WO2022253309A1 - Composés hétérocycliques substitués et leur utilisation - Google Patents

Composés hétérocycliques substitués et leur utilisation Download PDF

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Publication number
WO2022253309A1
WO2022253309A1 PCT/CN2022/096814 CN2022096814W WO2022253309A1 WO 2022253309 A1 WO2022253309 A1 WO 2022253309A1 CN 2022096814 W CN2022096814 W CN 2022096814W WO 2022253309 A1 WO2022253309 A1 WO 2022253309A1
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Prior art keywords
alkyl
cycloalkyl
halogen
methyl
tert
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PCT/CN2022/096814
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English (en)
Chinese (zh)
Inventor
袁保昆
陈坤成
白云
许新合
刘志华
陈曦
任仁
雷永珂
段小伟
刘希杰
李红娟
孙颖慧
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首药控股(北京)股份有限公司
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Priority to CN202280039475.4A priority Critical patent/CN117412964A/zh
Publication of WO2022253309A1 publication Critical patent/WO2022253309A1/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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention generally relates to novel substituted heterocyclic compounds having Menin-MLL interaction inhibitory activity, methods for their preparation, and pharmaceutical compositions thereof, as well as to such compounds and pharmaceutical compositions thereof, which benefit from the inhibition of Menin-MLL interaction diseases, such as the treatment of acute leukemia.
  • Acute leukemias are usually caused by acquired mutations in hematopoietic progenitor cells.
  • chromosomal abnormalities are often a discrete mutational signature.
  • Many chromosomal abnormalities are due to specific translocations leading to the formation of fusion genes that become drivers of tumorigenesis.
  • Acute leukemia in both adults and children can be caused by a rearrangement of the MLL gene located on chromosome 11q23, which produces a chimeric gene that encodes an oncogenic fusion protein consisting of the N-terminus of MLL with more than 80 It is fused to the C-terminus of one of the known fusion partners (Meyer et al., 2018).
  • MLL fusion proteins bind to DNA/chromatin and induce leukemic transformation of hematopoietic stem and progenitor cells by deregulating transcription of fusion protein target genes.
  • MLLr can manifest as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or a minority of mixed-phenotype acute leukemia (MPAL).
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • MPAL mixed-phenotype acute leukemia
  • MLL translocations can also be observed in ⁇ 33% of treatment-associated acute leukemias, usually following treatment with topoisomerase II inhibitors (Winters 2017).
  • MLL gene rearrangements occur in 5-10% of acute leukemias and are more prevalent especially in infants (up to 70% of cases) (Krivtsov 2007).
  • the incidence of MLLr-ALL has a peak in the first 2 years, declines in childhood and adolescence, and then increases steadily with age.
  • a similar pattern was observed in patients with MLLr AML, which was observed in nine other cases except for a postnatal peak in infants with ALL (Meyer 2018).
  • the MLLr leukemia subtype is characterized by aggressiveness, resistance to treatment, and high frequency of early relapses even after an initial complete remission (Armstrong 2002; Krivtsov 2007; Pieters 2007; Sloan 2012; Sanjuan Pla, 2015 year).
  • MLLr in childhood ALL is a strong predictor of poor outcome (Inaba 2013; Zhang 2019).
  • EFS event-free survival
  • OS overall survival
  • Pediatric MLLr acute leukemia is a disease with a poor prognosis, and new therapeutic approaches are urgently needed to improve prognosis.
  • Menin protein encoded by the multiple endocrine neoplasia (MEN) gene, is a ubiquitously expressed nuclear protein that interacts with DNA processing and repair proteins, chromatin modifying proteins, and various transcription factors. Binding of Menin to MLL fusion proteins is mediated by amino acid residues 9–13 of the N-terminus of MLL1, binding of Menin localizes these fusions to chromatin and is essential for the oncogenic activity of MLL fusion proteins (Yokoyama 2005; Casellini 2007) . This association has been shown to constitutively upregulate the expression of the HOX and MESI oncogenes and impair the proliferation and differentiation of hematopoietic cells, leading to the development of leukemia. Since Menin is a common oncogenic cofactor in MLL-associated leukemia, the interaction of Menin and MLL fusion proteins or MLL is a potential therapeutic target.
  • MEN multiple endocrine neoplasia
  • NPM1c nucleophosmin 1
  • Inhibitors of the Menin-MLL interaction demonstrated activity in a line of cells containing MLLr fusions, disrupting the interaction between Menin and the MLL1 fusion protein required for leukemogenesis activity, thereby affecting the expression of key oncogenes and leading to growth arrest and inhibition of cell proliferation.
  • Such inhibitors have shown strong single-agent activity in a variety of leukemia xenograft models, and have good survival benefits after oral administration in non-clinical models (Cierpicki 2014; Bojin 2015).
  • these data suggest that pharmacological inhibition of the Menin-MLL interaction is a potential targeted strategy for the treatment of MLLr acute leukemia.
  • Syndax's inhibitor SNDX-5613 first entered phase I/II clinical research (NCT04065399) on August 22, 2019, targeting acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) with MLL rearrangement or NPM1 mutation , mixed lineage acute leukemia (MLAL), mixed phenotype acute leukemia (MPAL), and unknown lineage acute leukemia (ALAL).
  • AML acute myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • MLL mixed lineage acute leukemia
  • MPAL mixed phenotype acute leukemia
  • ALAL unknown lineage acute leukemia
  • Kura's inhibitor KO-539 started phase I/II clinical research (NCT04067336) on August 26, 2019, targeting advanced malignant tumors, AML, mixed lineage leukemia (MLL), MLAL, MPAL, ALAL. Recently, Janssen started the clinical phase I study of JNJ-75276617 (NCT04065399) on March 21, 2021, targeting acute leukemia, AML, and ALL.
  • the molecular structures of the first two inhibitors have been disclosed, but the structure of the latter has not. Bayer, Agios, University of Michigan, University of Pennsylvania, Sumitomo, etc. also have patent arrangements.
  • the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,
  • Y 3 is NR 6 or
  • L is a bond, -(CO)-, or -CH 2 -,
  • V is N or CH
  • U is N or CR 16 .
  • Ring A is a 3-12 membered carbocyclic ring or a 3-12 membered heterocyclic ring
  • Ring B is a benzene ring or a 5-6 membered heteroaromatic ring
  • the C ring is a 3-12 member nitrogen-containing heterocycle
  • Y 1 is -O-, -S-, -NR 13 -, or -CR 11 R 12 -,
  • Y 2 is a bond, -O-, -S-, or -NR 13 -,
  • the alkyl, aryl and heteroaryl groups can be optionally substituted by halogen, CF 3 , C 1-6 alkyl, -NR 13 R 14 or -OR 1 ,
  • R 7 is hydrogen, -OR 13 , -NR 13 R 14 , C 1-6 alkyl, or C 3-8 cycloalkyl, and the C 1-6 alkyl or C 3-8 cycloalkyl can be optionally replaced by halogen,
  • Z is -(CO)-NR 13 R 14 or -(CO)-OR 13 ,
  • R 1 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -( CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R 2 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -(CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS (O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R3 is halogen
  • R 4 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -( CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R 5 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -(CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS (O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R 11 and R 12 are each independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkyl-O-, C 3-8 cycloalkyl, amino, C 1-6 alkane Baseamino or C 2-8 dialkylamino; said C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution,
  • R 15 are each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, C 2 -6 alkenyl and C 2-6 alkynyl, the C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered hetero
  • R 41 is H or C 1-6 alkyl, said alkyl may be optionally substituted by halogen, -CN, -NR 13 R 14 or -OR 13 ,
  • R 42 and R 43 are each independently selected from H and halogen
  • R 13 and R 14 are each independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl, said C 1-6 alkyl or C 3-8 cycloalkyl may be optionally substituted by halogen ,
  • R 16 is selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, amino, C 1-6 alkylamino or C 2-8 di Alkylamino; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution,
  • R 30 and R 31 are each independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl,
  • R 40 is selected from hydrogen, -CN, -(CO)-CH ⁇ CH 2 , C 1-6 alkyl and C 3-8 cycloalkyl, the C 1-6 alkyl or C 3-8 cycloalkyl optionally substituted by halogen,
  • n is each independently 0, 1, or 2
  • n is each independently 0, 1, 2, or 3
  • p is each independently 0 or 1.
  • Y3 is
  • ring C is a 3-6 membered nitrogen-containing heterocycle.
  • the C ring is
  • L is a bond
  • V is N.
  • p is 1.
  • each m is independently 0 or 1.
  • each n is independently 0 or 1.
  • Z is -(CO)-NR 13 R 14 .
  • Y 2 is a bond or -NR 13 -.
  • Y 1 is -NR 13 -.
  • U is N.
  • R 6 is
  • Z is -(CO)-NR 13 R 14 .
  • R 1 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, or C 2 -6 alkynyl.
  • each R 2 is independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , or -OR 13 .
  • R 3 is fluoro
  • R 4 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, CF 3 , -NR 13 R 14 , or -OR 13 .
  • each R 5 is independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , or -OR 13 .
  • R 11 and R 12 are hydrogen.
  • R 13 and R 14 are each independently selected from hydrogen and C 1-6 alkyl, preferably hydrogen and C 1-3 alkyl;
  • R 15 is selected from C 1-6 alkyl and C 3-8 cycloalkyl, preferably C 1-6 alkyl.
  • R 42 and R 43 are H.
  • the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,
  • Y 3 is NR 6 or
  • L is a bond, -(CO)-, or -CH 2 -,
  • V is N or CH
  • U is N or CR 16 .
  • Ring A is a 3-12 membered carbocyclic ring or a 3-12 membered heterocyclic ring
  • Ring B is a benzene ring or a 5-6 membered heteroaromatic ring
  • the C ring is a 3-12 member nitrogen-containing heterocycle
  • Y 1 is -O-, -S-, -NR 13 -, or -CR 11 R 12 -,
  • Y 2 is a bond, -O-, -S-, or -NR 13 -,
  • the alkyl group can be optionally substituted by halogen,
  • R 7 is hydrogen, -OR 13 , -NR 13 R 14 , C 1-6 alkyl, or C 3-8 cycloalkyl, and the C 1-6 alkyl or C 3-8 cycloalkyl can be optionally replaced by halogen,
  • Z is -(CO)-NR 13 R 14 or -(CO)-OR 13 ,
  • R 1 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -( CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R 2 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -(CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS (O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R3 is halogen
  • R 4 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -( CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R 5 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -(CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS (O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R 11 and R 12 are each independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkyl-O-, C 3-8 cycloalkyl, amino, C 1-6 alkane Baseamino or C 2-8 dialkylamino; said C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution,
  • R 41 is H or C 1-6 alkyl, the alkyl may be optionally substituted by -NR 13 R 14 or -OR 13 ,
  • R 13 and R 14 are each independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl, said C 1-6 alkyl or C 3-8 cycloalkyl may be optionally substituted by halogen ,
  • R 16 is selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, amino, C 1-6 alkylamino or C 2-8 di Alkylamino; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution,
  • R 30 and R 31 are each independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl,
  • R 40 is selected from hydrogen, -CN, -(CO)-CH ⁇ CH 2 , C 1-6 alkyl and C 3-8 cycloalkyl, the C 1-6 alkyl or C 3-8 cycloalkyl optionally substituted by halogen,
  • n is each independently 0, 1, or 2
  • n is each independently 0, 1, 2, or 3
  • p is each independently 0 or 1.
  • Y3 is
  • ring C is a 3-6 membered nitrogen-containing heterocycle.
  • L is a bond
  • V is N.
  • p is 1.
  • each m is independently 0 or 1.
  • each n is independently 0 or 1.
  • Z is -(CO)-NR 13 R 14 .
  • Y 2 is a bond or -NR 13 -.
  • Y 1 is -NR 13 -.
  • U is N.
  • R 6 is
  • Z is -(CO)-NR 13 R 14 .
  • R 1 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, or C 2 -6 alkynyl.
  • each R 2 is independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , or -OR 13 .
  • R 3 is fluoro
  • R 4 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, CF 3 , -NR 13 R 14 , or -OR 13 .
