WO2022199586A1 - Inhibiteur de pyrimidopyridine, son procédé de préparation et son utilisation - Google Patents

Inhibiteur de pyrimidopyridine, son procédé de préparation et son utilisation Download PDF

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WO2022199586A1
WO2022199586A1 PCT/CN2022/082327 CN2022082327W WO2022199586A1 WO 2022199586 A1 WO2022199586 A1 WO 2022199586A1 CN 2022082327 W CN2022082327 W CN 2022082327W WO 2022199586 A1 WO2022199586 A1 WO 2022199586A1
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alkyl
group
membered
cycloalkyl
substituted
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PCT/CN2022/082327
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吕彬华
崔大为
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苏州泽璟生物制药股份有限公司
上海泽璟医药技术有限公司
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Publication of WO2022199586A1 publication Critical patent/WO2022199586A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • 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
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention belongs to the field of medicine, in particular to a pyrimidopyridine inhibitor and a preparation method and application thereof.
  • KRAS mutations account for 85% of all RAS mutations. KRAS mutations are found in nearly 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% of lung cancers, mainly non-small cell lung cancers. G12C and G12D mutations are the most important mutations in KRAS mutations, of which G12C mutation mainly occurs in HSCLC, while G12D mutation occurs mainly in pancreatic cancer. So far, there are still no approved drugs targeting the KRAS G12D mutation on the market.
  • the current clinical routine treatment regimens for pancreatic cancer include gemcitabine monotherapy, gemcitabine combined with nab-paclitaxel, and FOLFIRINOX regimen (oxaliplatin + irinotecan + 5-FU/LV).
  • gemcitabine monotherapy gemcitabine combined with nab-paclitaxel
  • FOLFIRINOX regimen oxaliplatin + irinotecan + 5-FU/LV.
  • liposomal irinotecan is suitable for use in combination with fluorouracil and leucovorin in the treatment of patients with advanced pancreatic cancer (second-line therapy) who have not responded well to gemcitabine chemotherapy.
  • the current effective treatments for pancreatic cancer are limited, and the overall survival time of patients is less than 1 year.
  • KRAS G12D target proteins are pathologically associated with various diseases, especially pancreatic cancer, there is a need for novel KRAS G12D inhibitors for clinical treatment.
  • Highly selective and highly active KRAS G12D inhibitors can be more effective in the treatment of diseases such as cancer caused by KRAS G12D mutations, and have the potential to reduce off-target effects, so there is a more urgent clinical need.
  • the purpose of the present invention is to provide a new class of compounds with selective inhibitory effect on KRAS G12D and/or better pharmacodynamic properties and uses thereof.
  • the first aspect of the present invention provides a compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug:
  • X is selected from the group consisting of substituted or unsubstituted groups: 4-14-membered saturated or unsaturated heterocyclic group, 5-14-membered heteroaryl; wherein, the substitution refers to being substituted by one or more R 12 ;
  • A is selected from: C or N;
  • R 12 is selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 alkoxy, C 3 -C 20 cycloalkyl, 4-20 membered heterocyclic group, C 6 -C 14 aryl group, 5-14-membered heteroaryl, halogen, nitro, hydroxyl, oxo, cyano, ester, amine, amide, sulfonamide or urea; wherein, the substitution refers to a substitution of one or Multiple R substitutions;
  • Y is selected from: O or NR 5 ';
  • Z is a substituted or unsubstituted C 1 -C 18 alkylene; wherein, the substitution refers to being substituted by one or more R;
  • W 1 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 14 cycloalkyl, 4-14-membered saturated or unsaturated heterocyclic group; wherein, the substitution refers to being replaced by one or more R is substituted; wherein, the substitution refers to being substituted by one or more Rs;
  • W 2 is selected from: O, S, NR 5” , CONR 5” , NR 5” CO, SO 2 NR 5” or NR 5” SO 2 ;
