38B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS38C) 2, -ORS38C, -SRS38C, -S (=O) RS38D, -S (=O) 2RS38D, -C (=O) RS38D, -C (=O) ORS38C, -OC (=O) RS38D, -C (=O) N (RS38C) 2, -NRS38CC (=O) RS38D, -OC (=O) ORS38C, -NRS38CC (=O) ORS38C, -NRS38CC (=S) ORS38C, -OC (=O) N (RS38C) 2, -NRS38CC (=O) N (RS38C) 2, -S (=O) ORS38C, -OS (=O) RS38D, -S (=O) N (RS38C) 2, -NRS38CS (=O) RS38D, -S (=O) 2ORS38C, -OS (=O) 2RS38D, -S (=O) 2N (RS38C) 2, -NRS38CS (=O) 2RS38D, -OS (=O) 2ORS38C, -NRS38CS (=O) 2ORS38C, -OS (=O) 2N (RS38C) 2, -NRS38CS (=O) 2N (RS38C) 2, -P (RS38C) 2, -P (=O) (RS38D) 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;Optionally, two RS38 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS381;Optionally, two adjacent RS38 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 unsubstituted or substituted with one or more RS382;Optionally, two nonadjacent RS38 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 independently not replaced or 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 independently unsubstituted or substituted with RS383;m8 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;RS39 is selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS39A) 2, -ORS39A, -SRS39A, -S (=O) RS39B, -S (=O) 2RS39B, -C (=O) RS39B, -C (=O) ORS39A, -OC (=O) RS39B, -C (=O) N (RS39A) 2, -NRS39AC (=O) RS39B, -OC (=O) ORS39A, -NRS39AC (=O) ORS39A, -NRS39AC (=S) ORS39A, -OC (=O) N (RS39A) 2, -NRS39AC (=O) N (RS39A) 2, -S (=O) ORS39A, -OS (=O) RS39B, -S (=O) N (RS39A) 2, -NRS39AS (=O) RS39B, -S (=O) 2ORS39A, -OS (=O) 2RS39B, -S (=O) 2N (RS39A) 2, -NRS39AS (=O) 2RS39B, -OS (=O) 2ORS39A, -NRS39AS (=O) 2ORS39A, -OS (=O) 2N (RS39A) 2, -NRS39AS (=O) 2N (RS39A) 2, -P (RS39A) 2, -P (=O) (RS39B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS39C) 2, -ORS39C, -SRS39C, -S (=O) RS39C, -S (=O) 2RS39D, -C (=O) RS39D, -C (=O) ORS39C, -OC (=O) RS39D, -C (=O) N (RS39C) 2, -NRS39CC (=O) RS39D, -OC (=O) ORS39C, -NRS39CC (=O) ORS39C, -NRS39CC (=S) ORS39C, -OC (=O) N (RS39C) 2, -NRS39CC (=O) N (RS39C) 2, -S (=O) ORS39C, -OS (=O) RS39C, -S (=O) N (RS39C) 2, -NRS39CS (=O) RS39D, -S (=O) 2ORS39C, -OS (=O) 2RS39D, -S (=O) 2N (RS39C) 2, -NRS39CS (=O) 2RS39D, -OS (=O) 2ORS39C, -NRS39CS (=O) 2ORS39C, -OS (=O) 2N (RS39C) 2, -NRS39CS (=O) 2N (RS39C) 2, -P (RS39C) 2, -P (=O) (RS39D) 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;Optionally, two RS39 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS391;Optionally, two adjacent RS39 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 unsubstituted or substituted with one or more RS392;Optionally, two nonadjacent RS39 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 independently not replaced or 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 independently unsubstituted or substituted with RS393;m9 is selected from 0, 1, 2, 3, 4, 5 or 6;RS315 is selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS315A) 2, -ORS315A, -SRS315A, -S (=O) RS315B, -S (=O) 2RS315B, -C (=O) RS315B, -C (=O) ORS315A, -OC (=O) RS315B, -C (=O) N (RS315A) 2, -NRS315AC (=O) RS315B, -OC (=O) ORS315A, -NRS315AC (=O) ORS315A, -NRS315AC (=S) ORS315A, -OC (=O) N (RS315A) 2, -NRS315AC (=O) N (RS315A) 2, -S (=O) ORS315A, -OS (=O) RS315B, -S (=O) N (RS315A) 2, -NRS315AS (=O) RS315B, -S (=O) 2ORS315A, -OS (=O) 2RS315B, -S (=O) 2N (RS315A) 2, -NRS315AS (=O) 2RS315B, -OS (=O) 2ORS315A, -NRS315AS (=O) 2ORS315A, -OS (=O) 2N (RS315A) 2, -NRS315AS (=O) 2N (RS315A) 2, -P (RS315A) 2, -P (=O) (RS315B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS315C) 2, -ORS315C, -SRS315C, -S (=O) RS315C, -S (=O) 2RS315D, -C (=O) RS315D, -C (=O) ORS315C, -OC (=O) RS315D, -C (=O) N (RS315C) 2, -NRS315CC (=O) RS315D, -OC (=O) ORS315C, -NRS315CC (=O) ORS315C, -NRS315CC (=S) ORS315C, -OC (=O) N (RS315C) 2, -NRS315CC (=O) N (RS315C) 2, -S (=O) ORS315C, -OS (=O) RS315C, -S (=O) N (RS315C) 2, -NRS315CS (=O) RS315D, -S (=O) 2ORS315C, -OS (=O) 2RS315D, -S (=O) 2N (RS315C) 2, -NRS315CS (=O) 2RS315D, -OS (=O) 2ORS315C, -NRS315CS (=O) 2ORS315C, -OS (=O) 2N (RS315C) 2, -NRS315CS (=O) 2N (RS315C) 2, -P (RS315C) 2, -P (=O) (RS315D) 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;Optionally, two RS315 together with the carbon atom to which they are both attached forma 3-10 membered carbocyclic ring or a 3-10 heterocyclic ring; wherein, said3-10 membred carbocylic ring or 3-10 heterocyclic ring is independently unsubstituted or substituted with one or more RS3151;Optionally, two adjacent RS315 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 unsubstituted or substituted with one or more RS3152;Optionally, two nonadjacent RS315 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 independently not replaced or 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 independently unsubstituted or substituted with RS3153;m10 is selected from 0, 1, 2, 3, 4, 5 or 6;R4 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, wherein said 6-10 membered aryl, 5-10 membered heteroaryl, is independently unsubstituted or substituted with one or more RS4;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;RS4 is independently selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS4A) 2, -ORS4A, -SRS4A, -S (=O) RS4B, -S (=O) 2RS4B, -C (=O) RS4B, -C (=O) ORS4A, -OC (=O) RS4B, -C (=O) N (RS4A) 2, -NRS4AC (=O) RS4B, -OC (=O) ORS4A, -NRS4AC (=O) ORS4A, -NRS4AC (=S) ORS4A, -OC (=O) N (RS4A) 2, -NRS4AC (=O) N (RS4A) 2, -S (=O) ORS4A, -OS (=O) RS4B, -S (=O) N (RS4A) 2, -NRS4AS (=O) RS4B, -S (=O) 2ORS4A, -OS (=O) 2RS4B, -S (=O) 2N (RS4A) 2, -NRS4AS (=O) 2RS4B, -OS (=O) 2ORS4A, -NRS4AS (=O) 2ORS4A, -OS (=O) 2N (RS4A) 2, -NRS4AS (=O) 2N (RS4A) 2, -P (RS4A) 