  • each R 5 is independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , or -OR 13 .
  • R 11 and R 12 are hydrogen.
  • R 13 and R 14 are each independently selected from hydrogen and C 1-6 alkyl, preferably hydrogen and C 1-3 alkyl;
  • R 15 is selected from C 1-6 alkyl and C 3-8 cycloalkyl, preferably C 1-6 alkyl.
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,
  • L is a bond or -CH 2 -
  • V is N or CH
  • U is N or CR 16 .
  • Ring A is a 3-12 membered carbocyclic ring or a 3-12 membered heterocyclic ring
  • Ring B is a benzene ring or a 5-6 membered heteroaromatic ring
  • the C ring is a 3-12 member nitrogen-containing heterocycle
  • Y 1 is -O-, -S-, -NR 13 -, or -CR 11 R 12 -,
  • Y 2 is a bond, -O-, -S-, or -NR 13 -,
  • R 6 is C 1-6 alkyl, or The alkyl group can be optionally substituted by halogen,
  • R 7 is hydrogen, -OR 13 , -NR 13 R 14 , C 1-6 alkyl, or C 3-8 cycloalkyl, and the C 1-6 alkyl or C 3-8 cycloalkyl can be optionally replaced by halogen,
  • Z is -(CO)-NR 13 R 14 or -(CO)-OR 13 ,
  • R 1 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -( CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R 2 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -(CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS (O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R3 is halogen
  • R 4 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -( CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R 5 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -(CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS (O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R 11 and R 12 are each independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkyl-O-, C 3-8 cycloalkyl, amino, C 1-6 alkane Baseamino or C 2-8 dialkylamino; said C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution,
  • R 13 and R 14 are each independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl, said C 1-6 alkyl or C 3-8 cycloalkyl may be optionally substituted by halogen ,
  • R 15 are each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl, the C 1-6 alkyl, C 3- 8 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl may be optionally substituted by halogen,
  • R 16 is selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, amino, C 1-6 alkylamino or C 2-8 di Alkylamino; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution,
  • R 30 and R 31 are each independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl,
  • n is each independently 0, 1, or 2
  • n is each independently 0, 1, 2, or 3
  • p is each independently 0 or 1.
  • L is a bond
  • V is N.
  • p is 1.
  • each m is independently 0 or 1.
  • each n is independently 0 or 1.
  • Z is -(CO)-NR 13 R 14 .
  • Y 2 is a bond or -NR 13 -.
  • Y 1 is -NR 13 -.
  • U is N.
  • R 6 is
  • Z is -(CO)-NR 13 R 14 .
  • R 1 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, or C 2 -6 alkynyl.
  • each R 2 is independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , or -OR 13 .
  • R 3 is fluoro
  • R 4 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, CF 3 , -NR 13 R 14 , or -OR 13 .
  • each R 5 is independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , or -OR 13 .
  • R 11 and R 12 are hydrogen.
  • R 13 and R 14 are each independently selected from hydrogen and C 1-6 alkyl, preferably hydrogen and C 1-3 alkyl;
  • R 15 is selected from C 1-6 alkyl and C 3-8 cycloalkyl, preferably C 1-6 alkyl.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,
  • U is N or CR 16 .
  • Ring A is a 3-12 membered carbocyclic ring or a 3-12 membered heterocyclic ring
  • Ring B is a benzene ring or a 5-6 membered heteroaromatic ring
  • the C ring is a 3-12 member nitrogen-containing heterocycle
  • Y 1 is -O-, -S-, -NR 13 -, or -CR 11 R 12 -,
  • Y 2 is a bond, -O-, -S-, or -NR 13 -,
  • R6 is or
  • R 7 is hydrogen, -OR 13 , -NR 13 R 14 , C 1-6 alkyl, or C 3-8 cycloalkyl, and the C 1-6 alkyl or C 3-8 cycloalkyl can be optionally replaced by halogen,
  • Z is -(CO)-NR 13 R 14 or -(CO)-OR 13 ,
  • R 1 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -( CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R 2 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -(CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS (O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R3 is halogen
  • R 4 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -( CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R 5 are each independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl , CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -(CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS (O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R 11 and R 12 are each independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkyl-O-, C 3-8 cycloalkyl, amino, C 1-6 alkane Baseamino or C 2-8 dialkylamino; said C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution,
  • R 13 and R 14 are each independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl, said C 1-6 alkyl or C 3-8 cycloalkyl may be optionally substituted by halogen ,
  • R 15 is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl, the C 1-6 alkyl, C 3-8 cycloalkane Base, C 2-6 alkenyl or C 2-6 alkynyl may be optionally substituted by halogen,
  • R 16 is selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, amino, C 1-6 alkylamino or C 2-8 di Alkylamino; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution,
  • n is each independently 0, 1, or 2
  • n is each independently 0, 1, 2, or 3
  • p is each independently 0 or 1.
  • p is 1.
  • each m is independently 0 or 1.
  • each n is independently 0 or 1.
  • Z is -(CO)-NR 13 R 14 .
  • Y 2 is a bond or -NR 13 -.
  • Y 1 is -NR 13 -.
  • U is N.
  • R 6 is
  • Z is -(CO)-NR 13 R 14 .
  • R 1 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, or C 2 -6 alkynyl.
  • each R 2 is independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , or -OR 13 .
  • R 3 is fluoro
  • R 4 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, CF 3 , -NR 13 R 14 , or -OR 13 .
  • each R 5 is independently hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , or -OR 13 .
  • R 11 and R 12 are hydrogen.
  • R 13 and R 14 are each independently selected from hydrogen and C 1-6 alkyl, preferably hydrogen and C 1-3 alkyl;
  • R 15 is selected from C 1-6 alkyl and C 3-8 cycloalkyl, preferably C 1-6 alkyl.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,
  • U is N or CR 16 .
  • Ring A is a 3-12 membered carbocyclic ring or a 3-12 membered heterocyclic ring
  • Ring B is a benzene ring or a 5-6 membered heteroaromatic ring
  • the C ring is a 3-8 membered nitrogen-containing heterocycle
  • Y 1 is -O-, -S-, -NR 13 -, or -CR 11 R 12 -,
  • Y 2 is -O-, -S-, or -NR 13 -,
  • R6 is or
  • R 7 is hydrogen, -OR 13 , -NR 13 R 14 , C 1-6 alkyl, or C 3-8 cycloalkyl, and the C 1-6 alkyl or C 3-8 cycloalkyl can be optionally replaced by halogen,
  • Z is -(CO)-NR 13 R 14 or -(CO)-OR 13 ,
  • R 1 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -( CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R 2 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -( CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R3 is halogen
  • R 4 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -( CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R 5 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CF 3 , -NR 13 R 14 , -OR 13 , -(CO)-R 15 , -O-(CO)-R 15 , -NR 13 -(CO)-R 15 , -(CO)-OR 13 , -( CO)-NR 13 R 14 , -S(O)R 15 , -S(O) 2 R 15 , -S(O) 2 NR 13 R 14 , -S(O) 2 OR 13 , -OS(O) 2 R 15 , -NR 13 -S(O) 2 R 15 , or
  • R 11 and R 12 are each independently selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkyl-O-, C 3-8 cycloalkyl, amino, C 1-6 alkane Baseamino or C 2-8 dialkylamino; said C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution,
  • R 13 and R 14 are each independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl, said C 1-6 alkyl or C 3-8 cycloalkyl may be optionally substituted by halogen ,
  • R 15 is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl and C 2-6 alkynyl, the C 1-6 alkyl, C 3-8 cycloalkane Base, C 2-6 alkenyl or C 2-6 alkynyl may be optionally substituted by halogen,
  • R 16 is selected from H, halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, amino, C 1-6 alkylamino or C 2-8 di Alkylamino; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 1-6 alkylamino or C 2-8 dialkylamino can optionally be halogen substitution,
  • n is each independently 0, 1, or 2
  • n is each independently 0, 1, 2, or 3
  • p is each independently 0 or 1.
  • p is 1.
  • each m is independently 0 or 1.
  • each n is independently 0 or 1.
  • Z is -(CO)-NR 13 R 14 .
  • Y 2 is -NR 13 -.
  • Y 1 is -NR 13 -.
  • U is N.
  • R 6 is
  • Z is -(CO)-NR 13 R 14 .
  • R 1 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, or C 2 -6 alkynyl.
  • R 2 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, CF 3 , -NR 13 R 14 , or -OR 13 .
  • R 3 is fluoro
  • R 4 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, CF 3 , -NR 13 R 14 , or -OR 13 .
  • R 5 is hydrogen, halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, CF 3 , -NR 13 R 14 , or -OR 13 .
  • R 11 and R 12 are hydrogen.
  • R 13 and R 14 are each independently selected from hydrogen and C 1-6 alkyl, preferably hydrogen and C 1-3 alkyl;
  • R 15 is selected from C 1-6 alkyl and C 3-8 cycloalkyl, preferably C 1-6 alkyl.
  • the present invention provides the following compound or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, and optionally a pharmaceutically acceptable Carrier.
  • the present invention provides a method for treating a disease associated with MLL activity, comprising administering to a subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph, tautovariant Constructs, metabolites or prodrugs, or the pharmaceutical composition of the present invention;
  • the disease associated with MLL activity is cancer, preferably acute leukemia (including MLL acute leukemia, MLL partial tandem repeat acute leukemia , NPM mutant acute leukemia, MOZ acute leukemia, NUP98 acute leukemia and CALM acute leukemia), chronic lymphocytic leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma (including B-cell lymphoid cancer), myeloma (including multiple myeloma), brain tumors, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell
  • the different agents are selected from antitum
  • the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention for use in the preparation of
  • the disease associated with MLL activity is cancer, preferably acute leukemia (including MLL acute leukemia, MLL partial tandem repeat acute leukemia, NPM mutation Acute leukemia, MOZ acute leukemia, NUP98 acute leukemia and CALM acute leukemia), chronic lymphocytic leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma (including B-cell lymphoma), Myeloma (including multiple myeloma), brain tumors, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, gastric cancer, gallbladder and bile duct cancer, liver cancer, he
  • optionally substituted alkyl means "unsubstituted alkyl” or "substituted alkyl”.
  • optionally substituted groups can be unsubstituted (eg: -CH 2 CH 3 ), fully substituted (eg: -CF 2 CF 3 ), monosubstituted (eg: -CH 2 CH 2 F) or Any hierarchy between monosubstitution and full substitution (for example: -CH2CHF2 , -CF2CH3 , -CFHCHF2 , etc. ). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
  • group and "chemical group” as used herein refer to a specific part or functional group of a molecule. Chemical groups are often thought of as chemical entities embedded or attached to a molecule.
  • C 1 -C 6 alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms.
  • the total number of carbon atoms indicated by the abbreviation does not include the carbon atoms on the possible substituents.
  • halogen refers to bromine, chlorine, fluorine or iodine.
  • aromatic refers to a planar ring or ring moiety having 4n+2 A delocalized electron conjugate system of electrons, where n is an integer.
  • Aromatic rings may be formed by 5, 6, 7, 8, 9 or more atoms.
  • the aromatic compound may be optionally substituted and may be monocyclic or polycyclic with fused rings.
  • aromatic includes all carbocyclic rings (eg benzene rings) and rings containing one or more heteroatoms (eg pyridine).
  • heteroatom or “hetero” as used herein alone or as part of another constituent refers to an atom other than carbon and hydrogen. Heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.
  • fused or "fused ring”, as used herein, alone or in combination, refer to a cyclic structure in which two or more rings share one or more bonds.
  • spiro or “spirocycle” as used herein, alone or in combination, refer to a ring structure in which two or more rings share one or more atoms.
  • alkyl refers to an optionally substituted linear or optionally substituted branched monovalent saturated hydrocarbon having 1-12 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, are connected to other parts of the molecule through single bonds, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, etc.
  • alkenyl defined herein appears in a numerical range
  • “C 2 -C 6 alkenyl” or “C 2 - 6 alkenyl” means that it can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms Atoms or alkenyl groups composed of 6 carbon atoms
  • the alkenyl group herein also covers the case where the numerical range is not specified.