  • R 2 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 14 cycloalkyl, 4-14-membered saturated or unsaturated heterocyclyl, C 6 -C 14 aryl, 5-14-membered heteroaryl base, -(CH 2 ) h NR 5 R 7 , -(CH 2 ) h SR 7 , -(CH 2 ) h S(O) q R 7 , -(CH 2 ) h S(O) q NR 5 R 7 , -(CH 2 ) h NR 5 S(O) q NR 5 R 7 , -(CH 2 ) h OR 8 , -(CH 2 ) h R 9 , -OR 10 or -NR 5 R 11 ; wherein, The H in CH 2 can be substituted; wherein, the substitution refers to being substituted by one or more R;
  • R 3 and R 6 are the same or different, each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, cyano, C 1 -C 3 alkyl, deuterated C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, deuterated C 3 -C 6 cycloalkyl, halogenated C 3 -C 6 cycloalkyl;
  • R 4 is selected from the group consisting of substituted or unsubstituted groups: 4-14-membered heterocyclic group, C 6 -C 14 -membered aryl group, 5-14-membered heteroaryl group; wherein, the substitution refers to being replaced by one or more R replace;
  • R 5 , R 5' , R 5" and R 7 are the same or different, each independently selected from the group consisting of substituted or unsubstituted hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halogenated C 1 -C 18 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 18 alkoxy, deuterated C 1 -C 18 alkoxy, halogenated C 1 -C 18 Alkoxy, amino, hydroxyl, 4-20-membered heterocyclic group, C 6 -C 14 -membered aryl, 5-14-membered heteroaryl; wherein, the substitution refers to being substituted by one or more R;
  • R 8 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 14 cycloalkyl, 4-14-membered saturated or unsaturated heterocyclic group; wherein, the substitution refers to being substituted by one or more R ;
  • R 9 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 14 cycloalkyl; wherein, the substitution refers to being substituted by one or more R;
  • R 10 is a substituted C 6 -C 14 aryl group, wherein the aryl group is not a phenyl group; or R 10 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 14 cycloalkyl, 4- 14-membered saturated or unsaturated heterocyclyl, 5-14-membered heteroaryl, (C 3 -C 14 cycloalkyl)C 1 -C 18 alkyl, (4-14-membered heterocyclyl)C 1 -C 18 alkyl, (C 6 -C 14 aryl) C 1 -C 18 alkyl or (5-14-membered heteroaryl) C 1 -C 18 alkyl; wherein, the substitution refers to being replaced by one or more R replace;
  • R 11 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 14 cycloalkyl, 4-14-membered saturated or unsaturated heterocyclic group, C 6 -C 14 aryl, 5-14-membered heteroaryl group, halogenated C 1 -C 18 alkyl, (C 1 -C 18 alkoxy) C 1 -C 18 alkyl, (C 3 -C 14 cycloalkyl) C 1 -C 18 alkyl, (4 -14-membered heterocyclyl) C 1 -C 18 alkyl, (C 6 -C 14 aryl) C 1 -C 18 alkyl, (5-14-membered heteroaryl) C 1 -C 18 alkyl; wherein , the substitution refers to being replaced by one or more R;
  • R 13 is selected from the group consisting of substituted or unsubstituted groups: C 4 -C 20 alkyl, C 3 -C 20 cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 aryl, 5-14 Membered heteroaryl, halogenated C 1 -C 18 alkyl, (C 3 -C 18 cycloalkyl) C 1 -C 18 alkyl, (4-20 membered heterocyclyl) C 1 -C 18 alkyl, (C 1 -C 18 alkoxy) C 1 -C 18 alkyl, (C 3 -C 20 cycloalkyloxy) C 1 -C 18 alkyl, (4-20 membered heterocyclyloxy) C 1 -C 18 alkyl, vinyl, ethynyl, (C 1 -C 6 alkyl) vinyl, deuterated (C 1 -C 6 alkyl) vinyl, halogenated (C 1 -C 6 alkyl) vinyl,
  • R is selected from: hydrogen, deuterium, C 1 -C 18 alkyl, deuterated C 1 -C 18 alkyl, halo C 1 -C 18 alkyl, (C 3 -C 18 cycloalkyl)C 1 -C 18 alkyl, (4-20 membered heterocyclyl) C 1 -C 18 alkyl, (C 1 -C 18 alkoxy) C 1 -C 18 alkyl, (C 3 -C 18 cycloalkyloxy) ) C 1 -C 18 alkyl, (4-20 membered heterocyclyloxy) C 1 -C 18 alkyl, vinyl, ethynyl, (C 1 -C 6 alkyl) vinyl, deuterated (C 1 -C 6 alkyl) vinyl, halogenated (C 1 -C 6 alkyl) vinyl, (C 1 -C 6 alkyl) ethynyl, deuterated (C 1 -C 6 alkyl) ethyn
  • h is each independently an integer of 1, 2, 3, 4, 5 or 6;
  • n is each independently an integer of 0, 1, 2, 3, 4, 5 or 6;
  • q is each independently an integer of 1 or 2;
  • n is not 0; where p is an integer of 0, 1, 2, 3, 4, 5, or 6.
  • Z and R 2 can be attached to any atom of W 1 , including the same atom attached to W 1 .
  • R 6 is H.
  • A is N.
  • R 1 is H.