2, -P (=O) (RS4B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RS4C) 2, -ORS4C, -SRS4C, -S (=O) RS4D, -S (=O) 2RS4D, -C (=O) RS4D, -C (=O) ORS4D, -OC (=O) RS4D, -C (=O) N (RS4C) 2, -NRS4CC (=O) RS4D, -OC (=O) ORS4C, -NRS4CC (=O) ORS4C, -NRS4CC (=S) ORS4C, -OC (=O) N (RS4C) 2, -NRS4CC (=O) N (RS4C) 2, -S (=O) ORS4C, -OS (=O) RS4D, -S (=O) N (RS4C) 2, -NRS4CS (=O) RS4D, -S (=O) 2ORS4C, -OS (=O) 2RS4D, -S (=O) 2N (RS4C) 2, -NRS4CS (=O) 2RS4D, -OS (=O) 2ORS4C, -NRS4CS (=O) 2ORS4C, -OS (=O) 2N (RS4C) 2, -NRS4CS (=O) 2N (RS4C) 2, -P (RS4C) 2, -P (=O) (RS4D) 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;R5 is selected from hydrogen, deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (R5A) 2, -OR5A, -SR5A, -S (=O) R5B, -S (=O) 2R5B, -C (=O) R5B, -C (=O) OR5A, -OC (=O) R5B, -C (=O) N (R5A) 2, -NR5AC (=O) R5B, -OC (=O) OR5A, -NR5AC (=O) OR5A, -NR5AC (=S) OR5A, -OC (=O) N (R5A) 2, -NR5AC (=O) N (R5A) 2, -S (=O) OR5A, -OS (=O) R5B, -S (=O) N (R5A) 2, -NR5AS (=O) R5B, -S (=O) 2OR5A, -OS (=O) 2R5B, -S (=O) 2N (R5A) 2, -NR5AS (=O) 2R5B, -OS (=O) 2OR5A, -NR5AS (=O) 2OR5A, -OS (=O) 2N (R5A) 2, -NR5AS (=O) 2N (R5A) 2, -P (R5A) 2, -P (=O) (R5B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (R5C) 2, -OR5C, -SR5C, -S (=O) R5D, -S (=O) 2R5D, -C (=O) R5D, -C (=O) OR5D, -OC (=O) R5D, -C (=O) N (R5C) 2, -NR5CC (=O) R5D, -OC (=O) OR5C, -NR5CC (=O) OR5C, -NR5CC (=S) OR5C, -OC (=O) N (R5C) 2, -NR5CC (=O) N (R5C) 2, -S (=O) OR5C, -OS (=O) R5D, -S (=O) N (R5C) 2, -NR5CS (=O) R5D, -S (=O) 2OR5C, -OS (=O) 2R5D, -S (=O) 2N (R5C) 2, -NR5CS (=O) 2R5D, -OS (=O) 2OR5C, -NR5CS (=O) 2OR5C, -OS (=O) 2N (R5C) 2, -NR5CS (=O) 2N (R5C) 2, -P (R5C) 2, -P (=O) (R5D) 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;R6 is selected from hydrogen, deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (R5A) 2, -OR6A, -SR6A, -S (=O) R6B, -S (=O) 2R6B, -C (=O) R6B, -C (=O) OR6A, -OC (=O) R6B, -C (=O) N (R6A) 2, -NR6AC (=O) R6B, -OC (=O) OR6A, -NR6AC (=O) OR6A, -NR6AC (=S) OR6A, -OC (=O) N (R6A) 2, -NR6AC (=O) N (R6A) 2, -S (=O) OR6A, -OS (=O) R6B, -S (=O) N (R6A) 2, -NR6AS (=O) R6B, -S (=O) 2OR6A, -OS (=O) 2R6B, -S (=O) 2N (R6A) 2, -NR6AS (=O) 2R6B, -OS (=O) 2OR6A, -NR6AS (=O) 2OR6A, -OS (=O) 2N (R6A) 2, -NR6AS (=O) 2N (R6A) 2, -P (R6A) 2, -P (=O) (R6B) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -CN, -NO2, -N3, oxo, -N (R6C) 2, -OR6C, -SR6C, -S (=O) R6D, -S (=O) 2R6D, -C (=O) R6D, -C (=O) OR6D, -OC (=O) R6D, -C (=O) N (R6C) 2, -NR6CC (=O) R6D, -OC (=O) OR6C, -NR6CC (=O) OR6C, -NR6CC (=S) OR6C, -OC (=O) N (R6C) 2, -NR6CC (=O) N (R6C) 2, -S (=O) OR6C, -OS (=O) R6D, -S (=O) N (R6C) 2, -NR6CS (=O) R6D, -S (=O) 2OR6C, -OS (=O) 2R6D, -S (=O) 2N (R6C) 2, -NR6CS (=O) 2R6D, -OS (=O) 2OR6C, -NR6CS (=O) 2OR6C, -OS (=O) 2N (R6C) 2, -NR6CS (=O) 2N (R6C) 2, -P (R6C) 2, -P (=O) (R6D) 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;Each of R1A, R1C, RS1A, RS1C, RS2A, RS2C, RS31A, RS31C, RS32A, RS32C, R37A, RS38A, RS38C, RS39A, RS39C, RS315A, RS315C, RS4A, RS4C, R5A, R5C, R6A and R6C is independently selected from hydrogen, deuterium, -C1-6alkyl, haloC1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -S (=O) RB, -S (=O) 2RB, -C (=O) RB, -C (=O) ORB, -C (=O) N (RB) 2, -S (=O) ORB, -S (=O) N (RB) 2, -S (=O) 2ORB, -S (=O) 2N (RB) 2, -P (=O) (RB) 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 -C1-6alkyl, haloC1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RC) 2, -ORC, -SRC, -S (=O) RD, -S (=O) 2RD, -C (=O) RD, -C (=O) ORC, -OC (=O) RD, -C (=O) N (RC) 2, -NRCC (=O) RD, -OC (=O) ORC, -NRCC (=O) ORD, -OC (=O) N (RC) 2, -NRCC (=O) N (RC) 2, -S (=O) ORC, -OS (=O) RD, -S (=O) N (RC) 2, -NRCS (=O) RD, -S (=O) 2ORC, -OS (=O) 2RD, -S (=O) 2N (RC) 2, -NRCS (=O) 2RD, -OS (=O) 2ORC, -NRCS (=O) 2ORC, -OS (=O) 2NRC, -NRCS (=O) 2N (RC) 2, -P (RC) 2, -P (=O) (RD) 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;Optionally, (two R1A, two R1C, two RS1A, two RS1C, two RS2A, two RS2C, two RS31A, two RS31C, two RS32A, two RS32C, two R37A, two RS38A, two RS38C, two RS39A, two RS315A, two RS315C, two RS39C, two RS4A, two RS4C, two R5A, two R5C, two R6A and two R6C) together with the nitrogen atom to which they are both attached forms a 3-10 membered heterocyclic ring or a 5-10 membered heteroaryl ring, wherein, said 3-10 membered heterocyclic ring or 5-10 membered heteroaryl ring is independently unsubstituted or substituted with one or more RSS;Each of R1B, R1D, RS1B, RS1D, RS2B, RS2D, RS31B, RS31D, RS32B, RS32D, RS38B, RS38D, RS39B, RS315B, RS315D, RS39D, RS4B, RS4D, R5B, R5D, R6B and R6D is independently selected from hydrogen, deuterium, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, haloC2-6alkenyl, -C2-6alkynyl, haloC2-6alkynyl, -N (RA) 2, -ORA, -SRA, 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -CN, -NO2, -N3, oxo, -N (RC) 2, -ORC, -SRC, -S (=O) RD, -S (=O) 2RD, -C (=O) RD, -C (=O) ORC, -OC (=O) RD, -C (=O) N (RC) 2, -NRCC (=O) RD, -OC (=O) ORC, -NRCC (=O) ORD, -OC (=O) N (RC) 2, -NRCC (=O) N (RC) 2, -S (=O) ORC, -OS (=O) RD, -S (=O) N (RC) 2, -NRCS (=O) RD, -S (=O) 2ORC, -OS (=O) 2RD, -S (=O) 2N (RC) 2, -NRCS (=O) 2RD, -OS (=O) 2ORC, -NRCS (=O) 2ORC, -OS (=O) 2NRC, -NRCS (=O) 2N (RC) 2, -P (RC) 2, -P (=O) (RD) 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;Each of (RA, RB, RC and RD) is independently selected from hydrogen, deuterium, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, 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 unsubsituted or substituted with one or more RSA;Each of RS11, RS12, RS13, RS21, RS22, RS23, RS33, RS34, RS35, RS311, RS312, RS313, RS321, RS322, RS323, RS37, RS310, RS316, RS381, RS382, RS383, RS391, RS392, RS393, RS3151, RS3152, RS3153, RSS