WO2023143312A1 - Composé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation - Google Patents

Composé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation Download PDF

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WO2023143312A1
WO2023143312A1 PCT/CN2023/072929 CN2023072929W WO2023143312A1 WO 2023143312 A1 WO2023143312 A1 WO 2023143312A1 CN 2023072929 W CN2023072929 W CN 2023072929W WO 2023143312 A1 WO2023143312 A1 WO 2023143312A1
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substituted
membered
alkyl
independently
fluoro
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PCT/CN2023/072929
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Chinese (zh)
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罗会兵
姜佳俊
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上海艾力斯医药科技股份有限公司
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Publication of WO2023143312A1 publication Critical patent/WO2023143312A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention relates to a nitrogen-containing heterocyclic compound, its preparation method and application.
  • the RAS protein When the RAS protein binds to GDP, it is in an "inactive" state; when stimulated by specific upstream cell growth factors, the guanine nucleotide exchange factor (GEF) catalyzes the RAS protein to release GDP, binds to GTP, and is in an "activated” state. "state.
  • the RAS protein combined with GTP can activate downstream proteins and activate downstream signaling pathways.
  • RAS protein itself has weak GTPase activity, which can hydrolyze GTP to GDP, thereby realizing the conversion from activated state to inactive state. In this hydrolysis process, GTPase-activating protein (GAP) is also required to participate, which can interact with RAS protein and greatly promote its ability to hydrolyze GTP to GDP.
  • GAP GTPase-activating protein
  • RAS protein Any mutation in a RAS protein that affects its own GTPase activity or its interaction with GAP or its ability to hydrolyze GTP to GDP will result in a prolonged active state of the RAS protein that continues to be administered Downstream protein growth signals, causing cells to grow and differentiate continuously, which may eventually lead to cancer.
  • RAS gene family There are three members of the RAS gene family: KRAS, NRAS and HRAS.
  • the KRAS G12D inhibitor MRTX1133 developed by Mitati Therapeutics, Inc. has been disclosed in WO2021041671. Its structure is as follows, and preclinical data have been published so far.
  • KRAS G12D and/or KRAS G12V mutations Although some progress has been made in this field, there is currently no approved treatment for KRAS G12D and/or KRAS G12V mutations, so there is still a need to continue to develop effective, stable, and safe small-molecule KRAS G12D and/or KRAS G12V inhibitors. Yu Zhi Treatment of diseases, such as cancer, mediated by KRAS G12D and/or KRAS G12V mutations.
  • the technical problem to be solved by the present invention is the problem of single structure of KRAS G12D and KRAS G12V inhibitors in the prior art, and a kind of nitrogen-containing heterocyclic compound, its preparation method and application are provided, which are effective for KRAS G12D and/or KRAS G12V Has a good inhibitory effect.
  • the present invention provides compounds as shown in formula I, stereoisomers thereof or pharmaceutically acceptable salts thereof:
  • Ring A is 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkenyl; said 4-10 membered heterocycloalkyl and The number of heteroatoms in the 4-10 membered heterocycloalkenyl is 1 or 2, wherein the heteroatoms are selected from one or both of N, O and S;
  • n 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • R 1a , R 1b , R 1c and R 1d is independently deuterium, -CN, halogen or -OH;
  • L is -(CR 6a R 6b ) n1 - * , -O-(CR 6a R 6b ) n2 - * , -S-(CR 6a R 6b ) n3 - * or -N(R 5 )(CR 6a R 6b ) n4- * ; * represents one end connected with R 2 ;
  • Each Q is independently a connecting single bond or -O-;
  • R 2-a and R 2-b are independently deuterium, -CN, halogen or -OH;
  • R 4-a , R 4-b , R 4-c , R 4-d , R 4-e and R 4-f is independently -OH, deuterium, halogen, -(CH 2 ) n6 N(R 5 ) 2 , -CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl -S-, C 2 -C 6 alkenyl, C 2 -C 6 Alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5 to 14 membered heterocycloalkenyl, Aryl, C 1 -C 6 alkyl substituted by one or more R 4-a-1 , C 1 -C 6 alkyl substituted by one or more R 4-a-2 -O-, by one or C 1 -
  • R 4-a-1 to R 4-a-11 and R 4-g-1 to R 4-g-11 is independently deuterium, halogen, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S- or 3-7 membered cycloalkyl;
  • R 4b is H, deuterium, -N(R 5 ) 2 , halogen, -OH, C 1 -C 6 alkyl, -CN, C 1 -C 6 alkane substituted by one or more R 4-b-1 C 1 -C 6 alkyl-O-, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;
  • Each R 4-b-1 is independently deuterium, halogen, -CN or -OH;
  • n1, n2, n3, n4, n5, n6, n7, n8 and n9 are independently 0, 1, 2, 3, 4 or 5;
  • Each R 6a and R 6b are independently H, deuterium, halogen, -CN, -OH, C 1 -C 6 alkyl or deuterated C 1 -C 6 alkyl;
  • R 7 is independently H, deuterium, C 1 -C 6 alkyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl , C 6 -C 10 aryl or 5 to 14 membered heteroaryl;
  • R 8 is independently H, deuterium, -OH or C 1 -C 6 alkyl.
