[go: up one dir, main page]

CN118679170A - Nitrogen-containing heterocyclic compound, and preparation method and application thereof - Google Patents

Nitrogen-containing heterocyclic compound, and preparation method and application thereof Download PDF

Info

Publication number
CN118679170A
CN118679170A CN202380019027.2A CN202380019027A CN118679170A CN 118679170 A CN118679170 A CN 118679170A CN 202380019027 A CN202380019027 A CN 202380019027A CN 118679170 A CN118679170 A CN 118679170A
Authority
CN
China
Prior art keywords
substituted
membered
alkyl
independently
fluoro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202380019027.2A
Other languages
Chinese (zh)
Inventor
罗会兵
姜佳俊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Allist Medicine Polytron Technologies Inc
Original Assignee
Shanghai Allist Medicine Polytron Technologies Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Allist Medicine Polytron Technologies Inc filed Critical Shanghai Allist Medicine Polytron Technologies Inc
Publication of CN118679170A publication Critical patent/CN118679170A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

公开了一种如式I所示的含氮杂环化合物、其制备方法及应用，该式I所示的化合物、其立体异构体或其药学上可接受的盐对KRASG12D和/或KRAS G12V具有较好的抑制作用。 Disclosed are a nitrogen-containing heterocyclic compound as shown in formula I, a preparation method and application thereof. The compound as shown in formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof has a good inhibitory effect on KRASG12D and/or KRAS G12V.

Description

Nitrogen-containing heterocyclic compound, and preparation method and application thereof
The present application claims priority from China patent application 2022101085764 with the application date 2022/1/28. The present application incorporates the entirety of the above-mentioned chinese patent application.
Technical Field
The invention relates to a nitrogen-containing heterocyclic compound, a preparation method and application thereof.
Background
The RAS protein is a Guanine Trinucleotide Phosphate (GTP) binding protein with molecular weight of 21kDa, which is positioned on cell membrane and consists of 188 or 189 amino acids. The active state of RAS proteins has an effect on cell growth, differentiation, cytoskeleton, protein trafficking and secretion, etc., and its activity is regulated by binding to GTP or Guanine Dinucleotide Phosphate (GDP). When RAS proteins bind to GDP, they are in an "inactive" state; when stimulated by an upstream specific cell growth factor, guanine nucleotide exchange factor (GEF) catalyzes the release of GDP from RAS proteins, binds to GTP, and is in an "activated" state. RAS proteins that bind to GTP activate downstream proteins, activating downstream signaling pathways. RAS proteins themselves have weak gtpase activity, capable of hydrolyzing GTP to GDP, thereby effecting conversion from an activated state to an inactivated state. During this hydrolysis, there is also a need for the involvement of the GTPase Activating Protein (GAP), which interacts with the RAS protein and greatly promotes its ability to hydrolyze GTP to GDP. Any mutation in the RAS protein that affects its own gtpase activity or its ability to interact with GAP or hydrolyze GTP to GDP will result in the RAS protein being in a prolonged activated state, which continues to signal downstream protein growth, resulting in continued growth and differentiation of cells, ultimately possibly leading to cancer. Three members of the RAS gene family: KRAS, NRAS, and HRAS.
KRAS mutations are the most common oncogenic driver, present in a variety of tumors: lung adenocarcinoma (32%), colorectal carcinoma (41%), pancreatic carcinoma (86%). KRAS mutations are most frequently seen in the G12 mutation at codon 12, e.g., in KRAS mutated lung adenocarcinoma, colorectal carcinoma and pancreatic carcinoma, G12 mutations account for 85%, 68% and 91%, respectively; the G12 mutation comprises mutant forms such as G12C, G, D, G, V, G R and the like. Of the KRAS G12 mutated lung adenocarcinoma, colorectal cancer, pancreatic cancer patients, KRAS G12D mutated patients account for 17%, 45%, respectively, and KRAS G12V mutated patients account for 23%, 30%, 35%, respectively (see, e.g., moore, A.R.et al Nat Rev Drug discovery 19,533 (2020)).
KRAS G12D inhibitor MRTX1133 developed by Mitati Therapeutics, inc. Has been disclosed in WO2021041671, the structure of which is as follows, and preclinical data has been disclosed.
MRTX1133
While there has been some progress in this area, there is currently no approved treatment for KRAS G12D and/or KRAS G12V mutations, and there is a continuing need to develop potent, stable, safe small molecule KRAS G12D and/or KRAS G12V inhibitors for treating diseases mediated by KRAS G12D and/or KRAS G12V mutations, such as cancer.
Disclosure of Invention
The invention aims to solve the technical problem that KRAS G12D and KRAS G12V inhibitors in the prior art have single structure, and provides a nitrogen-containing heterocyclic compound, a preparation method and application thereof, which have better inhibition effect on KRAS G12D and/or KRAS G12V.
The present invention provides a compound as shown in formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein ring A is a 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkenyl; the number of heteroatoms in the 4-10 membered heterocycloalkyl and 4-10 membered heterocycloalkenyl is 1 or 2, wherein the heteroatoms are selected from one or two of N, O and S;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
Each R 1 is independently deuterium, halogen, -CN, -OH, -N (R 5)2, nitro, C 1-C6 alkyl, C 1-C6 alkyl substituted with one or more R 1a, C 1-C6 alkyl-O-, C 1-C6 alkyl-O-, C 2-C6 alkenyl substituted with one or more R 1b, C 2-C6 alkenyl substituted with one or more R 1c, C 2-C6 alkynyl, C 2-C6 alkynyl substituted with one or more R 1d, -C (=O) H, -CO 2R5、-C(＝O)N(R5)2, 5 to 14 membered heteroaryl or oxo (= O), wherein the heteroatoms in the 5 to 14 membered heteroaryl are selected from one or more of N, O and S, and the number of heteroatoms is 1,2 or 3;
Each R 1a、R1b、R1c and R 1d is independently deuterium, -CN, halogen or-OH;
l is -(CR6aR6b)n1-*、-O-(CR6aR6b)n2-*、-S-(CR6aR6b)n3-* or-N (R 5)(CR6aR6b)n4-*;* represents one end connected with R 2;
R 2 is H, -COOH, -N (R 5)2、C1-C6 alkyl, C 1-C6 alkyl-O-, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5 to 14 membered heteroaryl 、-NHC(＝NH)NH2,-C(O)N(R5)2、-CH(CH2OR5)[(CH2)n5OR5]、-N(R5)C(＝O)-(C6-C10 aryl), -C (=o) O- (C 1-C6 alkyl), C 1-C6 alkyl substituted by one or more R 2a, C 1-C6 alkyl-O-substituted with one or more R 2b, 3-7 membered cycloalkyl substituted with one or more R 2c, 3-7 membered cycloalkenyl substituted with one or more R 2d, 4-10 membered heterocycloalkyl substituted by one or more R 2e, -C (=o) O- (C 1-C6 alkyl) substituted by one or more R 2f, C 6-C10 aryl substituted by one or more R 2g, 5 to 14 membered heteroaryl substituted with one or more R 2h, -N (R 5) C (=o) - (C 6-C10 aryl substituted with one or more R 2i) or 4-10 membered heterocycloalkenyl substituted with one or more R 2j; The hetero atoms in the 4-10 membered heterocycloalkyl group and the 4-10 membered heterocycloalkyl group substituted by one or more R 2e are selected from one or more of N, O and S, and the number of the hetero atoms is 1,2 or 3; the hetero atoms in the 4-10 membered heterocyclic alkenyl groups and the 4-10 membered heterocyclic alkenyl groups substituted by one or more R 2j are selected from one or more of N, O and S, and the number of the hetero atoms is 1,2 or 3; The heteroatoms in the 5-to 14-membered heteroaryl groups substituted by one or more R 2h are selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3;
Each R 2a、R2b、R2c、R2d、R2e、R2f and R 2j is independently halogen, -OH, deuterium, -CN, -C (=O) H, C 1-C6 alkyl, C 1-C6 alkyl substituted with one or more R 2-a, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkyl-O-, C 1-C6 alkyl-O-, substituted with one or more R 2- b, phenyl-Q-, FO 2 S-phenylene-Q-, phenyl-C (=o) NH-, -N (R 5)2、(Cl-C6 alkyl) -O- (C 1-C6 alkyl) -, (C l-C6 alkyl) -C (=o) -, Oxo (=o), (C l-C6 alkyl) -C (=o) -, -SO 2F、(Cl-C6 alkyl) -SO 2-、(Cl-C6 alkyl) -O- (C l-C6 alkyl) -O-, substituted by one or more halogens, -CH 2OC(＝O)N(R5)2、(Cl-C6 alkyl) -O-C (=o) -NHCH 2-、-CH2NHC(＝O)N(R5)2、(Cl-C6 alkyl) -C (=o) NHCH 2 -, (pyrazolyl) -CH 2-、(Cl-C6 alkyl) -SO 2-NHCH2 -, (4-10 membered heterocycloalkyl) -C (=o) -OCH 2-、(R5)2N-C(＝O)-O-、(Cl-C6 alkyl) -O- (C l-C6 alkyl) -NH-C (=o) -O-, phenyl- (C l-C6 alkyl) -NH-C (=o) -O-, (4-10 membered heterocycloalkyl) -C (=o) -O-, or (4-10 membered heterocycloalkyl) -CH 2 -; The "phenyl" in said "phenyl-C (=o) NH-" and "phenyl- (C l-C6 alkyl) -NH-C (=o) -O-" are optionally substituted by-C (=o) H, halogen, CN or OH; the "4-10 membered heterocycloalkyl" in "(4-10 membered heterocycloalkyl) -C (=o) -OCH 2 -", "(4-10 membered heterocycloalkyl) -C (=o) -O-" and "(4-10 membered heterocycloalkyl) -CH 2 -" is optionally substituted with 0,1 or 2 oxo (=o); The heteroatoms in the "(4-10 membered heterocycloalkyl) -C (=O) -OCH 2 -", "(4-10 membered heterocycloalkyl) -C (=O) -O-", and "(4-10 membered heterocycloalkyl) -CH 2 -" "4-10 membered heterocycloalkyl" are selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3;
each Q is independently a connecting single bond or-O-;
Each R 2-a and R 2-b is independently deuterium, -CN, halogen or-OH;
Each R 2g、R2h and R 2i is independently halogen, -OH, -C (=o) H, C 1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkyl-O-, C 1-C6 alkyl substituted with one or more halogens or OH, or-N (R 5)2;
R 3 is halogen, -OH, deuterium, -CN, C 1-C6 alkyl, C 1-C6 alkyl-O-, C 1-C6 alkyl-S- C 2-C6 alkenyl, C 2-C6 alkynyl, nitro 、-(CH2)n6N(R5)2、-NHC(＝NH)NH2、-(CH2)n7C(＝O)N(R5)2、-(CH2)n8C(＝O)R5、-N(R5)C(＝O)-(C6-C10 aryl), - (CH 2)n9C(＝O)O-(C1-C6 alkyl), 3-to 7-membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted with one or more R 3a, C 1-C6 alkyl-O-substituted with one or more R 3b, C, C 1-C6 alkyl-S-, substituted by one or more R 3c, C 2-C6 alkenyl substituted by one or more R 3d, C 2-C6 alkynyl substituted with one or more R 3e, 3-7 membered cycloalkyl substituted with one or more R 3f, 3-7 membered cycloalkenyl substituted with one or more R 3g, a 4-10 membered heterocycloalkyl substituted with one or more R 3h, a 4-10 membered heterocycloalkenyl substituted with one or more R 3i, a C 6-C10 aryl substituted with one or more R 3j, or a 5-to 14-membered heteroaryl substituted with one or more R 3k; The heteroatoms in the 5-to 14-membered heteroaryl groups substituted by one or more R 3k are selected from one or more of N, O and S, and the number of the heteroatoms is 1,2 or 3; the hetero atoms in the 4-10 membered heterocycloalkyl group and the 4-10 membered heterocycloalkyl group substituted by one or more R 3h are selected from one or more of N, O and S, and the number of the hetero atoms is 1,2 or 3; The hetero atoms in the 4-10 membered heterocyclic alkenyl groups and the 4-10 membered heterocyclic alkenyl groups substituted by one or more R 3i are selected from one or more of N, O and S, and the number of the hetero atoms is 1, 2 or 3;
Each R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j and R 3k is independently deuterium, halogen, -OH, -CN, C 1-C6 alkyl, C 1-C6 alkyl-O-, deuterium, C 1-C6 alkyl-S-, C 2-C6 alkenyl-, C 2-C6 alkynyl, -N (R 5)2、-(CH2)-C(＝O)N(R5)2, 3-7 membered cycloalkyl), 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted with one or more R 3-a, C 1-C6 alkyl-O-substituted with one or more R 3-b, C, C 1-C6 alkyl-S-, substituted by one or more R 3-c, C 2-C6 alkenyl substituted by one or more R 3-d, C 2-C6 alkynyl substituted with one or more R 3-e, 3-7 membered cycloalkyl substituted with one or more R 3-f, 4-10 membered heterocycloalkyl substituted with one or more R 3-g, A5 to 14 membered heteroaryl substituted with one or more R 3-h, a 3 to 7 membered cycloalkenyl substituted with one or more R 3-i, a 4 to 10 membered heterocyclenyl substituted with one or more R 3-j, or a C 6-C10 aryl substituted with one or more R 3-k; The hetero atoms in the 4-10 membered heterocycloalkyl group and the 4-10 membered heterocycloalkyl group substituted by one or more R 3-g are selected from one or more of N, O and S, and the number of the hetero atoms is 1,2 or 3; the hetero atoms in the 4-10 membered heterocyclic alkenyl groups and the 4-10 membered heterocyclic alkenyl groups substituted by one or more R 3-j are selected from one or more of N, O and S, and the number of the hetero atoms is 1,2 or 3; The heteroatoms in the 5-to 14-membered heteroaryl groups substituted by one or more R 3-h are selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3;
Each R3-a、R3-b、R3-c、R3-d、R3-e、R3-f、R3-g、R3-h、R3-i、R3-j and R 3-k is independently deuterium, halogen, -CN, -OH, C 1-C6 alkyl, C 1-C6 alkyl-O-or 3-7 membered cycloalkyl;
R 4a is deuterium, -OH, -CN, C 1-C6 alkyl, C 1-C6 alkyl-O-, C 1-C6 alkyl -S-、-(CH2)n7C(＝O)N(R5)2、-C(＝O)OR7、-C[N(R5)2](＝NR8)、C2-C6 alkenyl, C 2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted by one or more R 4-a, C 1-C6 alkyl-O-, substituted with one or more R 4-b, C 1-C6 alkyl-S-, substituted with one or more R 4-c, C 2-C6 alkenyl substituted with one or more R 4-d, C 2-C6 alkynyl substituted with one or more R 4-e, C 6-C10 aryl substituted with one or more R 4-f, 3-7 membered cycloalkyl substituted with one or more R 4-g, 3-7 membered cycloalkenyl substituted with one or more R 4-h, A 4-10 membered heterocycloalkyl substituted with one or more R 4-i, a 4-10 membered heterocycloalkenyl substituted with one or more R 4-j, or a 5-14 membered heteroaryl substituted with one or more R 4-k; The heteroatoms in the 5-to 14-membered heteroaryl groups substituted by one or more R 4-k are selected from one or more of N, O and S, and the number of the heteroatoms is 1,2 or 3; the hetero atoms in the 4-10 membered heterocycloalkyl group and the 4-10 membered heterocycloalkyl group substituted by one or more R 4-i are selected from one or more of N, O and S, and the number of the hetero atoms is 1,2 or 3; The hetero atoms in the 4-10 membered heterocyclic alkenyl groups and the 4-10 membered heterocyclic alkenyl groups substituted by one or more R 4-j are selected from one or more of N, O and S, and the number of the hetero atoms is 1, 2 or 3;
Each R 4-a、R4-b、R4-c、R4-d、R4-e and R 4-f is independently-OH, deuterium, halogen, - (CH 2)n6N(R5)2、-CN、C1-C6 alkyl, C 1-C6 alkyl-O-), C 1-C6 alkyl-S-, C 2-C6 alkenyl-, C 2-C6 alkynyl-, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, A 5 to 14 membered heteroaryl, C 1-C6 alkyl substituted with one or more R 4-a-1, C 1-C6 alkyl-O-substituted with one or more R 4-a-2, C 1-C6 alkyl-S-, substituted by one or more R 4-a-3, C 2-C6 alkenyl substituted by one or more R 4-a-4, C 2-C6 alkynyl substituted with one or more R 4-a-5, 3-7 membered cycloalkyl substituted with one or more R 4-a-6, 3-7 membered cycloalkenyl substituted with one or more R 4-a-7, A 4-10 membered heterocycloalkyl substituted with one or more R 4-a-8, a 4-10 membered heterocycloalkenyl substituted with one or more R 4-a-9, a C 6-C10 aryl substituted with one or more R 4-a-10, or a 5-to 14-membered heteroaryl substituted with one or more R 4-a-11; The heteroatoms in the 5-to 14-membered heteroaryl groups substituted by one or more R 4-a-11 are selected from one or more of N, O and S, and the number of the heteroatoms is 1,2 or 3; the hetero atoms in the 4-10 membered heterocycloalkyl group and the 4-10 membered heterocycloalkyl group substituted by one or more R 4-a-8 are selected from one or more of N, O and S, and the number of the hetero atoms is 1,2 or 3; The hetero atoms in the 4-10 membered heterocyclic alkenyl groups and the 4-10 membered heterocyclic alkenyl groups substituted by one or more R 4-a-9 are selected from one or more of N, O and S, and the number of the hetero atoms is 1, 2 or 3;
Each R 4-g、R4-h、R4-i、R4-j and R 4-k is independently-OH, deuterium, halogen 、-(CH2)n6N(R5)2、-CN、-(CH2)n7C(＝O)N(R5)2、C1-C6 alkyl, C 1-C6 alkyl-O- C 1-C6 alkyl-S-, C 2-C6 alkenyl, C 2-C6 alkynyl, oxo (= O), thio (= S), -C (= O) OR 7, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted by one or more R 4-g-1, C 1-C6 alkyl-O-substituted by one or more R 4-g-2, C, C 1-C6 alkyl-S-, substituted by one or more R 4-g-3, C 2-C6 alkenyl substituted by one or more R 4-g-4, C 2-C6 alkynyl substituted with one or more R 4-g-5, 3-7 membered cycloalkyl substituted with one or more R 4-g-6, 3-7 membered cycloalkenyl substituted with one or more R 4-g-7, a 4-10 membered heterocycloalkyl substituted with one or more R 4-g-8, a 4-10 membered heterocycloalkenyl substituted with one or more R 4-g-9, a C 6-C10 aryl substituted with one or more R 4-g-10, or a 5-to 14-membered heteroaryl substituted with one or more R 4-g-11; The heteroatoms in the 5-to 14-membered heteroaryl groups substituted by one or more R 4-g-11 are selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3; the hetero atoms in the 4-10 membered heterocycloalkyl group and the 4-10 membered heterocycloalkyl group substituted by one or more R 4- g-8 are selected from one or more of N, O and S, and the number of the hetero atoms is 1, 2 or 3; The hetero atoms in the 4-10 membered heterocyclic alkenyl groups and the 4-10 membered heterocyclic alkenyl groups substituted by one or more R 4-g-9 are selected from one or more of N, O and S, and the number of the hetero atoms is 1, 2 or 3;
Each R 4-a-1～R4-a-11 and R 4-g-1～R4-g-11 is independently deuterium, halogen, -CN, -OH, C 1-C6 alkyl, C 1-C6 alkyl-O-, C 1-C6 alkyl-S-, or 3-7 membered cycloalkyl;
R 4b is H, deuterium, -N (R 5)2, halogen, -OH, C 1-C6 alkyl, -CN, C 1-C6 alkyl substituted with one or more R 4-b-1, C 1-C6 alkyl-O-, C 2-C6 alkenyl or C 2-C6 alkynyl;
Each R 4-b-1 is independently deuterium, halogen, -CN, or-OH;
n1, n2, n3, n4, n5, n6, n7, n8, and n9 are each independently 0, 1, 2, 3,4, or 5;
Each R 5 is independently H, -C (=o) OR 7 OR C 1-C6 alkyl;
each R 6a and R 6b is independently H, deuterium, halogen, -CN, -OH, C 1-C6 alkyl or deuterated C 1-C6 alkyl;
R 7 is independently H, deuterium, C 1-C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, or 5-14 membered heteroaryl;
R 8 is independently H, deuterium, -OH or C 1-C6 alkyl.