  • R is selected from: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, (C 3 -C 8 ring Alkyl) C 1 -C 6 alkyl, (4-8 membered heterocyclyl) C 1 -C 6 alkyl, (C 1 -C 6 alkoxy) C 1 -C 6 alkyl, (C 3 - C 8 cycloalkyloxy) C 1 -C 6 alkyl, (4-8 membered heterocyclyloxy) C 1 -C 6 alkyl, vinyl, ethynyl, (C 1 -C 6 alkyl) vinyl, deuterated (C 1 -C 6 alkyl) vinyl, halo (C 1 -C 6 alkyl) vinyl, (C 1 -C 6 alkyl) ethynyl, deuterated (C 1 -C 6 alkyl) ethy
  • R 5 , R 5' , R 5" and R 7 are each independently selected from the group consisting of substituted or unsubstituted groups: hydrogen, deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, amino, hydroxyl, 4-8-membered heterocyclyl, phenyl, 5-6-membered heteroaryl; wherein, the substitution refers to being substituted by one or more groups selected from the group : deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, (C 3 -C 8 cycloalkyl) C 1 -C 6 alkyl, ( 4
  • the compound has the structures shown in formula (I-A) and (I-B):
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 13 , A, X, Y, Z, W 1 , W 2 and n are as defined above.
  • the compound has the structures represented by general formula (II-A) and formula (II-B):
  • R 1 , R 2 , R 3 , R 4 , R 6 , X, Y, Z, W 1 , W 2 , R 13 , and n are defined as described above.
  • the compound has the structures represented by general formula (III-A) and formula (III-B):
  • R 1 , R 2 , R 3 , R 4 , X, Y, Z, W 1 , W 2 , R 13 and n are as defined above.
  • the 4-14 membered saturated or unsaturated heterocyclic group contains 1-3 (preferably 1-2) heteroatoms selected from N, O and S.
  • the 4-14-membered saturated or unsaturated heterocyclic group contains 1, 2, 3 N atoms and 0, 1 or 2 hetero atoms selected from O and S; preferably, Contains 1 or 2 N atoms and 0 heteroatoms selected from O and S.
  • the 4-14-membered saturated or unsaturated heterocyclic group is a bicyclic or tricyclic, preferably a 7-10-membered bicyclic or tricyclic heterocyclic group.
  • the 4- to 14-membered saturated or unsaturated heterocyclic group preferably contains 7, 8, 9 or 10 ring atoms.
  • R 5" is a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, or a C3-C8 cycloalkyl group.
  • W 1 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 6 monocyclic cycloalkyl, C 7 -C 10 spirocyclic cycloalkyl, C 7 -C 10 bridged ring Cycloalkyl, C 7 -C 10 fused ring cycloalkyl, 4-6 membered saturated or unsaturated monocyclic heterocyclic group, 7-10 membered saturated or unsaturated spirocyclic heterocyclic group, 7-10 membered saturated or Unsaturated bridged ring heterocyclic group, 7-10 membered saturated or unsaturated fused ring heterocyclic group; wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, C 1 - C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, (C 3 -C 8 cycloalkyl) C 1 -C
  • W 1 is selected from the following groups of substituted or unsubstituted:
  • R 2 is selected from: C 3 -C 8 cycloalkyl, 4-8 membered heterocyclyl, -(CH 2 )NR 5 R 7 , -NR 5 R 7 , -(CH 2 ) S(O) 2 R 7 , S(O) 2 R 7 , -(CH 2 )S(O) 2 NR 5 R 7 , -S(O) 2 NR 5 R 7 , -(CH 2 )OR 8 , -OR 10 ; wherein R 5 , R 7 , R 8 and R 10 are as defined above.
  • R 13 is a substituted or unsubstituted C 6 -C 14 cycloalkyl group, preferably a substituted or unsubstituted C 8 -C 12 cycloalkyl group.
  • R 13 is a substituted or unsubstituted C 6 -C 14 bridged cycloalkyl group, more preferably a substituted or unsubstituted adamantyl group.
  • R 13 is selected from the group consisting of substituted or unsubstituted groups: C 4 -C 10 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 14 -aryl, 5-14-membered heteroaryl, halogenated C 1 -C 6 alkyl, (C 3 -C 10 cycloalkyl) C 1 -C 6 alkyl, (4-10-membered heterocyclyl) C 1 -C 6 alkyl, (C 1 -C 6 alkoxy) C 1 -C 6 alkyl, (C 3 -C 10 cycloalkyloxy) C 1 -C 6 alkyl, (4-10 membered Heterocyclyloxy) C 1 -C 6 alkyl, vinyl, ethynyl, (C 1 -C 6 alkyl) vinyl, deuterated (C 1 -C 6 alkyl) vinyl, halogenated (C 1 -C 10 al
  • R 13 is selected from: substituted or unsubstituted C 3 -C 10 cycloalkyl (preferably C4-C6 monocyclic cycloalkyl or C7-C10 bicyclic or tricyclic cycloalkyl), substituted or unsubstituted 4 -10-membered heterocyclic group (preferably 4-6-membered monocyclic heterocyclic group or 7-10-membered bicyclic or tricyclic heterocyclic group); more preferably, R 13 is selected from:
  • R 4 is selected from the group consisting of substituted or unsubstituted groups: C 6 -C 14 aryl, 5-14-membered heteroaryl; wherein, the substitution refers to the group selected from the group One or more group substitutions: deuterium, C1 - C6 alkyl, deuterated C1 - C6 alkyl, halo C1 - C6 alkyl, vinyl, ethynyl, C3 - C6 ring Alkyl, halogen, nitro, hydroxyl, cyano, ester, amine, amide, sulfone or urea groups.