  • alkynyl refers to an optionally substituted linear or branched monovalent hydrocarbon group having one or more C ⁇ C triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like.
  • alkynyl group defined herein appears in a numerical range
  • “C 2 -C 6 alkynyl” or “C 2 - 6 alkynyl” means that it can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms atom or an alkynyl group composed of 6 carbon atoms
  • the alkynyl group herein also covers the situation where the numerical range is not specified.
  • aryl refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, having 6-14 carbon atoms, preferably 6-12 carbon atoms, most preferably 6 carbon atoms .
  • Aryl can be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, sulfonyl , sulfinyl, phosphoryl and heteroalicyclic.
  • substituents examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, sulfonyl , sulfinyl, phosphoryl and heteroalicyclic.
  • Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and an
  • heteroaryl refers to a single or condensed ring of 5-12 ring atoms, having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, containing 1, 2, 3 or 4 ring atoms selected from N, O, S, the rest of the ring atoms are C, and have a fully conjugated ⁇ -electron system.
  • Heteroaryl groups can be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl, and hetero Alicyclic.
  • Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, iso Quinolinyl, tetrazolyl, triazinyl.
  • cycloalkyl refers to a stable monovalent non-aromatic monocyclic or polycyclic hydrocarbon radical containing only carbon and hydrogen atoms, which may include fused, spiro or bridged ring systems, including 3-15 ring-forming carbon atoms, preferably 3-10 ring-forming carbon atoms, more preferably 3-8 ring-forming carbon atoms, can be saturated or unsaturated, connected to other parts of the molecule through a single bond.
  • Non-limiting examples of "cycloalkyl” include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • heterocyclyl refers to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1 -6 heteroatoms selected from nitrogen, oxygen and sulfur.
  • a heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused, spiro or bridged ring systems, and the nitrogen, carbon or sulfur on the heterocyclyl can be optionally The nitrogen atom can be optionally quaternized, and the heterocyclic group can be partially or fully saturated.
  • a heterocyclyl group can be attached to the rest of the molecule by a single bond through a ring carbon atom or a heteroatom.
  • a heterocyclyl group containing fused rings may contain one or more aromatic or heteroaryl rings, as long as the non-aromatic ring atoms are attached to the rest of the molecule.
  • the heterocyclic group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable A 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclyl examples include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuryl, indolinyl, dioxolyl, 1,1 -dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, Piperazinyl, piperidinyl, 4-piperidinonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinazinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like.
  • Carbocycle refers to a structure covalently closed by carbon, which may be saturated or partially unsaturated. Carbocyclic rings may be formed by 3, 4, 5, 6, 7, 8, 9 or more atoms. The difference between the terms carbocycle and heterocycle is that the ring skeleton of the heterocycle contains at least one atom different from carbon.
  • the "carbocycle” herein may be monocyclic or polycyclic, and polycyclic carbocycles include spiro rings, fused rings and bridged rings. Carbocycles can be optionally substituted.
  • a "carbocycle” herein preferably contains from about 5 to about 20 or 5 to 10 or 5-8 or 5-6 skeletal ring atoms.
  • polymorph or “polymorphism (phenomenon)" means that the compounds of the present invention have multiple crystal lattice forms. Some compounds of the present invention may have more than one crystal form, and the present invention covers all polymorphic forms or mixtures thereof.
  • olefinic double bonds contained in the compounds of the present invention include both E and Z isomers.
  • Compounds of the present invention include compounds having one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of that element.
  • a reference to hydrogen includes within its scope1H, 2H (D) and3H ( T ).
  • references to carbon and oxygen include within their scope12C, 13C , and14C and16O and18O , respectively .
  • compounds of the present invention may contain asymmetric centers. These asymmetric centers can independently be in the R or S configuration. It will be apparent to those skilled in the art that some of the compounds of the present invention may also exhibit cis-trans isomerism. It is to be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers as well as mixtures thereof, including racemic mixtures. These isomers may be isolated from their mixtures by implementation or adaptation of known methods, such as chromatographic techniques and recrystallization techniques, or they may be prepared separately from appropriate isomers of their intermediates.
  • pharmaceutically acceptable salt includes both salts and bases.
  • “Pharmaceutically acceptable salt addition” refers to those salts that retain the biological potency and properties of the free base of the compound, are not biologically or otherwise undesirable, and are combined with inorganic acids such as, but not limited to, hydrochloric acid, hydrogen Bromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids, such as but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, Salts of capric acid, caproic acid, carbonic acid, cinnamic acid, citric acid, etc.
  • inorganic acids such as, but not limited to, hydrochloric acid, hydrogen Bromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
  • organic acids such as but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alg
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acid of the compound and are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic or organic base. Salts formed by reacting with inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and manganese salts.
  • Salt-forming organic bases include, but are not limited to, primary, secondary, tertiary, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine , dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline and caffeine, etc.
  • Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
  • solvate refers to a combination of one or more molecules of a compound of the present invention and one or more molecules of a solvent.
  • the solvent may be water, in which case the solvate is a hydrate.
  • organic solvents are also possible.
  • the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, etc., and the corresponding solvated forms.
  • the compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may only incidentally retain water or a mixture of water and some other solvent.
  • the compounds of the present invention can be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
  • composition refers to a preparation of a compound of the present invention in admixture with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal, such as a human.
  • This medium contains all pharmaceutically acceptable carriers.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively nontoxic, i.e., 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.
  • “Pharmaceutically acceptable carriers” include but are not limited to adjuvants, carriers, excipients, auxiliary agents, deodorants, diluents, preservatives, Dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizing agents, isotonic agents, solvents, or emulsifying agents.
  • subject refers to an individual suffering from a disease, disorder or condition, etc., including mammals and non-mammals.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (such as chimpanzees and other apes and monkeys); livestock such as cattle, horses, sheep, goats, pigs; domesticated animals , such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs.
  • non-human mammals include, but are not limited to, birds, fish, and the like.
  • the mammal is a human.
  • treatment refers to the treatment of relevant diseases or conditions in mammals, especially humans, including
  • disease and “disorder” can be used interchangeably or with different meanings, as some specific diseases or conditions do not have a known causative agent (so the cause of the disease is unknown), so they cannot yet be recognized as Diseases can only be seen as unwanted conditions or syndromes with more or less specific symptoms that have been confirmed by clinical researchers.
  • a therapeutically effective amount refers to at least one agent or compound which, when administered, is sufficient to relieve to some extent one or more symptoms of the disease or condition being treated amount. The result may be a reduction and/or alleviation of a sign, symptom or cause, or any other desired change in a biological system.
  • a therapeutically “effective amount” is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant disease-modifying effect. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation assays.
  • administering refers to methods capable of delivering a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
  • silica gel 200-300 mesh
  • Thin layer chromatography adopts the prefabricated plate (silica gel 60 PF 254 , 0.25 mm) produced by E.Merck Company.
  • Chiral compound separation and enantiomeric excess value (ee) determination using Agilent LC 1200 series (column: CHIRALPAK AD-H, mm, 5 microns, 30°C).
  • Nuclear magnetic resonance chromatography was determined using a Varian VNMRS-400 nuclear magnetic resonance instrument; liquid mass spectrometry (LC/MS) was measured using FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200 series (column: Waters Symmetry C18, mm, 5 ⁇ m, 35°C), using ESI (+) ion mode.
  • N-(trans-4-formylcyclohexyl)methanesulfonamide was synthesized according to the method of intermediate 47 in patent WO2017214367.
  • Step 1 4-(((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidine-1- tert-butyl carboxylate
  • Step 2 N-Ethyl-5-fluoro-N-isopropyl-2-((4-((piperidin-4-ylmethyl)amino)pyrimidin-5-yl)oxy)benzamide
  • Step 1 (1R,5S,6s)-6-(((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino) Methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester
  • step 1 in intermediate 6 replace 4- Aminomethylpiperidine-1-carboxylate tert-butyl ester to get (1R,5S,6s)-6-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluoro phenoxy)pyrimidin-4-yl)amino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester.
  • Step 2 2-((4-((((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)amino)pyrimidin-5-yl)oxy )-N-Ethyl-5-fluoro-N-isopropylbenzamide
  • step 2 in intermediate 6 use (1R,5S,6s)-6-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy) Pyrimidin-4-yl)amino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl )carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester to get 2-((4-((((1R,5S ,6r)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)amino)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl benzamide.
  • Step 1 (1R,5S,6s)-6-((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)- tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate
  • step 1 in intermediate 6 replace 4-aminomethylpiperene with (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl Pyridine-1-carboxylic acid tert-butyl ester to get (1R,5S,6s)-6-((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester.
  • Step 2 2-((4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)amino)pyrimidin-5-yl)oxy)-N- Ethyl-5-fluoro-N-isopropylbenzamide
  • step 2 in intermediate 6 use (1R,5S,6s)-6-((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)aminomethyl) Acyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylate tert-butyl ester to get 2-((4-(((1R,5S,6s)-3 -Azabicyclo[3.1.0]hexan-6-yl)amino)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide.
  • Step 1 ((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)azetidin-3-yl) Methyl) tert-butyl carbamate
  • step 1 in intermediate 6 replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with (azetidin-3-ylmethyl) tert-butyl carbamate to obtain ((1 -(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)azetidin-3-yl)methyl)carbamate butyl ester.
  • Step 2 2-((4-(3-(Aminomethyl)azetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl phenylbenzamide
  • step 2 in intermediate 6 use ((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)azepine Cyclobutan-3-yl)methyl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine- 4-base) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester, get 2-((4-(3-(aminomethyl) azetidin-1-yl) pyrimidin-5-yl )oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 388.22 [M+1].
  • Step 1 tert-butyl (1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-4-yl)carbamate ester
  • step 1 in intermediate 6 replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with piperidin-4-ylcarbamic acid tert-butyl ester to obtain (1-(5-(2-( tert-butyl ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-4-yl)carbamate.
  • Step 2 2-((4-(4-Aminopiperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide
  • step 2 in intermediate 6 use (1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidine- 4-yl) tert-butyl carbamate instead of 4-(((5-(2-(ethyl(isopropyl) carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl Base) piperidine-1-carboxylate tert-butyl ester to get 2-((4-(4-aminopiperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro- N-isopropylbenzamide.
  • Step 1 (R)-(1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl) tert-butyl carbamate
  • step 1 in intermediate 6 replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with (R)-pyrrolidin-3-ylcarbamic acid tert-butyl ester to obtain (R)-(1 -(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate tert-butyl ester.
  • Step 2 (R)-2-((4-(3-Aminopyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzyl Amide
  • step 2 in intermediate 6 use (R)-(1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )pyrrolidin-3-yl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )amino)methyl)piperidine-1-carboxylic acid tert-butyl ester, to get (R)-2-((4-(3-aminopyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N -Ethyl-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 388.22 [M+1].
  • step 1 in intermediate 6 substituting azetidin-3-ylmethanol for tert-butyl 4-aminomethylpiperidine-1-carboxylate, N-ethyl-5-fluoro-2- ((4-(3-(Hydroxymethyl)azetidin-1-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide.
  • Step 1 4-(((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)-4-fluoropiper tert-butyl pyridine-1-carboxylate
  • step 1 in intermediate 6 replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with 4-aminomethyl-4-fluoropiperidine-1-carboxylic acid tert-butyl ester to obtain (4 -(((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidine-1- Tert-Butyl Carboxylate.MS m/z[LC-MS]:534.29[M+1].
  • Step 2 N-Ethyl-5-fluoro-2-((4-(((4-fluoropiperidin-4-yl)methyl)amino)pyrimidin-5-yl)oxy)-N-isopropyl phenylbenzamide
  • step 2 in intermediate 6 use 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino) Methyl)-4-fluoropiperidine-1-carboxylate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester, to get N-ethyl-5-fluoro-2-((4-(((4-fluoropiperidin-4-yl) Methyl)amino)pyrimidin-5-yl)oxy)-N-isopropylbenzamide.