In certain preferred embodiments of the present invention, certain groups in the compounds of formula I, stereoisomers or pharmaceutically acceptable salts thereof are as defined below, and the unrecited groups are as described in any of the embodiments of the present invention (in some embodiments),
In some embodiments, the compound of formula I is not any of the following:
in some embodiments, R 4a is deuterium, -CN, C 1-C6 alkyl -S-、-(CH2)n7C(＝O)N(R5)2、-C(＝O)OR7、-C[N(R5)2](＝NR8)、C2-C6 alkenyl, C 2-C6 alkynyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted with one or more R 4-a, C 1-C6 alkyl-O-substituted with one or more R 4-b, C, C 1-C6 alkyl-S-, substituted by one or more R 4-c, C 2-C6 alkenyl substituted by one or more R 4-d, C 2-C6 alkynyl substituted with one or more R 4- e, C 6-C10 aryl substituted with one or more R 4-f, 3-7 membered cycloalkyl substituted by one or more R 4-g, 3-7 membered cycloalkenyl substituted by one or more R 4-h, 4-10 membered heterocycloalkyl substituted by one or more R 4-i, 4-10 membered heterocycloalkenyl substituted by one or more R 4-j, or 5-14 membered heteroaryl substituted by one or more R 4-k;
Each R 4-a is independently-OH, deuterium, - (CH 2)n6N(R5)2、-CN、C1-C6 alkyl, C 1-C6 alkyl-O-, C 1-C6 alkyl-S- C 2-C6 alkenyl, C 2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted with one or more R 4-a-1, C 1-C6 alkyl-O-, substituted with one or more R 4-a-2, C 1-C6 alkyl-S-, substituted with one or more R 4-a-3, C 2-C6 alkenyl substituted with one or more R 4-a-4, C 2-C6 alkynyl substituted with one or more R 4-a-5, 3-7 membered cycloalkyl substituted with one or more R 4-a-6, 3-7 membered cycloalkenyl substituted with one or more R 4-a-7, 4-10 membered heterocycloalkyl substituted with one or more R 4-a-8, 4-10 membered heterocycloalkenyl substituted with one or more R 4-a-9, A C 6-C10 aryl substituted with one or more R 4-a-10 or a 5 to 14 membered heteroaryl substituted with one or more R 4-a-11;
Each R 4-b is independently-OH, deuterium, - (CH 2)n6N(R5)2、-CN、C1-C6 alkyl, C 1-C6 alkyl-O-, C 1-C6 alkyl-S- C 2-C6 alkenyl, C 2-C6 alkynyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted with one or more R 4-a-1, C 1-C6 alkyl-O-, substituted with one or more R 4-a-2, C 1-C6 alkyl-S-, substituted with one or more R 4-a-3, C 2-C6 alkenyl substituted with one or more R 4-a-4, C 2-C6 alkynyl substituted with one or more R 4-a-5, 3-7 membered cycloalkyl substituted with one or more R 4-a-6, 3-7 membered cycloalkenyl substituted with one or more R 4-a-7, 4-10 membered heterocycloalkyl substituted with one or more R 4-a-8, 4-10 membered heterocycloalkenyl substituted with one or more R 4-a-9, A C 6-C10 aryl substituted with one or more R 4-a-10 or a 5 to 14 membered heteroaryl substituted with one or more R 4-a-11;
Each R 4-c、R4-d、R4-e and R 4-f is independently-OH, deuterium, halogen, - (CH 2)n6N(R5)2、-CN、C1-C6 alkyl, C 1-C6 alkyl-O-), C 1-C6 alkyl-S-, C 2-C6 alkenyl-, C 2-C6 alkynyl-, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, A 5 to 14 membered heteroaryl, C 1-C6 alkyl substituted with one or more R 4-a-1, C 1-C6 alkyl-O-substituted with one or more R 4-a-2, C 1-C6 alkyl-S-, substituted by one or more R 4-a-3, C 2-C6 alkenyl substituted by one or more R 4-a-4, C 2-C6 alkynyl substituted with one or more R 4-a-5, 3-7 membered cycloalkyl substituted with one or more R 4-a-6, 3-7 membered cycloalkenyl substituted with one or more R 4-a-7, A 4-10 membered heterocycloalkyl substituted with one or more R 4-a-8, a 4-10 membered heterocycloalkenyl substituted with one or more R 4-a-9, a C 6-C10 aryl substituted with one or more R 4-a-10, or a 5-to 14-membered heteroaryl substituted with one or more R 4-a-11;
Each R 4-g、R4-h、R4-i、R4-j and R 4-k is independently-OH, deuterium, halogen 、-(CH2)n6N(R5)2、-CN、-(CH2)n7C(＝O)N(R5)2、C1-C6 alkyl, C 1-C6 alkyl-O- C 1-C6 alkyl-S-, C 2-C6 alkenyl, C 2-C6 alkynyl, oxo (= O), thio (= S), -C (= O) OR 7, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted by one or more R 4-g-1, C 1-C6 alkyl-O-substituted by one or more R 4-g-2, C, C 1-C6 alkyl-S-, substituted by one or more R 4-g-3, C 2-C6 alkenyl substituted by one or more R 4-g-4, C 2-C6 alkynyl substituted with one or more R 4-g-5, 3-7 membered cycloalkyl substituted with one or more R 4-g-6, 3-7 membered cycloalkenyl substituted with one or more R 4-g-7, A 4-10 membered heterocycloalkyl substituted with one or more R 4-g-8, a 4-10 membered heterocycloalkenyl substituted with one or more R 4-g-9, a C 6-C10 aryl substituted with one or more R 4-g-10, or a 5-to 14-membered heteroaryl substituted with one or more R 4-g-11.
In some embodiments, R 4a is- (CH 2)n7C(＝O)N(R5)2), 4-10 membered heterocyclenyl substituted with one or more R 4-j, 5-14 membered heteroaryl substituted with one or more R 4-k, C 6-C10 aryl substituted with one or more R 4-f, C 6-C10 aryl, 5-14 membered heteroaryl, or C 1-C6 alkyl substituted with one or more R 4-a;
each R 4-a is independently-OH, -CN, - (CH 2)n6N(R5)2) or C 2-C6 alkynyl;
Each R 4-f is independently-OH, halogen, - (CH 2)n6N(R5)2 or C 2-C6 alkynyl;
Each R 4-j and R 4-k is independently halogen 、-(CH2)n6N(R5)2、-CN、-(CH2)n7C(＝O)N(R5)2、C1-C6 alkyl, C 1-C6 alkyl-O-, oxo (=o), 4-10 membered heterocycloalkyl, or C 1-C6 alkyl substituted with one or more R 4-g-1.
In some embodiments, R 4a is a 5-to 14-membered heteroaryl substituted with one or more R 4-k, a C 6-C10 aryl substituted with one or more R 4-f, a C 6-C10 aryl, or a 5-to 14-membered heteroaryl;
Each R 4-f is independently halogen, -OH or C 2-C6 alkynyl;
Each R 4-k is independently halogen, C 1-C6 alkyl substituted with one or more R 4-g-1, - (CH 2)n6N(R5)2、C1-C6 alkyl or-CN.
In some embodiments, ring A is a 4-10 membered heterocycloalkyl or a 4-10 membered heterocycloalkenyl, preferably a 4-10 membered heterocycloalkyl.
In some embodiments, n is 0 or 1, preferably 0.
In some embodiments, each R 1 is independently halogen, -CN, -OH, -N (R 5)2、C1-C6 alkyl or C 1-C6 alkyl substituted with one or more R 1a).
In some embodiments, each R 1a、R1b、R1c and R 1d is independently-CN, halogen, or-OH.
In some embodiments, L is-O- (CR 6aR6b)n2-*,*) which represents the end attached to R 2.
In some embodiments, R 2 is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl substituted with one or more R 2e, preferably 4-10 membered heterocycloalkyl substituted with one or more R 2e.
In some embodiments, each R 2a、R2b、R2c、R2d、R2e、R2f and R 2j is independently halogen or C 1-C6 alkyl; halogen is preferred.
In some embodiments, R 3 is halogen, C 6-C10 aryl, 5 to 14 membered heteroaryl, C 6-C10 aryl substituted with one or more R 3j, or 5 to 14 membered heteroaryl substituted with one or more R 3k; preferably halogen or C 6-C10 aryl substituted with one or more R 3j.
In some embodiments, each R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j and R 3k is independently halogen, -OH, -N (R 5)2、C1-C6 alkyl, C 1-C6 alkyl substituted with one or more R 3-a, or C 2-C6 alkynyl; preferably halogen, -OH, or C 2-C6 alkynyl.
In some embodiments, each R3-a、R3-b、R3-c、R3-d、R3-e、R3-f、R3-g、R3-h、R3-i、R3-j and R 3-k is independently halogen, -CN, or-OH.
In some embodiments, R 4a is C 1-C6 alkyl, - (CH 2)n7C(＝O)N(R5)2, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted with one or more R 4-a, C 6-C10 aryl substituted with one or more R 4-f, 4-10 membered heterocycloalkenyl substituted with one or more R 4-j, or 5-14 membered heteroaryl substituted with one or more R 4-k, preferably 5-14 membered heteroaryl substituted with one or more R 4-k, C 6-C10 aryl substituted with one or more R 4-f, C 6-C10 aryl, 5-14 membered heteroaryl, or C 1-C6 alkyl substituted with one or more R 4-a.
In some embodiments, R 4a is 4-10 membered heterocyclenyl substituted with one or more R 4-j, 5-14 membered heteroaryl substituted with one or more R 4-k, C 6-C10 aryl substituted with one or more R 4-f, C 6-C10 aryl, or 5-14 membered heteroaryl; preferably a 5 to 14 membered heteroaryl substituted with one or more R 4-k, a C 6-C10 aryl substituted with one or more R 4-f, a C 6-C10 aryl or a 5 to 14 membered heteroaryl.
In some embodiments, each R 4-a、R4-b、R4-c、R4-d、R4-e and R 4-f is independently-OH, halogen, - (CH 2)n6N(R5)2, -CN, or C 2-C6 alkynyl, preferably OH, halogen, or C 2-C6 alkynyl.
In some embodiments, each R 4-a is independently-OH, - (CH 2)n6N(R5)2, -CN, or C 2-C6 alkynyl; preferably-OH, - (CH 2)n6N(R5)2) or-CN, more preferably-OH.
In some embodiments, each R 4-b、R4-c、R4-d、R4-e and R 4-f is independently-OH, halogen, - (CH 2)n6N(R5)2 or C 2-C6 alkynyl, preferably halogen, -OH or C 2-C6 alkynyl.
In some embodiments, each R 4-g、R4-h、R4-i、R4-j and R 4-k is independently halogen 、-(CH2)n6N(R5)2、-CN、-(CH2)n7C(＝O)N(R5)2、C1-C6 alkyl, C 1-C6 alkyl-O-, oxo (=o), 4-10 membered heterocycloalkyl, or C 1-C6 alkyl substituted with one or more R 4- g-1; preferably halogen, C 1-C6 alkyl substituted by one or more R 4-g-1, - (CH 2)n6N(R5)2、C1-C6 alkyl or-CN; more preferably halogen, C 1-C6 alkyl substituted by one or more R 4-g-1, - (CH 2)n6N(R5)2 or C 1-C6 alkyl).
In some embodiments, each R 4-a-1～R4-a-11 and R 4-g-1～R4-g-11 is independently halogen.
In some embodiments, R 4b is halogen.
In some embodiments, n1, n2, n3, n4, n5, n6, n7, n8, and n9 are each independently 0 or 1.
In some embodiments, n2 is 1.
In some embodiments, n1, n3, n4, n5, n6, n7, n8, and n9 are each independently 0.
In some embodiments, each R 6a and R 6b is independently H.
In some embodiments, ring a is a 4-10 membered heterocycloalkyl;
n is 0;
L is-O- (CR 6aR6b)n2-*,* represents one end connected with R 2;
R 2 is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl substituted by one or more R 2e;
Each R 2e is independently halogen;
R 3 is halogen or C 6-C10 aryl substituted with one or more R 3j;
Each R 3j is independently halogen, -OH or C 2-C6 alkynyl;
R 4a is a 5-to 14-membered heteroaryl substituted with one or more R 4-k, a C 6-C10 aryl substituted with one or more R 4-f, a C 6-C10 aryl, a 5-to 14-membered heteroaryl, or a C 1-C6 alkyl substituted with one or more R 4-a;
Each R 4-a and R 4-f is independently OH, halogen or C 2-C6 alkynyl;
Each R 4-k is independently halogen, C 1-C6 alkyl substituted with one or more R 4-g-1, - (CH 2)n6N(R5)2 or C 1-C6 alkyl;
Each R 4-g-1 is independently halogen;
R 4b is halogen;
Each R 5 is independently H or C 1-C6 alkyl;
n2 is 1;
n6 is 0;
each R 6a and R 6b is independently H.
In some embodiments, ring a is a 4-10 membered heterocycloalkyl;
n is 0;
L is-O- (CR 6aR6b)n2-*,* represents one end connected with R 2;
R 2 is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl substituted by one or more R 2e;
Each R 2e is independently halogen;
R 3 is halogen or C 6-C10 aryl substituted with one or more R 3j;
Each R 3j is independently halogen, -OH or C 2-C6 alkynyl;
R 4a is a 5-to 14-membered heteroaryl substituted with one or more R 4-k, a C 6-C10 aryl substituted with one or more R 4-f, a C 6-C10 aryl, a 5-to 14-membered heteroaryl, or a C 1-C6 alkyl substituted with one or more R 4-a;
Each R 4-a is independently-OH;
Each R 4-f is independently-OH, halogen, or C 2-C6 alkynyl;
Each R 4-k is independently halogen, -CN, C 1-C6 alkyl substituted with one or more R 4-g-1, - (CH 2)n6N(R5)2 or C 1-C6 alkyl;
Each R 4-g-1 is independently halogen;
R 4b is halogen;
Each R 5 is independently H or C 1-C6 alkyl;
n2 is 1;
n6 is 0;
each R 6a and R 6b is independently H.
In some embodiments, ring a is a 4-10 membered heterocycloalkyl;
n is 0;
L is-O- (CR 6aR6b)n2-*,* represents one end connected with R 2;
R 2 is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl substituted by one or more R 2e;
Each R 2e is independently halogen or C 1-C6 alkyl;
R 3 is halogen, C 6-C10 aryl, 5 to 14 membered heteroaryl, C 6-C10 aryl substituted with one or more R 3j, or 5 to 14 membered heteroaryl substituted with one or more R 3k;
Each R 3j and R 3k is independently halogen, -OH, -N (R 5)2、C1-C6 alkyl, C 1-C6 alkyl substituted with one or more R 3-a, or C 2-C6 alkynyl;
Each R 3-a is independently halogen, -CN or-OH;
R 4a is- (CH 2)n7C(＝O)N(R5)2, 4-10 membered heterocycloalkenyl substituted by one or more R 4-j, 4-10 membered heterocycloalkenyl, 5-14 membered heteroaryl substituted by one or more R 4-k, C 6-C10 aryl substituted by one or more R 4-f, C 6-C10 aryl, 5-14 membered heteroaryl or C 1-C6 alkyl substituted by one or more R 4-a;
Each R 4-a is independently-OH, - (CH 2)n6N(R5)2) or-CN;
Each R 4-f is independently-OH, halogen, or C 2-C6 alkynyl;
Each R 4-k is independently halogen, 4-10 membered heterocycloalkyl, - (CH 2)n7C(＝O)N(R5)2), C 1-C6 alkyl substituted by one or more R 4-g-1, C 1-C6 alkyl-O-, - (CH 2)n6N(R5)2、C1-C6 alkyl or-CN;
Each R 4-g-1 is independently halogen;
Each R 4-j is oxo (=o);
R 4b is halogen;
Each R 5 is independently H or C 1-C6 alkyl;
n2 is 1;
n6 is 0;
n7 is 0;
each R 6a and R 6b is independently H.
In some embodiments, each of said "4-10 membered heterocycloalkyl" is independently a 5-8 membered heterocycloalkyl, e.g (Preferably)、
In some embodiments, each of the "4-10 membered heterocycloalkyl" is independentlyWherein saidIs that
In some embodiments, each of the halogens is independently fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.
In some embodiments, each of the "C 6-C10 aryl" groups is independently phenyl or naphthyl.
In some embodiments, each of the "C 1-C6 alkyl" is independently a C 1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, preferably methyl or ethyl.
In some embodiments, each of the "C 2-C6 alkynyl" is independently a C 2-C3 alkynyl, such as ethynyl, propynyl, or propargyl, preferably ethynyl.
In some embodiments, each of the "5-to 14-membered heteroaryl" is independently "heteroatom is N or S, 5-to 10-membered heteroaryl having 1 or 2 heteroatoms", such as pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, indolyl, indazolyl, pyrazolopyridinyl, pyrimidinyl, or benzothienyl, for example, further such as
In some embodiments, each of the "4-10 membered heterocycloalkenyl" is independently a 5-8 membered heterocycloalkenyl, e.g.
In some embodiments, each of the "3-7 membered cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
In some embodiments, each of the "3-7 membered cycloalkenyl" is independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.
In some embodiments, each of the "C 2-C6 alkenyl" is independently vinyl, 1-propenyl, n-allyl, but-1-enyl, but-2-enyl, pent-1-enyl, or pent-1, 4-dienyl.
In some embodiments, in rings A, R 2、R4-g、R4-h、R4-i、R4-j and R 4-k, the "4-10 membered heterocycloalkyl" in the "4-10 membered heterocycloalkyl" and "4-10 membered heterocycloalkyl substituted with one or more R 2e" are each independently 5-8 membered heterocycloalkyl, e.g(Preferably
In some embodiments ,R2a、R2b、R2c、R2d、R2e、R2f、R2j、R3、R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j、R3k、R4-a、R4-b、R4-c、R4-d、R4-e、R4-f、R4-g、R4-h、R4-i、R4-j、R4-k、R4-a-1～R4-a-11、R4- g-1～R4-g-11 and R 4b, the halogen is each independently fluorine, chlorine, bromine or iodine.
In some embodiments, in R 3 and R 4a, "C 6-C10 aryl" in the "C 6-C10 aryl substituted with one or more R 3j", "C 6-C10 aryl", and "C 6-C10 aryl substituted with one or more R 4-f" are each independently phenyl or naphthyl.
In some embodiments ,R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j、R3k、R4a、R4-g、R4-h、R4- i、R4-j、R4-k and R 5, "C 1-C6 alkyl" in the "C 1-C6 alkyl", "C 1-C6 alkyl substituted with one or more R 4-a", "C 1-C6 alkyl-O-" and "C 1-C6 alkyl substituted with one or more R 4-g-1" are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In some embodiments ,R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j、R3k、R4-a、R4-b、R4-c、R4-d、R4-e and R 4-f, the "C 2-C6 alkynyl" groups are each independently a C 2-C3 alkynyl group, such as ethynyl, propynyl, or propargyl.
In some embodiments, in R 4a, the "5-to 14-membered heteroaryl" and "5-to 14-membered heteroaryl" in "5-to 14-membered heteroaryl substituted with one or more R 4-k" are each independently "a heteroatom is N or S, a heteroatom number of 1 or 2 of 5-to 10-membered heteroaryl", e.g., pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, indolyl, indazolyl, pyrazolopyridinyl, pyrimidinyl, or benzothienyl ", e.g., further, e.g.