  • the compound shown in formula I is not any of the following compounds:
  • Each R 4-b is independently -OH, deuterium, -(CH 2 ) n6 N(R 5 ) 2 , -CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkene radical, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R 4-a-1 , one or more R 4-a-2 Substituted C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S- substituted by one or more R 4-a-3 , substituted by one or more R 4-a-4 C 2 -C 6 alkenyl, C 2 -C 6 alkyn
  • Each R 4-f is independently -OH, halogen, -(CH 2 ) n6 N(R 5 ) 2 or C 2 -C 6 alkynyl;
  • R 4a is 5 to 14 membered heteroaryl substituted by one or more R 4-k , C 6 -C 10 aryl substituted by one or more R 4-f , C 6 - C 10 aryl or 5 to 14 membered heteroaryl;
  • Each R 4-f is independently halogen, -OH or C 2 -C 6 alkynyl
  • Each R 4-k is independently halogen, C 1 -C 6 alkyl substituted by one or more R 4-g-1 , -(CH 2 ) n6 N(R 5 ) 2 , C 1 -C 6 Alkyl or -CN.
  • n is 0 or 1, preferably 0.
  • each R 1 is independently halogen, -CN, -OH, -N(R 5 ) 2 , C 1 -C 6 alkyl, or C 1 -C substituted by one or more R 1a 6 alkyl.
  • each of R 1a , R 1b , R 1c , and R 1d is independently —CN, halogen, or —OH.
  • L is -O-(CR 6a R 6b ) n2 - * , and * represents the end connected to R 2 .
  • R is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl substituted by one or more R 2e , preferably 4-10 membered substituted by one or more R 2e Heterocycloalkyl.
  • each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f and R 2j is independently halogen or C 1 -C 6 alkyl; preferably halogen.
  • R 3 is halogen, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 6 -C 10 aryl substituted by one or more R 3j or substituted by one or more R 3k substituted 5- to 14-membered heteroaryl; preferably halogen or C 6 -C 10 aryl substituted by one or more R 3j .
  • each of R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j and R 3k is independently halogen, -OH, -N (R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl or C 2 -C 6 alkynyl substituted by one or more R 3-a ; preferably halogen, -OH or C 2 - C 6 alkynyl.
  • each of R 3-a , R 3-b , R 3-c , R 3-d , R 3-e , R 3-f , R 3-g , R 3-h , R 3- i , R 3-j and R 3-k are each independently halogen, -CN or -OH.
  • R 4a is 4-10 membered heterocycloalkenyl substituted by one or more R 4-j , 5 to 14 membered heteroaryl substituted by one or more R 4-k , substituted by one C 6 -C 10 aryl, C 6 -C 10 aryl or 5 to 14 membered heteroaryl substituted by or multiple R 4- f ; preferably 5 to 14 membered by one or more R 4-k Heteroaryl, C 6 -C 10 aryl substituted by one or more R 4-f , C 6 -C 10 aryl or 5 to 14 membered heteroaryl.
  • each of R 4-a , R 4-b , R 4-c , R 4-d , R 4-e and R 4-f is independently -OH, halogen, -(CH 2 ) n6 N(R 5 ) 2 , —CN or C 2 -C 6 alkynyl; preferably OH, halogen or C 2 -C 6 alkynyl.
  • each R 4-a is independently -OH, -(CH 2 ) n6 N(R 5 ) 2 , -CN or C 2 -C 6 alkynyl; preferably -OH, -(CH 2 ) n6 N(R 5 ) 2 or -CN, more preferably -OH.
  • each of R 4-a-1 to R 4-a-11 and R 4-g-1 to R 4-g-11 is independently halogen.
  • R 4b is halogen
  • n1, n2, n3, n4, n5, n6, n7, n8 and n9 are each independently 0 or 1.
  • Ring A is a 4-10 membered heterocycloalkyl
  • n 0;
  • L is -O-(CR 6a R 6b ) n2 - * , * represents one end connected to R 2 ;
  • R 2 is a 4-10 membered heterocycloalkyl group or a 4-10 membered heterocycloalkyl group substituted by one or more R 2e ;
  • each R 2e is independently halogen
  • R 4a is a 5- to 14-membered heteroaryl group substituted by one or more R 4-k , a C 6 -C 10 aryl group substituted by one or more R 4-f , a C 6 -C 10 aryl group, 5 to 14-membered heteroaryl or C 1 -C 6 alkyl substituted by one or more R 4-a ;
  • Each R 4-k is independently halogen, C 1 -C 6 alkyl substituted by one or more R 4-g-1 , -(CH 2 ) n6 N(R 5 ) 2 or C 1 -C 6 alkyl;
  • Each R 4-g-1 is independently halogen
  • R 4b is halogen
  • n2 1;
  • n6 is 0
  • Each R 6a and R 6b are each independently H.