and RSA is independently selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -CN, -NO2, -N3, oxo, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH, -O (C1-6alkyl) , -SH, -S (C1-6alkyl) , -S (=O) (C1-6alkyl) , -S (=O) 2 (C1-6alkyl) , -C (=O) (C1-6alkyl) , -C (=O) OH, -C (=O) (OC1-6alkyl) , -OC (=O) (C1-6alkyl) , -C (=O) NH2, -C (=O) NH (C1-6alkyl) , -C (=O) N (C1-6alkyl) 2, -NHC (=O) (C1-6alkyl) , -N (C1-6alkyl) C (=O) (C1-6alkyl) , -OC (=O) O (C1-6alkyl) , -NHC (=O) (OC1-6alkyl) , -N (C1-6alkyl) C (=O) (OC1-6alkyl) , -OC (=O) NH (C1-6alkyl) , -OC (=O) N (C1-6alkyl) 2, -NHC (=O) NH2, -NHC (=O) NH (C1-6alkyl) , -NHC (=O) N (C1-6alkyl) 2, -N (C1-6alkyl) C (=O) NH2, -N (C1-6alkyl) C (=O) NH (C1-6alkyl) , -N (C1-6alkyl) C (=O) N (C1-6alkyl) 2, -S (=O) (OC1-6alkyl) , -OS (=O) (C1-6alkyl) , -S (=O) NH2, -S (=O) NH (C1-6alkyl) , -S (=O) N (C1-6alkyl) 2, -NHS (=O) (C1-6alkyl) , -N (C1-6alkyl) S (=O) (C1-6alkyl) , -S (=O) 2 (OC1-6alkyl) , -OS (=O) 2 (C1-6alkyl) , -S (=O) 2NH2, -S (=O) 2NH (C1-6alkyl) , -S (=O) 2N (C1-6alkyl) 2, -NHS (=O) 2 (C1-6alkyl) , -N (C1-6alkyl) S (=O) 2 (C1-6alkyl) , -OS (=O) 2O (C1-6alkyl) , -NHS (=O) 2O (C1-6alkyl) , -N (C1-6alkyl) S (=O) 2O (C1-6alkyl) , -OS (=O) 2NH2, -OS (=O) 2NH (C1-6alkyl) , -OS (=O) 2N (C1-6alkyl) 2, -NHS (=O) 2NH2, -NHS (=O) 2NH (C1-6alkyl) , -NHS (=O) 2N (C1-6alkyl) 2, -N (C1-6alkyl) S (=O) 2NH2, -N (C1-6alkyl) S (=O) 2NH (C1-6alkyl) , -N (C1-6alkyl) S (=O) 2N (C1-6alkyl) 2, -PH (C1-6alkyl) , -P (C1-6alkyl) 2, -P (=O) H (C1-6alkyl) , -P (=O) (C1-6alkyl) 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 -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, 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 unsubstituted or substituted with one or more substituents selected from deuterium, halogen, -C1-3alkyl, haloC1-3alkyl, haloC1-3alkoxy, -C2-3alkenyl, -C2-3alkynyl, -CN, -NO2, -N3, oxo, -NH2, -NH (C1-3alkyl) , -N (C1-3alkyl) 2, -OH, -O (C1-3alkyl) , -SH, -S (C1-3alkyl) , -S (=O) (C1-3alkyl) , -S (=O) 2 (C1-3alkyl) , -C (=O) (C1-3alkyl) , -C (=O) OH, -C (=O) (OC1-3alkyl) , -OC (=O) (C1-3alkyl) , -C (=O) NH2, -C (=O) NH (C1-3alkyl) , -C (=O) N (C1-3alkyl) 2, -NHC (=O) (C1-3alkyl) , -N (C1-3alkyl) C (=O) (C1-3alkyl) , -OC (=O) O (C1-3alkyl) , -NHC (=O) (OC1-3alkyl) , -N (C1-3alkyl) C (=O) (OC1-3alkyl) , -OC (=O) NH (C1-3alkyl) , -OC (=O) N (C1-3alkyl) 2, -NHC (=O) NH2, -NHC (=O) NH (C1-3alkyl) , -NHC (=O) N (C1-3alkyl) 2, -N (C1-3alkyl) C (=O) NH2, -N (C1-3alkyl) C (=O) NH (C1-3alkyl) , -N (C1-3alkyl) C (=O) N (C1-3alkyl) 2, -S (=O) (OC1-3alkyl) , -OS (=O) (C1-3alkyl) , -S (=O) NH2, -S (=O) NH (C1-3alkyl) , -S (=O) N (C1-3alkyl) 2, -NHS (=O) (C1-3alkyl) , -N (C1-3alkyl) S (=O) (C1-3alkyl) , -S (=O) 2 (OC1-3alkyl) , -OS (=O) 2 (C1-3alkyl) , -S (=O) 2NH2, -S (=O) 2NH (C1-3alkyl) , -S (=O) 2N (C1-3alkyl) 2, -NHS (=O) 2 (C1-3alkyl) , -N (C1-3alkyl) S (=O) 2 (C1-3alkyl) , -OS (=O) 2O (C1-3alkyl) , -NHS (=O) 2O (C1-3alkyl) , -N (C1-3alkyl) S (=O) 2O (C1-3alkyl) , -OS (=O) 2NH2, -OS (=O) 2NH (C1-3alkyl) , -OS (=O) 2N (C1-3alkyl) 2, -NHS (=O) 2NH2, -NHS (=O) 2NH (C1-3alkyl) , -NHS (=O) 2N (C1-3alkyl) 2, -N (C1-3alkyl) S (=O) 2NH2, -N (C1-3alkyl) S (=O) 2NH (C1-3alkyl) , -N (C1-3alkyl) S (=O) 2N (C1-3alkyl) 2, -PH (C1-3alkyl) , -P (C1-3alkyl) 2, -P (=O) H (C1-3alkyl) , -P (=O) (C1-3alkyl) 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;Each of heterocyclyl or heterocyclic at each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, S (=O) or S (=O) 2;Each of heteroaryl at each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S. - The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of claim 1, wherein, ring A1 is selected from 7 membered heterocyclic ring optionally further comprising 1 heteroatom selected from O.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of claim 1 or 2, wherein, ring A1 is a 1, 4-oxazepane ring.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 3, wherein, the compound is selected from any one of the following formulas:
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 4, wherein, ring A2 is selected from a 3-6 membered carbocyclic ring.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 5, wherein, ring A2 is selected from a cyclopropyl ring.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 6, wherein, the compound is selected from any one of the following formulas:
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 7, wherein, m1 is selected from 0, 1 or 2.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 8, wherein, RS1 is selectd from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -OH, -OC1-6alkyl, -CN, -NH2, -NH (C1-6alkyl) or -N (C1-6alkyl) 2; wherein, said -C1-6alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 9, wherein, RS1 is selectd from methyl, -F or -OH.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 10, wherein, RS1 is selectd from methyl or -F.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 11, wherein, m2 is selected from 0, 1 or 2.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 12, wherein, RS2 is selectd from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -OH, -OC1-6alkyl, -CN, -NH2, -NH (C1-6alkyl) or -N (C1-6alkyl) 2; wherein, said -C1-6alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 13, wherein, RS2 is selectd from deuterium, methyl, -F or -OH.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 14, wherein, RS2 is selectd from deuterium, methyl or -F.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 15, wherein, the compound is selected from any one of following formulas:
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 16, wherein, R1 is selected from hydrogen, halogen, -CN, -OC1-6alkyl, -O-haloC1-6alkyl, -S-haloC1-6alkyl, -C1-6alkyl or 3-6 membered cycloalkyl; said -OC1-6alkyl, -C1-6alkyl or 3-6 membered cycloalkyl is unsubsituted or substituted with 1, 2 or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 15, wherein, R1 is selected from hydrogen, -F, -Cl, -CH2CF3, -CH2CH2CN, -SCF3, -CF3, -Br, -CN, -OCH3, methyl, ethyl, or cyclopropyl.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 18, wherein, Y1 is selected from O.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 19, wherein, each of R38 and R39 is independently selected form hydrogen or deuterium.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 20, wherein, n5 is selected from 1.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21, wherein,Ring I is a 4-6 membered cycloalkyl ring.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 22, wherein:Ring J is a 4-6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O or S.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 23, wherein:The moiety ofis selected fromWherein, RS381 is selected from hydrogen or RS38;m81 is selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 24, wherein:RS381 is selected from hydrogen, deuterium, -C1-6alkyl or 3-6 membered cycloalkyl wherein, said -C1-6alkyl or 3-6 membered cycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 25, wherein, RS381 is selected from hydrogen, deuterium, -CH3, -CH2CH3 or cyclopropyl.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 26, wherein, m81 is selected from 0.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 27, wherein:m9 is selected from 0, 1 or 2.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 28, wherein:m9 is selected from 0.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 29, wherein:m9 is selected from 1.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 30, wherein:The moiety ofis selected fromWherein, RS394 is selected from hydrogen or RS391.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 31, wherein:RS39 is selected from halogen;Preferably, RS39 is selected from -F.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 32, wherein:RS391 is selected from hydrogen, deuterium, halogen, or -C1-6alkyl; wherein, said -C1-6alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly;Preferably, RS391 is selected from hydrogen, deuterium, -F, or -CH3.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 33, wherein:The moiety ofis selected from
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 34, wherein:The moiety ofis selected from
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21, wherein:Ring B is a 4-6 membered heterocyclic ring containing the fused N atom.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21 and 36, wherein:Ring C is a 4-6 membered heterocyclic ring containing the fused N atom.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21 and 36 to 37, wherein:The moiety ofis selected from
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21 and 36 to 38, wherein, m3 is selected from 0, 1, 2, 3, or 4.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21 and 31 to 39, wherein, RS31 is selected from deuterium or -F;Optionally, two RS31 together with the carbon atom to which they are both attached formor cyclopropyl; wherein, saidor cyclopropyl is independently unsubstituted or substituted with 1, 2 or 3 RS311; orOptionally, two adjacent RS31 together with the carbon atoms to which they are respectively attached form a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, a phenyl ring or a 5-10 membered heteroaryl ring containing 1 or 2 heteroatoms selected from N, O or S, wherein, each of rings is independently unsubstituted or substituted with 1, 2 or 3 RS312.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21 and 36 to 40, wherein:The moiety ofis selected fromWherein,Ring G is selected from a 5-6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, a phenyl ring, a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, or S;Ring H is selected from a 5-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, a phenyl ring, a 5-10 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, or S;The definition of RS36 is same as RS31;RS314 is selected from hydrogen or RS311;m31 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;m32 is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;m33 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;m34 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;m5 is selected from 0, 1, 2, 3, 4, 5, or 6;m6 is selected from 0, 1, 2, 3, 4, 5, or 6.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21 and 36 to 41, wherein:The moiety ofis selected fromWherein,m31 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;m32 is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;m33 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;m34 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;m5 is selected from 0, 1, 2, 3, 4, 5, or 6;m6 is selected from 0, 1, 2, 3, 4, 5, or 6.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21 and 36 to 42, wherein:RS311 is independently selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -OH, -OC1-6alkyl, -CN, -NH2, -NH (C1-6alkyl) or -N (C1-6alkyl) 2; wherein, said -C1-6alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly;RS312 is independently selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -OH, -OC1-6alkyl, -CN, -NH2, -NH (C1-6alkyl) or -N (C1-6alkyl) 2; wherein, said -C1-6alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly;RS314 is independently selected from hydrogen, deuterium, halogen, -C1-6alkyl, wherein, said -C1-6alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21 and 36 to 43, wherein:RS311 is independently selected from deuterium, -F or -OCH3;RS312 is independently selected from deuterium, -F, -OCH3, or -CH2OCH3;RS314 is independently selected from hydrogen, deuterium, -F, -CH3, -CH2OCH3, -CH2CH2CH3, -CH (CH3) 2, -CHF2, -CH2CH (CH3) 2.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21 and 36 to 44, wherein:RS36 is selected from deuterium or -F.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21 and 36 to 45, wherein:m31 is selected from 0 or 1;m32 is selected from 0 or 1;m33 is selected from 0 or 1;m34 is selected from 0 or 1;m5 is selected from 0 or 1;m6 is selected from 0 or 1.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21 and 36 to 46, wherein:The moiety ofis selected from