In some embodiments, in R 4a, "4-10 membered heterocycloalkenyl" in "4-10 membered heterocycloalkenyl substituted with one or more R 4-j" are each independently 5-8 membered heterocycloalkenyl, e.g.
In some embodiments, ring a is
In some embodiments, n is 0.
In some embodiments, L is-O-CH 2-*,* represents the end attached to R 2.
In some embodiments, R 2 isPreferably
In some embodiments, R 4b is F.
In some embodiments, R 3 isOr Cl.
In some embodiments, R 4a is Preferably More preferably
In some embodiments, the compound of formula I is any one of the following:
in some embodiments, the pharmaceutically acceptable salt of the compound of formula I is any one of the following: Is a trifluoroacetate salt of (a).
The invention also provides a compound (intermediate) shown as follows:
the invention also provides a hydrochloride salt of any one of the following compounds:
the invention also provides a preparation method of the compound shown in the formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, which can be the following route:
Route one:
Wherein P 1 is an amino protecting group such as Boc, PMB, bn, cbz, fmoc and the like,
L, R 2、R3 and R 4a are as defined above;
Step 1: in a solvent, carrying out Suzuki reaction on a compound shown as a formula SM-1 in the presence of alkali and a catalyst to obtain a compound shown as a formula SM-2;
Step 2: in a solvent, carrying out Suzuki reaction on a compound shown as a formula SM-2 in the presence of alkali and a catalyst to obtain a compound shown as a formula SM-3;
Step 3: deprotection reaction [ R 3 wherein the substituent R 3a、R3b (e.g., -OH, -NH 2、C2-C6 alkynyl) is protected with a protecting group, may be carried out to give a compound of formula I ];
the deprotection reaction in step 3 satisfies one or more of the following conditions:
(1) Under acidic conditions, deamination protecting groups and dehydroxylation protecting groups are reacted;
(2) Removing TIPS protection in the presence of tetrabutylammonium fluoride, tetramethylammonium fluoride or cesium fluoride;
Route two:
Wherein P 1 is an amino protecting group such as Boc, PMB, bn, cbz, fmoc and the like,
L, R 2 and R 4a are as defined above;
Step 1: in a solvent, carrying out Suzuki reaction on a compound shown as a formula SM-1 in the presence of alkali and a catalyst to obtain a compound shown as a formula SM-4;
step 2: under acidic conditions, the compound shown as the formula SM-4 is subjected to deamination protecting group reaction.
The invention also provides a pharmaceutical composition, which comprises a substance A and a pharmaceutic adjuvant (or a pharmaceutically acceptable carrier); the substance A is the compound shown in the formula I, the stereoisomer or the pharmaceutically acceptable salt thereof. The substance a may be in a therapeutically effective amount.
The invention also provides application of the substance A in preparing an RAS inhibitor, wherein the substance A is a compound shown in the formula I, a stereoisomer or a pharmaceutically acceptable salt thereof. In such applications, the RAS inhibitors may be used in mammalian organisms; it is also useful in vitro, mainly as an experimental use, for example: the kit can be used as a standard sample or a control sample for comparison or prepared according to a conventional method in the field, and can be used for rapidly detecting the RAS inhibition effect.
The invention also provides an application of the substance A in preparing medicines for treating and/or preventing RAS mediated diseases; the substance A is the compound shown in the formula I, the stereoisomer or the pharmaceutically acceptable salt thereof; the substance A is in a therapeutically effective amount.
The invention also provides application of the substance A in preparing a medicament for treating and/or preventing cancers; the substance A is the compound shown in the formula I, the stereoisomer or the pharmaceutically acceptable salt thereof; the substance A is in a therapeutically effective amount.
The present invention also provides a method of inhibiting RAS comprising administering a therapeutically effective amount of substance a to a patient; the substance A is the compound shown in the formula I, the stereoisomer or the pharmaceutically acceptable salt thereof.
The present invention also provides a method of treating and/or preventing a RAS-mediated disease comprising administering a therapeutically effective amount of substance a to a patient; the substance A is the compound shown in the formula I, the stereoisomer or the pharmaceutically acceptable salt thereof.
The present invention also provides a method of treating and/or preventing cancer comprising administering to a patient a therapeutically effective amount of substance a; the substance A is the compound shown in the formula I, the stereoisomer or the pharmaceutically acceptable salt thereof.
The RAS as described above may be KRAS or KRAS mutations; such as KRAS G12D, KRAS G12V.
RAS mediated diseases such as cancer as described above.
The cancer as described above may be selected from one or more of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, colorectal cancer, non-small cell lung cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.
In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below, unless otherwise specified.
The term "plurality" refers to 2, 3, 4, or 5.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, diethanolamine salt. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in pure solution or in a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids (e.g., hydrochloric acid), organic acids (e.g., trifluoroacetic acid, formic acid). See, for example, berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science 66:1-19 (1977), or 、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002).
In the present invention, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds of the present invention may exist as stereoisomers and thus encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, atropisomers and the like, as well as any combination or mixture of the aforementioned stereoisomers, for example, meso, racemates, equivalent mixtures of atropisomers and the like; for example, a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. When the compounds of the present invention contain olefinic double bonds, they include cis-isomers and trans-isomers, as well as any combination thereof, unless specified otherwise.
In the present invention, "pharmaceutical composition" refers to a formulation comprising a compound of the present invention and a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.
In the present invention, "pharmaceutically acceptable" refers to a substance (e.g., pharmaceutical excipient) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
The term "pharmaceutical excipients" or "pharmaceutically acceptable carriers" refers to excipients and additives used in the manufacture of medicaments and formulation prescriptions, and are all substances contained in pharmaceutical preparations except the active ingredient. See the pharmacopoeia of the people's republic of China (2015 edition), or, handbook of Pharmaceutical Excipients (Raymond C Rowe,2009 Sixth Edition). Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.
The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
When used as a medicament, the compounds of formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof, may be administered in any form of a pharmaceutical composition. These compositions may be prepared according to methods well known in the pharmaceutical arts and may be administered by various routes, depending upon the local or systemic treatment and the area to be treated. Administration may be in the form of topical (including epidermal and transdermal, ocular and mucosal, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by powder or aerosol inhalation or insufflation, including by nebulizer; intratracheal or intranasal), oral (solid and liquid formulations) or parenteral administration. Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations which may be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, emulsions, ointments, gels, drops, suppositories, sprays, liquids and powders. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants. Oral administration may include dosage forms formulated for once-a-day or twice-a-day (BID) administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose or may be by a continuous infusion pump. Conventional pharmaceutical carriers, water, powder or oily bases, thickeners and the like may be necessary or desirable. Pharmaceutical compositions comprising the invention may also be in controlled or delayed release dosage forms (e.g. liposomes or microspheres).
The term "treatment" refers to therapeutic therapy or palliative measures. When specific conditions are involved, treatment refers to: (1) alleviating a disease or one or more biological manifestations of a disorder, (2) interfering with (a) one or more points in a biological cascade that results in or causes a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of a disorder or one or more biological manifestations of a disorder. "treatment" may also refer to an extended survival period compared to the expected survival without treatment.
The term "preventing" refers to a reduced risk of acquiring or developing a disease or disorder.
The term "therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat a disease or disorder described herein when administered to a patient. The "therapeutically effective amount" will vary depending on the compound, the condition and severity thereof, and the age of the patient to be treated, but can be adjusted as desired by one of ordinary skill in the art.
The term "patient" refers to any animal, preferably a mammal, most preferably a human, that is about to or has received administration of the compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being preferred.
In the present invention, the term "substitution" or "substituent" is the replacement of a hydrogen atom in a group by the specified group. When no substitution positions are indicated, substitution may be at any position, but only formation of a stable or chemically feasible chemical is allowed. The following are illustrated: The structure represents that the hydrogen atom on ring A is replaced by p R 4.
When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with one or more R, the group may optionally be substituted with at least one R, and R in each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.
In the present invention, the term "alkyl" refers to a saturated straight or branched monovalent hydrocarbon group. C 1-C6 alkyl means alkyl having 1 to 6 carbon atoms, preferably alkyl having 1 to 4 carbon atoms, which is in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In the present invention, the term "phenylene" means a group obtained by removing two hydrogen atoms from a benzene ring, i.e., one hydrogen in a phenyl group is substituted.
In the present invention, the term "heterocycloalkyl" means a group formed by substitution of at least one carbon atom in the heterocycloalkyl group with a heteroatom selected from N, O and S. The 4-to 10-membered heterocycloalkyl group may be in particular a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered heterocycloalkyl group. Examples of heterocycloalkyl groups include, but are not limited to(Preferably
In the present invention, the term "aryl" refers to an aromatic group in which each ring is aromatic, such as phenyl or naphthyl.
In the present invention, the term "heteroaryl" refers to an aromatic group containing a heteroatom, preferably an aromatic 5-6 membered monocyclic ring or a 9-10 membered bicyclic ring containing 1,2 or 3 rings independently selected from nitrogen, oxygen and sulfur, where each ring has aromaticity, such as pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, indolyl, indazolyl, pyrazolopyridinyl, pyrimidinyl or benzothienyl, and further such as Etc.
In the present invention, the term "alkynyl" refers to a straight or branched hydrocarbon group having one or more triple bonds of a specified carbon number (e.g., C 2-C6 alkynyl, and also e.g., C 2-C3 alkynyl). The one or more carbon-carbon triple bonds may be internal or terminal, e.g. a triple bond internal to propynyl groupOr a three-bond terminal propynyl groupEtc.
In the present invention, the term "heterocycloalkenyl" means a cyclic alkenyl group linked through a heteroatom or a heteroatom group. In one embodiment, the "heterocycloalkenyl" is a stable 3 to 20 membered (preferably 3 to 12 membered, more preferably 4 to 10 membered, most preferably 5 to 8 membered), monocyclic or polycyclic (e.g., bicyclic, tricyclic or more bridged, fused or spiro) non-aromatic ring system consisting of 2 to 14 (preferably 2 to 6) carbon atoms and 1to 6 heteroatoms or heteroatom-containing groups selected from N, O, S, S (=o) and S (=o) 2, containing an unsaturated double bond, e.g.
In the present invention, the term "alkenyl" refers to a straight or branched hydrocarbon chain group having at least one double bond, consisting of only carbon and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6, most preferably 2 to 4) carbon atoms, and being attached to the remainder of the molecule by a single bond, including, for example, but not limited to, vinyl, 1-propenyl, n-allyl, but-1-enyl, but-2-enyl, pent-1-enyl, or pent-1, 4-dienyl, and the like.
In the present invention, the term "cycloalkyl" means a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more bridged, fused or spiro ring systems) carbocyclic substituent, and which may be attached to the remainder of the molecule by a single bond via any suitable carbon atom; such as a 3-15 membered cycloalkyl group having 3 to 15 carbon atoms, preferably a 3-12 membered cycloalkyl group having 3 to 12 carbon atoms, more preferably a 3-7 membered cycloalkyl group having 3 to 7 carbon atoms, most preferably a 3-6 membered cycloalkyl group having 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.
In the present invention, the term "cycloalkenyl" means a partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more bridged, fused or spiro ring system) non-aromatic carbocyclic substituent having at least one double bond (e.g., a carbon-carbon double bond) and which may be attached to the remainder of the molecule by a single bond via any suitable carbon atom; such as a 3-15 membered cycloalkenyl group having 3 to 15 carbon atoms, preferably a 3-12 membered cycloalkenyl group having 3 to 12 carbon atoms, more preferably a 3-7 membered cycloalkenyl group having 3 to 7 carbon atoms, most preferably a 3-6 membered cycloalkenyl group having 3 to 6 carbon atoms. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl (e.g.) Cyclopentadienyl (e.g) Cyclohexenyl (e.g) Cycloheptenyl, cyclohexadienyl, and the like.
In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine, in particular F or Cl.
Those skilled in the art will appreciate that, in accordance with the convention used in the art, the present application describes the structural formula of the group usedAndIt means that the corresponding group R is linked to other fragments, groups in the compound through this site.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the nitrogen-containing heterocyclic compounds are expected to treat and/or prevent a variety of diseases mediated by KRAS, particularly KRAS G12D and/or KRAS G12V.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
The abbreviations of the Chinese and English words in the present application are shown below,
Boc: t-butoxycarbonyl; TIPS: triisopropyl silicon group; MOM: methoxymethyl (CH 3OCH2 -); FA: formic acid; MEOH: methanol; etOH: ethanol; DMSO: dimethyl sulfoxide; ACN: acetonitrile; CDCl 3: deuterated chloroform.
Intermediate 1: (1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
Step 1:2, 6-dichloro-3-fluoropyridin-4-amine
2, 6-Dichloropyridin-4-amine (6.52 g,39.99mmol,1 eq) was dissolved in N, N-dimethylformamide (30 mL) and acetonitrile (30 mL), and 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (17 g,47.99mmol,1.2 eq) was added to react at 80℃for half an hour. LCMS monitored reaction was complete. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate and column purification of the residue (ethyl acetate/petroleum ether: 0-10%) gave 2, 6-dichloro-3-fluoropyridin-4-amine (4.2 g, yield: 58.03%) as a white solid.
MS m/z:181.1/183.1[M+H]+
Step 2: tert-butyl-N- [ (tert-butoxy) carbonyl ] -N- (2, 6-dichloro-3-fluoropyridin-4-yl) aminomethyl ester
2, 6-Dichloro-3-fluoropyridin-4-amine (4.2 g,23.21mmol,1 eq) was dissolved in dichloromethane (40 mL), BOC anhydride (10.29 g,47.15mmol,2.03 eq) was added, and 4-dimethylaminopyridine (457.28 mg,3.74mmol,0.16 eq) was reacted at room temperature for 16 hours. LCMS monitored reaction was complete. The reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 0-20%) to give tert-butyl-N- [ (tert-butoxy) carbonyl ] -N- (2, 6-dichloro-3-fluoropyridin-4-yl) carbamate (7.0 g, yield: 79.13%) as a white solid.
MS m/z:381.1/383.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.06-8.01(m,1H),1.42(s,18H).
Step 3: tert-butyl-4- ((tert-butoxycarbonyl) amino) -2, 6-dichloro-5-fluoronicotine ester
Tert-butyl-N- [ (tert-butoxy) carbonyl ] -N- (2, 6-dichloro-3-fluoropyridin-4-yl) carbamate (5.84 g,15.32mmol,1 eq) was dissolved in tetrahydrofuran (30 mL), lithium diisopropylamide (2M, 15.32mL,2 eq) was added dropwise at-78℃and the temperature was raised to room temperature for 2 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave the residue as a brown solid, which was purified by column (ethyl acetate/petroleum ether: 0-20%) to give tert-butyl-4- ((tert-butoxycarbonyl) amino) -2, 6-dichloro-5-fluoronicotine ester (5.0 g, yield: 85.62%).
MS m/z:381.1/383.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),1.54(s,9H),1.45(s,9H).
Step 4:2, 6-dichloro-3-fluoropyridin-4-amine
Tert-butyl-4- ((tert-butoxycarbonyl) amino) -2, 6-dichloro-5-fluoronicotine ester (13 g,34.10mmol,1 eq) was dissolved in dichloromethane (100 mL), trifluoroacetic acid (30 mL) was added and reacted at room temperature for 16 hours. LCMS monitored reaction was complete. The reaction solution was concentrated to give 2, 6-dichloro-3-fluoropyridin-4-amine (7.67 g, crude) as a brown solid which was used directly in the next step.
MS m/z:225.1[M+H]+
Step 5: ethyl-4-amino-2, 6-dichloro-5-fluoronicotine ester
2, 6-Dichloro-3-fluoropyridin-4-amine (7.67 g,34.09mmol,1 eq) was dissolved in ethanol (100 mL), and concentrated sulfuric acid (102.35 g,1.02mol,30 eq) was added to react at 80℃for 40 hours. Cooled to room temperature, and saturated aqueous sodium bicarbonate was added to the reaction solution to adjust ph=7. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate and column purification of the residue (ethyl acetate/petroleum ether: 20-40%) gave ethyl-4-amino-2, 6-dichloro-5-fluoronicotine ester (8.0 g, yield: 92.76%) as a brown solid.
MS m/z:253.1/255.1[M+H]+
Step 6: ethyl-2, 6-dichloro-5-fluoro-4- (3- (2, 2-trichloroacetyl) ureido) nicotine ester
Ethyl-4-amino-2, 6-dichloro-5-fluoronicotine ester (1.13 g,4.47mmol,1 eq) was dissolved in tetrahydrofuran (10 mL), and trichloroacetyl isocyanate (993.57 mg,5.27mmol,1.18 eq) was added and reacted at room temperature for 1 hour. LCMS monitored reaction was complete. The reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 20-50%) to give ethyl-2, 6-dichloro-5-fluoro-4- (3- (2, 2-trichloroacetyl) ureido) nicotine ester (1.5 g, yield: 76.14%) as a white solid.
MS m/z:441.9/443.9[M+H]+
Step 7:5, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidine-2, 4-diol
Ethyl-2, 6-dichloro-5-fluoro-4- (3- (2, 2-trichloroacetyl) ureido) nicotine ester (3.0 g,6.80mmol,1 eq) was dissolved in methanol (40 mL), and an methanolic ammonia solution (7M, 2.77mL,2.85 eq) was added and reacted at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction solution was concentrated, and the residue was slurried with methyl tert-butyl ether to give 5, 7-dichloro-8-fluoropyrido [4,3-d ] pyrimidine-2, 4-diol (1.8 g, yield: 100%) as a white solid.
MS m/z:250.1/252.1[M+H]+
Step 8:2,4,5, 7-tetrachloro-8-fluoropyrido [4,3-d ] pyrimidine
5, 7-Dichloro-8-fluoropyrido [4,3-d ] pyrimidine-2, 4-diol (12 g,48.00mmol,1 eq) was dissolved in phosphorus oxychloride (100 mL), and N, N-diisopropylethylamine (30.71 g,237.59mmol,41.38mL,4.95 eq) was slowly added dropwise. The reaction was carried out at 100℃for 16 hours with nitrogen substitution. LCMS monitored completion of the reaction and the reaction concentrated under reduced pressure to give 2,4,5, 7-tetrachloro-8-fluoropyrido [4,3-d ] pyrimidine (30 g, crude) as a dark brown oil. The crude product was used directly in the next step.
MS m/z:288.2/290.2[M+H]+
Step 9: (1R, 5S) -tert-butyl-3- (2, 5, 7-trichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
2,4,5, 7-Tetrachloro-8-fluoropyrido [4,3-d ] pyrimidine (13.3 g,27.81mmol,1 eq) was dissolved in dichloromethane (100 mL) and N, N-diisopropylethylamine (10.78 g,83.44mmol,14.53mL,3 eq) was added. 8-BOC-3, 8-diazabicyclo [3.2.1] octane (5.90 g,27.81mmol,1 eq) was slowly added at-30℃and reacted for half an hour. LCMS monitored completion of the reaction, and the reaction was quenched by slow addition to saturated aqueous ammonium chloride. The mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate and column purification of the residue (ethyl acetate/petroleum ether: 0-16%) gave (1R, 5S) -tert-butyl-3- (2, 5, 7-trichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (8.6 g, two-step yield: 38.74%) as a white solid.
MS m/z:462.1/464.1[M+H]+
Step 10: (1R, 5S) -tert-butyl-3- (5, 7-dichloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (2, 5, 7-trichloro-8-fluoropyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (8.6 g,18.59mmol,1 eq) methanol (2.96 g,18.59mmol,1 eq) was dissolved in dichloromethane (100 mL) and sodium tert-butoxide (3.57 g,37.17mmol,2 eq) was slowly added to the mixture at room temperature under nitrogen atmosphere for 1 hour. LCMS monitored completion of the reaction, and the reaction was slowly poured into saturated aqueous ammonium chloride and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate and column purification of the residue (ethyl acetate/petroleum ether: 30-60%) gave (1R, 5S) -tert-butyl-3- (5, 7-dichloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (9 g, yield: 82.71%) as a yellow solid.