  • L is -O-(CR 6a R 6b ) n2 - * , * represents one end connected to R 2 ;
  • R 2 is a 4-10 membered heterocycloalkyl group or a 4-10 membered heterocycloalkyl group substituted by one or more R 2e ;
  • each R 2e is independently halogen
  • R 3 is halogen or C 6 -C 10 aryl substituted by one or more R 3j ;
  • R 4a is a 5- to 14-membered heteroaryl group substituted by one or more R 4-k , a C 6 -C 10 aryl group substituted by one or more R 4-f , a C 6 -C 10 aryl group, 5 to 14-membered heteroaryl or C 1 -C 6 alkyl substituted by one or more R 4-a ;
  • Each R 4-a is independently -OH
  • Each R 4-f is independently -OH, halogen or C 2 -C 6 alkynyl
  • Each R 4-k is independently halogen, -CN, C 1 -C 6 alkyl substituted by one or more R 4-g-1 , -(CH 2 ) n6 N(R 5 ) 2 or C 1 -C 6 alkyl;
  • Each R 4-g-1 is independently halogen
  • R 4b is halogen
  • Each R 5 is independently H or C 1 -C 6 alkyl
  • n6 is 0
  • Each R 6a and R 6b are each independently H.
  • Ring A is a 4-10 membered heterocycloalkyl
  • n 0;
  • L is -O-(CR 6a R 6b ) n2 - * , * represents one end connected to R 2 ;
  • R 2 is a 4-10 membered heterocycloalkyl group or a 4-10 membered heterocycloalkyl group substituted by one or more R 2e ;
  • Each R 2e is independently halogen or C 1 -C 6 alkyl
  • R 3j and R 3k is independently halogen, -OH, -N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 3-a , or C 2 -C 6 alkynyl;
  • Each R 3-a is independently halogen, -CN or -OH;
  • Each R 4-a is independently -OH, -(CH 2 ) n6 N(R 5 ) 2 or -CN;
  • Each R 4-f is independently -OH, halogen or C 2 -C 6 alkynyl
  • Each R 4-g-1 is independently halogen
  • R 4b is halogen
  • Each R 5 is independently H or C 1 -C 6 alkyl
  • n2 1;
  • n6 is 0
  • n7 is 0;
  • Each R 6a and R 6b are each independently H.
  • each of the "4-10 membered heterocycloalkyl groups” is independently a 5-8 membered heterocycloalkyl group, for example (preferred ),
  • each of the "4-10 membered heterocycloalkyl" is independently which stated for
  • each of said halogens is independently fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • each "C 6 -C 10 aryl” is independently phenyl or naphthyl.
  • each of the "C 1 -C 6 alkyl groups” is independently a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl or tert-butyl, preferably methyl or ethyl.
  • each of the "C 2 -C 6 alkynyl groups” is independently a C 2 -C 3 alkynyl group, such as ethynyl, propynyl or propargyl, preferably ethynyl.
  • each of the "5- to 14-membered heteroaryl groups” is independently "a 5-10-membered heteroaryl group whose heteroatom is N or S, and the number of heteroatoms is 1 or 2", for example Pyrazolyl, pyridyl, quinolinyl, isoquinolyl, quinazolinyl, indolyl, indazolyl, pyrazolopyridyl, pyrimidinyl or benzothienyl, for example
  • each of the "4-10 membered heterocycloalkenyl groups” is independently a 5-8 membered heterocycloalkenyl group, for example
  • each of the "3-7 membered cycloalkyl groups" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • each of the "3-7 membered cycloalkenyl groups" is independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.
  • each of the "C 2 -C 6 alkenyl” is independently vinyl, 1-propenyl, n-allyl, but-1-ene but-2-enyl, pent-1-enyl or pent-1,4-dienyl.
  • the "4-10 membered heterocycloalkyl” and “4-10 membered heterocycloalkyl” in “4-10 membered heterocycloalkyl substituted by one or more R 2e " are independently 5-8 membered heterocycloalkyl, for example (preferred
  • the halogens are each independently fluorine, chlorine, bromine or iodine.
  • the “C 6 -C 10 aryl” in “C 6 -C 10 aryl substituted by R 4-f " is independently phenyl or naphthyl.
  • R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , R 4a , R 4 -g , R 4- h , R 4- i , R 4-j , R 4-k and R 5 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • the "5 to 14 membered heteroaryl” in the “5 to 14 membered heteroaryl” and “5 to 14 membered heteroaryl substituted by one or more R 4-k “"Aryl” is independently "the heteroatom is N or S, and the number of heteroatoms is 1 or 2 5-10 membered heteroaryl", such as pyrazolyl, pyridyl, quinolinyl, isoquinolyl , quinazolinyl, indolyl, indazolyl, pyrazolopyridyl, pyrimidinyl or benzothienyl, and for example
  • R 4a in “4-10 membered heterocycloalkenyl” in “4-10 membered heterocycloalkenyl substituted by one or more R 4-j " is independently 5-8 membered heterocycloalkenyl, such as
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • n 0.