  • Step 1 (S)-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl ) methyl) tert-butyl carbamate
  • step 1 in intermediate 6 replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with (R)-pyrrolidin-3-ylmethylcarbamate tert-butyl ester to obtain (S)- ((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)carbamate butyl ester.
  • Step 2 (R)-2-((4-(3-Aminopyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzyl Amide
  • step 2 in intermediate 6 use (S)-((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- Base)pyrrolidin-3-yl)methyl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester to get (S)-2-((4-(3-aminomethylpyrrolidin-1-yl)pyrimidin-5-yl )oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide.
  • Step 1 ((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-4-yl)methyl) tert-butyl carbamate
  • step 1 in intermediate 6 replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with 4-aminomethyl-4-fluoropiperidine-1-carboxylic acid tert-butyl ester to obtain (( tert-Butyl 1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-4-yl)methyl)carbamate .
  • Step 2 2-((4-(4-(Aminomethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzyl Amide
  • step 2 in intermediate 6 use ((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidine -4-yl)methyl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl ) amino) methyl) piperidine-1-carboxylate tert-butyl ester, to get 2-((4-(4-(aminomethyl) piperidin-1-yl) pyrimidin-5-yl) oxy)-N -Ethyl-5-fluoro-N-isopropylbenzamide.
  • Step 1 ((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-fluoroazetidine- 3-yl)methyl)carbamate tert-butyl ester
  • step 1 in intermediate 6 replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with ((3-fluoroazetidin-3-yl)methyl)tert-butyl carbamate , to give ((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-fluoroazetidine-3 -yl) methyl) tert-butyl carbamate.
  • Step 2 2-((4-(3-(Aminomethyl)-3-fluoroazetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro- N-isopropylbenzamide
  • step 2 in intermediate 6 use ((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3 -Fluoroazetidin-3-yl)methyl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy Base) pyrimidin-4-yl) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester, get 2-((4-(3-(aminomethyl)-3-fluoroazetidine-1 -yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 406.21 [M+1].
  • Step 1 (R)-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl ) methyl) tert-butyl carbamate
  • step 1 in intermediate 6 replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with (S)-(pyrrolidin-3-ylmethyl)carbamate tert-butyl ester to obtain (R )-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)amino tert-butyl formate.
  • Step 2 (R)-2-((4-(3-(Aminomethyl)pyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-iso Propyl benzamide
  • step 2 in intermediate 6 use (R)-((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- Base)pyrrolidin-3-yl)methyl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester to get (R)-2-((4-(3-(aminomethyl)pyrrolidin-1-yl)pyrimidine-5 -yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide.
  • Step 1 (3-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-azabicyclo[3.1.0] Hexan-6-yl) tert-butyl carbamate
  • step 1 in intermediate 6 replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with (3-azabicyclo[3.1.0]hexane-6-yl)carbamate tert-butyl , to get (3-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexyl alk-6-yl) tert-butyl carbamate.
  • Step 2 2-((4-(6-Amino-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro- N-isopropylbenzamide
  • step 2 in intermediate 6 use (3-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3- Azabicyclo[3.1.0]hexan-6-yl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy Base) pyrimidin-4-yl) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester, get 2-((4-(6-amino-3-azabicyclo[3.1.0]hexane-3 -yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 400.22 [M+1].
  • Step 1 (1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)azetidin-3-yl)amino tert-butyl formate
  • step 1 in intermediate 6 replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with azetidin-3-ylcarbamate tert-butyl to obtain (1-(5-( tert-butyl 2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)azetidin-3-yl)carbamate.
  • Step 2 2-((4-(3-Aminoazetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide
  • step 2 in intermediate 6 use (1-(5-(2-(ethyl(isopropyl) carbamoyl)-4-fluorophenoxy) pyrimidin-4-yl) azacyclic Butan-3-yl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl) Amino) methyl) piperidine-1-carboxylic acid tert-butyl ester to get 2-((4-(3-aminoazetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl Base-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 374.20 [M+1].
  • Step 1 2-(((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)morpholine-4- tert-butyl carboxylate
  • step 1 in intermediate 6 replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with 2-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester to obtain ((1- (5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-4-yl)methyl)carbamate tert-butyl ester 2- (((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)morpholine-4-carboxylic acid tert-butyl ester .
  • Step 2 N-Ethyl-5-fluoro-N-isopropyl-2-((4-((morpholin-2-ylmethyl)amino)pyrimidin-5-yl)oxy)benzamide
  • step 2 in intermediate 6 use 2-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino) Methyl)morpholine-4-carboxylate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl ) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester, get N-ethyl-5-fluoro-N-isopropyl-2-((4-((morpholin-2-ylmethyl) amino)pyrimidin-5-yl)oxy)benzamide. MS m/z [LC-MS]: 418.23 [M+1].
  • Step 1 (S)-(1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl) tert-butyl carbamate
  • step 1 in intermediate 6 replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester to obtain (S)-(1 -(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)carbamate tert-butyl ester.
  • Step 2 (S)-2-((4-(3-Aminopyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzyl Amide
  • step 2 in intermediate 6 use (S)-(1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )pyrrolidin-3-yl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )amino)methyl)piperidine-1-carboxylic acid tert-butyl ester, to get (S)-2-((4-(3-aminopyrrolidin-1-yl)pyrimidin-5-yl)oxyl)-N -Ethyl-5-fluoro-N-isopropylbenzamide.
  • Step 1 ((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylazetidine -3-yl)methyl)carbamate tert-butyl ester
  • step 1 in intermediate 6 replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with ((3-methylazetidin-3-yl)methyl)tert-butyl carbamate ester to give ((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylazetidine -3-yl)methyl)carbamate tert-butyl ester.
  • Step 2 2-((4-(3-(Aminomethyl)-3-methylazetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro -N-Isopropylbenzamide
  • step 2 in intermediate 6 use ((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3 -Methylazetidin-3-yl)methyl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorobenzene Oxygen) pyrimidin-4-yl) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester, get 2-((4-(3-(aminomethyl)-3-methylazetidine -1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 402.23 [M+1].
  • Step 1 ((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-4-hydroxypiperidin-4-yl ) methyl) tert-butyl carbamate
  • step 1 in intermediate 6 replace tert-butyl 4-aminomethylpiperidine-1-carboxylate with ((4-hydroxypiperidin-4-yl) methyl) tert-butyl carbamate to obtain ( (1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-4-hydroxypiperidin-4-yl)methyl) tert-butyl carbamate.
  • Step 2 2-((4-(4-Aminomethyl)-4-hydroxypiperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropyl phenylbenzamide
  • step 2 in intermediate 6 use ((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-4 -Hydroxypiperidin-4-yl)methyl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)amino)methyl)piperidine-1-carboxylate tert-butyl ester to give 2-((4-(4-aminomethyl)-4-hydroxypiperidin-1-yl)pyrimidine-5- base)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide.
  • Step 1 ((3-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-azabicyclo[3.1.0 ]Hexan-6-yl)methyl)carbamate tert-butyl ester
  • step 1 in intermediate 6 replace 4-aminomethylpiperidine-1-carboxylate with ((3-azabicyclo[3.1.0]hexane-6-yl)methyl)carbamate tert-butyl ester Acid tert-butyl ester, get ((3-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-azabicyclo[ 3.1.0] Hexan-6-yl)methyl)carbamate tert-butyl ester.
  • Step 2 2-((4-(6-(aminomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)oxy)-N-ethyl- 5-Fluoro-N-isopropylbenzamide
  • step 2 in intermediate 6 use ((3-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3 -Azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate tert-butyl ester instead of 4-(((5-(2-(ethyl(isopropyl)carbamoyl)-4 -Fluorophenoxy)pyrimidin-4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester to give 2-((4-(6-(aminomethyl)-3-azabicyclo[ 3.1.0] Hexan-3-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide. MS m/z [LC-MS]: 414.23 [M+1].
  • N-(trans-4-formylcyclohexyl)ethanesulfonamide was synthesized according to the method of intermediate 47 in patent WO2017214367.
  • Step 1 (R)-3-(((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)pyrrole tert-butyl alkane-1-carboxylate
  • the target compound was obtained from (R)-3-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester.
  • Step 2 (S)-N-Ethyl-5-fluoro-N-isopropyl-2-((4-((pyrrolidin-3-ylmethyl)amino)pyrimidin-5-yl)oxy) benzamide
  • step 2 in intermediate 6 use (R)-3-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- base)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester as raw material to obtain the target compound.
  • Step 1 (S)-3-(((5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)amino)methyl)pyrrole tert-butyl alkane-1-carboxylate
  • the target compound was obtained from (S)-3-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester.
  • Step 2 (R)-N-ethyl-5-fluoro-N-isopropyl-2-((4-((pyrrolidin-3-ylmethyl)amino)pyrimidin-5-yl)oxy) benzamide
  • step 2 in intermediate 6 use (S)-3-(((5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- base)amino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester as raw material to obtain the target compound.
  • Step 1 tert-butyl 3-(aminomethyl)-3-hydroxypyrrolidine-1-carboxylate
  • Step 2 tert-Butyl 3-Hydroxy-3-((((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)amino)methyl)pyrrolidine-1-carboxylate
  • Step 3 N-((1r,4r)-4-((((3-hydroxypyrrolidin-3-yl)methyl)amino)methyl)cyclohexyl)methanesulfonamide
  • Step 1 (S)-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-3-yl ) methyl) tert-butyl carbamate
  • the target compound was obtained from tert-butyl (R)-(piperidin-3-ylmethyl)carbamate. MS m/z [LC-MS]: 516.30 [M+1].
  • Step 2 (S)-2-((4-(3-(Aminomethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-iso Propyl benzamide
  • step 2 in intermediate 6 use (S)-((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- base) piperidin-3-yl) methyl) tert-butyl carbamate as raw material to obtain the target compound.
  • Step 1 (R)-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)piperidin-3-yl ) methyl) tert-butyl carbamate
  • the target compound was obtained from tert-butyl (S)-(piperidin-3-ylmethyl)carbamate. MS m/z [LC-MS]: 516.30 [M+1].
  • Step 2 (R)-2-((4-(3-(Aminomethyl)piperidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-iso Propyl benzamide
  • step 2 in intermediate 6 use (R)-((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- base) piperidin-3-yl) methyl) tert-butyl carbamate as raw material to obtain the target compound.
  • Step 1 (R)-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylpyrrole tert-butyl (alk-3-yl)methyl)carbamate
  • the target compound was obtained from tert-butyl (S)-((3-methylpyrrolidin-3-yl)methyl)carbamate. MS m/z [LC-MS]: 516.30 [M+1].
  • Step 2 (R)-2-((4-(3-(Aminomethyl)-3-methylpyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5- Fluoro-N-isopropylbenzamide
  • step 2 in intermediate 6 use (R)-((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- Base)-3-methylpyrrolidin-3-yl)methyl)carbamate tert-butyl ester as raw material to obtain the target compound.
  • Step 1 (S)-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylpyrrole tert-butyl (alk-3-yl)methyl)carbamate
  • the target compound was obtained from tert-butyl (R)-((3-methylpyrrolidin-3-yl)methyl)carbamate. MS m/z [LC-MS]: 516.30 [M+1].
  • Step 2 (S)-2-((4-(3-(Aminomethyl)-3-methylpyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5- Fluoro-N-isopropylbenzamide
  • step 2 in intermediate 6 use (S)-((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- Base)-3-methylpyrrolidin-3-yl)methyl)carbamate tert-butyl ester as raw material to obtain the target compound.
  • Step 1 tert-butyl 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate
  • Step 1 ((3-Ethyl-1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)azetidine -3-yl)methyl)carbamate tert-butyl ester
  • the target compound was obtained from tert-butyl ((3-ethylazetidin-3-yl)methyl)carbamate. MS m/z [LC-MS]: 516.30 [M+1].
  • Step 2 2-((4-(3-(Aminomethyl)-3-ethylazetidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro -N-Isopropylbenzamide
  • step 2 in intermediate 6 use ((3-ethyl-1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4 -yl) azetidin-3-yl) methyl) tert-butyl carbamate as starting material to obtain the target compound.