  • R 4 is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl, preferably, R 4 is selected from
  • R 3 is halogen, preferably F.
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 13 , R 5 , R 5′ , R 5′′ , R 7 , A, X, Y, Z, W 1 , W 2 and n correspond to the groups shown in the specific compounds in the examples.
  • the compound is selected from the following group:
  • the compound is preferably the compound prepared in the examples.
  • the second aspect of the present invention provides a method for preparing the compound of formula (I), its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof , including steps:
  • X 1 , X 2 and X 3 are each independently selected from: OH, halogen, OTf, OTs or OMs;
  • LG 1 is selected from: H or -B(OH) 2 , -B(KBF 3 ),
  • LG 2 is selected from: -B(OH) 2 , -B(KBF 3 ), -Sn( n Bu) 3 ,
  • R 1 , R 2 , R 3 , R 4 , R 6 , X, Y, Z and Q are as described in the first aspect of the present invention.
  • the third aspect of the present invention provides a pharmaceutical composition, comprising one or more of the compounds described in any one of the first aspects of the present invention, its stereoisomers, tautomers, crystal forms , a pharmaceutically acceptable salt, hydrate, solvate or prodrug; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises a drug selected from the group consisting of PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI- 308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzum
  • BTK inhibitors such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.
  • EGFR inhibitors such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.
  • VEGFR inhibitors eg Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, Su nitinib, donafenib, etc.
  • HDAC inhibitors such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quis
  • the fourth aspect of the present invention provides a compound according to the first aspect of the present invention, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or
  • the prodrug, or the use of the pharmaceutical composition described in the third aspect of the present invention is used to prepare a medicament for preventing and/or treating a disease related to the activity or expression level of KRAS G12D .
  • the disease is a tumor or a disordered disease.
  • the disease is selected from the group consisting of lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, blood cancer , brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
  • a non-diagnostic, non-therapeutic method of inhibiting KRAS G12D comprising the step of administering to a subject in need thereof an effective amount of a compound as described above, its stereoisomers, tautomers form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or administer a pharmaceutical composition as described above.
  • the subject is a mammal, preferably a human.
  • a method for inhibiting the activity of KRAS G12D in vitro comprising the steps of: mixing the above-mentioned compound, its stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, The solvate or prodrug, or pharmaceutical composition as described above, is contacted with the protein or cell, thereby inhibiting the activity of KRAS G12D .
  • the cells are selected from the group consisting of macrophages, intestinal cells (including intestinal stem cells, intestinal epithelial cells), or a combination thereof.
  • the cells are from rodents (eg, mice, rats), or primates (eg, humans).
  • the present inventors unexpectedly prepared a new class of compounds with selective inhibition of KRAS G12D and/or better pharmacodynamic properties. On this basis, the inventors have completed the present invention.
  • alkyl refers to a straight-chain or branched or cyclic alkane group containing 1-20 carbon atoms, such as 1-18 carbon atoms, especially 1-18 carbon atoms, preferably 1-10 carbon atoms carbon atoms, more preferably 1 to 6 carbon atoms.
  • alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, Pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and many more.
  • C1-C18 alkyl refers to straight or branched chain or cyclic alkyl groups, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17 or 18 carbon atoms such as methyl, ethyl, propyl, isopropyl n-butyl, tert-butyl, isobutyl (such as ), n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl.
  • the alkyl group also includes a substituted alkyl group.
  • alkylene refers to a group formed by removing one hydrogen atom from an "alkyl or substituted alkyl group", such as methylene, ethylene, propylene, isopropylidene (such as ), butylene (such as ), pentylene (such as ), ahexyl (such as ), heptidene (such as ), Wait.
  • the term also includes the replacement of a methylene group of an alkylene group (eg, a C1-C18 alkylene group) with a cycloalkylene group (eg, a C3-C20 cycloalkylene group), eg "C1-C18 alkylene group""C3-C20cycloalkylene” or "C3-C20 cycloalkylene C1-C18 alkylene".
  • C1-C18 alkylene C3-C20 cycloalkylene or "C3-C20 cycloalkylene C1-C18 alkylene” have the same meaning and refer to the removal of cycloalkylalkyl or alkylcycloalkyl A group formed by two hydrogen atoms, such as Wait.
  • C3 - C20 cycloalkyl means a group containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 A fully saturated cyclic hydrocarbon group of carbon atoms, including 1-4 rings, each ring containing 3-8 carbon atoms.