  • L is -O-CH 2 - * , and * represents the end connected to R 2 .
  • R is preferred
  • R 4b is F.
  • R 3 is or Cl.
  • R 4a is preferred more preferred
  • the compound shown in formula I is any one of the following compounds:
  • the pharmaceutically acceptable salt of the compound shown in formula I is any of the following compounds: of trifluoroacetate.
  • the present invention also provides a compound (intermediate) as shown below:
  • the present invention also provides the hydrochloride salt of any of the following compounds:
  • the present invention also provides a preparation method of the compound shown in formula I, its stereoisomer or a pharmaceutically acceptable salt thereof, which can be the following route:
  • P is an amino protecting group, such as Boc, PMB, Bn, Cbz, Fmoc, etc.,
  • R 2 , R 3 and R 4a are as defined above;
  • Step 1 In a solvent, in the presence of a base and a catalyst, the compound shown in formula SM-1 is subjected to Suzuki reaction to obtain the compound shown in formula SM-2;
  • Step 3 deprotection reaction [substituents R 3a and R 3b (such as -OH, -NH 2 , C 2 -C 6 alkynyl) in R 3 are protected by a protecting group, and a deprotection reaction can be performed to obtain a compound of formula I ];
  • Step 1 In a solvent, in the presence of a base and a catalyst, the compound shown in formula SM-1 is subjected to a Suzuki reaction to obtain a compound shown in formula SM-4;
  • the present invention also provides a pharmaceutical composition, which comprises substance A and pharmaceutical excipients (or pharmaceutically acceptable carrier); said substance A is the above-mentioned compound shown in formula I, its stereoisomer or a pharmaceutically acceptable salt thereof. Said substance A may be in a therapeutically effective amount.
  • the present invention also provides an application of substance A in the preparation of RAS inhibitors, wherein said substance A is the above-mentioned compound represented by formula I, its stereoisomer or a pharmaceutically acceptable salt thereof.
  • the RAS inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample to provide comparison, or to prepare according to conventional methods in the art A kit is developed to provide rapid detection of the effect of inhibiting RAS.
  • the present invention also provides the application of a substance A in the preparation of medicines, and the medicine is used for treating and/or preventing RAS-mediated diseases;
  • the substance A is the above-mentioned compound shown in formula I, its Stereoisomers or pharmaceutically acceptable salts thereof; said substance A is in a therapeutically effective amount.
  • the present invention also provides the application of a substance A in the preparation of medicines, and the medicine is used for treating and/or preventing cancer;
  • the substance A is the above-mentioned compound shown in formula I and its stereoisomers or a pharmaceutically acceptable salt thereof; the substance A is in a therapeutically effective amount.
  • the present invention also provides a method for inhibiting RAS, which comprises administering a therapeutically effective amount of substance A to a patient; said substance A is the above-mentioned compound represented by formula I, its stereoisomer or its pharmaceutically acceptable Accepted salt.
  • the present invention also provides a method for treating and/or preventing cancer, which comprises administering a therapeutically effective amount of substance A to a patient; said substance A is the above-mentioned compound represented by formula I, its stereoisomer or its pharmaceutically acceptable salt.
  • the RAS as described above may be KRAS or a KRAS mutation; eg KRAS G12D, KRAS G12V.
  • RAS mediated diseases such as cancer as described above.
  • Cancer as mentioned above may be selected from colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer Cancer, liver cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, esophageal cancer, gastric cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base.
  • the base addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, diethanolamine salts.
  • acid addition can be achieved by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
  • a pharmaceutically acceptable acid include inorganic acids (such as hydrochloric acid), organic acids (such as trifluoroacetic acid, formic acid).
  • inorganic acids such as hydrochloric acid
  • organic acids such as trifluoroacetic acid, formic acid.
  • stereoisomer includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers.
  • the compounds of the present invention may exist in the form of stereoisomers, and thus encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, Atropisomers, etc., the compound of the present invention can also be in the form of any combination or any mixture of the aforementioned stereoisomers, such as mesoform, racemate, atropisomer equivalent mixture, etc.
  • pharmaceutical composition refers to a preparation comprising a compound of the present invention and a vehicle generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.
  • pharmaceutically acceptable refers to a substance (such as a pharmaceutical excipient) that does not affect the biological activity or properties of the compound of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological effects. React or interact in an undesirable manner with any component contained in the composition.
  • pharmaceutical excipient or “pharmaceutically acceptable carrier” refers to the excipients and additives used in the production of drugs and formulation of prescriptions, and refers to all substances contained in pharmaceutical preparations except active ingredients.
  • Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method for the subject to dissolve the active ingredient at a desired rate after administration, or to promote the activity of the subject after administration of the composition. The ingredients are effectively absorbed.
  • the pharmaceutical excipients can be inert fillers, or provide certain functions, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredients of the composition.