  • Step 1 (((3R,4S)-1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-4-fluoro tert- butyl pyrrolidin-3-yl)methyl)carbamate
  • the target compound was obtained from tert-butyl (((3S,4S)-4-fluoropyrrolidin-3-yl)methyl)carbamate. MS m/z [LC-MS]: 520.27 [M+1].
  • Step 2 2-((4-((3R,4S)-3-(aminomethyl)-4-fluoropyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5 -Fluoro-N-isopropylbenzamide
  • step 2 in intermediate 6 using (((3R,4S)-1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine- 4-yl)-4-fluoropyrrolidin-3-yl)methyl)carbamate tert-butyl ester as starting material to obtain the target compound.
  • Step 1 (((3S,4S)-1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-4-fluoro tert- butyl pyrrolidin-3-yl)methyl)carbamate
  • the target compound was obtained from tert-butyl (((3R,4S)-4-fluoropyrrolidin-3-yl)methyl)carbamate. MS m/z [LC-MS]: 520.27 [M+1].
  • Step 2 2-((4-((3S,4S)-3-(aminomethyl)-4-fluoropyrrolidin-1-yl)pyrimidin-5-yl)oxy)-N-ethyl-5 -Fluoro-N-isopropylbenzamide
  • step 2 in intermediate 6 use (((3S,4S)-1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine- 4-yl)-4-fluoropyrrolidin-3-yl)methyl)carbamate tert-butyl ester as starting material to obtain the target compound.
  • Step 1 (S)-((4-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)morpholinyl-2- base) methyl) tert-butyl carbamate
  • the target compound was obtained by using tert-butyl (S)-(piperidin-3-ylmethyl)carbamate as a starting material.
  • Step 2 (S)-2-((4-(2-(Aminomethyl)morpholinyl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzene Formamide
  • step 2 in intermediate 6 use (S)-((4-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine-4- base) morpholinyl-2-yl) methyl) tert-butyl carbamate as raw material to obtain the target compound.
  • Step 1 (S)-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl ) tert-butyl carbamate
  • Step 2 (S)-2-((4-(3-Aminomethylpyrrolidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzyl Amide
  • step 2 in intermediate 6 use (S)-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrole Alk-3-yl)methyl)carbamate tert-butyl ester as starting material to obtain the target compound.
  • Step 1 ((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methylazetidine-3- base) methyl) tert-butyl carbamate
  • Step 2 2-((4-(3-(Aminomethyl)-3-methylazetidin-1-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N- Diisopropylbenzamide
  • step 2 in intermediate 6 use ((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-methyl Azetidin-3-yl) methyl) carbamate tert-butyl ester as starting material to obtain the target compound.
  • Step 1 tert-butyl 3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptan-2-yl)methyl)azetidine-1-carboxylate
  • step 1 in intermediate 35 using tert-butyl 3-formylazetidine-1-carboxylate and N-(2-azaspiro[3.3]heptane-6-yl)ethanesulfonamide
  • the target compound is obtained as a starting material.
  • step 2 in intermediate 35 using 3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptane-2-yl)methyl)azetidine-1-
  • the target compound was obtained from tert-butyl carboxylate. MS m/z [LC-MS]: 274.16 [M+1].
  • Step 1 (R)-tert-butyl 3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptan-2-yl)methyl)pyrrolidine-1-carboxylate
  • step 1 in intermediate 35 using tert-butyl (S)-3-formylpyrrolidine-1-carboxylate and N-(2-azaspiro[3.3]heptane-6-yl)ethanesulfonate Amides are used as starting materials to obtain the target compounds.
  • step 2 in intermediate 35 use (R)-3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptane-2-yl)methyl)pyrrolidin-1 - tert-butyl carboxylate as starting material to obtain the target compound.
  • Step 1 (S)-tert-butyl 3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptan-2-yl)methyl)pyrrolidine-1-carboxylate
  • step 1 in intermediate 35 using tert-butyl (R)-3-formylpyrrolidine-1-carboxylate and N-(2-azaspiro[3.3]heptane-6-yl)ethanesulfonate Amides are used as starting materials to obtain the target compounds. MS m/z [LC-MS]: 388.23 [M+1].
  • step 2 in intermediate 35 use (S)-3-((6-(ethanesulfonamido)-2-azaspiro[3.3]heptan-2-yl)methyl)pyrrolidin-1 - tert-butyl carboxylate as starting material to obtain the target compound.
  • Step 1 tert-butyl 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)azetidine-1-carboxylate
  • the target compound was obtained from tert-butyl 3-formylazetidine-1-carboxylate.
  • step 2 in intermediate 35 using 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)azetidine-1-
  • the target compound was obtained from tert-butyl carboxylate.
  • Step 1 (S)-tert-butyl 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate
  • the target compound was obtained from (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester. MS m/z [LC-MS]: 416.26 [M+1].
  • step 2 in intermediate 35 use (S)-3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1 - tert-butyl carboxylate as starting material to obtain the target compound.
  • Step 1 (R)-tert-butyl 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate
  • the target compound was obtained from (S)-tert-butyl 3-formylpyrrolidine-1-carboxylate. MS m/z [LC-MS]: 416.26 [M+1].
  • step 2 in intermediate 35 use (R)-3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1 - tert-butyl carboxylate as starting material to obtain the target compound.
  • Step 1 (S)-tert-butyl 3-((7-(methylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate
  • the target compound was obtained from (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester.
  • step 2 in intermediate 35 using (S)-3-((7-(methylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1 - tert-butyl carboxylate as starting material to obtain the target compound.
  • Step 1 (R)-tert-butyl 3-((7-(methylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate
  • step 1 in intermediate 35 replace tert-butyl 3-formylpyrrolidine-1-carboxylate with (S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester, and use N-(2-nitro Heterospiro[3.5]nonan-7-yl)methanesulfonamide replaces N-(2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide to obtain (R)-3-((7-( Methanesulfonylamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester.
  • step 2 in intermediate 35 use (R)-3-((7-(methylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1 - tert-butyl formate replaces 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-formate tert-butyl to give (S )-N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)methanesulfonamide hydrochloride.
  • Step 1 (S)-tert-butyl 3-((7-(trifluoromethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate
  • step 1 in intermediate 35 replace tert-butyl 3-formylpyrrolidine-1-carboxylate with (R)-tert-butyl 3-formylpyrrolidine-1-carboxylate, 1,1,1-tri Fluoro-N-(2-azaspiro[3.5]nonan-7-yl)methanesulfonamide replaces N-(2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide to obtain (S) - tert-butyl 3-((7-(trifluoromethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate.
  • step 2 in intermediate 35 using (S)-3-((7-(trifluoromethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine -1- tert-butyl carboxylate instead of 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester, to obtain (R)-1,1,1-Trifluoro-N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)methanesulfonamide hydrochloride .
  • Step 1 (3S)-tert-butyl 3-((6-(ethanesulfonamido)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)pyrrolidine-1-carboxylate
  • step 1 in intermediate 35 replace tert-butyl 3-formylpyrrolidine-1-carboxylate with (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester, N-(3-aza Bicyclo[3.1.0]hexane-6-yl)ethanesulfonamide replaces N-(2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide to obtain (3S)-3-((6- (Ethylsulfonamido)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester.
  • Step 2 N-(3-(((R)-pyrrolidin-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)ethanesulfonamide hydrochloride
  • step 2 in intermediate 35 use (3S)-3-((6-(ethanesulfonamido)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)pyrrolidine -1- tert-butyl carboxylate instead of 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester, to obtain N-(3-(((R)-pyrrolidin-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)ethanesulfonamide hydrochloride.
  • Step 1 tert-butyl 7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylate
  • Step 3 (S)-3-((7-((N,N-Dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine- tert-Butyl 1-formate
  • Step 4 N-(2-(((R)-pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)-N',N'-dimethyl Sulfonylurea hydrochloride
  • Step 1 (S)-tert-butyl 3-((7-(cyclopropylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate
  • step 1 in intermediate 35 replace tert-butyl 3-formylpyrrolidine-1-carboxylate with (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester, N-(2-aza Spiro[3.5]nonan-7-yl)cyclopropylsulfonamide replaces N-(2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide to obtain (S)-3-((7- (Cyclopropylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester.
  • step 2 in intermediate 35 using (S)-3-((7-(cyclopropylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine -1- tert-butyl carboxylate instead of 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester, to obtain (R)-N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)cyclopropylsulfonamide hydrochloride.
  • Step 1 (S)-tert-butyl 3-((7-(propylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate
  • step 1 in intermediate 35 replace tert-butyl 3-formylpyrrolidine-1-carboxylate with (R)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester, N-(2-aza Spiro[3.5]nonan-7-yl)propane-1-sulfonamide replaces N-(2-azaspiro[3.5]nonan-7-yl)ethanesulfonamide to obtain (S)-3-((7 -(Propylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester.
  • step 2 in intermediate 35 using (S)-3-((7-(propylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine- 1-formic acid tert-butyl ester replaces 3-((7-(ethanesulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain ( R)-N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)propane-1-sulfonamide hydrochloride.
  • Step 1 tert-butyl 4-(ethanesulfonamidomethyl)piperidine-1-carboxylate
  • Step 3 (S)-tert-butyl 3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate
  • Step 1 tert-butyl 7-(ethylsulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate
  • step 1 in intermediate 55 substituting tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate for tert-butyl 4-(aminomethyl)piperidine-1-carboxylate to give tert-butyl 7-(ethylsulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate.
  • step 2 in intermediate 55 replace 4-(ethanesulfonylamidomethyl) with tert-butyl 7-(ethylsulfonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate Piperidine-1-carboxylic acid tert-butyl ester, in 7-(ethylsulfonyl)-2,7-diazaspiro[3.5]nonane hydrochloride. MS m/z [LC-MS]: 219.12 [M+1].
  • Step 3 (S)-tert-butyl 3-((7-(ethylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate
  • step 3 in intermediate 55 replace N-(piperidin-4-ylmethyl)ethanesulfonate with 7-(ethylsulfonyl)-2,7-diazaspiro[3.5]nonane hydrochloride
  • Step 4 (R)-7-(Ethylsulfonyl)-2-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonane hydrochloride
  • step 4 in intermediate 55 using (S)-3-((7-(ethylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidine -1- tert-butyl carboxylate instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain (R) -7-(Ethylsulfonyl)-2-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonane hydrochloride.
  • Step 1 tert-butyl 7-aminosulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxylate
  • step 1 in intermediate 55 replace tert-butyl 4-(aminomethyl)piperidine-1-carboxylate with tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate, and use Aminosulfonyl chloride replaces ethylsulfonyl chloride to obtain tert-butyl 7-aminosulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxylate.
  • step 2 in intermediate 55 replace 4-(ethanesulfonamidomethyl)piperidine with tert-butyl 7-aminosulfonyl-2,7-diazaspiro[3.5]nonane-2-carboxylate -1-tert-butyl formate, in 2,7-diazaspiro[3.5]nonane-7-sulfonamide hydrochloride.
  • Step 3 (S)-tert-butyl 3-((7-aminosulfonyl-2,7-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate
  • step 3 in intermediate 55 replace N-(piperidin-4-ylmethyl)ethanesulfonamide hydrochloride with 2,7-diazaspiro[3.5]nonane-7-sulfonamide hydrochloride salt to obtain (S)-3-((7-aminosulfonyl-2,7-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester.
  • step 4 in intermediate 55 use (S)-3-((7-aminosulfonyl-2,7-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-
  • Tert-butyl formate replaces (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate tert-butyl to obtain (R)-2- (Pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonane-7-sulfonamide hydrochloride.
  • Step 1 tert-butyl 2-(ethanesulfonamido)-7-azaspiro[3.5]nonane-7-carboxylate
  • step 1 in intermediate 55 tert-butyl 4-(aminomethyl)piperidine-1-carboxylate was replaced with tert-butyl 2-amino-7-azaspiro[3.5]nonane-7-carboxylate, tert-butyl 2-(ethanesulfonamido)-7-azaspiro[3.5]nonane-7-carboxylate was obtained.