MS m/z:585.1/587.1[M+H]+
1H NMR(400MHz,CDCl3)δ5.35(br d,J＝53.2Hz,1H),4.35-4.15(m,4H)3.57-3.20(m,4H),3.08(br s,1H),2.47-1.95(m,5H),1.89-1.59(m,8H),1.53(s,9H).
19F NMR(376MHz,CDCl3)δ-137.27(s),-172.89(s).
Step 11: (1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
Tert-butyl- (1- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 3-difluoropiperidin-4-yl) carbamate (5.0 g,8.54mmol,1 eq) and ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (5.03 g,9.82mmol,1.15 eq). Potassium carbonate (3.54 g,25.62mmol,3 eq), 2-dicyclohexylphosphine-2, 6-diisopropyloxy-1, 1-biphenyl (797.02 mg,1.71mmol,0.2 eq) and methanesulfonic acid (2-dicyclohexylphosphino-2, 6-diisopropyloxy-1, 1-biphenyl) (2-amino-1, 1-biphenyl-2-yl) palladium (II) (1.43 g,1.71mmol,0.2 eq) were dissolved in a mixed solvent of toluene (50 mL), water (25 mL) and ethanol (25 mL), nitrogen was replaced, and reacted at 80℃for 16 hours. LCMS monitored the end of the reaction. The reaction solution was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to give (1 r,5 s) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (2.5 g, yield: 25%) as a yellow solid.
MS m/z:935.4/937.4[M+H]+
Intermediate 2: (1R, 5S) -tert-butyl-3- (5-chloro-7- (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
Step 1: (1R, 5S) -tert-butyl-3- (5-chloro-7- (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5, 7-dichloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1060 mg,1.81mmol,1 eq) was dissolved in dioxane (10 mL) and water (5 mL), 2- (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (697.37 mg,1.99mmol,1.1 eq), cesium carbonate (1.18 g,3.62mmol,2 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (132.48 mg,0.1 eq) was added and the mixture was reacted for 1 hour at 80℃under nitrogen. LCMS monitored reaction was complete. The reaction solution was concentrated, and the residue was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (tetrahydrofuran/petroleum ether: 10-30%) to give (1R, 5S) -tert-butyl-3- (5-chloro-7- (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (310 mg, yield: 22.1%) as a brown solid.
MS m/z:773.3[M+H]+
Example 1: compound 1
4,4' - (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5, 7-ylidene) bis (5, 6-difluoronaphthalene-2-ol)
Step 1: (1R, 5S) -tert-butyl-3- (5, 7-bis (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5, 7-dichloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (500 mg, 0.254 mmol,1 eq) was dissolved in dioxane (3 mL) and water (1 mL), 2- (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (747.6 mg,2.14mmol,2.5 eq), cesium carbonate (834.76 mg,2.56mmol,3 eq), 1-bis (tert-butylphosphorus) ferrocene palladium chloride (83.5 mg,0.128 eq, 0.15 eq) was added and the mixture was reacted for 1 hour under nitrogen protection at 100 ℃. LCMS monitored reaction was complete. The reaction solution was concentrated, and the residue was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtering and concentrating the filtrate. The crude product was purified by column chromatography (tetrahydrofuran/petroleum ether: 10-30%) to give (1R, 5S) -tert-butyl-3- (5, 7-bis (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (250 mg, yield: 30.5%) as a brown solid.
MS m/z:961.3[M+H]+
Step 2: compound 1
4,4' - (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5, 7-ylidene) bis (5, 6-difluoronaphthalene-2-ol)
(1R, 5S) -tert-butyl-3- (5, 7-bis (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg,0.208mmol,1 eq) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.6 mL) was added to react at room temperature for 1 hour. LCMS detected complete reaction. The reaction solution was concentrated, and the residue was purified by HPLC to give 4,4' - (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5, 7-ylidene) bis (5, 6-difluoronaphthalen-2-ol) (31.3 mg, yield: 18.8%) as a white solid.
HPLC separation conditions:
Column Phenomnex C18X 30mm X3 um.
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%:36% -76%; retention time: 9min.
MS m/z:773.2[M+H]+
19F NMR(376MHz,DMSO-d6)δ-143.60(s),-143.96(s),-144.88(s),-144.94(s),-172.01(s),-172.04(s),-172.15(s).
1H NMR(400MHz,DMSO-d6)δ7.79-7.67(m,2H),7.63-7.46(m,2H),7.41-7.30(m,2H),7.28-7.18(m,1H),6.99(br s,1H),5.30(br d,J＝54.4Hz,1H),4.27-4.03(m,2H),3.26-3.18(m,3H),3.17-3.06(m,3H),3.07-2.97(m,3H),2.90-2.80(m,1H),2.21-1.98(m,5H),1.91-1.75(m,3H),1.40(br s,2H).
Example 2: compound 2
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1-methyl-1H-pyrazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1-methyl-1H-pyrazol-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (400 mg,0.428mmol,1 eq) was dissolved in dioxane (4 mL) and water (2 mL), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (177.9 mg,0.855mmol,2 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (62.6 mg,0.08 mmol, 0.08 eq) and cesium carbonate (9 mg, 80.417 mmol) were added and the reaction was performed under nitrogen at 80.417 mmol. LCMS monitored reaction was complete. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, concentration of filtrate, purification of residue by column [ tetrahydrofuran (0.5% ammonia water)/petroleum ether: 0-35% ], to give (1 r,5 s) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1-methyl-1H-pyrazol-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (240 mg, yield: 57.2%) as a yellow solid.
MS m/z:981.4[M+H]+
Step 2: hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1-methyl-1H-pyrazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (1-methyl-1H-pyrazol-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (220 mg,0.224mmol,1 eq) was dissolved in acetonitrile (2 mL), dioxane hydrochloride solution (4M, 2 mL) was added and the reaction was allowed to react at room temperature for 1 hour, and LCMS was monitored to completion. The reaction solution was concentrated to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1-methyl-1H-pyrazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol hydrochloride (195.8 mg, crude product) as a yellow solid, which was used directly in the next step.
MS m/z:837.4[M+H]+
Step 3: compound 2
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1-methyl-1H-pyrazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1-methyl-1H-pyrazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol (195.8 mg,0.224mmol,1 eq) was dissolved in N, N-dimethylformamide (2 mL), and cesium fluoride (1.70 g,11.21mmol,50 eq) was added and reacted at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1-methyl-1H-pyrazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (5 mg, yield: 3.3%) as a yellow solid.
HPLC separation conditions:
column YMC-TRIART PREP C150 x 40mm x 7um
Mobile phase a: water (NH 3H2O+NH4HCO3), mobile phase B: ACN; gradient B%:29% -69%; retention time: 9min.
MS m/z:681.7[M+H]+
19F NMR(377MHz,DMSO-d6)δ-110.33(s),-145.53(s),-171.98(s),-172.21(s).
1H NMR(400MHz,DMSO-d6)δ10.17(br s,1H),8.09-7.70(m,2H),7.63-7.16(m,4H),5.30(br d,J＝53.6Hz,1H),5.01(br d,J＝10.5Hz,1H),4.20-4.10(m,1H),4.07-3.98(m,1H),3.87(s,3H),3.51(br s,1H),3.24-2.92(m,8H),2.88-2.78(m,1H),2.65-2.55(m,1H),2.21-1.96(m,3H),1.93-1.64(m,4H),1.62-1.43(m,2H),0.91(br s,1H).
Example 3: compound 3
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1H-pyrazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (5- (1- (tert-butoxycarbonyl) -1H-pyrazol-4-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (400 mg,0.428mmol,1 eq) was dissolved in dioxane (4 mL) and water (2 mL), tert-butyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate (251.5 mg,0.855mmol,2 eq), 1-bis (diphenylphosphorus) ferrocene chloride (62.6 mg,0.08 mmol, 0.417 mmol) and cesium carbonate (9.417 mmol) were added and the mixture was reacted under nitrogen atmosphere at 80.2880 mmol. LCMS monitored reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column [ tetrahydrofuran (0.5% aqueous ammonia)/petroleum ether: 0-35% ], to give (1 r,5 s) -tert-butyl-3- (5- (1- (tert-butoxycarbonyl) -1H-pyrazol-4-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (130 mg, yield: 28.5%) as a yellow solid.
MS m/z:967.5[M+H-100]+
Step 2: hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1H-pyrazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (5- (1- (tert-butoxycarbonyl) -1H-pyrazol-4-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (110 mg,0.103mmol,1 eq) was dissolved in acetonitrile (1 mL), and dioxane hydrochloride solution (4M, 1 mL) was added and reacted at room temperature for 1 hour. LCMS monitored reaction was complete. The reaction solution was concentrated to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1H-pyrazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol hydrochloride (88.6 mg, crude product) as a yellow solid, the crude product was used directly in the next step.
MS m/z:823.4[M+H]+
Step 3: compound 3
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1H-pyrazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride salt (88.6 mg,0.103mmol,1 eq) of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1H-pyrazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol was dissolved in N, N-dimethylformamide (1 mL), and cesium fluoride (782.1 mg,5.15mmol,50 eq) was added for reaction at room temperature for 3 hours. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1H-pyrazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (5 mg, yield: 7.28%) as a yellow solid.
HPLC separation conditions:
column YMC-TRIART PREP C150 x 40mm x 7um
Mobile phase a: water (NH 3H2O+NH4HCO3), mobile phase B: ACN; gradient B%:25% -65%; retention time: 9min.
MS m/z:667.6[M+H]+
19F NMR(377MHz,DMSO-d6)δ-110.30(s),-145.48(s),-171.98(s),-172.22(s).
1H NMR(400MHz,DMSO-d6)δ13.15(br s,1H),10.14(br s,1H),8.07-7.88(m,2H),7.56-7.11(m,4H),5.30(br d,J＝54.4Hz,1H),5.00(br d,J＝10.8Hz,1H),4.20-4.10(m,1H),4.08-3.98(m,1H),3.51-3.41(m,1H),3.14-2.80(m,9H),2.10-1.99(m,3H),1.93-1.75(m,5H),1.52-1.42(m,2H),0.88(br s,1H).
Example 4: compound 4
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-fluoropyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (5-fluoropyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (400 mg,0.428mmol,1 eq) was dissolved in dioxane (4 mL) and water (2 mL), 3-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (190.72 mg,0.855mmol,2 eq), 1-bis (diphenylphosphorus) ferrocene (62.57 mg,0.08 mmol,0.2 eq) and cesium carbonate (1.417 mmol, 80.284 eq) were added and the mixture was allowed to react under nitrogen at 80.417 mmol. LCMS monitored reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column [ tetrahydrofuran (0.5% aqueous ammonia)/petroleum ether: 0-35% ], to give (1 r,5 s) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-fluoropyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (260 mg, yield: 61.0%) as a yellow solid.
MS m/z:996.4[M+H]+
Step 2: hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-fluoropyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (5-fluoropyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (240 mg,0.241mmol,1 eq) was dissolved in acetonitrile (2 mL) and hydrochloric acid/dioxane (4M, 2 mL) was added and reacted at room temperature for 1 hour, LCMS monitoring reaction was complete. The reaction solution was concentrated to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-fluoropyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol hydrochloride (214 mg, crude) as a yellow solid, the crude was used directly in the next step.
MS m/z:852.4[M+H]+
Step 3: compound 4
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-fluoropyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride salt (214 mg,0.241mmol,1 eq) of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-fluoropyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol was dissolved in N, N-dimethylformamide (2 mL), and cesium fluoride (1.83 g,12.04mmol,50 eq) was added to react at room temperature for 3 hours. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-fluoropyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (5 mg, yield: 2.98%) as a yellow solid.
HPLC separation conditions:
column YMC-TRIART PREP C150 x 40mm x 7um
Mobile phase a: water (NH 3H2O+NH4HCO3), mobile phase B: ACN; gradient B%:35% -75%; retention time: 9min.
MS m/z:696.6[M+H]+
19F NMR(377MHz,DMSO-d6)δ-110.10(s),-110.57(s),-110.76(s),-127.30(s),-140.20(s),-141.27(s),-141.99(s),-172.07(s),-172.15(s).
1H NMR(400MHz,DMSO-d6)δ10.18(br s,1H),8.74-8.38(m,2H),8.06-7.72(m,2H),7.52-7.37(m,2H),7.28(br s,1H),5.31(br d,J＝53.6Hz,1H),4.93(br s,1H),4.22-4.03(m,2H),3.24-2.77(m,11H),2.25-1.95(m,3H),1.94-1.69(m,4H),1.47(br s,2H),0.99-0.81(m,1H).
Example 5: compound 5
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (3-fluorophenyl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (3-fluorophenyl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg,0.214mmol,1 eq) was dissolved in dioxane (2 mL) and water (0.5 mL), 3-fluoro-phenylboronic acid (59.8 mg,0.428mmol,2 eq), cesium carbonate (209.0 mg,0.641mmol,3 eq) and methanesulfonyloxy (di-adamantyl-n-butylphosphino) -2-amino-1, 1-biphenyl-2-yl) palladium (II) (31.04 g, 0.284 mmol,0.2 eq) were added. The reaction was carried out at 80℃for 2 hours under nitrogen protection. LCMS monitored reaction was complete. The reaction solution was concentrated, and the residue was extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to give the product (0.13 g, yield: 61.1%).
MS m/z:995.5[M+H]+
Step 2: hydrochloride of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (3-fluorophenyl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (3-fluorophenyl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (100 mg,0.100mmol,1 eq) was dissolved in acetonitrile (1 mL), and dioxane hydrochloride solution (4M, 1.67 mL) was added and reacted at room temperature for 2 hours. LCMS detected complete reaction. The reaction solution was concentrated to give the product (86 mg, crude) which was used directly in the next step.
MS m/z:851.5[M+H]+
Step 3: compound 5
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (3-fluorophenyl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride salt (85 mg,0.099mmol,1 eq) of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (3-fluorophenyl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol was dissolved in N, N-dimethylformamide (0.5 mL), and cesium fluoride (758.56 mg,4.99mmol,50 eq) was added and reacted at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (3-fluorophenyl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (20 mg, yield: 28.8%) as a white solid.
HPLC separation conditions:
Column: phenomnex C18 80 x 30mm x 5um;
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%:50% -70%; retention time: and 10min.
MS m/z:695.2[M+H]+
19F NMR(377MHz,DMSO-d6)δ-110.22(s),-110.72(s),-142.22(s),-143.21(s),-172.21(s).
1H NMR(400MHz,DMSO-d6)δ10.22(br s,1H),7.99(br s,1H),7.59-7.00(m,7H),5.31(br d,J＝54Hz,1H),4.96(br s,1H),4.26-4.01(m,2H),3.95-3.58(m,2H),3.19-2.72(m,8H),2.23-1.98(m,4H),1.94-1.65(m,4H),1.49(br s,2H),0.96(br s,1H).
Example 6: compound 6
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (naphthalen-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (naphthalen-1-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg,0.214mmol,1 eq) was dissolved in dioxane (1 mL) and water (1 mL), and pinacol 1-naphthalene borate (108.7 mg,0.428mmol,2 eq), cesium carbonate (209.0 mg,0.641mmol,3 eq) and 1,1' -di-tert-butylphosphino ferrocene palladium dichloride (27.86 mg,0.043mmol,0.2 eq) were added. The reaction was carried out at 80℃for 2 hours under nitrogen protection. LCMS monitored reaction was complete. The reaction solution was concentrated, and the residue was extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to give the product (90 mg, yield: 41.0%).
MS m/z:1027.5[M+H]+
Step 2: hydrochloride of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (naphthalen-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (naphthalen-1-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (90 mg,0.088mmol,1 eq) was dissolved in acetonitrile (1 mL), and dioxane hydrochloride solution (4M, 1 mL) was added and reacted at room temperature for 2 hours. LCMS detected complete reaction. The reaction solution was concentrated to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (naphthalen-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol hydrochloride (70 mg, crude).
MS m/z:883.1[M+H]+
Step 3: compound 6
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (naphthalen-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methoxy) -5- (naphthalen-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol (70 mg,0.079mmol,1 eq) was dissolved in N, N-dimethylformamide (1 mL), and cesium fluoride (760 mg,5.00mmol,63.12 eq) was added and reacted at room temperature for 3 hours. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (naphthalen-1-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (15 mg, yield: 26.0%) as a white solid.
MS m/z:727.0[M+H]+
HPLC separation conditions:
Column: YMC-TRIART PREP C18.150.40.7.um;
Mobile phase a: water (NH 3H2O+NH4HCO3), mobile phase B: ACN; gradient B%:43% -83%, retention time: 9min.
19F NMR(376MHz,DMSO-d6)δ-110.65(s),-144.13(s),-172.00(s),-172.16(s).
1H NMR(400MHz,DMSO-d6)δ8.07-7.90(m,3H),7.64-7.00(m,8H),5.31(br d,J＝54.4Hz,1H),4.27-4.01(m,2H),3.95-3.80(m,1H),3.24-2.91(m,7H),2.90-2.71(m,3H),2.24-2.01(m,4H),1.93-1.73(m,4H),1.44-1.19(m,3H).
Example 7: compound 7
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1-methyl-1H-indol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1-methyl-1H-indol-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (400 mg,0.428mmol,1 eq) was dissolved in dioxane (4 mL) and water (4 mL), and 1-methyl-1H-indole-4-boronic acid pinacol ester (164.9 mg,0.641mmol,1.5 eq), cesium carbonate (278.6 mg,0.855mmol,2 eq) and methanesulfonyloxy (di-adamantyl-n-butylphosphino) -2-amino-1, 1-biphenyl-2-II palladium (62.0.08 mg,0.2 eq) were added. The reaction was carried out at 80℃for 2 hours under nitrogen protection. LCMS monitored reaction was complete. The reaction solution was concentrated, and the residue was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (tetrahydrofuran/petroleum ether: 0-30%) to give (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1-methyl-1H-indol-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (330 mg, yield: 74.9%).
MS m/z:1030.5[M+H]+
Step 2: hydrochloride of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1-methyl-1H-indol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1-methyl-1H-indol-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (100 mg,0.097mmol,1 eq) was dissolved in acetonitrile (0.5 mL) and dioxane hydrochloride solution (4M, 0.5 mL) was added for reaction at room temperature for 1 hour. LCMS detected complete reaction. The reaction solution was concentrated to give a crude product (86 mg, crude) which was used directly in the next step.
MS m/z:886.5[M+H]+
Step 3: compound 7
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1-methyl-1H-indol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol
Hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1-methyl-1H-indol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol (85 mg,0.096mmol,1 eq) was dissolved in N, N-dimethylformamide (1.5 mL), and cesium fluoride (728.6 mg,4.80mmol,50 eq) was added and reacted at room temperature for 1 hour. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1-methyl-1H-indol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (20 mg, yield: 28.6%) as a white solid.
HPLC separation conditions:
Column: phenomnex C18 75 x 30mm x 3um;
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B percent 37-77 percent, retention time: 9min.
MS m/z:730.3[M+H]+
19F NMR(377MHz,DMSO-d6)δ-110.53(s),-145.10(s),-172.04(s).
1H NMR(400MHz,DMSO-d6)δ10.15(br s,1H),8.00(br s,1H),7.69-7.09(m,7H),6.71(br s,1H),5.32(d,J＝55.2Hz,1H),4.96(br s,1H),4.30-4.01(m,2H),3.82(br s,3H),3.75-3.50(m,3H),3.19-2.80(m,8H),2.25-1.99(m,3H),1.96-1.75(m,4H),1.63-1.37(m,2H),1.07-0.84(m,1H).