  • Described pharmaceutical adjuvant can comprise one or more in the following adjuvant: binding agent, suspending agent, emulsifying agent, diluent, filler, granulating agent, adhesive, disintegrating agent, lubricant, antiadhesive Glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweeteners.
  • compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, milling, encapsulating, entrapping or freeze-drying processes.
  • the compound shown in formula I, its stereoisomer or pharmaceutically acceptable salt thereof can be formulated as Any form of administration of the compound.
  • These compositions may be prepared according to methods well known in the art of pharmacy and may be administered by various routes depending upon the need for local or systemic treatment and the area to be treated. Administration can be topical (including epidermal and transdermal, ocular and mucosal, including intranasal, vaginal, and rectal delivery), pulmonary (eg, by powder or aerosol inhalation or insufflation, including by nebulizer; intratracheal or intranasal) , oral (solid and liquid preparations) or parenteral administration forms.
  • Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, gelcaps, and tablets.
  • Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions.
  • Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations.
  • Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in pharmaceutically acceptable carriers, suspensions for injection, and emulsions for injection.
  • compositions and formulations for topical administration may include transdermal patches, salves, emulsions, ointments, gels, drops, suppositories, sprays, liquids and powders.
  • suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosols: such as nasal sprays or inhalants.
  • Oral administration may include dosage forms formulated for once-daily or twice-daily (BID) administration.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, eg, intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or it can be by a continuous infusion pump.
  • Conventional pharmaceutical carriers, water, powder or oil bases, thickeners and the like may be necessary or desirable.
  • Pharmaceutical compositions comprising the present invention may also be in controlled or delayed release dosage forms (eg liposomes or microspheres).
  • treatment refers to therapeutic therapy or palliative measures.
  • treatment means: (1) amelioration of one or more biological manifestations of the disease or condition, (2) interference with (a) one or more points in the biological cascade leading to or causing the condition or (b ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, Or (4) slowing the development of the disorder or one or more biological manifestations of the disorder.
  • Treatment can also refer to prolonging survival as compared to expected survival if not receiving treatment.
  • prevention refers to a reduction in the risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a patient.
  • a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as necessary by those skilled in the art.
  • patient refers to any animal that is about to or has received the administration of the compound or composition according to the embodiments of the present invention, preferably a mammal, and most preferably a human.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being most preferred.
  • substituted or "substituent” is a group in which a hydrogen atom is replaced by the designated group.
  • substitutions are at any position, but are permitted only if they result in a stable or chemically viable chemical. Examples are as follows: The structure indicates that the hydrogen atom on ring A is replaced by p R4 .
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with at least one R, with independent options for each occurrence of R.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • alkyl refers to a saturated linear or branched monovalent hydrocarbon group.
  • C 1 -C 6 alkyl means having 1-6 carbon atoms
  • An alkyl group, preferably an alkyl group having 1 to 4 carbon atoms, is specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • phenylene refers to a group obtained by removing two hydrogen atoms from a benzene ring, that is, one hydrogen in the phenyl is replaced.
  • heterocycloalkyl refers to a group formed by replacing at least one carbon atom in a cycloalkyl group with a heteroatom selected from N, O and S.
  • the 4-10 membered heterocycloalkyl group can specifically be 4, 5, 6, 7, 8, 9 or 10 membered heterocycloalkyl group.
  • Examples of heterocycloalkyl include, but are not limited to (preferred
  • aryl refers to an aromatic group in which each ring is aromatic, such as phenyl or naphthyl.
  • heteroaryl refers to an aromatic group containing heteroatoms, preferably containing 1, 2 or 3 aromatic 5-6-membered monocyclic or 9-membered rings independently selected from nitrogen, oxygen and sulfur -10-membered bicyclic ring, when bicyclic, each ring has aromaticity, such as pyrazolyl, pyridyl, quinolinyl, isoquinolyl, quinazolinyl, indolyl, indazolyl, pyrazolyl, Azolopyridyl, pyrimidinyl or benzothienyl, and for example wait.
  • aromaticity such as pyrazolyl, pyridyl, quinolinyl, isoquinolyl, quinazolinyl, indolyl, indazolyl, pyrazolyl, Azolopyridyl, pyrimidinyl or benzothienyl, and for example wait.
  • alkynyl refers to a straight-chain or branched chain hydrocarbon group (such as C 2 -C 6 alkynyl, another example C 2 -C 3 alkynyl) having one or more triple bonds with a specific number of carbon atoms ).
  • the one or more carbon-carbon triple bonds may be internal or terminal, such as propynyl with a triple bond internal or propynyl with a triple bond at the end wait.
  • heterocycloalkenyl means a cyclic alkenyl linked through a heteroatom or a heteroatom group.
  • alkenyl refers to a straight or branched hydrocarbon chain group having at least one double bond, consisting only of carbon atoms and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6, most preferably 2 to 4) carbon atoms and are attached to the rest of the molecule by a single bond, examples including but not limited to vinyl, 1-propenyl, n-allyl, but-1-ene group, but-2-enyl, pent-1-enyl or pent-1,4-dienyl, etc.