  • step 2 in intermediate 55 replace 4-(ethanesulfonamidomethyl)piperidine with 2-(ethanesulfonamido)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester -1-tert-butyl carboxylate to obtain N-(7-azaspiro[3.5]nonan-2-yl)ethanesulfonamide hydrochloride.
  • Step 3 (S)-tert-butyl 3-((2-(ethanesulfonamido)-7-azaspiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylate
  • step 3 in intermediate 55 replace N-(piperidin-4-ylmethyl)ethanesulfonate with N-(7-azaspiro[3.5]nonan-2-yl)ethanesulfonamide hydrochloride Amide hydrochloride to get (S)-3-((2-(ethanesulfonamido)-7-azaspiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester . MS m/z [LC-MS]: 416.26 [M+1].
  • Step 4 (R)-N-(7-(pyrrolidin-3-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)ethanesulfonamide hydrochloride
  • step 4 in intermediate 55 using (S)-3-((2-(ethanesulfonamido)-7-azaspiro[3.5]nonan-7-yl)methyl)pyrrolidin-1 - tert-butyl formate instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate tert-butyl to give (R)-N -(7-(Pyrrolidin-3-ylmethyl)-7-azaspiro[3.5]nonan-2-yl)ethanesulfonamide hydrochloride. MS m/z [LC-MS]: 316.21 [M+1].
  • Step 1 tert-butyl 9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-carboxylate
  • step 1 in intermediate 55 replace tert-butyl 4-(aminomethyl)piperidine-1-carboxylate with 9-amino-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester , in tert-butyl 9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-carboxylate.
  • step 2 in intermediate 55 replace 4-(ethanesulfonamidomethyl)piperene with 9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester Pyridine-1-carboxylic acid tert-butyl ester to obtain N-(3-azaspiro[5.5]undecyl-9-yl)ethanesulfonamide hydrochloride.
  • Step 3 (S)-tert-butyl 3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidine-1-carboxylate
  • step 3 in intermediate 55 replace N-(piperidin-4-ylmethyl)ethane with N-(3-azaspiro[5.5]undec-9-yl)ethanesulfonamide hydrochloride Sulfonamide hydrochloride, get (S)-3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrolidine-1-carboxylic acid tert butyl ester. MS m/z [LC-MS]: 444.29 [M+1].
  • step 4 in intermediate 55 using (S)-3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecyl-3-yl)methyl)pyrrolidine- 1-formic acid tert-butyl ester replaces (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain (R)- N-(3-(pyrrolidin-3-ylmethyl)-3-azaspiro[5.5]undec-9-yl)ethanesulfonamide hydrochloride.
  • Step 1 (S)-tert-butyl 1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-carboxylate
  • step 1 in intermediate 55 replace 4-(aminomethyl)piperidine-1-carboxylic acid with (S)-1-amino-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester Tert-butyl ester to get (S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester.
  • step 2 in intermediate 55 replace 4-(ethanesulfonamidomethanol with (S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl Base) tert-butyl piperidine-1-carboxylate to obtain (S)-N-(8-azaspiro[4.5]decane-1-yl)ethanesulfonamide hydrochloride.
  • Step 3 (S)-3-(((S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • step 3 in intermediate 55 replace N-(piperidin-4-ylmethyl) with (S)-N-(8-azaspiro[4.5]decane-1-yl)ethanesulfonamide hydrochloride Base) ethanesulfonamide hydrochloride, get (S)-3-(((S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-yl)methyl)pyrrole tert-butyl alkane-1-carboxylate. MS m/z [LC-MS]: 430.27 [M+1].
  • Step 4 N-((S)-8-(((R)-pyrrolidin-3-yl)methyl)-8-azaspiro[4.5]decane-1-yl)ethanesulfonamide hydrochloride
  • step 4 in intermediate 55 use (S)-3-(((S)-1-(ethanesulfonamido)-8-azaspiro[4.5]decane-8-yl)methyl) Pyrrolidine-1-carboxylic acid tert-butyl ester replaces (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain N -((S)-8-(((R)-Pyrrolidin-3-yl)methyl)-8-azaspiro[4.5]decane-1-yl)ethanesulfonamide hydrochloride.
  • Step 1 tert-butyl 3-(ethanesulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate
  • step 1 in intermediate 55 replace 4-(aminomethyl)piperidine-1- with 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate Formate tert-butyl ester to get 3-(ethanesulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester.
  • step 2 in intermediate 55 replace 4-(ethanesulfonylamino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl Methyl)piperidine-1-carboxylic acid tert-butyl ester to obtain N-(1-oxa-8-azaspiro[4.5]decane-3-yl)ethanesulfonamide hydrochloride.
  • Step 3 (3S)-3-((3-(Ethylsulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-yl)methyl)pyrrolidine-1-carboxylic acid tert Butyl ester
  • step 3 in intermediate 55 replace N-(piperidin-4-yl) with N-(1-oxa-8-azaspiro[4.5]decane-3-yl)ethanesulfonamide hydrochloride Methyl)ethanesulfonamide hydrochloride, to get (3S)-3-((3-(ethanesulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-yl)methyl ) tert-butyl pyrrolidine-1-carboxylate. MS m/z [LC-MS]: 432.25 [M+1].
  • Step 4 N-(8-(((R)-pyrrolidin-3-yl)methyl)-1-oxa-8-azaspiro[4.5]decane-3-yl)ethanesulfonamide hydrochloride Salt
  • step 4 in intermediate 55 using (3S)-3-((3-(ethanesulfonamido)-1-oxa-8-azaspiro[4.5]decane-8-yl)methyl ) tert-butyl pyrrolidine-1-carboxylate instead of (S)-3-((4-(ethanesulfonamidomethyl) piperidin-1-yl) methyl) tert-butyl pyrrolidine-1-carboxylate, to obtain N-(8-(((R)-pyrrolidin-3-yl)methyl)-1-oxa-8-azaspiro[4.5]decane-3-yl)ethanesulfonamide hydrochloride.
  • Step 1 tert-butyl 6-(ethanesulfonamidomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
  • step 1 in intermediate 55 replace 4-(aminomethyl)piperidine-1 with 6-(aminomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester - tert-butyl formate to obtain tert-butyl 6-(ethanesulfonamidomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate.
  • tert-butyl 6-(ethanesulfonamidomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate was used instead of 4-(ethanesulfonamidomethyl Base) piperidine-1-carboxylic acid tert-butyl ester to obtain N-((3-azabicyclo[3.1.0]hexane-6-yl)methyl)ethanesulfonamide hydrochloride.
  • Step 3 (3S)-tert-butyl 3-((6-(ethanesulfonamidomethyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)pyrrolidine-1-carboxylate ester
  • step 3 in intermediate 55 replace N-((3-azabicyclo[3.1.0]hexane-6-yl)methyl)ethanesulfonamide hydrochloride with N-(piperidine-4- (3S)-3-((6-(ethanesulfonamidomethyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl ) tert-butyl pyrrolidine-1-carboxylate.
  • Step 4 N-((3-(((R)-pyrrolidin-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)ethanesulfonamide salt salt
  • step 4 in intermediate 55 use (3S)-3-((6-(ethanesulfonamidomethyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl) Pyrrolidine-1-carboxylic acid tert-butyl ester replaces (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain N -((3-(((R)-Pyrrolidin-3-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)ethanesulfonamide hydrochloride.
  • Step 1 tert-butyl 7-((2-hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5]nonane-2-carboxylate
  • step 2 in intermediate 55 replace 4-( Ethylsulfonylamidomethyl)piperidine-1-carboxylate tert-butyl ester to get 1-((2-azaspiro[3.5]nonan-7-yl)amino)-2-methylpropan-2-alcohol salt salt.
  • Step 3 (S)-3-((7-((2-Hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine- tert-Butyl 1-formate
  • step 3 in intermediate 55 use 1-((2-azaspiro[3.5]nonan-7-yl)amino)-2-methylpropan-2-ol hydrochloride instead of N-(piper Pyridine-4-ylmethyl)ethanesulfonamide hydrochloride, to get (S)-3-((7-((2-hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5] Nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester.
  • Step 4 (R)-2-Methyl-1-((2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)amino)propan-2- Alcohol hydrochloride
  • step 4 in intermediate 55 use (S)-3-((7-((2-hydroxy-2-methylpropyl)amino)-2-azaspiro[3.5]nonane-2- Base)methyl)pyrrolidine-1-carboxylate tert-butyl instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate tert Butyl ester to get (R)-2-methyl-1-((2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)amino)propan-2 -alcohol hydrochloride. MS m/z [LC-MS]: 296.27 [M+1].
  • Step 1 tert-Butyl 7-((aminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylate
  • step 1 in intermediate 52 using aminosulfonyl chloride instead of dimethylaminosulfonyl chloride, 7-((aminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester.
  • step 2 in intermediate 52 replace 7-((N,N-dimethyl Aminosulfonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester, N-(2-azaspiro[3.5]nonane-7-yl)sulfonylurea hydrochloride Salt.
  • Step 3 (S)-tert-butyl 3-((7-((aminosulfonyl)amino)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate
  • step 3 in intermediate 52 replace N-(2-azaspiro[3.5]nonane- 7-yl)-N', N'-dimethylsulfonylurea hydrochloride, to obtain (S)-3-((7-((aminosulfonyl)amino)-2-azaspiro[3.5]nonane Alk-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester.
  • Step 4 N-(2-(((R)-pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)sulfonylurea hydrochloride
  • step 4 in intermediate 52 using (S)-3-((7-((aminosulfonyl)amino)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine -1-tert-butyl carboxylate instead of (S)-3-((7-((N,N-dimethylaminosulfonyl)amino)-2-azaspiro[3.5]nonan-2-yl)methyl Base) pyrrolidine-1-carboxylic acid tert-butyl ester, N-(2-(((R)-pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl) Sulfonylurea hydrochloride. MS m/z [LC-MS]: 303.19 [M+1].
  • Step 1 tert-butyl 6-(ethanesulfonamidomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
  • step 1 in intermediate 55 tert-butyl 4-(aminomethyl)piperidine-1-carboxylate was replaced with tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate, tert-butyl 7-(isopropylsulfonamido)-2-azaspiro[3.5]nonane-2-carboxylate was obtained.
  • step 2 in intermediate 55 replace 4-(ethanesulfonamidomethyl) with 7-(isopropylsulfonamido)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester Piperidine-1-carboxylic acid tert-butyl ester to obtain N-(2-azaspiro[3.5]nonan-7-yl)propane-2-sulfonamide hydrochloride. MS m/z [LC-MS]: 247.15 [M+1].
  • Step 3 (S)-tert-butyl 3-((7-(isopropylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate
  • step 3 in intermediate 55 replace N-(piperidin-4-ylmethyl with N-(2-azaspiro[3.5]nonan-7-yl)propane-2-sulfonamide hydrochloride ) ethanesulfonamide hydrochloride, to get (S)-3-((7-(isopropylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1 - tert-butyl formate.
  • Step 4 (R)-N-(2-(Pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)propane-2-sulfonamide hydrochloride
  • step 4 in intermediate 55 using (S)-3-((7-(isopropylsulfonamido)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine -1- tert-butyl carboxylate instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain (R) -N-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)propane-2-sulfonamide hydrochloride.
  • Step 1 tert-butyl 7-(((benzyloxy)carbonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylate
  • step 1 in intermediate 55 replace tert-butyl 4-(aminomethyl)piperidine-1-carboxylate with tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate ester, and benzyl chloroformate was substituted for ethylsulfonyl chloride to give the title compound.
  • step 2 in intermediate 55 7-(((benzyloxy)carbonyl)amino)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl methyl)piperidine-1-carboxylate tert-butyl to give the title compound.
  • Step 3 (S)-3-((7-(((benzyloxy)carbonyl)amino)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 4 Benzyl (R)-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl)carbamate hydrochloride
  • step 4 in intermediate 55 using (S)-3-((7-((((benzyloxy)carbonyl)amino)-2-azaspiro[3.5]nonan-2-yl)methyl )pyrrolidine-1-carboxylate tert-butyl instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate tert-butyl , to obtain the target compound.