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21 and 36 to 47, wherein:The moiety ofis selected from
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21, wherein, each of R310 and R311 is independently selected form hydrogen or deuterium.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21, or 49 wherein, n6 is selected from 1 or 2.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21, 49 or 50, wherein:Ring K is a 4-10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N or O atom.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21, 49 to 51, wherein:The moiety ofis selected fromWherein, ring L is selected from a 4-6 membered heterocyclic ring optionally further comtaining 1 or 2 heteroatoms selected from N or O.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21, 49 to 52, wherein:The moiety ofis selected from
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21, 49 to 53, wherein:RS315 is independently selected from deuterium, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -OH, -OC1-6alkyl, -CN, -NH2, -NH (C1-6alkyl) or -N (C1-6alkyl) 2; wherein, said -C1-6alkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents slected from deuterium, halogen, haloC1-6alkyl, haloC1-6alkoxy, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH or -OC1-6alkly.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21, 49 to 54, wherein, RS315 is independently selected from -F or -CH3.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21, 49 to 55, wherein, m10 is selected from 0, 1, 2, or 3.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21, 49 to 56, wherein:The moiety ofis selected from
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21, 49 to 57, wherein:The moiety ofis selected from
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 21, wherein, is selected from:
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 59, wherein, R4 is selected from phenyl, pyridyl, naphthyl, quinolyl, isoquinolyl, indazolyl, benzothiaphenyl or benzothiozolyl, said phenyl, pyridyl, naphthyl, quinolyl, isoquinolyl, indazolyl, benzothiaphenyl or benzothiozolyl is unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 RS4.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 60, wherein, R4 is selected fromm7 is selected from 0, 1, 2 or, 3;RS4a is selected from -OH or -NH2;RS4b is selected from hydrogen, deuterium, halogen;RS4c is selected from hydrogen, deuterium, -C1-3alkyl, -C2-3alkenyl or -C2-3alkynyl;RS4d is selected from hydrogen, deuterium or halogen;RS4e is selected from hydrogen, deuterium, halogen, -C1-3alkyl or haloC1-3alkyl;RS4f is selected from -OH or -NH2;RS4g is selected from hydrogen, deuterium, halogen, -C1-3alkyl or haloC1-3alkyl;RS4h is selected from hydrogen, deuterium, halogen, -C1-3alkyl or haloC1-3alkyl;RS4i is selected from hydrogen, deuterium, halogen, -C1-3alkyl or haloC1-3alkyl;RS4j is selected from hydrogen, deuterium, halogen, -CN, -C1-3alkyl, halogC1-3alkyl or -OhaloC1-3alkyl;RS4k is selected from hydrogen, deuterium, halogen, -CN, -C1-3alkyl, halogC1-3alkyl or -OhaloC1-3alkyl;RS4l is selected from hydrogen, deuterium, halogen, -CN, -C1-3alkyl, halogC1-3alkyl or -OhaloC1-3alkyl;RS4m is selected from hydrogen, deuterium, halogen, -CN, -C1-3alkyl, halogC1-3alkyl or -OhaloC1-3alkyl;RS4n is selected from hydrogen, deuterium, halogen, -CN, -C1-3alkyl, halogC1-3alkyl or -OhaloC1-3alkyl;RS4o is selected from hydrogen, deuterium, halogen, -CN, -C1-3alkyl, halogC1-3alkyl or -OhaloC1-3alky;RS4p is selected from hydrogen, deuterium, halogen, -CN, -C1-3alkyl, halogC1-3alkyl or -OhaloC1-3alky.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 61, wherein:m7 is selected from 0;RS4a is selected from -OH or -NH2;RS4b is selected from -F;RS4c is selected from ethyl, ethenyl or ethynyl;RS4d is selected from hydrogen, or -F;RS4e is selected from -F;RS4f is selected from -NH2;RS4g is selected from hydrogen, -F, or methyl;RS4h is selected from hydrogen, -F or methyl;RS4i is selected from -I or -CF3;RS4j is selected from -CN;RS4k is selected from hydrogen;RS4l is selected from methyl;RS4m is selected from -CF3, -OCF2Cl, -OCF3 or -CF2H;RS4n is selected from hydrogen, -F, -Cl, -CH3 or -CF3;RS4o is selected from hydrogen, -F, -Cl, -CH3 or -CF3;RS4p is selected from hydrogen, -F, -Cl, -CH3 or -CF3.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 62, wherein:R4 is selected from
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 63, wherein, R5 is selected from halogen;Preferably, R5 is selected from -F.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 64, wherein, R6 is selected from hydrogen, deuterium, halogen, -OH, -OC1-6alkyl, -NH2, -NHC1-6alkyl or -N (C1-6alkyl) 2;Preferably, R6 is selected from hydrogen, -F, -OCH3, -OCH2CH3, or -NHCH3;More preferably, R6 is selected from hydrogen.