Example 8: compound 8
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1H-indazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300.0 mg,0.321mmol,1 eq) was dissolved in a mixed solvent of dioxane (3.0 mL) and water (1.0 mL), and 1- (tetrahydro-2H-pyran-2-yl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole (157.9 mg,0.481, 1.5 eq), cesium carbonate (313.4 mg,0.321mmol, 1.2 eq), and bis (2 mg, 0.064.41 mmol) of bis (tert-butyl) phosphine was added. Nitrogen substitution, reaction at 100 ℃ for 2 hours. LCMS monitored completion of the reaction, the reaction was filtered, the filtrate was concentrated and the residue was purified by column [ tetrahydrofuran/petroleum ether: 0-35% ], to give (1 r,5 s) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (150 mg, yield: 32.4%) as a yellow solid.
MS m/z:1101.7[M+H]+
Step 2: hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1H-indazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg,0.182mmol,1 eq) was dissolved in acetonitrile (2.0 mL) and dioxane hydrochloride solution (4M, 2 mL) was added. After 2 hours at room temperature, LCMS monitored complete reaction, the reaction was concentrated to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1H-indazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-phenolate hydrochloride (180 mg, crude), yellow solid, crude product was used directly in the next step.
MS m/z:873.6[M+H]+
Step 3: compound 8
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1H-indazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1H-indazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol (200 mg, 0.67 mmol,1 eq) was dissolved in N, N-dimethylformamide (3.0 mL), and cesium fluoride (1.27 g,8.37mmol,50 eq) was added. The reaction was allowed to react at room temperature for 2 hours, and LCMS monitored the reaction was complete and the reaction was filtered. Purification of the filtrate by HPLC gave 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (1H-indazol-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (2.0 mg, yield: 1.7%) as a yellow solid.
HPLC separation conditions:
Column Boston Prime C18 150 x 30mm x 5um
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B% 40% -60%, retention time: 11min.
MS m/z:717.3[M+H]+
19F NMR(377MHz,DMSO-d6)δ-110.39(s),-144.44(s),-171.88(s),-172.00(s),-172.18(s),
1H NMR(400MHz,DMSO-d6)δ13.20(br s,1H),10.18(br s 1H),8.24-7.91(m,2H),7.73-7.28(m,6H),5.32(br d,J＝54.4Hz,1H),4.95(br s,1H),4.20-4.03(m,2H),4.00-3.50(m,6H),3.18-2.75(m,5H),2.21-1.96(m,3H),1.92-1.78(m,4H),1.39(br s,2H),0.94(br s,1H).
Example 9: compound 9
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (pyrazolo [1,5-a ] pyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300 mg,0.321mmol,1 eq) was dissolved in a mixed solvent of dioxane (5.0 mL), water (1.0 mL) and ethanol (2.0 mL). 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazolo [1,5-a ] pyridine (117.4 mg,0.481mmol,1.5 eq) and cesium carbonate (313.4 mg,0.962mmol,3 eq) were added. The reaction was carried out at 80℃for 2 hours with nitrogen substitution. LCMS monitored completion of the reaction, quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate, the residue was purified by column chromatography (tetrahydrofuran/petroleum ether: 0-35%) to give (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyrazolo [1,5-a ] pyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (150 mg, yield: 46.0%) as a yellow solid.
MS m/z:1017.6[M+H]+
Step 2: hydrochloride of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyrazolo [1,5-a ] pyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (pyrazolo [1,5-a ] pyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (150 mg,0.147mmol,1 eq) was dissolved in acetonitrile (2.0 mL) and dioxane hydrochloride solution (4M, 2 mL) was added. The reaction was carried out at room temperature for 1 hour. LCMS monitored completion of the reaction and concentrated the reaction solution to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyrazolo [1,5-a ] pyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol hydrochloride (150 mg, crude), yellow solid, crude product was used directly in the next step.
MS m/z:873.6[M+H]+
Step 3: compound 9
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride salt (150 mg,0.172mmol,1 eq) of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyrazolo [1,5-a ] pyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol was dissolved in N, N-dimethylformamide (2 mL), and cesium fluoride (2.61 g,17.2mmol,100 eq) was added thereto for reaction at room temperature under nitrogen atmosphere for 2 hours. LCMS monitored reaction was complete, the reaction was filtered and the filtrate was separated by HPLC to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (20 mg, yield: 16.2%) as a yellow solid.
HPLC separation conditions:
Column Boston Prime C18 150 x 30mm x 5um
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B percent is 31 to 51 percent, retention time: 13min
MS m/z:717.2[M+H]+
19F NMR(376MHz,DMSO-d6)δ110.28(s),-145.79(s),-171.98(s),-172.21(s).
1H NMR(400MHz,DMSO-d6)δ10.17(br s,1H),8.79(d,J＝7.0Hz,1H),8.10(br s,1H),8.06-7.92(m,1H),7.75(br s,1H),7.58-7.38(m,2H),7.38-7.23(m,2H),7.01(t,J＝7.4Hz,1H),5.31(br d,J＝53.2Hz 1H),5.08-4.84(m,1H),4.29-4.01(m,2H),3.50-3.36(m,2H),3.19-2.75(m,8H),2.54-2.52(m,1H),2.25-2.00(m,3H),1.92-1.63(m,4H),1.56-1.40(m,2H),0.94-0.81(m,1H).
Example 10: compound 10
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (pyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (400 mg,0.428mmol,1 eq) was dissolved in a mixed solution of dioxane (4 mL) and water (2 mL), and pyridine-3-ylboronic acid (105.12 mg,0.855mmol,2 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (62.6 mg,0.086mmol,0.2 eq) and cesium carbonate (417.9 mg,1.28mmol,3 eq) were added and reacted at 80℃for 2 hours under nitrogen. LCMS monitored reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column [ tetrahydrofuran (0.5% aqueous ammonia)/petroleum ether: 0-35% ], to give (1 r,5 s) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (210 mg, yield: 50.2%) as a yellow solid.
MS m/z:978.5[M+H]+
Step 2: hydrochloride of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (pyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (210 mg,0.215mmol,1 eq) was dissolved in acetonitrile (4 mL) and dioxane hydrochloride solution (4M, 4 mL) was added and reacted at room temperature for 1 hour, and S was monitored to be complete. The reaction solution was concentrated to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol hydrochloride (186.9 mg, crude product) as a yellow solid, which was used directly in the next step.
MS m/z:834.6[M+H]+
Step 3: compound 10
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol (186.9 mg,0.215mmol,1 eq) was dissolved in N, N-dimethylformamide (2 mL), cesium fluoride (4.89 g,32.20mmol,150 eq) was added and reacted at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (25 mg, yield: 19.0%) as a white solid
HPLC separation conditions:
Column Phenomnex C18X 30mm X3 um
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B percent 28% -68%, retention time: 9min
MS m/z:678.3[M+H]+
19F NMR(377MHz,DMSO-d6)δ-110.18(s),-110.44(s),-110.64(s),-142.30(s),-143.13(s),-143.40(s),-172.27(s).
1H NMR(400MHz,DMSO-d6)δ10.18(br s,1H),8.66(br d,J＝3.7Hz,2H),8.11-7.69(m,2H),7.59-7.16(m,4H),5.30(br d,J＝53.6Hz,1H),4.92(br s,1H),4.24-4.01(m,2H),3.96-3.56(m,1H),3.49-3.34(m,2H),3.18-2.93(m,5H),2.92-2.70(m,2H),2.24-1.97(m,3H),1.96-1.58(m,5H),1.44(br s,2H),0.90(br s,1H).
Example 11: compound 11
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyrimidin-5-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyrimidin-5-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300 mg,0.321mmol,1 eq) was dissolved in dioxane (3 mL) and water (1.5 mL), and pyrimidine-5-ylboronic acid (79.4 mg,0.641mmol,2 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (46.9 mg,0.641mmol,0.2 eq) and cesium carbonate (313.4 mg,0.962mmol,3 eq) were added and reacted under nitrogen protection for 2 hours at 80 ℃. LCMS monitored reaction was complete. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, concentration of filtrate, purification of residue by column [ tetrahydrofuran (0.5% ammonia water)/petroleum ether: 0-35% ], to give (1 r,5 s) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyrimidin-5-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (180 mg, yield: 57.3%) as a yellow solid.
MS m/z:979.5[M+H]+
Step 2: hydrochloride of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyrimidin-5-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (pyrimidin-5-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg,0.204mmol,1 eq) was dissolved in acetonitrile (2 mL) and dioxane hydrochloride solution (4M, 2 mL) was added and the reaction was allowed to react at room temperature for 1 hour and S was monitored to completion. The reaction solution was concentrated to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyrimidin-5-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol hydrochloride (178.0 mg, crude product) as a yellow solid, which was used directly in the next step.
MS m/z:835.6[M+H]+
Step 3: compound 11
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyrimidin-5-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyrimidin-5-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol (178.0 mg,0.204mmol,1 eq) was dissolved in N, N-dimethylformamide (2 mL), cesium fluoride (4.65 g,30.64mmol,150 eq) was added and reacted at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyrimidin-5-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (25 mg, yield: 18.0%) as a yellow solid.
HPLC separation conditions:
column YMC-TRIART PREP C150 x 40mm x 7um
Mobile phase a: water (NH 3H2O+NH4HCO3), mobile phase B: ACN; gradient B%:29% -69% and retention time of 9min
MS m/z:679.3[M+H]+
19F NMR(376MHz,DMSO-d6)δ-110.08(s),-110.58(s),-141.13(s),-141.68(s),-172.09(s),-172.15(s).
1H NMR(400MHz,DMSO-d6)δ10.26(br s,1H),9.30(br s,1H),8.93(br s,2H),8.00(br s,1H),7.63-7.36(m,2H),7.29(br s,1H),5.31(br d,J＝54.0Hz,1H),4.92(br s,1H),4.30-4.01(m,2H),3.96-3.57(m,1H),3.45-3.34(m,3H),3.25-2.95(m,5H),2.90-2.70(m,2H),2.24-2.00(m,3H),1.95-1.74(m,4H),1.46(br s,2H),1.02-0.73(m,1H)
Example 12: compound 12
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-methoxypyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (5-methoxypyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (400 mg,0.428mmol,1 eq) was dissolved in a mixed solution of dioxane (4 mL) and water (2 mL), 3-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (201.0 mg,0.856mmol,2 eq), 1-bis (di-tert-butylphosphine) ferrocene palladium chloride (55.7 mg,0.08 mmol, 0.08 eq) and cesium carbonate (9 mg, 417 mmol) were added, and the mixture was allowed to react under nitrogen at a temperature of 3.417 mmol and a small mol. LCMS monitored reaction was complete. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, concentration of filtrate, purification of residue by column [ tetrahydrofuran (0.5% ammonia water)/petroleum ether: 0-35% ], to give (1 r,5 s) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-methoxypyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (340 mg, yield: 78.9%) as a yellow solid.
MS m/z:1008.5[M+H]+
Step 2: hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-methoxypyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (5-methoxypyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (320 mg,0.317mmol,1 eq) was dissolved in acetonitrile (2 mL), dioxane hydrochloride solution (4M, 2 mL) was added and the reaction was allowed to react at room temperature for 1 hour, and LCMS was monitored to be complete. The reaction solution was concentrated to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-methoxypyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol hydrochloride (274.0 mg, crude product) as a yellow solid, the crude product was used directly in the next step.
MS m/z:864.3[M+H]+
Step 3: compound 12
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-methoxypyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride salt (274.0 mg,0.317mmol,1 eq) of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-methoxypyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol was dissolved in N, N-dimethylformamide (3 mL), and cesium fluoride (7.23 g,47.56mmol,150 eq) was added and reacted at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-methoxypyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (35.0 mg, yield: 15.6%) as a white solid.
HPLC separation conditions:
Column Boston Prime C18 150 x 30mm x 5um
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B% 40% -60%, retention time: 13min
MS m/z:708.3[M+H]+
19F NMR(377MHz,DMSO-d6)δ-110.18(s),-141.97(s),-142.64(s),-172.22(s).
1H NMR(400MHz,DMSO-d6)δ10.13(br s,1H),8.46-8.08(m,2H),8.04-7.93(m,1H),7.63-7.11(m,4H),5.30(br d,J＝54.0Hz,1H),5.15-4.75(br s,1H),4.23-4.04(m,2H),3.85(s,3H),3.54-3.31(m,4H),3.24-2.97(m,5H),2.96-2.73(m,2H),2.27-1.99(m,3H),1.97-1.62(m,4H),1.48(br s,2H),0.87(br s,1H).
Example 13: compound 13
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300 mg,0.321mmol,1 eq) was dissolved in dioxane (3 mL) and water (1.5 mL), 3-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (140.5 mg,0.641mmol,2 eq), cesium carbonate (209.0.64mmol, 3 eq) and [1, 1-bis (di-tert-butylphosphine) ferrocene (0.41 mmol) were added and nitrogen was allowed to react (0.064 mmol, 41.06 mmol). LCMS monitored reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the crude residue was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to give (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (240 mg, yield: 75.4%) as a yellow oil.
MS m/z:992.5[M+H]+
Step 2: hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (120 mg,0.121mmol,1 eq) was dissolved in acetonitrile (1 mL), and dioxane hydrochloride solution (4M, 0.5 mL) was added and reacted at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction solution was concentrated to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol hydrochloride (102.5 mg, crude product) as a tan oil, which was used directly in the next step.
MS m/z:848.6[M+H]+
Step 3: compound 13
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride salt (100 mg,0.101mmol,1 eq) of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol was dissolved in N, N-dimethylformamide (1 mL), and cesium fluoride (1.53 g,10.08mmol,100 eq) was added for reaction at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (10 mg, yield: 14.3%) as a white solid.
HPLC separation conditions:
Column: phenomnex C18 75 x 30mm x 3um;
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN, gradient B% 39% -79%, retention time: 9min
MS m/z:692.5[M+H]+
19F NMR(376MHz,DMSO-d6)δ-110.18(s),-110.67(s),-142.31(s),-143.12(s),-172.00(s),-172.24(s).
1H NMR(400MHz,DMSO-d6)δ10.20(br s,1H),8.66-8.10(m,2H),8.00(br s,1H),7.76(br s,1H),7.56-7.37(m,2H),7.29(br s,1H),5.31(br d,J＝53.2Hz,1H),4.94(br s,1H),4.25-4.00(m,2H),3.97-3.43(m,2H),3.21-2.97(m,5H),2.96-2.55(m,3H),2.36(s,3H),2.20-1.98(m,3H),1.98-1.62(m,5H),1.57-1.33(m,2H),1.03-0.83(m,1H).
Example 14: compound 14
5- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) nicotine nitrile formate salt
Step 1: (1R, 5S) -tert-butyl-3- (5- (5-cyanopyridin-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300 mg,0.321mmol,1 eq) was dissolved in dioxane (3 mL), 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) nicotinonitrile (147.6 mg,0.641mmol,2 eq), cesium carbonate (313.4 mg,0.962mmol,3 eq) and methanesulfonyloxy (diamantane-n-butylphosphino) -2-amino-1, 1-biphenyl-2-palladium (0.06 eq) were added and the reaction was carried out at 0.80 mmol, 2.062℃under nitrogen atmosphere. LCMS monitored reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (tetrahydrofuran/petroleum ether: 0-30%) to give (1R, 5S) -tert-butyl-3- (5- (5-cyanopyridin-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (240 mg, yield: 74.6%) as a pale yellow solid.
MS m/z:1003.5[M+H]+
Step 2: hydrochloride of 5- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) nicotine nitrile
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (5- (5-cyanopyridin-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg,0.199mmol,1 eq) was dissolved in acetonitrile (2 mL) and dioxane hydrochloride solution (4M, 2.00 mL) was added and reacted at room temperature for 1 hour. LCMS monitored reaction was complete. The reaction solution was concentrated to give 5- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) nicotine nitrile hydrochloride (200 mg, crude product) as a yellow solid, the crude product was used directly in the next step.
MS m/z:859.3[M+H]+
Step 3: compound 14
5- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) nicotine nitrile formate salt
5- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) nicotine nitrile hydrochloride (200 mg,0.233mmol,1 eq) was dissolved in N, N-dimethylformamide (2 mL), cesium fluoride (3.54 g,23.28mmol,100 eq) was added and reacted at room temperature for 12 hours. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give 5- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) nicotine carbonitrile formate (30 mg, yield: 18.3%) as a pale yellow solid.
HPLC separation conditions:
Column: phenomnex C18 75 x 30mm x 3um;
Mobile phase a: water (FA), mobile phase B: ACN; gradient B%:1% -41%, retention time: 9min
MS m/z:702.9[M+H]+
19F NMR(376MHz,DMSO-d6)δ-109.95(s),-110.11(s),-110.32(s),-110.53(s),-140.72(s),-141.50(s),-172.88(s),-172.15(s).
1H NMR(400MHz,DMSO-d6)δ9.24-8.79(m,2H),8.58-8.31(m,1H),8.23(s,1H),7.99(br s,1H),7.55-7.35(m,2H),7.28(br s,1H),5.31(br d,J＝54.0Hz,1H),4.95(br s,1H),4.28-4.00(m,2H),3.81-3.44(m,4H),3.22-2.97(m,5H),2.91-2.76(m,2H),2.22-1.97(m,3H),1.95-1.64(m,4H),1.50(br s,2H),0.95(br s,1H).
Example 15: compound 15
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5- (5- (dimethylamino) pyridin-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (5- (5- (dimethylamino) pyridin-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.3 g,0.321mmol,1 eq) was dissolved in dioxane (5 mL) and water (1 mL), and N, N-dimethyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-amine (159.1 mg,0.641mmol,2 eq), cesium carbonate (313.4 mg,0.962mmol,3 eq) and [1, 1-bis (tert-butylphosphine ] dichloride (0.41 mg, 4 eq) were added. The reaction was carried out at 80℃for 2 hours under nitrogen protection. LCMS monitored reaction was complete. The reaction solution was concentrated, and the residue was extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to give the product (0.23 g, yield: 70.2%).
MS m/z:1021.6[M+H]+
Step 2: hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5- (5- (dimethylamino) pyridin-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (5- (5- (dimethylamino) pyridin-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.2 g,0.196mmol,1 eq) was dissolved in acetonitrile (2 mL) and a dioxane solution (4M, 1 mL) of hydrochloric acid was added and reacted at room temperature for 1 hour. LCMS detected complete reaction. The reaction solution was concentrated to give the product (171.8 mg, crude) which was used directly in the next step.
MS m/z:877.6[M+H]+
Step 3:4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5- (5- (dimethylamino) pyridin-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5- (5- (dimethylamino) pyridin-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol (0.2 g,0.228mmol,1 eq) was dissolved in N, N-dimethylformamide (3 mL), and cesium fluoride (3.46 g,22.80mmol,100 eq) was added to the solution overnight at room temperature. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5- (5- (dimethylamino) pyridin-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (20 mg, yield: 12.2%) as a white solid.
MS m/z:721.5[M+H]+
HPLC separation conditions:
Column: phenomnex C18 80 x 30mm x 5um flow rate: 35mL/min
Mobile phase a: [ Water (0.1% ammonia v/v) -ACN ] mobile phase B: ACN; gradient: 40% -60% (v/v), 10min
19F NMR(377MHz,DMSO-d6)δ-110.23,-110.74,-142.49,-172.03,-172.24.
1H NMR(400MHz,DMSO-d6)δ10.18(br s,1H),8.42-7.70(m,3H),7.64-6.72(m,4H),5.40-5.21(m,1H),4.95(br s,1H),4.23-4.01(m,2H),3.99-3.55(m,1H),3.51-3.36(m,2H),3.26-3.00(m,5H),2.95(s,6H),2.89-2.71(m,2H),2.60-2.50(m,1H),2.28-1.95(m,4H),1.94-1.63(m,3H),1.46(br s,2H),0.91(br s,1H).
Example 16: compound 16
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5- (5-chloropyridin-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (5- (5-chloropyridin-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (400 mg,0.428mmol,1 eq) was dissolved in a mixed solution of dioxane (4 mL) and water (2 mL), and (5-chloropyridin-3-yl) boronic acid (134.56 mg,0.855mmol,2 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (62.57 mg,0.086mmol,0.2 eq) and cesium carbonate (417.90 mg,1.28mmol,3 eq) were added and reacted at 80℃under nitrogen protection for 2 hours. LCMS monitored reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column [ tetrahydrofuran (0.5% aqueous ammonia)/petroleum ether: 0-35% ], to give (1 r,5 s) -tert-butyl-3- (5- (5-chloropyridin-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (300 mg, yield: 69.3%) as a yellow solid.