  • Step 5 (S)-(2-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl )methyl)-2-azaspiro[3.5]nonan-7-yl)benzyl carbamate
  • intermediate 26 was used instead of intermediate 1, and (R)-(2-(pyrrolidin-3-ylmethyl)-2-azaspiro[3.5]nonan-7-yl ) benzyl carbamate hydrochloride instead of intermediate 29 to obtain the target compound.
  • Step 6 (S)-2-((4-(3-((7-Amino-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidine-5 -yl)oxy)-5-fluoro-N,N-diisopropylbenzamide
  • Step 1 tert-butyl 7-(ethanesulfonamidomethyl)-2-azaspiro[3.5]nonane-2-carboxylate
  • step 1 in intermediate 55 replace 4-(aminomethyl)piperidine-1- with 7-(aminomethyl)-2-azaspiro[3.5]nonane-2-carboxylate tert-butyl carboxylate to obtain the target compound.
  • step 2 in intermediate 55 replace 4-(ethanesulfonamidomethyl) with tert-butyl 7-(ethanesulfonamidomethyl)-2-azaspiro[3.5]nonane-2-carboxylate ) tert-butyl piperidine-1-carboxylate to obtain the title compound.
  • Step 3 (S)-tert-butyl 3-((7-(ethanesulfonamidomethyl)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine-1-carboxylate
  • N-((2-azaspiro[3.5]nonan-7-yl)methyl)ethanesulfonamide hydrochloride was used instead of N-(piperidin-4-ylmethyl base) ethanesulfonamide hydrochloride to obtain the target compound.
  • step 4 in intermediate 55 using (S)-3-((7-(ethanesulfonamidomethyl)-2-azaspiro[3.5]nonan-2-yl)methyl)pyrrolidine -1-carboxylic acid tert-butyl ester instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain the target compound.
  • Step 1 tert-Butyl 7-((Benzyloxy)carbonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate
  • step 1 in intermediate 55 replace tert-butyl 4-(aminomethyl)piperidine-1-carboxylate with 2,7-diazaspiro[3.5]nonane-2-carboxylate tert-butyl , substituting benzyl chloroformate for ethylsulfonyl chloride gave the title compound. MS m/z [LC-MS]: 361.21 [M+1].
  • Step 2 Benzyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride
  • step 2 in intermediate 55 replace 4-(ethanesulfonamide with 7-((benzyloxy)carbonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate methyl)piperidine-1-carboxylate tert-butyl to give the title compound.
  • Step 3 (S)-Benzyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate
  • step 3 in intermediate 55 replace N-(piperidin-4-ylmethyl)ethanesulfonamide with 2,7-diazaspiro[3.5]nonane-7-carboxylate benzyl ester hydrochloride hydrochloride to obtain the target compound.
  • Step 4 Benzyl (R)-(2-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride
  • step 4 in intermediate 55 use (S)-2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane
  • Benzyl alkane-7-carboxylate instead of tert-butyl (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate affords the target compound.
  • Step 5 (S)-(2-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl )methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate benzyl ester
  • intermediate 26 was used instead of intermediate 1, and (R)-(2-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5]nonane- Benzyl 7-carboxylate hydrochloride was used instead of intermediate 29 to obtain the target compound.
  • Step 6 (S)-2-((4-(3-((2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)pyrimidine-5- base)oxy)-5-fluoro-N,N-diisopropylbenzamide
  • step 6 in intermediate 66 use (S)-(2-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-4- Base)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate benzyl ester instead of (S)-(2-((1-(5-(2 -(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl ) benzyl carbamate to obtain the target compound.
  • Step 1 (S)-tert-butyl 3-((9-oxo-3-azaspiro[5.5]undecane-3-)methyl)pyrrolidine-1-carboxylate
  • step 4 in intermediate 55 using (S)-3-((9-oxo-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidine-1-carboxylic acid Substitution of (S)-tert-butyl 3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate with tert-butyl ester afforded the title compound. MS m/z [LC-MS]: 251.21 [M+1].
  • Step 3 (S)-5-fluoro-N,N-diisopropyl-2-((4-(3-((9-oxo-3-azaspiro[5.5]undecane-3- Base) methyl) pyrrolidin-1-yl) pyrimidin-5-yl) oxy) benzamide
  • Step 1 tert-butyl 8-(ethanesulfonamido)-2-azaspiro[4.5]decane-2-carboxylate
  • step 1 in intermediate 55 replace tert-butyl 4-(aminomethyl)piperidine-1-carboxylate with 8-amino-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester ester to obtain the target compound.
  • step 2 in intermediate 55 replace 4-(ethanesulfonamidomethyl)piperene with 8-(ethanesulfonamido)-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester Pyridine-1-carboxylic acid tert-butyl ester to obtain the target compound.
  • Step 3 (S)-tert-butyl 3-((8-(ethanesulfonamido)-2-azaspiro[4.5]decane-2-yl)methyl)pyrrolidine-1-carboxylate
  • step 3 in intermediate 55 replace N-(piperidin-4-ylmethyl)ethanesulfonate with N-(2-azaspiro[4.5]decane-8-yl)ethanesulfonamide hydrochloride Amide hydrochloride, to obtain the target compound.
  • Step 4 (R)-N-(2-(Pyrrolidin-3-ylmethyl)-2-azaspiro[4.5]decane-8-yl)ethanesulfonamide hydrochloride
  • step 4 in intermediate 55 use (S)-3-((8-(ethanesulfonamido)-2-azaspiro[4.5]decane-2-yl)methyl)pyrrolidin-1 - tert-butyl carboxylate instead of (S)-tert-butyl 3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate gave the title compound. MS m/z [LC-MS]: 330.22 [M+1].
  • Step 1 tert-butyl 9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-carboxylate
  • step 1 in intermediate 55 replace 4-(aminomethyl)piperidine-1-carboxylate tert-butyl with 9-amino-3-azaspiro[5.5]undecane-3-carboxylate butyl ester to obtain the target compound.
  • step 2 in intermediate 55 replace 4-(ethanesulfonamidomethyl) with 9-(ethanesulfonamido)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester tert-butyl piperidine-1-carboxylate to give the title compound.
  • Step 3 (S)-tert-butyl 3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidine-1-carboxylate
  • step 3 in intermediate 55 replace N-(piperidin-4-ylmethyl)ethane with N-(3-azaspiro[5.5]undec-9-yl)ethanesulfonamide hydrochloride Sulfonamide hydrochloride, to obtain the target compound.
  • step 4 in intermediate 55 using (S)-3-((9-(ethanesulfonamido)-3-azaspiro[5.5]undecyl-3-yl)methyl)pyrrolidine- tert-butyl 1-carboxylate instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate tert-butyl yields the title compound . MS m/z [LC-MS]: 344.24 [M+1].
  • Step 1 3-Benzyl 9-(tert-butyl) 3,9-diazaspiro[5.5]undecane-3,9-dicarboxylate
  • step 1 in intermediate 55 replace tert-butyl 4-(aminomethyl)piperidine-1-carboxylate with 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester ester, and benzyl chloroformate was substituted for ethylsulfonyl chloride to give the title compound.
  • Step 2 Benzyl 3,9-diazaspiro[5.5]undecane-3-carboxylate hydrochloride
  • step 2 in intermediate 55 replace 4-(ethyl Sulfonamidomethyl) piperidine-1-carboxylic acid tert-butyl ester to obtain the target compound.
  • Step 3 Benzyl (S)-9-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate ester
  • step 3 in intermediate 55 replace N-(piperidin-4-ylmethyl)ethanesulfonate with 3,9-diazaspiro[5.5]undecane-3-carboxylic acid benzyl ester hydrochloride Amide hydrochloride, to obtain the target compound.
  • Step 4 Benzyl (R)-9-(pyrrolidin-3-ylmethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate hydrochloride
  • step 4 in intermediate 55 use (S)-9-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-3,9-diazaspiro[5.5]deca Benzyl monoalkane-3-carboxylate instead of tert-butyl (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate gives target compound. MS m/z [LC-MS]: 372.27 [M+1].
  • Step 5 (S)-9-((1-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl) Benzyl methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
  • Step 6 (S)-2-((4-(3-((3,9-diazaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidine-5 -yl)oxy)-5-fluoro-N,N-diisopropylbenzamide
  • step 6 in intermediate 66 use (S)-9-((1-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl )pyrrolidin-3-yl)methyl)-3,9-diazaspiro[5.5]benzyl undecane-3-carboxylate instead of (S)-(2-((1-(5-(2 -(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2-azaspiro[3.5]nonan-7-yl ) benzyl carbamate to obtain the target compound.
  • Step 1 tert-butyl 9-(ethanesulfonamidomethyl)-3-azaspiro[5.5]undecane-3-carboxylate
  • step 1 in intermediate 55 replace 4-(aminomethyl)piperidine-1 with 9-(aminomethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester - tert-butyl carboxylate to give the target compound.
  • step 2 in intermediate 55 replace 4-(ethanesulfonamidomethyl) with 9-(ethanesulfonamidomethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester Base) tert-butyl piperidine-1-carboxylate to obtain the title compound.
  • Step 3 (S)-tert-butyl 3-((9-(ethanesulfonamidomethyl)-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidine-1-carboxylate ester
  • step 3 in intermediate 55 use N-((3-azaspiro[5.5]undec-9-yl)methyl)ethanesulfonamide hydrochloride to obtain the target compound.
  • Step 4 (R)-N-((3-(Pyrrolidin-3-ylmethyl)-3-azaspiro[5.5]undec-9-yl)methyl)ethanesulfonamide hydrochloride
  • step 4 in intermediate 55 using (S)-3-((9-(ethanesulfonamidomethyl)-3-azaspiro[5.5]undecane-3-yl)methyl)pyrrole
  • (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate tert-butyl gives target compound.
  • Step 1 tert-butyl 9-(chloroformyl)-3-azaspiro[5.5]undecane-3-carboxylate
  • Step 2 tert-Butyl 9-((ethylsulfonyl)carbamoyl)-3-azaspiro[5.5]undecane-3-carboxylate
  • step 2 in intermediate 55 replace 4-(ethanesulfonamidomethyl) with 9-(ethanesulfonamidomethyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester Base) tert-butyl piperidine-1-carboxylate to obtain the title compound.
  • Step 4 (S)-3-((9-((Ethyl)carbamoyl)-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • N-(ethylsulfonyl)-3-azaspiro[5.5]undecane-9-carboxamide hydrochloride was used to obtain the target compound.
  • step 4 in intermediate 55 using (S)-3-((9-((ethylsulfonyl)carbamoyl)-3-azaspiro[5.5]undecane-3-yl)methyl )pyrrolidine-1-carboxylate tert-butyl instead of (S)-3-((4-(ethanesulfonamidomethyl)piperidin-1-yl)methyl)pyrrolidine-1-carboxylate tert-butyl , to obtain the target compound.
  • Step 1 (4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5 ]nonan-7-yl)methyl)cyclohexyl)tert-butyl carbamate
  • step 1 in intermediate 63 use 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide in place of 1-amino-2-methylpropan-2-ol and tert-butyl (4-formylcyclohexyl)carbamate in place of 7-oxo-2-aza Spiro[3.5]nonane-2-carboxylate tert-butyl to obtain the target compound.
  • Step 2 2-((4-(7-((4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy )-5-fluoro-N,N-diisopropylbenzamide hydrochloride
  • step 2 in intermediate 55 with (4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2, Substituting tert-butyl 7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate for tert-butyl 4-(ethanesulfonamidomethyl)piperidine-1-carboxylate to give target compound. MS m/z [LC-MS]: 553.37 [M+1].
  • Step 1 4-((2-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro [3.5] Nonan-7-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester
  • step 1 in intermediate 63 replace 1-amino-2-methylpropan-2-ol with intermediate 5, and replace 7-oxo-2 with tert-butyl 4-formylpiperidine-1-carboxylate - tert-butyl azaspiro[3.5]nonane-2-carboxylate to give the title compound.