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 65, wherein, the prodrug is selected from the following formula:
R3, R5, R6, X2, Y1, RS1, RS2, m1, m2, ring A1, and ring A2 have the same definitions as above;R41 at each occurrence is independently selected fromR4c is selected from hydrogen, -C1-30alkyl, -C2-30alkenyl, -C2-30alkynyl, -C0-6alkylene- (3-20 membered carbocyclyl) , -C0-6alkylene- (3-20 membered heterocyclyl) , -C0-6alkylene- (6-10 membered aryl) or -C0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R4j;R4d and R4e are each selected from hydrogen, -C1-30alkyl, -C2-30alkenyl, -C2-30alkynyl, -C (=O) C1-6alkyl, -C0-6alkylene- (3-20 membered carbocyclyl) , -C0-6alkylene- (3-20 membered heterocyclyl) , -C0-6alkylene- (6-10 membered aryl) or -C0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R4j;R4f and R4g are each selected from hydrogen, -C1-30alkyl, -C2-30alkenyl, -C2-30alkynyl, -C (=O) C1-6alkyl, -C0-6alkylene- (3-20 membered carbocyclyl) , -C0-6alkylene- (3-20 membered heterocyclyl) , -C0-6alkylene- (6-10 membered aryl) or -C0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R4j;R4h, R4i, R4m, R4n and R4p are each selected from hydrogen, halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, oxo, -OH, -O (C1-6alkyl) , -SH, -S (C1-6alkyl) , -S (haloC1-6alkyl) , -S (=O) (C1-6alkyl) , -S (=O) 2 (C1-6alkyl) , -C (=O) (C1-6alkyl) , -C (=O) OH, -C (=O) (OC1-6alkyl) , -OC (=O) (C1-6alkyl) , -C (=O) NH2, -C (=O) NH (C1-6alkyl) , -C (=O) N (C1-6alkyl) 2, -NHC (=O) (C1-6alkyl) , -N (C1-6alkyl) C (=O) (C1-6alkyl) , -S (=O) 2NH2, -S (=O) 2NH (C1-6alkyl) , -S (=O) 2N (C1-6alkyl) 2, -NHS (=O) 2 (C1-6alkyl) , -N (C1-6alkyl) S (=O) 2 (C1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, 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, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -CN, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, oxo, -OH, -O (C1-6alkyl) , -SH, -S (C1-6alkyl) , -S (haloC1-6alkyl) , -S (=O) (C1-6alkyl) , -S (=O) 2 (C1-6alkyl) , -C (=O) (C1-6alkyl) , -C (=O) OH, -C (=O) (OC1-6alkyl) , -OC (=O) (C1-6alkyl) , -C (=O) NH2, -C (=O) NH (C1-6alkyl) , -C (=O) N (C1-6alkyl) 2, -NHC (=O) (C1-6alkyl) , -N (C1-6alkyl) C (=O) (C1-6alkyl) , -S (=O) 2NH2, -S (=O) 2NH (C1-6alkyl) , -S (=O) 2N (C1-6alkyl) 2, -NHS (=O) 2 (C1-6alkyl) , -N (C1-6alkyl) S (=O) 2 (C1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;Optionally, R4f and R4g 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 R4j;Optionally, R4f and R4h 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 R4j;R4j at each occurrence is independently selected from halogen, -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, -CN, oxo, -NO2, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2, -OH, -O (C1-6alkyl) , -SH, -S (C1-6alkyl) , -S (haloC1-6alkyl) , -S (=O) (C1-6alkyl) , -S (=O) 2 (C1-6alkyl) , -C (=O) (C1-6alkyl) , -C (=O) OH, -C (=O) (OC1-6alkyl) , -OC (=O) (C1-6alkyl) , -C (=O) NH2, -C (=O) NH (C1-6alkyl) , -C (=O) N (C1-6alkyl) 2, -NHC (=O) (C1-6alkyl) , -N (C1-6alkyl) C (=O) (C1-6alkyl) , -S (=O) 2NH2, -S (=O) 2NH (C1-6alkyl) , -S (=O) 2N (C1-6alkyl) 2, -NHS (=O) 2 (C1-6alkyl) , -N (C1-6alkyl) S (=O) 2 (C1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein said -C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, -C2-6alkenyl, -C2-6alkynyl, 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; -C1-6alkyl; haloC1-6alkyl; -CN; oxo; -OH; -NH2; -NH (C1-6alkyl) ; -N (C1-6alkyl) 2; -OC1-6alkyl; or -C1-6alkyl substituted with 1, 2 or 3 substituents selected from halogen, haloC1-6alkyl, -CN, -OH, -NH2, -NH (C1-6alkyl) , -N (C1-6alkyl) 2 or -OC1-6alkyl;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;Preferably, -OR41 is selected from:
- The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 66, wherein,the compound is selected from the following formula:
Wherein,The moiety ofis selected from:The moiety ofis selected from:R4 is selected from: R4 is selected from-OR41 is selected from: - The compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a PROTAC molecule thereof of any one of claims 1 to 67, wherein, the compound is selected from Table A in the description.