MS m/z:1012.4[M+H]+
Step 2: hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5- (5-chloropyridin-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (5- (5-chloropyridin-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300 mg,0.296mmol,1 eq) was dissolved in acetonitrile (6 mL) and dioxane hydrochloride solution (4M, 6 mL) was added and reacted at room temperature for 1 hour, LCMS monitoring the reaction was complete. The reaction solution was concentrated to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5- (5-chloropyridin-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol hydrochloride (268.1 mg, crude product) as a yellow solid, the crude product was used directly in the next step.
MS m/z:868.6[M+H]+
Step 3: compound 16
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5- (5-chloropyridin-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5- (5-chloropyridin-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol hydrochloride (268.1 mg,0.296mmol,1eq, hydrochloride) was dissolved in N, N-dimethylformamide (3 mL), and cesium fluoride (6.75 g,44.44mmol,150 eq) was added and reacted at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5- (5-chloropyridin-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (30 mg, yield: 15.1%) as a white solid.
HPLC separation conditions:
Column Phenomnex C18X 30mm X3 um
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%:38% -78%, retention time: 9min
MS m/z:712.3[M+H]+
19F NMR(376MHz,DMSO-d6)δ-110.12(s),-110.36(s),-110.62(s),-141.09(s),-172.26(s).
1H NMR(400MHz,DMSO-d6)δ10.23(br s,1H),8.75(br s,2H),8.00(br s,2H),7.60-7.15(m,3H),5.31(br d,J＝54.0Hz,1H),4.94(br s,1H),4.25-4.02(m,2H),4.00-3.63(m,1H),3.57-3.37(m,2H),3.20-2.98(m,5H),2.92-2.69(m,3H),2.25-1.97(m,3H),1.91-1.73(m,4H),1.47(br s,2H),0.91(br s,1H).
Example 17: compound 17
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-morpholinopyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2S, 7 aR) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (5-morpholinopyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (500 mg, 0.284 mmol,1 eq) was dissolved in dioxane (3 mL) and water (3 mL), 4- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-3-yl) morpholine (310.1 mg,1.07mmol,2 eq), cesium carbonate (522.4 mg,1.60mmol,3 eq) and 1,1' -di-tert-butylphosphino ferrocene (69.7 mmol, 0.107 eq) were added and nitrogen was allowed to react under the conditions of protection of nitrogen gas at 0.107 ℃. LCMS monitored reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (tetrahydrofuran/petroleum ether: 0-38%) to give (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2S, 7 aR) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-morpholinopyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (360 mg, yield: 63.4%).
MS m/z:1063.5[M+H]+
Step 2: hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 s,7 ar) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-morpholinopyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2S, 7 aR) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (5-morpholinopyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg,0.188mmol,1 eq) was dissolved in acetonitrile (2 mL), and dioxane hydrochloride solution (4M, 2.00 mL) was added and reacted at room temperature for half an hour. LCMS detected complete reaction. The reaction solution was concentrated to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 s,7 ar) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-morpholinopyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol hydrochloride (200 mg, crude product) as a yellow oil, the crude product was used directly in the next step.
MS m/z:919.7[M+H]+
Step 3: compound 17
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-morpholinopyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride salt (200 mg,0.218mmol,1 eq) of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 s,7 ar) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-morpholinopyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol was dissolved in N, N-dimethylformamide (2 mL), and cesium fluoride (4.96 g,32.64mmol,150 eq) was added and reacted at room temperature for 1 hour. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5-morpholinopyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (30 mg, yield: 18.1%) as a white solid.
HPLC separation conditions:
Column: phenomnex C18 75 x 30mm x 3um
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%:34% -74%, retention time: 9min
MS m/z:763.2[M+H]+
19F NMR(377MHz,DMSO-d6)δ-110.23(s),-110.70(s),-142.19(s),-172.08(s),-172.25(s).
1H NMR(400MHz,DMSO-d6)δ10.18(br s,1H),8.56-8.13(m,2H),7.99(br s,1H),7.57-6.91(m,4H),5.31(br d,J＝53.6Hz,1H),4.94(br s,1H),4.24-3.98(m,2H),3.98-3.54(m,6H),3.42(br s,1H),3.23-3.02(m,9H),2.89-2.73(m,2H),2.21-2.00(m,3H),1.93-1.62(m,5H),1.46(br s,2H),0.91(br s,1H).
Example 18: compound 18
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5- (trifluoromethyl) pyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5- (trifluoromethyl) pyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (400 mg,0.428mmol,1 eq) was dissolved in dioxane (2.5 mL), water (0.5 mL) and ethanol (1 mL), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5- (trifluoromethyl) pyridine (350.2 mg,1.28mmol,3 eq), tetrakis triphenylphosphine palladium (98.8 mg,0.08 mmol, 0.08 eq), and 3.417 mmol were added to the mixture under nitrogen at 3.417 mmol and 3.417 mmol. LCMS monitored completion of the reaction, the reaction was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate and purification of the residue by column chromatography (tetrahydrofuran/petroleum ether: 0-20%) afforded (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5- (trifluoromethyl) pyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (340 mg, crude product) as a yellow solid.
MS m/z:1046.5[M+H]+
Step 2: hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5- (trifluoromethyl) pyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5- (trifluoromethyl) pyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (330 mg,0.315mmol,1 eq) was dissolved in acetonitrile (3 mL) and dioxane hydrochloride solution (4M, 3 mL) was added and reacted at room temperature for 1 hour. LCMS monitored completion of the reaction and concentrated the reaction solution to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5- (trifluoromethyl) pyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol hydrochloride (280 mg, crude product) as a yellow solid, the crude product was directly fed to the next reaction.
MS m/z:902.3[M+H]+
Step 3: compound 18
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5- (trifluoromethyl) pyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5- (trifluoromethyl) pyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol (280 mg,0.310mmol,1 eq) was dissolved in N, N-dimethylformamide (5 mL), and cesium fluoride (7.07 g,46.56mmol,150 eq) was added and reacted at room temperature for 2 hours. LCMS monitored reaction was complete, the reaction was filtered and the filtrate was purified by HPLC to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (5- (trifluoromethyl) pyridin-3-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (45.07 mg, yield: 19.3%) as a white solid.
HPLC separation conditions:
column: phenomenex C18 x 30mm x 3um;
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B% 40% -80%, retention time: 9min
MS m/z:746.3[M+H]+
19F NMR(376MHz,DMSO-d6)δ-60.59(s),-110.63(s),-140.83(s),-172.11(s).
1H NMR(400MHz,DMSO-d6)δ10.24(br s,1H),9.10(s,2H),8.28(s,1H),8.00(s,1H),7.60-7.40(m,2H),7.29(s,1H),5.31(br d,J＝54.4Hz,1H),4.91(s,1H),4.29-4.04(m,2H),4.00-3.63(m,1H),3.30-2.60(m,9H),2.23-2.00(m,3H),1.94-1.68(m,5H),1.46(s,2H),1.16-0.81(m,1H).
Example 19: compound 19
Trifluoroacetate salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (isoquinolin-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol
Is (are) trifluoroacetate
Step 1: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (isoquinolin-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (600 mg,0.641mmol,1 eq), 4-isoquinolineboronic acid pinacol ester (490.8 mg,1.92mmol,3 eq), 1-bis (tert-butylphosphorus) ferrocene palladium chloride (83.6 mg,0.128mmol,0.2 eq), cesium carbonate (626.9 mg,1.92mmol,3 eq) were dissolved in dioxane (5 mL) and water (2.5 mL) and reacted overnight at 80℃under nitrogen. LCMS monitored completion of the reaction, the reaction was diluted with water, extracted with ethyl acetate and the organic phase was dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate and purification of the residue by column chromatography (tetrahydrofuran/petroleum ether: 0-20%) afforded (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (isoquinolin-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (400 mg, crude product) as a yellow solid.
MS m/z:1028.5[M+H]+
Step 2: (1R, 5S) -tert-butyl-3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (isoquinolin-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (isoquinolin-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg,0.195mmol,1 eq) was dissolved in N, N-dimethylformamide (2 mL), and cesium fluoride (147.7 mg,0.973mmol,5 eq) was added and reacted at room temperature for 1 hour. LCMS monitored completion of the reaction, the reaction was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave (1 r,5 s) -tert-butyl-3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (isoquinolin-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (160 mg, crude product) as a brown oil. The crude product was directly taken to the next step.
MS m/z:872.3[M+H]+
Step 3: trifluoroacetate salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (isoquinolin-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol
Is (are) trifluoroacetate
(1R, 5S) -tert-butyl-3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (isoquinolin-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (160 mg,0.184mmol,1 eq) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2.5 mL) was added and reacted at room temperature for 1 hour. LCMS monitored reaction was complete, the reaction was concentrated and the residue was purified by HPLC to give trifluoroacetate salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (isoquinolin-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (50 mg, yield: 31.4%) as a red solid.
MS m/z:728.4[M+H]+
HPLC separation conditions:
Column: YMC-Actus Triart C.times.150.30 mm.times.5 um; flow rate: 30mL/min
Mobile phase a: water (0.1% trifluoroacetic acid, v/v) mobile phase B: ACN gradient B%:0% -38% (v/v), retention time: 9min
19F NMR(376MHz,DMSO-d6)δ-74.00(s),-119.52(s),-134.08(s),-172.83(s),-173.00(s).
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.71(br s,1H),8.52(br s,1H),8.42(d,J＝32Hz,1H),8.09(br s,1H),8.00(br s,1H),7.93-7.86(m,1H),7.78-7.65(m,2H),7.59-7.46(m,1H),5.66(br d,J＝52.4Hz,1H),5.39-5.22(m,1H),5.05(br s,2H),4.85(br s,2H),4.10-3.76(m,5H),3.49-3.26(m,3H),2.81-2.56(m,3H),2.47-2.39(m,1H),2.37-2.09(m,3H),1.88-1.57(m,4H).
Example 20: compound 20
5- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) nicotinamide
Step 1: (1R, 5S) -tert-butyl-3- (5- (5-aminocarbonylpyridin-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5- (5-cyanopyridin-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg,0.199mmol,1 eq) was dissolved in dimethyl maple (2 mL) and potassium carbonate (165.3 mg,1.20mmol,6 eq) and aqueous hydrogen peroxide (470 mg,4.15mmol,20.8eq,30% content) were added. The reaction was carried out at room temperature for 3 hours. LCMS monitored reaction was complete. The reaction solution was quenched with saturated aqueous sodium sulfite solution and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product (200 mg, crude) was obtained and used directly in the next step.
MS m/z:1021.5[M+H]+
Step 2: hydrochloride salt of 5- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) nicotinamide
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (5- (5-aminocarbonylpyridin-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg,0.196mmol,1 eq) was dissolved in acetonitrile (2 mL) and dioxane hydrochloride solution (4M, 2 mL) was added and reacted at room temperature for 2 hours. LCMS detected complete reaction. The reaction solution was concentrated to give the product (150 mg, crude) which was used directly in the next step.
MS m/z:877.1[M+H]+
Step 3:5- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) nicotinamide
Hydrochloride salt (150 mg,0.171mmol,1 eq) of 5- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) nicotinamide was dissolved in N, N-dimethylformamide (2 mL), cesium fluoride (2.60 g,17.10mmol,100 eq) was added and reacted at room temperature for 6 hours. LCMS detected complete reaction. The reaction solution was filtered, and the filtrate was prepared by HPLC to give 5- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) nicotinamide (40 mg, yield: 32.4%) as a white solid.
HPLC separation conditions:
Column Phenomnex C18X 30mm X5 um; flow rate: 35mL/min
Mobile phase A Water (0.05% ammonia, v/v) mobile phase B ACN; gradient: 38% -58% (v/v), retention time: and 10min.
MS m/z:721.4[M+H]+
19F NMR(376MHz,DMSO-d6)δ-110.45(s),-141.72(s),-172.19(s).
1H NMR(400MHz,DMSO-d6)δ10.27(br s,1H),9.17(br s,2H),8.30(br s,2H),8.00(br d,J＝5.5Hz,1H),7.73(br s,1H),7.55-7.38(m,2H),7.29(br s,1H),5.34(d,J＝54.8Hz,1H),4.35-4.05(m,2H),3.85(br s,1H),3.29(br s,2H),3.18(br s,6H),2.90(br s,2H),2.24-2.03(m,3H),1.96-1.79(m,5H),1.73(br s,2H),1.24(s,1H).
Example 21: compound 21
4- (5- (6-Aminopyridin-3-yl) -4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (5- (6- ((tert-butoxycarbonyl) amino) pyridin-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (500 mg, 0.284 mmol,1 eq), tert-butyl- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) carbamate (342.2 mg,1.07mmol,2 eq) cesium carbonate (522.4 mg,1.60mmol,3 eq) was dissolved in dioxane (8 mL) and water (4 mL), 1-di (tert-butylphosphaferrocene) (69.7 mmol, 0.107 mmol) was added and nitrogen was replaced at 12.107 mmol, 0.80 times. LCMS monitored reaction was complete. The reaction solution was extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column (tetrahydrofuran/petroleum ether: 0-50%) to give the product (400 mg, yield: 68.5%)
MS m/z:1093.6[M+H]+
Step 2: hydrochloride salt of 4- (5- (6-aminopyridin-3-yl) -4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (5- (6- ((tert-butoxycarbonyl) amino) pyridin-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (400 mg,0.36mmol,1 eq) was dissolved in acetonitrile (8 mL) and dioxane hydrochloride solution (4M, 7 mL) was added and reacted at room temperature for 1 hour. LCMS monitored reaction was complete. The reaction solution was concentrated to give a product (crude 300 mg) which was directly used for the next reaction.
MS m/z:849.6[M+H]+
Step 3: compound 21
4- (5- (6-Aminopyridin-3-yl) -4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride salt (150 mg,0.177mmol,1 eq) of 4- (5- (6-aminopyridin-3-yl) -4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol was dissolved in N, N-dimethylformamide (2 mL), and cesium fluoride (4.03 g,26.50mmol,150 eq) was added for 2 hours at room temperature. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give the product (10 mg, yield: 8.2%) as a white solid.
HPLC separation conditions:
Column: phenomnex C18 75 x 30mm x 3um
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN, gradient B%:31% -71%, retention time: 9min
MS m/z:693.4[M+H]+
19F NMR(377MHz,DMSO-d6)δ-110.33(s),-145.86(s),-172.00(s),-172.21(s).
1H NMR(400MHz,DMSO-d6)δ10.17(br s,1H),8.06-7.91(m,1H),7.55-7.12(m,4H),6.56-6.28(m,3H),5.30(br d,J＝54.0Hz,1H),4.96(br d,J＝11.0Hz,1H),4.20-4.11(m,1H),4.05(br d,J＝9.9Hz,1H),3.64-3.43(m,4H),3.22-3.00(m,5H),2.99-2.80(m,3H),2.26-1.96(m,3H),1.94-1.75(m,4H),1.48(br d,J＝8.6Hz,2H),0.97-0.80(m,1H).
Example 22: compound 22
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300 mg,0.321mmol,1 eq) was dissolved in dioxane (2 mL) and water (1 mL), and pyridine-4-ylboronic acid (78.8 mg,0.641mmol,2 eq), 1-bis (di-tert-butylphosphine) ferrocene palladium chloride (41.8 mg,0.064mmol,0.2 eq) and cesium carbonate (313.962 mmol,3 eq) were added and reacted at 100℃for 2 hours under nitrogen. LCMS monitored reaction was complete. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, purification of the residue by column [ tetrahydrofuran/petroleum ether: 0-50% ], to give the product (170 mg, yield: 54.2%) as a yellow solid.
MS m/z:978.6[M+H]+
Step 2: hydrochloride of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (pyridin-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (170 mg,0.174mmol,1 eq) was dissolved in dioxane (2 mL), dioxane hydrochloride solution (4M, 1 mL) was added and the reaction was allowed to react at room temperature for 2 hours and LCMS monitoring the reaction was complete. The reaction solution was concentrated to give a crude product (145 mg), which was used directly in the next step as a yellow solid.
MS m/z:834.4[M+H]+
Step 3: compound 22
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride salt (145 mg,0.174mmol,1 eq) of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol was dissolved in N, N-dimethylformamide (2 mL), cesium fluoride (2.42 g,15.90mmol,91.51 eq) was added and reacted overnight at room temperature. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give the product (50 mg, yield: 42.5%) as a white solid.
HPLC separation conditions:
column Phenomnex C18X 30mm X5 um
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B% 50% -70%, retention time: 15min
MS m/z:678.2[M+H]+
19F NMR(377MHz,DMSO-d6)δ-110.13(s),-110.39(s),-110.62(s),-141.18(s),-142.00(s),-172.09(s),-172.21(s).
1H NMR(400MHz,DMSO-d6)δ10.19(br s,1H),8.67(br d,J＝5.0Hz,2H),8.00(br s,1H),7.83-7.17(m,5H),5.31(br d,J＝54Hz,1H),4.94(br s,1H),4.25-4.04(m,2H),3.96-3.35(m,4H),3.20-2.95(m,5H),2.91-2.77(m,2H),2.22-1.98(m,3H),1.94-1.60(m,4H),1.45(br s,2H),0.96(br s,1H).
Example 23: compound 23
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-2-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (pyridin-2-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300 mg,0.320mmol,1 eq) was dissolved in dioxane (5.0 mL) and 2- (tributylstannyl) pyridine (177.1 mg,0.481mmol,1.5 eq) was added, and tetrakis triphenylphosphine palladium (74.1 mg,0.0641mmol,0.2 eq). Nitrogen substitution, reaction at 100 ℃ for 4 hours. LCMS monitored completion of the reaction, and the reaction mixture was concentrated under reduced pressure, and the residue was purified by column (tetrahydrofuran/petroleum ether: 0-35%) to give (1 r,5 s) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-2-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (200 mg, yield: 63.7%) as a yellow solid.
MS m/z:978.4[M+H]+
Step 2: hydrochloride of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-2-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (pyrazolo [1,5-a ] pyridin-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg,0.204mol,1 eq) was dissolved in acetonitrile (2.0 mL) and dioxane hydrochloride solution (4M, 2 mL) was added. The reaction was carried out at room temperature for 1 hour. LCMS monitored completion of the reaction and concentrated the reaction solution under reduced pressure to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-2-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol hydrochloride (180 mg, crude) as a yellow solid.
MS m/z:834.4[M+H]+
Step 3: compound 23
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-2-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride salt (180 mg,0.215mmol,1 eq) of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-2-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol was dissolved in N, N-dimethylformamide (3.0 mL), cesium fluoride (1.64 g,10.79mmol,50 eq) was added and reacted at room temperature under nitrogen atmosphere for 2 hours. LCMS monitored reaction was complete, the reaction was filtered and the filtrate was separated by HPLC to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-2-yl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (30 mg, yield: 20.5%) as a yellow solid.
HPLC separation conditions:
Column Phenomnex C18X 30mm X3 um
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%:34% -74%, retention time: 9min
MS m/z:678.3[M+H]+
19F NMR(376MHz,DMSO-d6)δ110.25(s),-142.43(s),-171.98(s),-172.19(s).
1H NMR(400MHz,DMSO-d6)δ10.19(br s,1H),8.58(d,J＝4.5Hz,1H),8.08-7.89(m,3H),7.58-7.39(m,3H),7.38-7.15(m,1H),5.30(br d,J＝53.6Hz,1H),4.96(br s,1H),4.23-3.98(m,2H),3.82-3.60(m,1H),3.53-3.36(m,2H),3.16-2.91(m,5H),2.89-2.73(m,2H),2.21-1.98(m,3H),1.93-1.73(m,3H),1.71-1.31(m,4H),0.98(br s,1H).