  • cycloalkyl means a carbocyclic substituent of a saturated monocyclic or polycyclic ring (such as a bicyclic, tricyclic or more ring-bridged ring, a ring (fused ring) or a spiro ring system), and it may be attached to the remainder of the molecule by a single bond via any suitable carbon atom; such as having 3 to 3-15 membered cycloalkyl group with 15 carbon atoms, preferably 3-12 membered cycloalkyl group with 3 to 12 carbon atoms, more preferably 3-7 membered cycloalkyl group with 3 to 7 carbon atoms, most preferably 3-6 membered cycloalkyl having 3 to 6 carbon atoms.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.
  • cycloalkenyl means a partially unsaturated monocyclic or polycyclic (such as a bicyclic, tricyclic or more ring-bridged ring, an acyclic ring) having at least one double bond (such as a carbon-carbon double bond) (fused ring) or spiro ring system) and which may be attached to the rest of the molecule by a single bond via any suitable carbon atom; e.g.
  • Cycloalkenyl preferably 3-12 membered cycloalkenyl having 3 to 12 carbon atoms, more preferably 3-7 membered cycloalkenyl having 3 to 7 carbon atoms, most preferably 3 to 6 carbon atoms -6 membered cycloalkenyl.
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl (e.g. ), cyclopentadienyl (for example ), cyclohexenyl (for example ), cycloheptenyl, cyclohexadienyl, etc.
  • halogen means fluorine, chlorine, bromine or iodine, especially F or Cl.
  • the positive and progressive effect of the present invention is that the nitrogen-containing heterocyclic compound is expected to treat and/or prevent various diseases mediated by KRAS, especially various diseases mediated by KRAS G12D and/or KRAS G12V.
  • Boc tert-butoxycarbonyl
  • TIPS triisopropylsilyl
  • MOM methoxymethyl (CH 3 OCH 2 -)
  • FA formic acid
  • MEOH methanol
  • EtOH ethanol
  • DMSO dimethyl sulfoxide
  • ACN acetonitrile
  • CDCl 3 deuterated chloroform.
  • Step 2 tert-Butyl-N-[(tert-butoxy)carbonyl]-N-(2,6-dichloro-3-fluoropyridin-4-yl)aminomethyl ester
  • 2,6-Dichloro-3-fluoropyridin-4-amine (4.2g, 23.21mmol, 1eq) was dissolved in dichloromethane (40mL), BOC anhydride (10.29g, 47.15mmol, 2.03eq) was added, 4 -Dimethylaminopyridine (457.28mg, 3.74mmol, 0.16eq), react at room temperature for 16 hours. LCMS monitored the reaction to be complete.
  • reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 0-20%) to obtain tert-butyl-N-[(tert-butoxy)carbonyl]-N-(2,6-dichloro- 3-fluoropyridin-4-yl)aminomethyl ester (7.0 g, yield: 79.13%), white solid.
  • tert-Butyl-N-[(tert-butoxy)carbonyl]-N-(2,6-dichloro-3-fluoropyridin-4-yl)aminomethyl ester (5.84g, 15.32mmol, 1eq) was dissolved in In tetrahydrofuran (30mL), lithium diisopropylamide (2M, 15.32mL, 2eq) was added dropwise at -78°C and warmed to room temperature for 2 hours. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate.
  • Step 6 Ethyl-2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotine ester
  • reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 20-50%) to obtain ethyl-2,6-dichloro-5-fluoro-4-(3-(2,2,2- Trichloroacetyl)ureido)nicotine ester (1.5 g, yield: 76.14%), white solid.
  • Ethyl-2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotine ester (3.0 g, 6.80 mmol, 1 eq) was dissolved in methanol ( 40mL), add ammonia methanol solution (7M, 2.77mL, 2.85eq), and react at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was slurried with methyl tert-butyl ether to obtain 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (1.8g, yield: 100%), white solid.
  • Step 9 (1R,5S)-tert-butyl-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diaze Heterobicyclo[3.2.1]octane-8-carboxylate
  • Step 10 (1R,5S)-tert-butyl-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazine-7a -yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • reaction solution was slowly poured into a saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Step 1 (1R,5S)-tert-butyl-3-(5,7-bis(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- Diazabicyclo[3.2.1]octane-8-carboxylate
  • Mobile phase A water (ammonia hydroxide v/v)
  • mobile phase B ACN; gradient B%: 36%-76%; retention time: 9min.
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H -pyrazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidine- 7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; gradient B%: 29%-69%; retention time: 9min.
  • Step 1 (1R,5S)-tert-butyl-3-(5-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-8-fluoro-7-(7-fluoro- 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H -pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ester
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl)- 6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; gradient B%: 25%-65%; retention time: 9min.
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-fluoropyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)- 6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; gradient B%: 35%-75%; retention time: 9min.