- A pharmaceutical composition, comprising a therapeutically effective amount 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 PROTAC molecule thereof of any one of claims 1 to 68, and a pharmaceutically acceptable excipient.
- 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 or a PROTAC molecule thereof of any one of claims 1 to 68, or the pharmaceutical composition of claim 69 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 PROTAC molecule thereof of any one of claims 1 to 68, or the pharmaceutical composition of claim 69 to the subject in need thereof.
- 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 the PROTAC molecule thereof of any one of claims 1 to 68, or the pharmaceutical composition of claim 69 for use in therapy.
- 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 PROTAC molecule thereof of any one of claims 1 to 68, or the pharmaceutical composition of claim 69 for use as a medicament.
- 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 PROTAC molecule thereof of any one of claims 1 to 68, or the pharmaceutical composition of claim 69 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, the prodrug thereof, the deuterated molecule thereof or the conjugated form thereof of any one of claims 1 to 68, or the pharmaceutical composition of claim 69 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 PROTAC molecule thereof of any one of claims 1 to 68, or the pharmaceutical composition of claim 69 for the manufacture of a medicament for the treatment of cancer.
- The method for treating cancer of 70, the use in a method for the treatment of cancer of claim 74, the use for the treatment of cancer of claim 75, or the use for the manufacture of a medicament for the treatment of cancer of claim 76, 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 70 or 77, the use in a method for the treatment of cancer of claim 74 or 77, the use for the treatment of cancer of claim 75 or 77, or the use for the manufacture of a medicament for the treatment of cancer of claim 76 or 77, 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 70, 77 or 78, the use in a method for the treatment of cancer of claim 74, 77 or 78, the use for the treatment of cancer of claim 75, 77 or 78, or the use for the manufacture of a medicament for the treatment of cancer of claim 76, 77 or 78, wherein, the cancer a K-Ras G12C associated cancer.
- The method for treating cancer of 70, 77 or 78, the use in a method for the treatment of cancer of claim 74, 77 or 78, the use for the treatment of cancer of claim 75, 77 or 78, or the use for the manufacture of a medicament for the treatment of cancer of claim 76, 77 or 78, wherein, the cancer a K-Ras G12D associated cancer.
- The method for treating cancer of 70, 77 or 78, the use in a method for the treatment of cancer of claim 74, 77 or 78, the use for the treatment of cancer of claim 75, 77 or 78, or the use for the manufacture of a medicament for the treatment of cancer of claim 76, 77 or 78, wherein, the cancer a K-Ras G12V associated cancer.
- The method for treating cancer of 70, 77 or 78, the use in a method for the treatment of cancer of claim 74, 77 or 78, the use for the treatment of cancer of claim 75, 77 or 78, or the use for the manufacture of a medicament for the treatment of cancer of claim 76, 77 or 78, wherein, the cancer a K-Ras G13D associated cancer.
- The method for treating cancer of 70, 77 or 78, the use in a method for the treatment of cancer of claim 74, 77 or 78, the use for the treatment of cancer of claim 75, 77 or 78, or the use for the manufacture of a medicament for the treatment of cancer of claim 76, 77 or 78, wherein, the cancer a K-Ras G12R associated cancer.
- The method for treating cancer of 70, 77 or 78, the use in a method for the treatment of cancer of claim 74, 77 or 78, the use for the treatment of cancer of claim 75, 77 or 78, or the use for the manufacture of a medicament for the treatment of cancer of claim 76, 77 or 78, wherein, the cancer a K-Ras G12S associated cancer.
- The method for treating cancer of 70, 77 or 78, the use in a method for the treatment of cancer of claim 74, 77 or 78, the use for the treatment of cancer of claim 75, 77 or 78, or the use for the manufacture of a medicament for the treatment of cancer of claim 76, 77 or 78, wherein, the cancer a K-Ras G12A associated cancer.
- The method for treating cancer of 70, 77 or 78, the use in a method for the treatment of cancer of claim 74, 77 or 78, the use for the treatment of cancer of claim 75, 77 or 78, or the use for the manufacture of a medicament for the treatment of cancer of claim 76, 77 or 78, wherein, the cancer a K-Ras Q61H associated cancer.
- The method for treating cancer of 70, 77 or 78, the use in a method for the treatment of cancer of claim 74, 77 or 78, the use for the treatment of cancer of claim 75, 77 or 78, or the use for the manufacture of a medicament for the treatment of cancer of claim 76, 77 or 78, wherein, the cancer a K-Ras wild type amplification associated cancer.