  • it is C 3 -C 14 cycloalkyl, more preferably C 3 -C 10 cycloalkyl, such as C 3 -C 6 monocyclic cycloalkyl, C 7 -C 10 bicyclic or tricyclic cycloalkyl (such as adamantyl), more preferably C3 - C8 cycloalkyl, more preferably C3 - C6 cycloalkyl.
  • Substituted cycloalkyl means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which may be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include spiro, bridged or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spiroheterocycle (excluding heteroaryl), bridged cycloalkyl (eg, adamantyl) , bridged cycloalkenyl, bridged heterocyclic ring (excluding heteroaromatic ring), fused cycloalkyl, fused cyclic alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above cycloalkyl, cycloalkenyl, heterocyclic Cyclic and heterocyclic aryl groups may be optionally substituted.
  • Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
  • C3-C20 cycloalkylene refers to a group formed by removing two hydrogen atoms from a cycloalkyl group, such as: Wait.
  • heterocyclyl refers to a group containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms Fully saturated or partially unsaturated cyclic groups (including, but not limited to, such as 3-7 membered monocyclic, 4-7 membered monocyclic, 6-11 membered bicyclic or 8-16 membered tricyclic or polycyclic systems), At least one heteroatom is present in a ring having at least one carbon atom.
  • “Heterocyclyl” has the same meaning as "saturated or unsaturated heterocyclyl”.
  • 4-20 membered heterocyclyl is preferably a 4-14 membered heterocyclyl (including but not limited to, such as 4-6 membered monocyclic, 7-10 membered bicyclic or 8-14 membered tricyclic or polycyclic systems), More preferably 4-12 membered heterocyclyl, more preferably 4-10 membered heterocyclyl, such as 4-6 membered monocyclic heterocyclyl, 7-10 membered bicyclic or tricyclic heterocyclyl, more preferably is a 4-8 membered heterocyclic group, more preferably a 4-6 membered heterocyclic group.
  • Each heterocyclic ring containing a heteroatom may carry 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen or sulfur, wherein the nitrogen or sulfur may be oxidized or the nitrogen may Quaternized.
  • a heterocyclic group may be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule, preferably to an N or C atom of the ring or ring system molecule.
  • Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine base, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepanyl gene, 4-piperidinone, tetrahydropyranyl, morpholino, thiomorpholinyl, thiomorpholinosulfoxide, thiomorpholinone, 1,3-dioxanyl and Tetrahydro-1,1-dioxythiophene, etc.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected with other groups through a single bond, or through a ring Any two or more atoms on the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further cyclically connected; the heterocyclic group can be substituted or unsubstituted, and when substituted,
  • the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl and carboxylate.
  • C4-C20 heterocyclylene refers to a group formed by removing two hydrogen atoms from a heterocyclyl group, such as: Wait.
  • C 6 -C 14 aryl refers to an aromatic cyclic hydrocarbon group containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring carbon atoms, having 1-5 rings , especially monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic rings, etc.), the aromatic rings of the aryl group can be linked by a single bond (eg, biphenyl), or fused (eg, naphthalene, anthracene, etc.). "Substituted aryl” means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which may be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include fused ring substituents, especially fused cycloalkyl, fused cycloalkenyl, fused ring heterocyclyl or fused ring aryl, the aforementioned cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl groups may be optionally substituted.
  • heteroaryl refers to a heteroaromatic system comprising 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur.
  • Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl and tetrazolyl, etc.
  • Heteroaryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkane Thio, oxo, carboxyl and carboxylate groups.
  • C 1 -C 18 alkoxy refers to a straight or branched chain alkoxy group having 1 to 18 carbon atoms, including C 1 -C 18 alkyl-O-, -C 1 -C 6 alkyl -OC1 - C6 alkyl, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.
  • it is a C 1 -C 8 alkoxy group, more preferably a C 1 -C 6 alkoxy group.
  • C 3 -C 20 cycloalkyloxy refers to C 3 -C 20 cycloalkyl-O-, wherein C 3 -C 20 cycloalkyl is as defined above.
  • 4-20 membered heterocyclyloxy refers to 4-20 membered heterocyclyl-O-, wherein 4-20 membered heterocyclyl is as defined above.
  • C 1 -C 18 alkyleneoxy refers to a group obtained by removing one hydrogen atom from "C 1 -C 18 alkoxy”.
  • halogen refers to chlorine, bromine, fluorine, iodine.
  • halo refers to substitution with halogen.
  • deuterated refers to substitution with deuterium.
  • hydroxyl refers to a group with the structure OH.
  • nitro refers to a group with the structure NO2.
  • cyano refers to a group with the structure CN.
  • esters refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle.
  • amino refers to a group bearing the structure -NRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.
  • Amido refers to a group with the structure -CONRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.
  • sulfone refers to a group bearing the structure -SO2R , where R can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted Cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above.
  • ureido refers to a group having the structure -NRCONR'R", where R, R' and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl , cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamine moiety.