  • Embodiment 5 Compound 5
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(3-fluorophenyl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(3-fluorophenyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A water (ammonia hydroxide v/v)
  • mobile phase B ACN; gradient B%: 50%-70%; retention time: 10min.
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(naphthalen-1-yl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(naphthalen-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; gradient B%: 43%-83%, retention time: 9min.
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H -indol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 37%-77%, retention time: 9min.
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane Alkane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl)- 6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 40%-60%, retention time: 11min.
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrazolo[1, 5-a]pyridin-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrazolo[1,5-a]pyridin-3-yl)pyrido[4,3-d] Pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A water (ammonia hydroxide v/v)
  • mobile phase B ACN
  • gradient B% 31%-51%
  • retention time 13min
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-3-yl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrimidin-5-yl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrimidin-5-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; Gradient B%: 29%-69%, retention time 9min
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methoxypyridine -3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methoxypyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl )-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 40%-60%, retention time: 13min
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methylpyridine- 3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl) -6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A water (ammonia hydroxide v/v)
  • mobile phase B ACN
  • Step 1 (1R,5S)-tert-butyl-3-(5-(5-cyanopyridin-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy )-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazin-7a-yl) Methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3- Hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl) Methoxy)pyrido[4,3-d]pyrimidin-5-yl)nicotinenitrile hydrochloride
  • Mobile phase A Water (FA)
  • mobile phase B ACN
  • Gradient B% 1%-41%, retention time: 9min
  • Step 1 (1R,5S)-tert-butyl-3-(5-(5-(dimethylamino)pyridin-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxy Methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazine-7a -yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-(5-(dimethylamino)pyridine-3 -yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-7 -yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Step 3 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-(5-(dimethylamino)pyridine-3 -yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-7 -yl)-5-ethynyl-6-fluoronaphthalene-2-ol
  • Mobile phase A [Water (0.1% ammonia v/v)-ACN] mobile phase B: ACN; Gradient: 40%-60% (v/v), 10min
  • Step 1 (1R,5S)-tert-butyl-3-(5-(5-chloropyridin-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy) -8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazin-7a-yl)methyl Oxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-(5-chloropyridin-3-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)- 6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 38%-78%, retention time: 9min
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2S,7aR)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-morpholinopyridine -3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-(trifluoromethyl)pyridin-3-yl)pyrido[4,3-d]pyrimidine- 7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 40%-80%, retention time: 9min
  • Step 3 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(isoquinolin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5 -Trifluoroacetate of ethynyl-6-fluoronaphthalen-2-ol
  • Step 2 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3- Hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl) Methoxy)pyrido[4,3-d]pyrimidin-5-yl)nicotinamide hydrochloride
  • Step 3 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3 -Hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3- d] pyrimidin-5-yl) nicotinamide
  • Mobile phase A Water (0.05% ammonia water, v/v)
  • Mobile phase B ACN; gradient: 38%-58% (v/v), retention time: 10min.
  • Step 1 (1R,5S)-tert-Butyl-3-(5-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-8-fluoro-7-(7-fluoro- 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H -pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester
  • Step 2 4-(5-(6-aminopyridin-3-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)- 6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN, gradient B%: 31%-71%, retention time: 9min
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-4-yl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 50%-70%, retention time: 15min
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-2-yl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-2-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Step 1 Methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro- 7-(7-fluoro-3-(methoxy methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazine- 7a-yl)methoxy)pyrido[4,3-d]pyrimidine-5-carboxylate
  • Diisobutylaluminum hydride (1M, 1.04mL, 5eq) was slowly added dropwise at -70°C. After the dropwise addition was completed, it was slowly raised to room temperature and reacted at room temperature overnight. The completion of the reaction was monitored by LCMS, and the reaction solution was quenched with sodium sulfate decahydrate.
  • Mobile phase A Water (NH3H2O+NH4HCO3)
  • mobile phase B ACN
  • Gradient B% 24%-64%
  • retention time 9min
  • Step 1 (1R,5S)-tert-butyl-3-(5-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-Diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 (1R,5S)-tert-butyl-3-(5-(aminomethyl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1- Base)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4- base)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 45%-65%, retention time: 10min
  • Step 1 (1R,5S)-tert-butyl-3-(5-aminocarbonyl-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-Diazabicyclo[3.2.1]octane-8-carboxylate
  • Mobile phase A Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; Gradient B%: 34%-64% Retention time: 10min
  • Step 1 (1R,5S)-tert-butyl-3-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl ylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4, 3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-((Z)-N' -Hydroxyaminocarbaimidoyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 3 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-oxoylidene- 4,5-dihydro-1,2,4-oxadiazol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate
  • Mobile phase A Water (FA), mobile phase: ACN; Gradient B%: 46%-76%, retention time: 10min
  • Step 4 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3- Hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl) Methoxy)pyrido[4,3-d]pyrimidin-5-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride
  • Mobile phase A Water (FA)
  • mobile phase B ACN
  • gradient B% 0%-40%
  • retention time 9min
  • Step 1 tert-butyl-(1R,5S)-3-(7-chloro-8-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl Silyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidazin-7a(5H)-yl)methoxy)pyrido[ 4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 tert-butyl-(1R,5S)-3-(8-fluoro-5,7-bis(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethyl Silyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4 ,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 3 4,4'-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-5,7-diyl)bis(6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol) hydrochloride
  • Embodiment 29 Compound 29
  • Step 1 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-8-fluoro-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)-6-fluoro-5- ((Triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN, gradient B%: 25%-65%; retention time: 9min.