Applications Claiming Priority (34)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2022103727 | 2022-07-04 | ||
CN2022103723 | 2022-07-04 | ||
CNPCT/CN2022/103723 | 2022-07-04 | ||
CNPCT/CN2022/103727 | 2022-07-04 | ||
CNPCT/CN2022/113760 | 2022-08-19 | ||
CN2022113760 | 2022-08-19 | ||
CN2022113826 | 2022-08-22 | ||
CN2022113825 | 2022-08-22 | ||
CNPCT/CN2022/113825 | 2022-08-22 | ||
CNPCT/CN2022/113826 | 2022-08-22 | ||
CNPCT/CN2022/121011 | 2022-09-23 | ||
CN2022121011 | 2022-09-23 | ||
CNPCT/CN2022/121515 | 2022-09-27 | ||
CN2022121515 | 2022-09-27 | ||
CNPCT/CN2022/121635 | 2022-09-27 | ||
CN2022121635 | 2022-09-27 | ||
CNPCT/CN2022/123336 | 2022-09-30 | ||
CN2022123336 | 2022-09-30 | ||
CNPCT/CN2022/125526 | 2022-10-14 | ||
CN2022125526 | 2022-10-14 | ||
CN2022125647 | 2022-10-17 | ||
CNPCT/CN2022/125647 | 2022-10-17 | ||
CNPCT/CN2022/126756 | 2022-10-21 | ||
CN2022126756 | 2022-10-21 | ||
CN2022127360 | 2022-10-25 | ||
CNPCT/CN2022/127360 | 2022-10-25 | ||
CN2023070967 | 2023-01-06 | ||
CNPCT/CN2023/070967 | 2023-01-06 | ||
CNPCT/CN2023/071315 | 2023-01-09 | ||
CN2023071315 | 2023-01-09 | ||
CNPCT/CN2023/072558 | 2023-01-17 | ||
CN2023072558 | 2023-01-17 | ||
CNPCT/CN2023/094458 | 2023-05-16 | ||
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Citations (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021041671A1 (en) * | 2019-08-29 | 2021-03-04 | Mirati Therapeutics, Inc. | Kras g12d inhibitors |
WO2022002102A1 (en) * | 2020-06-30 | 2022-01-06 | InventisBio Co., Ltd. | Quinazoline compounds, preparation methods and uses thereof |
WO2022031678A1 (en) * | 2020-08-04 | 2022-02-10 | Mirati Therapeutics, Inc. | Kras g12d inhibitors |
WO2022061251A1 (en) * | 2020-09-18 | 2022-03-24 | Plexxikon Inc. | Compounds and methods for kras modulation and indications therefor |
WO2022068921A1 (en) * | 2020-09-30 | 2022-04-07 | 上海医药集团股份有限公司 | Quinazoline compound and application thereof |
WO2022105855A1 (en) * | 2020-11-20 | 2022-05-27 | Jacobio Pharmaceuticals Co., Ltd. | Kras g12d inhibitors |
WO2022132200A1 (en) * | 2020-12-15 | 2022-06-23 | Mirati Therapeutics, Inc. | Azaquinazoline pan-kras inhibitors |
WO2022173870A1 (en) * | 2021-02-09 | 2022-08-18 | Kumquat Biosciences Inc. | Heterocyclic compounds and uses thereof |
WO2022232332A1 (en) * | 2021-04-29 | 2022-11-03 | Amgen Inc. | 2-aminobenzothiazole compounds and methods of use thereof |
WO2022237649A1 (en) * | 2021-05-10 | 2022-11-17 | Nikang Therapeutics, Inc. | Exocyclic amino quinazoline derivatives as kras inhibitors |
WO2022248885A2 (en) * | 2021-05-28 | 2022-12-01 | Redx Pharma Plc. | Compounds |
WO2022258974A1 (en) * | 2021-06-10 | 2022-12-15 | Redx Pharma Plc | Quinazoline derivatives useful as ras inhibitiors |
WO2023018809A1 (en) * | 2021-08-10 | 2023-02-16 | Amgen Inc. | Heterocyclic compounds and methods of use |
WO2023018812A1 (en) * | 2021-08-10 | 2023-02-16 | Amgen Inc. | Heterocyclic compounds and methods of use |
WO2023018810A1 (en) * | 2021-08-10 | 2023-02-16 | Amgen Inc. | Heterocyclic compounds and methods of use |
WO2023020519A1 (en) * | 2021-08-18 | 2023-02-23 | Jacobio Pharmaceuticals Co., Ltd. | 1, 4-oxazepane derivatives and uses thereof |
WO2023020523A1 (en) * | 2021-08-18 | 2023-02-23 | Jacobio Pharmaceuticals Co., Ltd. | Bicyclic derivatives and use thereof |
WO2023056951A1 (en) * | 2021-10-08 | 2023-04-13 | 杭州德睿智药科技有限公司 | Aryl-substituted heterocyclic compound |
-
2023
- 2023-07-04 WO PCT/CN2023/105682 patent/WO2024008068A1/en unknown
Patent Citations (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021041671A1 (en) * | 2019-08-29 | 2021-03-04 | Mirati Therapeutics, Inc. | Kras g12d inhibitors |
WO2022002102A1 (en) * | 2020-06-30 | 2022-01-06 | InventisBio Co., Ltd. | Quinazoline compounds, preparation methods and uses thereof |
WO2022031678A1 (en) * | 2020-08-04 | 2022-02-10 | Mirati Therapeutics, Inc. | Kras g12d inhibitors |
WO2022061251A1 (en) * | 2020-09-18 | 2022-03-24 | Plexxikon Inc. | Compounds and methods for kras modulation and indications therefor |
WO2022068921A1 (en) * | 2020-09-30 | 2022-04-07 | 上海医药集团股份有限公司 | Quinazoline compound and application thereof |
WO2022105855A1 (en) * | 2020-11-20 | 2022-05-27 | Jacobio Pharmaceuticals Co., Ltd. | Kras g12d inhibitors |
WO2022132200A1 (en) * | 2020-12-15 | 2022-06-23 | Mirati Therapeutics, Inc. | Azaquinazoline pan-kras inhibitors |
WO2022173870A1 (en) * | 2021-02-09 | 2022-08-18 | Kumquat Biosciences Inc. | Heterocyclic compounds and uses thereof |
WO2022232332A1 (en) * | 2021-04-29 | 2022-11-03 | Amgen Inc. | 2-aminobenzothiazole compounds and methods of use thereof |
WO2022237649A1 (en) * | 2021-05-10 | 2022-11-17 | Nikang Therapeutics, Inc. | Exocyclic amino quinazoline derivatives as kras inhibitors |
WO2022236578A1 (en) * | 2021-05-10 | 2022-11-17 | Nikang Therapeutics, Inc. | Exocyclic amino quinazoline derivatives as kras inhibitors |
WO2022248885A2 (en) * | 2021-05-28 | 2022-12-01 | Redx Pharma Plc. | Compounds |
WO2022258974A1 (en) * | 2021-06-10 | 2022-12-15 | Redx Pharma Plc | Quinazoline derivatives useful as ras inhibitiors |
WO2023018809A1 (en) * | 2021-08-10 | 2023-02-16 | Amgen Inc. | Heterocyclic compounds and methods of use |
WO2023018812A1 (en) * | 2021-08-10 | 2023-02-16 | Amgen Inc. | Heterocyclic compounds and methods of use |
WO2023018810A1 (en) * | 2021-08-10 | 2023-02-16 | Amgen Inc. | Heterocyclic compounds and methods of use |
WO2023020519A1 (en) * | 2021-08-18 | 2023-02-23 | Jacobio Pharmaceuticals Co., Ltd. | 1, 4-oxazepane derivatives and uses thereof |
WO2023020523A1 (en) * | 2021-08-18 | 2023-02-23 | Jacobio Pharmaceuticals Co., Ltd. | Bicyclic derivatives and use thereof |
WO2023056951A1 (en) * | 2021-10-08 | 2023-04-13 | 杭州德睿智药科技有限公司 | Aryl-substituted heterocyclic compound |
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