  • alkylaminoalkyl refers to a group with the structure -RNHR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, Cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different.
  • dialkylaminoalkyl refers to a group with the structure -RNHR'R", where R, R' and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted Cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R" can be the same or different in the dialkylamine moiety.
  • heterocyclylalkyl refers to a group bearing the structure -RR', where R can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted Cycloalkenyl, aryl or substituted aryl; R' represents heterocycle or substituted heterocycle.
  • substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent.
  • substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples.
  • a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 ureido and so on.
  • a substituent is a non-terminal substituent, it is a subgroup of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl to heterocyclylene, alkoxy to Alkyleneoxy, etc.
  • compounds of the present invention refers to compounds of formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of compounds of formula I.
  • the compound of formula I has the following structure
  • R 1 , R 2 , R 3 , R 4 , R 6 , Q, A, X, Y, and Z are as described above.
  • the compound of formula I has the structures shown in formula (I-A) and (I-B):
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 13 , A, X, Y, Z, W 1 , W 2 and n are as defined above.
  • the compound of formula I has the structures shown in general formula (II-A) and formula (II-B):
  • R 1 , R 2 , R 3 , R 4 , R 6 , X, Y, Z, W 1 , W 2 , R 13 , and n are defined as described above.
  • the compound of formula I has the structures shown in general formula (III-A) and formula (III-B):
  • R 1 , R 2 , R 3 , R 4 , X, Y, Z, W 1 , W 2 , R 13 and n are as defined above.
  • R 6 is H; A is N; R 1 is H.
  • W 1 is selected from the group consisting of substituted or unsubstituted groups: C 3 -C 6 monocyclic cycloalkyl, C 7 -C 10 spirocyclic cycloalkyl, C 7 -C 10 Bridged ring cycloalkyl, 4-6 membered saturated or unsaturated monocyclic heterocyclyl, 7-10 membered saturated or unsaturated spirocyclic heterocyclyl, 7-10 membered saturated or unsaturated bridged heterocyclyl ;
  • R 2 is selected from: C 3 -C 8 cycloalkyl, 4-8 membered heterocyclyl, -(CH 2 )NR 5 R 7 , -NR 5 R 7 , -(CH 2 )S(O) 2 R 7 , S(O) 2 R 7 , -(CH 2 )S(O) 2 NR 5 R 7 , -S(O) 2 NR 5 R 7 , -(CH 2 )
  • substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl , (C 3 -C 8 cycloalkyl) C 1 -C 6 alkyl, (4-8 membered heterocyclyl) C 1 -C 6 alkyl, (C 1 -C 6 alkoxy) C 1 -C 6 alkyl, (C 3 -C 8 cycloalkyloxy) C 1 -C 6 alkyl, (4-8 membered heterocyclyloxy) C 1 -C 6 alkyl, vinyl, ethynyl, ( C 1 -C 6 alkyl) vinyl, deuterated (C 1 -C 6 alkyl) vinyl, halo (C 1 -C 6 alkyl) vinyl, (C 1 -C 6 alkyl) ethynyl , deuterated (C 1
  • R 5 , R 7 , R 8 and R 10 are defined as above.
  • Z is a substituted or unsubstituted C 1 -C 3 alkylene; wherein, the substitution refers to being substituted by one or more groups selected from the group consisting of deuterium, C 1 - C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, (C 3 -C 8 cycloalkyl) C 1 -C 6 alkyl, (4-8 membered heterocycle base) C 1 -C 6 alkyl, (C 1 -C 6 alkoxy) C 1 -C 6 alkyl, (C 3 -C 8 cycloalkyloxy) C 1 -C 6 alkyl, (4 -8-membered heterocyclyloxy) C 1 -C 6 alkyl, vinyl, ethynyl, (C 1 -C 6 alkyl) vinyl, deuterated (C 1 -C 6 alkyl) vinyl, halogen Substitute
  • salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, compounds in the present invention are understood to include their salts.
  • the term “salt” refers to salts formed with inorganic or organic acids and bases in the acid or basic form.
  • a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion (“inner salt”) that may be formed is contained in within the scope of the term "salt”.
  • compositions of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.
  • the compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetates (eg with acetic acid or trihaloacetic acids such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates , benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, diglycolate, lauryl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodate, isethionate (eg, 2-hydroxyethanesulfonate), lactate, maleate
  • Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed from organic bases (such as organic amines) such as benzathine, bicyclohexyl Amine, Hepamine (salt with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butyl amines, and salts with amino acids such as arginine, lysine, and the like.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate), long-chain halides (eg, decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides) and iodides), aralkyl halides (such as benzyl and phenyl bromides), and the like.
  • small halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate
  • Prodrugs and solvates of the compounds of the present invention are also contemplated.
  • the term "prodrug” as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to yield the compound, salt, or solvate of the present invention in the treatment of a related disease.