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%: 24%-64%; retention time: 10min
  • Step 1 (1R,5S)-tert-butyl-3-(5-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl )-7-chloro-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine Heterobicyclo[3.2.1]octane-8-carboxylate
  • Step 1 (1R,5S)-tert-butyl-3-(7-chloro-5-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] Octane-8-carboxylate
  • Step 2 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-chloro-8-fluoro-2-(((2R,7aS )-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)pyrido[ 4,3-d] pyrimidine hydrochloride
  • Step 3 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-chloro-5-(8-ethynylnaphthalen-1-yl )-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine
  • Mobile phase A Water (0.05% ammonia water, v/v)
  • Mobile phase B ACN; Gradient B%: 34%-74% (v/v), retention time: 11min
  • Step 1 (1R,5S)-tert-butyl-3-(7-chloro-5-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro Hexahydro-1H-pyrrolidinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylate
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 40%-80%, retention time: 9min
  • Test Example 1 Proliferation inhibitory activity on Ba/F3KRAS-G12D, Ba/F3KRAS-G12V stably transfected cell lines and AGS tumor cell lines containing KRAS G12D mutation:
  • This test example 1 is used to determine the Ba/F3KRAS-G12D and Ba/F3KRAS-G12V cells that the compound of the present invention stably expresses the KRAS G12D/V mutant protein in the original B cell Ba/F3 of the mouse in vitro, and expresses the KRAS G12D mutant protein Proliferation inhibitory activity of gastric cancer AGS cells.
  • Ba/F3KRAS-G12D and Ba/F3KRAS-G12V were purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd., product numbers KC-1259 and KC-1261, respectively; AGS was purchased from Shanghai Baili Biotechnology Co., Ltd.
  • the details are as follows: take the stock solution (10mM) of the compound dissolved in DMSO in advance, dilute it to 10 gradient concentrations by doubling ratio (4 times), and dilute it to 10 times of the target concentration in another 96-well plate with medium, and then in Add 10 ⁇ l/well of the compound solution to the 96-well plate inoculated with cells to reach the target concentration (10000, 2500, 625, 156, 39, 10, 2.5, 0.6, 0.15, 0.04 nM). Three replicate wells were set up for each concentration, and a blank control was set up.
  • Cell proliferation inhibition rate (%) [(luminous intensity 72 hours containing cell medium control group -luminous intensity 72 hours compound group )/(luminous intensity 72 hours containing cell medium control group -luminous intensity 72 hours no cell medium control group )] ⁇ 100%.
  • test results show that the compounds of the present invention (especially compound 4, compound 6, compound 10, compound 13, compound 18, compound 21, compound 22, compound 24, compound 29) are effective against Ba/F3KRAS-G12D containing KRAS G12D/V mutation, Ba/F3KRAS-G12V and AGS cells have good proliferation inhibitory activity.

Abstract

L'invention concerne un composé hétérocyclique contenant de l'azote tel que représenté par la formule I, son procédé de préparation et son utilisation. Le composé tel que représenté par la formule I, et un stéréoisomère de celui-ci ou un sel pharmaceutiquement acceptable de celui-ci a un bon effet inhibiteur sur KRAS G12D et/ou KRAS G12V.
PCT/CN2023/072929 2022-01-28 2023-01-18 Composé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation WO2023143312A1 (fr)

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US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2024061333A1 (fr) * 2022-09-21 2024-03-28 甘李药业股份有限公司 Inhibiteur de protéine mutante kras, son procédé de préparation et son utilisation

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WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2022015375A1 (fr) * 2020-07-16 2022-01-20 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2022042630A1 (fr) * 2020-08-26 2022-03-03 InventisBio Co., Ltd. Composés hétéroaryle, leurs procédés de préparation et leurs utilisations

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WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
WO2022015375A1 (fr) * 2020-07-16 2022-01-20 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
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WANG XIAOLUN, ALLEN SHELLEY, BLAKE JAMES F., BOWCUT VICKIE, BRIERE DAVID M., CALINISAN ANDREW, DAHLKE JOSHUA R., FELL JAY B., FISC: "Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS G12D Inhibitor", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 65, no. 4, 24 February 2022 (2022-02-24), US , pages 3123 - 3133, XP055952002, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.1c01688 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2024061333A1 (fr) * 2022-09-21 2024-03-28 甘李药业股份有限公司 Inhibiteur de protéine mutante kras, son procédé de préparation et son utilisation

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