  • Step 2 N-Ethyl-5-fluoro-N-isopropyl-2-((4-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonane Alk-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride
  • step 2 in intermediate 55 using 4-((2-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)- 2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester instead of 4-(ethanesulfonamidomethyl)piperidine-1-carboxylic acid tert-butyl ester to obtain the target compound.
  • the target compound was obtained from tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate. MS m/z [LC-MS]: 297.07 [M+1].
  • the target compound was obtained from tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate. MS m/z [LC-MS]: 311.08 [M+1].
  • the target compound was obtained from (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester. MS m/z [LC-MS]: 311.08 [M+1].
  • Step 1 (S)-2-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-2,7-di Benzyl azaspiro[3.5]nonane-7-carboxylate
  • the target compound was obtained by using the product of Step 4 in Intermediate 70 as a starting material.
  • Step 2 (S)-2-((1-(3-chloro-6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-triazine -5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester
  • step 2 in Example 82 use (S)-2-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl base)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester as raw material to obtain the target compound.
  • Step 3 (S)-2-((5-(3-((2,7-diazaspiro[3.5]nonan-2-yl)methyl)pyrrolidin-1-yl)-1,2 ,4-triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide
  • step 3 in Example 82 use (S)-2-((1-(3-chloro-6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)- 1,2,4-Triazin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester as starting material to obtain the target compound.
  • Step 1 tert-butyl 8-thio-3,9-diazaspiro[5.5]undecane-3-carboxylate
  • Step 2 3'-(Trifluoromethyl)-5',6'-dihydro-8'H-spiro[piperidine-4,7'-[1,2,4]triazolo[4,3 -a]pyridine]-1-carboxylic acid tert-butyl ester
  • Step 3 3'-(Trifluoromethyl)-5',6'-dihydro-8'H-spiro[piperidine-4,7'-[1,2,4]triazolo[4,3 -a]pyridine]hydrochloride
  • step 2 in intermediate 55 use 3'-(trifluoromethyl)-5',6'-dihydro-8'H-spiro[piperidine-4,7'-[1,2,4 ]Triazolo[4,3-a]pyridine]-1-carboxylic acid tert-butyl ester as raw material to obtain the target compound.
  • Step 4 (S)-3-((3'-(trifluoromethyl)-5',6'-dihydro-8'H-spiro[piperidine-4,7'-[1,2,4 ]triazolo[4,3-a]pyridin]-1-yl)methyl)pyrrolidine-1-carboxylate tert-butyl
  • step 3 in intermediate 55 use 3'-(trifluoromethyl)-5',6'-dihydro-8'H-spiro[piperidine-4,7'-[1,2,4 ]Triazolo[4,3-a]pyridine]hydrochloride as raw material to obtain the target compound.
  • step 4 in intermediate 55 use (S)-3-((3'-(trifluoromethyl)-5',6'-dihydro-8'H-spiro[piperidine-4,7 '-[1,2,4]triazolo[4,3-a]pyridin]-1-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester as raw material to obtain the target compound.
  • the target compound was obtained from tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate. MS m/z [LC-MS]: 353.13 [M+1].
  • Step 1 tert-Butyl 9-(((Benzyloxy)carbonyl)amino)-3-azaspiro[5.5]undecane-3-carboxylate
  • the target compound was obtained from tert-butyl 9-amino-3-azaspiro[5.5]undecane-3-carboxylate and benzyl chloroformate. MS m/z [LC-MS]: 403.26 [M+1].
  • step 2 in intermediate 55 the title compound was obtained from tert-butyl 9-(((benzyloxy)carbonyl)amino)-3-azaspiro[5.5]undecane-3-carboxylate as starting material.
  • Step 3 (S)-3-((9-(((Benzyloxy)carbonyl)amino)-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • the target compound was obtained from benzyl (3-azaspiro[5.5]undec-9-yl)carbamate hydrochloride. MS m/z [LC-MS]: 486.33 [M+1].
  • Step 4 Benzyl (R)-(3-(pyrrolidin-3-ylmethyl)-3-azaspiro[5.5]undec-9-yl)carbamate hydrochloride
  • step 4 in intermediate 55 use (S)-3-((9-(((((benzyloxy)carbonyl)amino)-3-azaspiro[5.5]undecyl-3-yl)methanol Base) pyrrolidine-1-carboxylic acid tert-butyl ester as raw material to obtain the target compound.
  • Step 1 (S)-(3-((1-(3,6-Dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-3-aza Benzyl spiro[5.5]undec-9-yl)carbamate
  • Step 2 (S)-(3-((1-(3-chloro-6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-tri Azin-5-yl)pyrrolidin-3-yl)methyl)-3-azaspiro[5.5]undec-9-yl)carbamate benzyl ester
  • step 2 in Example 82 use (S)-(3-((1-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl) Methyl)-3-azaspiro[5.5]undec-9-yl)benzyl carbamate was used as starting material to obtain the target compound.
  • Step 3 (S)-2-((5-(3-((9-Amino-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)-1 ,2,4-Triazin-6-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide
  • step 3 in Example 82 use (S)-(3-((1-(3-chloro-6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy) -1,2,4-triazin-5-yl)pyrrolidin-3-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)benzyl carbamate as raw material to obtain the target compound .
  • Step 1 4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5] Nonan-7-yl)methyl)piperidine-1-carboxylate tert-butyl
  • step 1 in intermediate 63 use 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide and tert-butyl 4-formylpiperidine-1-carboxylate were used as starting materials to obtain the target compound.
  • Step 2 5-fluoro-N,N-diisopropyl-2-((4-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonane- 2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride
  • step 2 in intermediate 55 use 4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7 -Diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester as raw material to obtain the target compound.
  • Step 1 (S)-(3-((1-(5-(2-(Ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)pyrrolidine- 3-yl)methyl)-3-azaspiro[5.5]undec-9-yl)benzyl carbamate
  • Step 2 (S)-2-((4-(3-((9-Amino-3-azaspiro[5.5]undec-3-yl)methyl)pyrrolidin-1-yl)pyrimidine- 5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide
  • step 6 in intermediate 66 using (S)-(3-((1-(5-(2-(ethyl(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidine -4-yl)pyrrolidin-3-yl)methyl)-3-azaspiro[5.5]undec-9-yl)benzyl carbamate as starting material to obtain the target compound.
  • Step 1 tert-butyl 7-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate
  • step 1 in intermediate 35 using benzyl 4-formylpiperidine-1-carboxylate and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate as raw materials to obtain the target compound .
  • Step 2 Benzyl 4-((2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate hydrochloride
  • step 2 in intermediate 35 using 7-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane -2-Tert-butyl carboxylate was used as starting material to obtain the target compound.
  • Step 1 4-((2-(3,6-Dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl)-2,7-diazaspiro[3.5]nonane Benzyl-7-yl)methyl)piperidine-1-carboxylate
  • the target compound was obtained using intermediate 100 as a starting material.
  • Step 2 4-((2-(3-chloro-6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl )-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylic acid benzyl ester
  • step 2 in Example 82 use 4-((2-(3,6-dichloro-1,2,4-triazin-5-yl)pyrrolidin-3-yl)-2,7-
  • the target compound was obtained from benzyl diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate.
  • Step 3 5-fluoro-N,N-diisopropyl-2-((5-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonane- 2-yl)-1,2,4-triazin-6-yl)oxy)benzamide
  • Step 1 (R)-3-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazepine Spiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylate tert-butyl
  • step 1 in intermediate 63 use 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide and (S)-3-formylpyrrolidine-1-carboxylic acid tert-butyl ester were used as raw materials to obtain the target compound.
  • Step 2 (S)-5-fluoro-N,N-diisopropyl-2-((4-(7-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5 ]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride
  • step 2 in intermediate 55 use (R)-3-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl) -2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was used as starting material to obtain the target compound.
  • Step 1 (S)-3-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazepine Spiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylate tert-butyl
  • step 1 in intermediate 63 use 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide was used as starting material to obtain the target compound.
  • Step 2 (R)-5-fluoro-N,N-diisopropyl-2-((4-(7-(pyrrolidin-3-ylmethyl)-2,7-diazaspiro[3.5 ]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride
  • step 2 in intermediate 55 using (S)-3-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl) -2,7-diazaspiro[3.5]nonan-7-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester was used as starting material to obtain the target compound.
  • Step 1 tert-butyl 4-(((methylsulfonyl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Step 2 4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5] Nonan-7-yl)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
  • Step 3 5-fluoro-N,N-diisopropyl-2-((4-(7-((1,2,3,6-tetrahydropyridin-4-yl)methyl)-2,7 -Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide hydrochloride
  • step 2 in intermediate 55 use 4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7 -Diazaspiro[3.5]nonan-7-yl)methyl)-3,6-dihydropyridine-1(2H)-tert-butyl carboxylate as starting material to obtain the target compound.
  • Step 1 4-((2-(5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5] Nonan-7-yl)methyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester
  • step 1 in intermediate 63 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide and tert-butyl 4-fluoro-4-formylpiperidine-1-carboxylate were used as raw materials to obtain the target compound.
  • Step 2 5-fluoro-2-((4-(7-((4-fluoropiperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl) Pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide hydrochloride
  • step 2 in intermediate 55 4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7 - Diazaspiro[3.5]nonan-7-yl)methyl)-4-fluoropiperidine-1-carboxylic acid tert-butyl ester as starting material to obtain the target compound.
  • Step 1 Benzyl 2-(3,6-dichloro-1,2,4-triazin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate
  • Step 2 2-(3-Chloro-6-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)-1,2,4-triazin-5-yl)-2, Benzyl 7-diazaspiro[3.5]nonane-7-carboxylate
  • Step 3 2-((5-(2,7-Diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl)oxy)-5-fluoro- N,N-Diisopropylbenzamide

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Abstract

La présente demande concerne une classe de composés hétérocycliques substitués qui sont représentés par la formule (III) et qui ont une activité inhibitrice de la prolifération cellulaire, leur procédé de préparation et leur utilisation. L'utilisation comprend une utilisation des composés représentés par la formule (III) dans la préparation d'un médicament pour le traitement de maladies associées à MLL. Dans le processus de préparation, les composés selon la présente invention sont obtenus au moyen d'une série de réactions telles que la substitution, la cyclisation et la déprotection.
PCT/CN2022/096814 2021-06-03 2022-06-02 Composés hétérocycliques substitués et leur utilisation WO2022253309A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2024046457A1 (fr) * 2022-09-02 2024-03-07 Hutchmed Limited Composés de triazine et leurs utilisations

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WO2017161028A1 (fr) * 2016-03-16 2017-09-21 Kura Oncology, Inc. Inhibiteurs substitués de ménine-mll et méthodes d'utilisation
WO2017214367A1 (fr) * 2016-06-10 2017-12-14 Vitae Pharmaceuticals, Inc. Inhibiteurs de l'interaction ménine-mll
WO2018175746A1 (fr) * 2017-03-24 2018-09-27 Kura Oncology, Inc. Méthodes de traitement d'hémopathies malignes et du sarcome d'ewing
WO2018226976A1 (fr) * 2017-06-08 2018-12-13 Kura Oncology, Inc. Procédés et compositions d'inhibition de l'interaction de la ménine avec les protéines mll

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WO2017161028A1 (fr) * 2016-03-16 2017-09-21 Kura Oncology, Inc. Inhibiteurs substitués de ménine-mll et méthodes d'utilisation
WO2017214367A1 (fr) * 2016-06-10 2017-12-14 Vitae Pharmaceuticals, Inc. Inhibiteurs de l'interaction ménine-mll
WO2018175746A1 (fr) * 2017-03-24 2018-09-27 Kura Oncology, Inc. Méthodes de traitement d'hémopathies malignes et du sarcome d'ewing
WO2018226976A1 (fr) * 2017-06-08 2018-12-13 Kura Oncology, Inc. Procédés et compositions d'inhibition de l'interaction de la ménine avec les protéines mll

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024046457A1 (fr) * 2022-09-02 2024-03-07 Hutchmed Limited Composés de triazine et leurs utilisations

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