  • the compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.
  • Stereoisomers of all compounds are contemplated by the present invention.
  • Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof.
  • the chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC).
  • the racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.
  • the compound in the present invention the compound obtained by successively preparing, isolating and purifying the compound whose weight content is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure” compound), is described in the text List. Herein such "very pure" compounds of the invention are also intended to be part of the invention.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.
  • a mixture of isomers may contain isomers in various ratios.
  • isomers in various ratios.
  • Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.
  • the present invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers.
  • isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically labeled reagents using the protocols disclosed in the Examples.
  • a synthesis of a particular enantiomer of a compound of the present invention can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer.
  • a suitable optically active acid or base can be used to form diastereomeric salts with it, and then the diastereomeric salts can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.
  • the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope.
  • the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with a specified structural substituent.
  • the substituents may be the same or different at each position.
  • substituted as used herein includes all permissible substitutions of organic compounds.
  • permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to supplement its valence.
  • the present invention is not intended to limit in any way the permissible substituted organic compounds.
  • the present invention contemplates that combinations of substituents and variable groups are well suited for the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds.
  • stable refers to compounds that are stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, as used herein for the above-mentioned purposes.
  • the preparation process of the compounds of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
  • the compounds of the present invention are prepared by the following methods
  • X 1 , X 2 and X 3 are each independently selected from: OH, halogen (such as chlorine, bromine or iodine), OTf, OTs or OMs, etc.;
  • LG 1 is selected from: H or -B(OH) 2 , -B(KBF 3 ), Plasma leaving group;
  • LG 2 is selected from: -B(OH) 2 , -B(KBF 3 ), -Sn( n Bu) 3 , Plasma leaving group;
  • R 1 , R 2 , R 3 , R 4 , R 6 , X, Y, Z and Q are as defined above.
  • the present invention adopts the following method to prepare
  • a first base such as DIPEA, TEA, DBU, Cs2CO3 , K2CO3 , K3PO4 , KOAc , or KF
  • base1 such as DIPEA, TEA, DBU, Cs2CO3 , K2CO3 , K3PO4 , KOAc , or KF
  • Pd catalyst such as Pd( dppf)Cl 2 , or Pd(PPh 3 ) 2 , etc.
  • a condensing agent such as BOP, pyBOP, HATU, or EDCI, etc.
  • X 1 , X 2 or X 3 are each independently selected from OH, halogen (such as chlorine, bromine, or iodine), OTf, OTs or OMs, etc.;
  • LG 1 is selected from H, or -B(OH) 2 , -B(KBF 3 ), Plasma leaving group;
  • LG 2 is selected from -B(OH) 2 , -B(KBF 3 ), -Sn( n Bu) 3 , Plasma leaving group;
  • R 1 , R 2 , R 3 , R 4 , R 6 , X, Y, Z, W and n are as defined above.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
  • the compounds of general formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions.
  • the mode and dosage of the original drug may remain unchanged, while the compound of formula I is administered concurrently or subsequently.
  • a pharmaceutical composition containing both one or more known drugs and the compound of formula I may preferably be used.
  • Drug combinations also include administration of a compound of formula I with one or more other known drugs at overlapping time periods.
  • the dose of the compound of formula I or known drugs may be lower than the doses of the compounds of formula I administered alone.
  • Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB- A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, 10-1000 mg of the compound of the present invention/dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the therapeutic methods of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compounds of the general formula (I-A) and formula (I-B) described in the present invention or their crystal forms, pharmaceutically acceptable
  • the salts, hydrates or solvates are mixed to form the pharmaceutical composition.
  • the present invention also provides a method of treatment, which comprises the steps of: administering the compound of general formula (I), or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, as described in the present invention to a subject in need of treatment , or administer the pharmaceutical composition of the present invention for selectively inhibiting KRAS G12D .
  • the present invention has the following main advantages:
  • the compound has a good selective inhibitory effect on KRAS G12D ;
  • the compound has better pharmacodynamics, pharmacokinetic properties and lower toxic and side effects.
  • the structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
  • LC-MS Liquid chromatography-mass spectrometry
  • TLC silica gel plate used Qingdao GF254 silica gel plate, TLC used 0.15-0.20mm, preparative thin layer chromatography used 0.4mm-0.5mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by adopting or according to the literature data reported in the field.