Example 24: compound 24
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (hydroxymethyl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: methyl 4- ((1 r,5 s) -8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidine-5-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (500 mg,0.454mmol,1 eq) was dissolved in methanol (10 mL) and triethylamine (137.90 mg,1.36mmol,3 eq) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (66.5 mg,0.0909mmol,0.2 eq) were added. The reaction was allowed to react overnight at 80℃under an atmosphere of carbon monoxide (50 Psi) with nitrogen sparge. LCMS monitored reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to give methyl 4- ((1 r,5 s) -8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidine-5-carboxylate (300 mg, yield: 68.9%) as a yellow solid.
MS m/z:959.4[M+H]+
Step 2: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (hydroxymethyl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
Methyl 4- ((1 r,5 s) -8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidine-5-carboxylate (200 mg,0.209mmol,1 eq) was dissolved in tetrahydrofuran (5.0 mL) and replaced with nitrogen. Diisobutylaluminum hydride (1M, 1.04mL,5 eq) was slowly added dropwise at-70℃and after the addition was completed, the mixture was slowly warmed to room temperature and reacted overnight at room temperature. LCMS monitored reaction was complete and the reaction quenched with sodium sulfate decahydrate. Dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to give (1 r,5 s) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (hydroxymethyl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (70 mg, yield: 36.1%) as a yellow solid.
MS m/z:931.7[M+H]+
Step 3: hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (hydroxymethyl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (hydroxymethyl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (60 mg,0.0644mmol,1 eq) was dissolved in acetonitrile (3.0 mL), and dioxane hydrochloride solution (4M, 1.6 mL) was added and reacted at room temperature for 1 hour. LCMS monitored completion of the reaction and concentrated the reaction solution to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (hydroxymethyl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol hydrochloride (55 mg, crude) as a yellow solid.
MS m/z:787.4[M+H]+
Step 4: compound 24
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (hydroxymethyl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (hydroxymethyl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol (55 mg,0.0668mmol,1 eq) was dissolved in N, N-dimethylformamide (3.0 mL), and (507.3 mg,3.34mmol,50 eq) was added and reacted at room temperature for 1 hour. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was separated by HPLC to give 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (hydroxymethyl) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (6.6 mg, yield: 15.7%) as a yellow solid.
HPLC separation conditions:
column YMC-TRIART PREP C150 x 40mm x 7um
Mobile phase a: water (NH 3 h2o+nh4hco3), mobile phase B: ACN; gradient B%:24% -64%, retention time: 9min
MS m/z:631.4[M+H]+
19F NMR(377MHz,DMSO-d6)δ-110.61(s),-110.70(s),-143.93(s),-172.06(s),-172.16(s).
1H NMR(400MHz,DMSO-d6)δ7.98(dd,J＝6.0,9.2Hz,1H),7.47(t,J＝9.0Hz,1H),7.40(d,J＝2.4Hz,1H),7.26(br s,1H),5.28(br d,J＝54.0Hz,1H),4.78-4.28(m,3H),4.19-3.95(m,2H),3.87-3.56(m,8H),3.15-2.95(m,3H),2.87-2.78(m,1H),2.17-1.93(m,4H),1.90-1.50(m,6H).
Example 25: compound 25
4- (5- (Aminomethyl) -4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (5-cyano-7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinozin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-cyano-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.2 g,0.216mmol,1 eq) was dissolved in N, N-dimethylformamide (5 mL), and cesium fluoride (984.07 mg,6.48mmol,30 eq) was added and reacted at room temperature for 1 hour. LCMS monitored reaction was complete. The reaction was filtered and concentrated to give (1 r,5 s) -tert-butyl-3- (5-cyano-7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.2 g, crude) as a brown oil.
MS m/z:770.4[M+H]+
Step 2: (1R, 5S) -tert-butyl-3- (5- (aminomethyl) -7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-cyano-7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.2 g,0.260mmol,1 eq) and Raney nickel (22.26 mg,0.260mmol,1 eq) were dissolved in dioxane (5 mL) and the reaction was reacted under hydrogen (45 psi) atmosphere at 60℃overnight. LCMS monitored reaction was complete. The reaction solution was concentrated by filtration, and the residue was purified by column chromatography (methanol/dichloromethane: 0-10%) to give (1 r,5 s) -tert-butyl-3- (5- (aminomethyl) -7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (0.08 g, yield: 39.6%) as a yellow solid.
MS m/z:778.5[M+H]+
Step 3: compound 25
4- (5- (Aminomethyl) -4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol
(1R, 5S) -tert-butyl-3- (5- (aminomethyl) -7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.08 g,0.103mmol,1 eq) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and after nitrogen substitution, the reaction was performed at room temperature for 1 hour. LCMS monitored reaction was complete. The reaction solution was concentrated, and the residue was purified by HPLC to give 4- (5- (aminomethyl) -4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -5-ethyl-6-fluoronaphthalene-2-ol (20 mg, yield: 30.7%) as a white solid.
HPLC separation conditions:
column Phenomnex C18X 30mm X5 um
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%:45% -65%, retention time: 10min
MS m/z:634.4[M+H]+
19F NMR(376MHz,DMSO-d6)δ-119.59(s),-143.17(s),-144.39(s),-172.17(s).
1H NMR(400MHz,DMSO-d6)δ7.76(dd,J＝6.1,9.0Hz,1H),7.37-7.31(m,2H),7.12(br s,1H),5.28(br d,J＝54.0Hz,1H),4.61-4.23(m,3H),4.22-3.97(m,4H),3.94-3.67(m,4H),3.09(br d,J＝7.7Hz,3H),3.05-2.97(m,2H),2.90-2.76(m,2H),2.12(br s,1H),2.05-1.95(m,3H),1.87-1.73(m,4H),1.53(br s,3H),0.69(br t,J＝7.1Hz,3H).
Example 26: compound 26
4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidine-5-carboxamide
Step 1: (1R, 5S) -tert-butyl-3- (5-aminocarbonyl-7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5-cyano-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (10.0 mg,0.0108mmol,1 eq) was dissolved in dimethyl sulfoxide (0.5 mL), and hydrogen peroxide (12.0 mg,0.106mmol,0.0102mL,30% content, 9.80 eq) and potassium carbonate (10.0 mg,0.0724mmol,6.70 eq) were added and reacted at room temperature for 3 hours. LCMS monitored reaction was complete. The reaction was quenched by addition of saturated aqueous sodium sulfite solution, diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, and separation of the residue by TLC plate (petroleum ether: tetrahydrofuran=1:1) gave the product (8 mg, yield: 94.0%) as a colorless oil.
MS m/z:788.4[M+H]+
Step 2: compound 26
4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidine-5-carboxamide
(1R, 5S) -tert-butyl-3- (5-aminocarbonyl-7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (10.0 mg,0.0127mmol,1 eq) was dissolved in acetonitrile (1 mL) and ethyl acetate hydrochloride solution (4M, 0.5 mL) was added and reacted at room temperature for 8 hours. LCMS monitored reaction was complete. The reaction solution was concentrated, and the residue was purified by HPLC to give 4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidine-5-carboxamide (3 mg, yield: 33.8%) as a white solid.
MS m/z:644.3[M+H]+
HPLC separation conditions:
Column Boston Prime C18 x 30mm x 5um;
Mobile phase a: water (NH 3H2O+NH4HCO3), mobile phase B: ACN; gradient B%:34% -64% retention time: 10min
19F NMR(376MHz,DMSO-d6)δ-110.38(s),-138.24(s),-172.10(s),-172.16(s).
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),7.99(dd,J＝6.0,9.0Hz,1H),7.83(s,1H),7.61(br s,1H),7.48(t,J＝8.9Hz,1H),7.41(d,J＝2.5Hz,1H),7.27(br s,1H),5.29(br d,J＝52.8Hz,1H),4.19-3.95(m,2H),3.74(br s,1H),3.56-3.43(m,1H),3.29-2.97(m,9H),2.90-2.77(m,1H),2.09-1.96(m,3H),1.91-1.73(m,4H),1.57(br s,3H).
Example 27: compound 27
3- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) -1,2, 4-oxadiazol-5 (4H) -one
Step 1: (1R, 5S) -tert-butyl-3- (5-cyano-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
(1R, 5S) -tert-butyl-3- (5-chloro-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1.0 g,1.07mmol,1 eq) was dissolved in N, N-dimethylformamide (20 mL), and zinc cyanide (627.6 mg,5.34mmol,5 eq), 1-bis (diphenylphosphino) ferrocene (237.0 mg,0.428mmol,0.4 eq) and tris (dibenzylideneacetone) palladium (391.5 mg,0.42 mmol,0.4 eq) were added and reacted under nitrogen atmosphere at 110℃for 1 hour. LCMS monitored reaction was complete. The reaction solution was quenched with water and filtered. The filtrate was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, purification of the residue by column [ tetrahydrofuran/petroleum ether: 0-30% ], to give the product (780 mg, yield: 78.7%) as a yellow solid.
MS m/z:926.5[M+H]+
Step 2: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- ((Z) -N' -hydroxycarbamimidoyl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
(1R, 5S) -tert-butyl-3- (5-cyano-8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.20 g,0.216mmol,1 eq) was dissolved in ethanol (10 mL), and an aqueous solution (1 mL) of hydroxylamine hydrochloride (30 mg,0.432mmol,2 eq) and sodium bicarbonate (54.4 mg,0.648mmol,3 eq) was slowly added dropwise and reacted at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated and the residue was prepared by HPLC to give the crude product (200 mg) as a yellow solid.
MS m/z:959.5[M+H]+
Step 3: (1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (5-oxolan-4, 5-dihydro-1, 2, 4-oxadiazol-3-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (-N' -hydroxycarbamimidoyl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg,0.209mmol,1 eq) was dissolved in acetonitrile (1.5 mL) and 1.8-diazabicyclo [5.4.0] undec-7-ene (119.0 mg,0.782mmol,3.75 eq) and 1, 1-carbonyldiimidazole (33.81 mg,0.209mmol,1 eq) were slowly added dropwise and reacted at 0℃for 1 hour under nitrogen. LCMS monitored reaction was complete. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL), filtered, extracted with acetonitrile, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate and HPLC of the residue gave the product (100 mg, yield: 64.9%) as a yellow solid.
MS m/z:985.6[M+H]+
HPLC separation conditions:
Column Boston Uni C18 x 150 x 5um;
Mobile phase a: water (FA), mobile phase: ACN; gradient B%:46% -76%, retention time: 10min
Step 4: hydrochloride of 3- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-7- (7-fluoro-3-hydroxy-8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) -1,2, 4-oxadiazol-5 (4H) -one
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) -5- (pyridin-4-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (30 mg,0.030mmol,1 eq) was dissolved in dioxane (4 mL), dioxane hydrochloride solution (4M, 1 mL) was added and reacted overnight at room temperature. LCMS monitored reaction was complete. The reaction was concentrated to give the product (30 mg, crude) as a yellow oil, which was used directly in the next step.
MS m/z:841.5[M+H]+
Step 5: compound 27
3- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) -1,2, 4-oxadiazol-5 (4H) -one
Hydrochloride salt of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (pyridin-4-yl) pyrido [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol (30 mg,0.036mmol,1 eq) was dissolved in N, N-dimethylformamide (4 mL), cesium fluoride (0.5 g,3.29mmol,92.28 eq) was added and reacted at room temperature for 1 hour. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give the product (20 mg, yield: 81.9%) as an off-white solid.
HPLC separation conditions:
Column Phenomnex C18X 30mm X3 um
Mobile phase a: water (FA), mobile phase B: ACN; gradient B% is 0% -40%; retention time: 9min
MS m/z:685.2[M+H]+
19F NMR(377MHz,DMSO-d6)δ-110.62(s),-141.11(s),-141.31(s),-141.48(s),-172.19(s).
1H NMR(400MHz,DMSO-d6)δ10.25(br s,1H),8.15(s,1H),8.00(dd,J＝6.0,9.0Hz,1H),7.49(t,J＝8.9Hz,1H),7.41(d,J＝2.3Hz,1H),7.27(br s,1H),5.30(br d,J＝53.6Hz,1H),4.21-4.03(m,2H),4.01-3.82(m,2H),3.77(s,1H),3.25-3.03(m,8H),2.90-2.81(m,1H),2.19-1.66(m,10H).
Example 28: compound 28
4,4' - (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidine-5, 7-diyl) bis (5-ethynyl-6-fluoronaphthalene-2-ol)
Step 1: tert-butyl- (1 r,5 s) -3- (7-chloro-8-fluoro-5- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
In a 100mL reaction flask, tert-butyl-3- (5, 7-dichloro-8-fluoro-2- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) pyridine [4,3-d ] pyrimidin-4-yl) -3, 8-diaza [3.2.1] octane-8-carboxylate (2 g,3.42mmol,1 eq) was dissolved in toluene (25 mL), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3-dioxolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (3.5 g,6.84mmol,2 eq), tetratriphenylphosphine palladium (791 mg,0.684mmol,0.2 mmol, 410mg,10.26mmol,3 eq) was added to an aqueous solution of sodium hydroxide in water (5 mL), nitrogen was replaced, and the mixture was naturally reacted to 100℃for a small reaction. LCMS monitored completion of the reaction. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave tert-butyl- (1R, 5S) -3- (7-chloro-8-fluoro-5- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolinazin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (340 mg, yield: 10.63%) as a yellow solid by column purification of the residue (ethyl acetate/dichloromethane: 0-100%).
MS m/z:935.3[M+H]+
Step 2: tert-butyl- (1 r,5 s) -3- (8-fluoro-5, 7-bis (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
Tert-butyl- (1 r,5 s) -3- (7-chloro-8-fluoro-5- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolinazin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (600 mg,0.642mmol,1 eq) was dissolved in toluene (10 mL) and water (2 mL), and ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) ethynyl) triisopropylsilane (987 mg,1.927mmol,3 eq), tetraphenylpalladium (148 mg,0.128mmol, 0.56 mmol, sodium hydroxide (2.103 mg, 4 mmol), and 100.8 mmol) were added and the reaction was monitored as complete stirring. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate, the residue preparation plate was purified (methanol/dichloromethane: 9%) to give tert-butyl- (1R, 5S) -3- (8-fluoro-5, 7-bis (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (350 mg, yield: 42.4%) as a pale yellow solid.
MS m/z:1285.5[M+H]+
Step 3: hydrochloride of 4,4' - (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidine-5, 7-diyl) bis (6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol)
Is the hydrochloride of (2)
Tert-butyl- (1 r,5 s) -3- (8-fluoro-5, 7-bis (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300 mg,0.233mmol,1 eq) was dissolved in acetonitrile (5 mL) and hydrochloric acid/1, 4-dioxane (4 m,5 mL) was added for reaction at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction solution was concentrated to give 4,4' - (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidine-5, 7-diyl) bis (6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol) hydrochloride (200 mg, yield: 78.3%) as a yellow solid.
MS m/z:1097.5[M+H]+
Step 4: compound 28
4,4' - (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidine-5, 7-diyl) bis (5-ethynyl-6-fluoronaphthalene-2-ol)
4,4' - (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidine-5, 7-diyl) bis (6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol) hydrochloride (180 mg,0.164mmol,1 eq) was dissolved in N, N-dimethylformamide (3 mL), cesium fluoride hydrochloride (62 mg,4.1mmol,25 eq) was added and reacted at room temperature for 16 hours. LCMS monitored reaction was complete. Purification by preparative chromatography gave 4,4' - (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidine-5, 7-diyl) bis (5-ethynyl-6-fluoronaphthalene-2-ol) (30 mg, yield: 23.3%) as a yellow solid.
HPLC separation conditions:
column: phenomenex C18 x 40mm x 3um;
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B% 25% -65%; retention time: 9min
MS m/z:785[M+H]+
19F NMR(377MHz,DMSO-d6)δ-172.10(s),-141.79(s),-110.90(s),-110.47(s).
1H NMR(400MHz,DMSO-d6)δ7.93(dt,J＝10.0,5.8Hz,1H),7.45-7.33(m,5H),7.10(s,1H),5.32(d,J＝54.2Hz,1H),4.53(s,2H),4.28-4.06(m,3H),3.91-3.82(m,2H),3.62(d,J＝6.1Hz,1H),3.15-3.06(m,4H),2.91-2.86(m,2H),2.56(s,1H),2.21-2.04(m,3H),1.94-1.77(m,4H),1.42(s,3H).
EXAMPLE 29 Compound 29
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: hydrochloride of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol
Is the hydrochloride of (2)
Tert-butyl- (1R, 5S) -3- (7-chloro-8-fluoro-5- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (900 mg,0.96mmol,1 eq) (prepared from the product of step 1 of reference example 28) was dissolved in acetonitrile (5 mL) and hydrochloric acid/1, 4-dioxane (4M, 5 mL) was added for reaction at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction solution was concentrated to give 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol hydrochloride (1 g, yield: 100%) as a pale yellow solid.
MS m/z:791[M+H]+
Step 2: compound 29
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Hydrochloride (240 mg, 0.228 mmol,1 eq) of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalene-2-ol was dissolved in N, N-dimethylformamide (2 mL), cesium fluoride (1.05 g,6.95mmol,25 eq) was added and reacted at room temperature for 16 hours. LCMS monitored reaction was complete. Preparative chromatography purification gave 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (25 mg, yield: 14.2%) as a yellow solid.
HPLC separation conditions:
column: phenomenex C18 x 40mm x 3um;
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN, gradient B%:25% -65%; retention time: 9min.
MS m/z:635[M+H]+
19F NMR(377MHz,DMSO-d6)δ-172.14(s),-139.46(s),-109.96(s).
1H NMR(400MHz,DMSO-d6)δ8.00(dd,J＝9.2,5.9Hz,1H),7.50(t,J＝9.0Hz,1H),7.38(d,J＝2.6Hz,1H),7.01(s,1H),5.36-5.21(m,1H),4.39(s,1H),4.22-4.03(m,2H),3.76(d,J＝12.0Hz,1H),3.45(br,3H),3.15-3.06(m,2H),3.02(d,J＝2.6Hz,1H),2.90-2.81(m,2H),2.15-2.00(m,3H),1.90-1.75(m,4H),1.37(s,3H).
Example 30: compound 30
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) -5, 6-difluoronaphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (7-chloro-5- (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5, 7-dichloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1060 mg,1.81mmol,1 eq) was dissolved in dioxane (10 mL) and water (5 mL), 2- (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (697.4 mg,1.99mmol,1.1 eq), cesium carbonate (1.18 g,3.62mmol,2 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (132.5 mg,0.181 eq) was added and the mixture was reacted for 1 hour at 80℃under nitrogen. LCMS monitored reaction was complete. The reaction solution was concentrated, and the residue was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (tetrahydrofuran/petroleum ether: 10-30%) to give a mixture of (1R, 5S) -tert-butyl-3- (7-chloro-5- (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (310 mg, yield: 22.2%) as a brown solid.
MS m/z:773.3[M+H]+
Step 2: compound 30
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) -5, 6-difluoronaphthalen-2-ol
(1R, 5S) -tert-butyl-3- (7-chloro-5- (7, 8-difluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300 mg, 0.3838 mmol,1 eq) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added and reacted at room temperature for 1 hour. LCMS detected complete reaction. The reaction solution was concentrated, and the residue was purified by HPLC to give 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) -5, 6-difluoronaphthalene-2-ol (42 mg, yield: 8.4%) as a white solid.
HPLC separation conditions:
waters Xbridge BEH C18.100.30.10 um columns;
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%:24% -64%; retention time: 10min
MS m/z:629.2[M+H]+
19F NMR(377MHz,DMSO-d6)δ-139.88(s),-139.91(s),-143.76(s),-172.07(s),-172.17(s).
1H NMR(400MHz,DMSO-d6)δ10.21(br s,1H),7.77(dd,J＝4.9,8.8Hz,1H),7.68-7.57(m,1H),7.38(s,1H),7.01(br s,1H),5.30(br d,J＝53.6Hz,1H),4.22-4.04(m,2H),3.44-3.33(m,5H),3.15-2.95(m,5H),2.88-2.79(m,1H),2.22-1.94(m,4H),1.91-1.70(m,3H),1.36(m,3H).