  • the first step the preparation of 1-(ethyl-methylcarbamoyl)-cyclopropanecarboxylic acid methyl ester
  • the second step preparation of (1-((ethyl-methyl-amino)-methyl)-cyclopropyl)-methanol
  • the first step preparation of (1-((((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol
  • the second step preparation of 1-((((tert-butyldimethylsilyl)oxy)methyl)cyclopropanecarbaldehyde
  • the third step preparation of (E)-tert-butyl((1-(2-(2-methoxyvinyl)cyclopropyl)methoxy)dimethylsilane
  • the fourth step the preparation of 2-(1-(hydroxymethyl)cyclopropyl)acetaldehyde
  • the fifth step the preparation of (1-(2-(dimethylamino)ethyl)cyclopropyl)methanol
  • the first step preparation of methyl 1-(pyrimidin-2-yl)cyclopropanecarboxylate
  • the first step the preparation of 2-chloro-3-fluoro-5-iodopyridin-4-amine
  • the second step the preparation of 4-amino-6-chloro-5-fluoronicotinic acid ethyl ester
  • the third step preparation of 7-chloro-8-fluoropyridine[4,3-d]pyrimidine-2,4-diol
  • the fourth step preparation of 2,4,7-trichloro-8-fluoropyridine[4,3-d]pyrimidine
  • the third step 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((1-((dimethylamino) Preparation of methyl)cyclopropyl)methoxy)-8-fluoropyridin[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
  • Example 7 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-((tetrahydro-1H-bis Fused pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
  • Example 8 4-(8-Fluoro-4-(2,7-diazaspiro[3.5]nonan-7-yl)-2-((tetrahydro-1H-bisfused pyrrolidine-7a(5H) -yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
  • Example 12 4-(8-Fluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)-2-((tetrahydro-1H-bisfused pyrrolidine-7a(5H) -yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)naphthalen-2-ol
  • the binding ability of the compounds to KRAS G12D protein was detected by TR-FRET technology.
  • Biotin-labeled GDP-loaded KRAS G12D recombinant human protein with Cy5-labeled tracer, Europium-labeled streptavidin, compound (2% DMSO final concentration) in buffer (HEPES (pH 7.5), MgCl 2 , Tween -20 and DTT) were co-incubated. After incubation at 22°C for 60 min, the reaction activity was detected by the EnVision multi-function microplate reader dual-wavelength technology, and the protein binding capacity (POC) was calculated by ratiometric emission factor.
  • POC protein binding capacity
  • POC means no compound; 0 POC means that the control compound completely inhibits the binding of the tracer to KRAS G12D at this concentration.
  • the POC value was fitted with a four-parameter Logistic model curve, and IC 50 represented the 50 POC concentration value.
  • the compounds to be tested were serially diluted, and each compound was diluted with 10 concentration gradients (diluted from 50 ⁇ M to 0.003 ⁇ M) and added 100 nL to the corresponding wells of the microplate. After dosing, 40 ⁇ L of phosphate buffer was added to each well in rows A and P and columns 1 and 24, and then the microplate was incubated in a carbon dioxide incubator for 5 days.
  • Example 11 1-10
  • Example 12 1-10
  • Example 13 1-10
  • Example 14 1-10
  • Example 15 0.1-1
  • Example 16 0.1-1
  • mice 100 uL of 5x10 6 MIA PaCa-2 tumor cell suspension was subcutaneously inoculated into the right hind flank of nude mice. Mice health were monitored daily, starting when tumors grew to palpable size.
  • the tumor volume calculation formula adopts: 0.5 ⁇ L ⁇ W 2 , where L and W represent the length and width of the tumor, respectively. Tumors grew to -200 mm3 and mice were randomized. Mice were given the corresponding dose of compound by gavage daily, while their general status was monitored. Tumors were measured 3 times a week and body weights were measured twice a week.
  • the compound of the present invention has a good anti-tumor effect.

Abstract

La présente invention concerne un inhibiteur de pyrimidopyridine, son procédé de préparation et son utilisation. Plus particulièrement, le composé selon la présente invention a une structure représentée par la formule (I). La présente invention concerne en outre un procédé de préparation du composé, et une utilisation du composé en tant qu'inhibiteur de KRASG12D. Le composé a une excellente aptitude à inhiber de manière sélective KRASG12D, et a une performance pharmacodynamique et pharmacocinétique améliorée et des effets toxiques et secondaires très faibles.
PCT/CN2022/082327 2021-03-22 2022-03-22 Inhibiteur de pyrimidopyridine, son procédé de préparation et son utilisation WO2022199586A1 (fr)

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WO2023134465A1 (fr) * 2022-01-11 2023-07-20 上海艾力斯医药科技股份有限公司 Composé hétérocyclique contenant de l'azote, son procédé de préparation, intermédiaire de celui-ci et utilisation associée
WO2023198078A1 (fr) * 2022-04-11 2023-10-19 杭州英创医药科技有限公司 Composés polycycliques en tant qu'inhibiteurs de kras g12d
WO2024067714A1 (fr) * 2022-09-30 2024-04-04 泰励生物科技（上海）有限公司 Composés ayant une activité tumorale mutante anti-kras
WO2024078555A1 (fr) * 2022-10-13 2024-04-18 广东东阳光药业股份有限公司 Composé pyrimidopyridine, composition pharmaceutique et leur utilisation

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