Example 31: compound 31
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -2-amino-7-fluorobenzo [ b ] thiophene-3-carbonitrile
Step 1: (1R, 5S) -tert-butyl-3- (5- (2- ((tert-butoxycarbonyl) amino) -3-cyano-7-fluorobenzo [ b ] thiophen-4-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5, 7-dichloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (500 mg, 0.284 mmol,1 eq) was dissolved in dioxane (5 mL), tert-butyl- (3-cyano-4- (5, 5-dimethyl-1, 3, 2-dioxan-2-yl) -7-fluorobenzo [ b ] thiophen-2-yl) carbamate (517.9 mg,1.28mmol,1.5 eq), cesium carbonate (834.8 mg,2.56mmol,3 eq) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (125.0 mg, 0.190 eq, 0.2 mmol) were added and the reaction was carried out under a nitrogen atmosphere of a small pressure of 1712 ℃. LCMS monitored reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to give (1 r,5 s) -tert-butyl-3- (5- (2- ((tert-butoxycarbonyl) amino) -3-cyano-7-fluorobenzo [ b ] thiophen-4-yl) -7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (200 mg, yield: 27.9%). Yellow solid.
MS m/z:841.4[M+H]+
Step 2: compound 31
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -2-amino-7-fluorobenzo [ b ] thiophene-3-carbonitrile
(1R, 5S) -tert-butyl-3- (5- (2- ((tert-butoxycarbonyl) amino) -3-cyano-7-fluorobenzo [ b ] thiophen-4-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300 mg,0.356mmol,1 eq) was dissolved in acetonitrile (2 mL), and dioxane hydrochloride solution (4M, 2.00 mL) was added and reacted at room temperature for 6 hours. LCMS monitored reaction was complete. The reaction solution was concentrated, and the residue was purified by HPLC to give 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-3-yl) -5-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) -2-amino-7-fluorobenzo [ b ] thiophene-3-carbonitrile (70 mg, yield: 15.3%). White solid.
HPLC separation conditions:
column: waters Xbridge BEH C18.100.30 mm.10 um;
mobile phase a: water (NH 3H2O+NH4HCO3), mobile phase B: ACN; gradient B% 23% -63%, retention time: 11min
MS m/z:663.2[M+Na]+
19F NMR(377MHz,DMSO-d6)δ-115.16(s),-139.91(s),-172.07(s),-172.16(s).
1H NMR(400MHz,DMSO-d6)δ8.20(br s,2H),7.40-6.73(m,2H),5.30(br d,J＝54.0Hz,1H),4.81(br s,1H),4.23-4.00(m,2H),3.33-2.80(m,9H),2.21-1.95(m,4H),1.93-1.71(m,4H),1.41(br s,2H),1.09-0.59(m,1H).
Example 32: compound 32
4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-5- (7, 8-difluoronaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidine
Step 1: (1R, 5S) -tert-butyl-3- (7-chloro-5- (7, 8-difluoronaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5, 7-dichloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg, 0.432 mmol,1 eq) was dissolved in a mixed solution of dioxane (2 mL) and water (1 mL), 2- (7, 8-difluoronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (89.2 mg,0.307mmol,0.9 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (50 mg,0.0683mmol,0.2 eq) and cesium carbonate (333.9 mg,1.02 eq) were added and reacted under nitrogen atmosphere at 80℃for 2 hours. LCMS monitored reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the residue was prepared by HPLC to give (1R, 5S) -tert-butyl-3- (7-chloro-5- (7, 8-difluoronaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester (25 mg, yield: 10.4%) as a white solid.
HPLC separation conditions:
column AgNO3_Silica 150 x 25mm x 15um
Mobile phase a: heptane, mobile phase B: etOH (0.1% nh3h2 o); gradient B%:0% -90%; retention time: 9min
MS m/z:713.3[M+H]+
19F NMR(377MHz,DMSO-d6)δ-138.50(s),-139.83(s),-172.09(s),-172.16(s).
1H NMR(400MHz,DMSO-d6)δ8.18(br d,J＝7.9Hz,1H),8.02(br s,1H),7.87-7.25(m,3H),5.29(br d,J＝54.8Hz,1H),4.29-4.01(m,2H),3.98-3.44(m,3H),3.20-2.96(m,3H),2.92-2.78(m,1H),2.26-1.72(m,8H),1.68-0.97(m,14H).
Step 2: compound 32
4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-5- (7, 8-difluoronaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidine
(1R, 5S) -tert-butyl-3- (7-chloro-5- (7, 8-difluoronaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (25 mg,0.0351mmol,1 eq) was dissolved in dichloromethane (0.9 mL), trifluoroacetic acid (0.3 mL) was added and the reaction was allowed to react at room temperature for 1 hour, and LCMS was monitored to completion. The reaction solution was concentrated, and the residue was prepared by HPLC to give 4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-5- (7, 8-difluoronaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidine (7 mg, yield: 23.9%) as a white solid.
HPLC separation conditions:
Column Phenomnex C18X 30mm X3 um
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%:47% -87%, retention time: 9min
MS m/z:613.2[M+H]+
19F NMR(377MHz,DMSO-d6)δ-138.44(s),-138.47(s),-140.05(s),-172.07(s),-172.17(s).
1H NMR(400MHz,DMSO-d6)δ8.12(br d,J＝64.8Hz,2H),7.90-7.22(m,3H),5.29(br d,J＝54.0Hz,1H),4.32-3.88(m,3H),3.19-2.77(m,8H),2.23-1.74(m,8H),1.48-1.04(m,4H).
Example 33: compound 33
4- (4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) naphthalen-2-ol
Step 1: (1R, 5S) -tert-butyl-3- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (3- (methoxymethoxy) naphthalen-1-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5, 7-dichloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxamide ester (600.0 mg,1.02mmol,1 eq) was dissolved in toluene (1 mL) and water (0.2 mL), 2- (3- (methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (322.0 mg,1.02mmol,1 eq), sodium hydroxide (172.5 mg,3.07mmol,3 eq), and tetraphenylphosphine palladium (236.9 mg,0.205mmol,0.2 eq) were added to the mixture, and the mixture was reacted at 100℃for 1 hour under nitrogen. LCMS monitored reaction was complete. The reaction solution was concentrated, and the residue was extracted with water and ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtering and concentrating the filtrate. The residue was resolved by SFC to give the product (200 mg, yield: 26.5%) as a white solid.
MS m/z:737.3[M+H]+
SFC chiral separation conditions:
Column: DAICEL CHIRALCEL OD (250 mm. Times.30 mm,10 um)
Mobile phase a:0.1% nh 3H2 O, mobile phase B: MEOH; gradient B percent is 35 to 35 percent
Step 2:4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) naphthalene-2-ol and 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -5-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-7-yl) naphthalene-2-ol
(1R, 5S) -tert-butyl-3- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (3- (methoxymethoxy) naphthalen-1-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-formate ester (190 mg,0.274mmol,1 eq) was dissolved in acetonitrile (3 mL), and dioxane hydrochloride solution (4M, 1.5 mL) was added to react at room temperature for 1 hour. LCMS detected complete reaction. The reaction solution was concentrated, and the residue was separated and purified by HPLC to give 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-3-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-5-yl) naphthalene-2-ol (10 mg, yield: 6.2%) as a white solid.
MS m/z:593.2[M+H]+
HPLC separation conditions:
the column is Kromasil Eternity XT.times.150.times.30.mm.times.10 um; flow rate: 60mL/min
Mobile phase A Water (0.05% ammonia, v/v) mobile phase B ACN; gradient B%:14% -54% (v/v), retention time: 9min
1H NMR(400MHz,DMSO-d6)δ9.67(br s,1H),8.09-7.88(m,1H),7.81(br d,J＝7.9Hz,1H),7.46(br t,J＝7.5Hz,1H),7.31(br s,2H),7.00(br s,1H),5.31(br d,J＝55.6Hz,1H),4.18(br s,3H),3.43-3.17(m,6H),2.90-2.80(m,2H),2.17-1.98(m,4H),1.96-1.62(m,5H),1.37(br s,3H).
Example 34: compound 34
4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-5- (8-ethynylnaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidine
Step 1: (1R, 5S) -tert-butyl-3- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid ester
(1R, 5S) -tert-butyl-3- (5, 7-dichloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolinazin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg, 0.432 mmol,1 eq) was dissolved in a mixed solution of toluene (3 mL) and water (0.6 mL), and triisopropyl ((8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) silane (222.6 mg,0.512mmol,1.5 eq), tetraphenylphosphine palladium (79.0 mg,0.068mmol,0.2 eq) and sodium hydroxide (41.0 mg,1.02mmol,3 eq) were added to react under nitrogen atmosphere at 100℃for 3 hours. LCMS monitored reaction was complete. The reaction mixture was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated by TLC plate [ tetrahydrofuran (0.5% aqueous ammonia): petroleum ether=3:1 ], yielding (1R, 5S) -tert-butyl-3- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluoro-hexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (110 mg, yield: 37.6%) as a brown solid.
MS m/z:857.5[M+H]+
Step 2: hydrochloride of 4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methoxy) -5- (8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) pyrido [4,3-d ] pyrimidine
Is the hydrochloride of (2)
(1R, 5S) -tert-butyl-3- (7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (80 mg,93.29umol,1 eq) was dissolved in acetonitrile (2 mL), dioxane hydrochloride solution (4M, 2 mL) was added and the reaction was allowed to react at room temperature for 2 hours, and LCMS monitoring the reaction was complete. The reaction solution was concentrated to give 4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) -5- (8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) pyrido [4,3-d ] pyrimidine hydrochloride (74.1 mg, 100%) as a brown solid.
MS m/z:757.2[M+H]+
Step 3:4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-5- (8-ethynylnaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidine
4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizine-7 a-yl) methoxy) -5- (8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) pyrido [4,3-d ] pyrimidine hydrochloride (74.1 mg,0.093mmol,1 eq) was dissolved in N, N-dimethylformamide (1 mL), and cesium fluoride (2.13 g,13.99mmol,150 eq) was added and reacted at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to give 4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-5- (8-ethynylnaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidine (20 mg, yield: 35.7%) as a white solid
HPLC separation conditions:
column: phenomenex C18 x 30mm x 3um; flow rate: 30mL/min
Mobile phase A Water (0.05% ammonia, v/v) mobile phase B ACN; gradient B%:34% -74% (v/v), retention time: 11min
MS m/z:601.4[M+H]+
19F NMR(376MHz,DMSO-d6)δ-139.86(s),-172.09(s),-172.20(s).
1H NMR(400MHz,DMSO-d6)δ8.15(d,J＝8.3Hz,2H),7.80(br d,J＝6.5Hz,1H),7.68-7.56(m,2H),7.40(br s,1H),5.30(br d,J＝54.4Hz,1H),4.25-4.01(m,3H),3.80(br d,J＝10.3Hz,1H),3.22-2.94(m,5H),2.91-2.72(m,2H),2.23-1.95(m,4H),1.93-1.53(m,5H),1.33(br s,3H),1.03(br s,1H).
Example 35: compound 35
4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-5- (8-chloronaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidine
Step 1: (1R, 5S) -tert-butyl-3- (7-chloro-5- (8-chloronaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
(1R, 5S) -tert-butyl-3- (5, 7-dichloro-8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (500 mg, 0.284 mmol,1 eq) was dissolved in toluene (10 mL) and water (2 mL), 2- (8-chloronaphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (369.7 mg,1.28mmol,1.5 eq), sodium hydroxide (102.5 mg,2.56mmol,3 eq), tetraphenylphosphine palladium (197.4 mg, 0.171eq), nitrogen protection, and reacted overnight at 100 ℃. LCMS monitored reaction was complete. The reaction solution was concentrated, and the residue was extracted with water and ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtering and concentrating the filtrate. The crude product was purified by column (ethyl acetate/petroleum ether: 0-35%) to give the product (200 mg, crude product) as a yellow solid.
MS m/z:711.3[M+H]+
Step 2: compound 35
4- ((1 R,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7-chloro-5- (8-chloronaphthalen-1-yl) -8-fluoro-2- (((2 r,7 as) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidine
(1R, 5S) -tert-butyl-3- (7-chloro-5- (8-chloronaphthalen-1-yl) -8-fluoro-2- (((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methoxy) pyrido [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (190 mg,0.267mmol,1 eq) was dissolved in acetonitrile (2 mL), and dioxane hydrochloride solution (4M, 0.6 mL) was added and reacted at room temperature for 1 hour. LCMS detected complete reaction. The reaction solution was concentrated, and the residue was purified by HPLC and resolved by SFC to give the product (15 mg, yield: 9.19%) as a white solid.
HPLC separation conditions:
column Kromasil Eternity XT 150.30.10 um.150.30 mm
Mobile phase a: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%:40% -80%, retention time: 9min
SFC chiral separation conditions:
Column: DAICEL CHIRALCEL OJ (250 mm 30mm,10 um)
Mobile phase a:0.1% nh 3H2 O, mobile phase B: ETOH; gradient B%: 35-35%
MS m/z:611.4[M+H]+
19F NMR(376MHz,DMSO-d6)δ-140.16(s),-172.08(s),-172.19(s).
1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝8.0Hz,1H),8.13(d,J＝7.8Hz,1H),7.73(br d,J＝7.5Hz,1H),7.68-7.56(m,2H),7.49(br s,1H),5.30(br d,J＝54.0Hz,1H),4.23-4.12(m,1H),4.11-4.01(m,1H),3.85-3.69(m,1H),3.50-3.35(m,3H),3.18-3.06(m,3H),3.03(s,1H),2.91(br s,1H),2.88-2.78(m,1H),2.23-1.95(m,4H),1.93-1.71(m,4H),1.42-1.26(m,2H),1.22-1.09(m,1H).
Test example 1: proliferation inhibitory Activity against Ba/F3KRAS-G12D, ba/F3KRAS-G12V stably transfected cell lines and AGS tumor cell lines containing KRAS G12D mutations:
This test example 1 was used to determine the proliferation inhibitory activity of the compounds of the present invention on in vitro Ba/F3KRAS-G12D and Ba/F3KRAS-G12V cells stably expressing KRAS G12D/V muteins in murine primordial B cells Ba/F3, and gastric cancer AGS cells expressing KRAS G12D muteins.
Cell source: ba/F3KRAS-G12D and Ba/F3KRAS-G12V are purchased from Kang Yuanbo Biotechnology (Beijing) Inc., KC-1259 and KC-1261 respectively; AGS is available from Shanghai Bayer biosciences Inc.
Cells in the logarithmic growth phase were inoculated into 96-well plates (Ba/F3 KRAS-G12D, ba/F3KRAS-G12V, AGS cells 8000,8000,4000/well, 90. Mu.l/well, respectively), cultured at 37℃for 1 day with 5% CO 2, and then the test compound was added in gradient dilution. The method comprises the following steps: stock solutions of the compounds (10 mM) dissolved in DMSO beforehand were diluted to 10 gradient concentrations at a ratio of 4 times and diluted to 10 times the target concentration with medium in another 96-well plate, and then 10. Mu.l/well of the compound solution was added to the 96-well plate inoculated with cells, i.e., the target concentrations (10000, 2500,625,156,39,10,2.5,0.6,0.15,0.04 nM) were reached. 3 duplicate wells were set for each concentration, and a blank was set. After continuous cultivation at 37℃in 5% CO 2 for 72h, 50. Mu.l of each well was added2.0 Reagent (luciferase ATP bioluminescence detection reagent, available from Promega, cat No. G9243), shaking for 2min, incubating at room temperature for 8min, and detecting fluorescence intensity (light receiving time 100 ms). The inhibition of cell proliferation by each concentration of compound was calculated.
The cell proliferation inhibition ratio (%) = [ (light emission intensity 72 Control group of cell-containing culture medium for hour -light emission intensity 72 Hourly compound group )/(light emission intensity 72 Control group of cell-containing culture medium for hour -light emission intensity 72 Cell-free medium control group for hours ) ]×100%.
The data were analyzed using GRAPHPAD PRISM 8.3.3 software, and a non-linear S-curve regression was used to fit the data to derive a dose-response curve, and IC 50 values were calculated therefrom, with the results given in the table below.
A≤1μM；1μM＜B≤5μM；5μM＜C≤10μM。
The test results show that the compounds (especially compound 4, compound 6, compound 10, compound 13, compound 18, compound 21, compound 22, compound 24 and compound 29) have good proliferation inhibition activity on Ba/F3KRAS-G12D, ba/F3KRAS-G12V and AGS cells containing KRAS G12D/V mutation.
While particular embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative, and that many changes and modifications may be made to these embodiments without departing from the principles and spirit of the invention. Accordingly, the scope of the invention is defined by the appended claims.

Claims (18)

  1. A compound as shown in formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    wherein ring A is a 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkenyl; the number of heteroatoms in the 4-10 membered heterocycloalkyl and 4-10 membered heterocycloalkenyl is 1 or 2, wherein the heteroatoms are selected from one or two of N, O and S;
    n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
    Each R 1 is independently deuterium, halogen, -CN, -OH, -N (R 5)2, nitro, C 1-C6 alkyl, C 1-C6 alkyl substituted with one or more R 1a, C 1-C6 alkyl-O-, C 1-C6 alkyl-O-, C 2-C6 alkenyl substituted with one or more R 1b, C 2-C6 alkenyl substituted with one or more R 1c, C 2-C6 alkynyl, C 2-C6 alkynyl substituted with one or more R 1d, -C (=O) H, -CO 2R5、-C(＝O)N(R5)2, 5 to 14 membered heteroaryl or oxo (= O), wherein the heteroatoms in the 5 to 14 membered heteroaryl are selected from one or more of N, O and S, and the number of heteroatoms is 1,2 or 3;
    Each R 1a、R1b、R1c and R 1d is independently deuterium, -CN, halogen or-OH;
    L is -(CR6aR6b)n1-*、-O-(CR6aR6b)n2-*、-S-(CR6aR6b)n3-* or-N (R 5)(CR6aR6b)n4; represents the end to which R 2 is attached;
    R 2 is H, -COOH, -N (R 5)2、C1-C6 alkyl, C 1-C6 alkyl-O-, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5 to 14 membered heteroaryl 、-NHC(＝NH)NH2,-C(O)N(R5)2、-CH(CH2OR5)[(CH2)n5OR5]、-N(R5)C(＝O)-(C6-C10 aryl), -C (=o) O- (C 1-C6 alkyl), C 1-C6 alkyl substituted by one or more R 2a, C 1-C6 alkyl-O-substituted with one or more R 2b, 3-7 membered cycloalkyl substituted with one or more R 2c, 3-7 membered cycloalkenyl substituted with one or more R 2d, 4-10 membered heterocycloalkyl substituted by one or more R 2e, -C (=o) O- (C 1-C6 alkyl) substituted by one or more R 2f, C 6-C10 aryl substituted by one or more R 2g, 5 to 14 membered heteroaryl substituted with one or more R 2h, -N (R 5) C (=o) - (C 6-C10 aryl substituted with one or more R 2i) or 4-10 membered heterocycloalkenyl substituted with one or more R 2j; The hetero atoms in the 4-10 membered heterocycloalkyl group and the 4-10 membered heterocycloalkyl group substituted by one or more R 2e are selected from one or more of N, O and S, and the number of the hetero atoms is 1,2 or 3; the hetero atoms in the 4-10 membered heterocyclic alkenyl groups and the 4-10 membered heterocyclic alkenyl groups substituted by one or more R 2j are selected from one or more of N, O and S, and the number of the hetero atoms is 1,2 or 3; The heteroatoms in the 5-to 14-membered heteroaryl groups substituted by one or more R 2h are selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3;
    Each R 2a、R2b、R2c、R2d、R2e、R2f and R 2j is independently halogen, -OH, deuterium, -CN, -C (=O) H, C 1-C6 alkyl, C 1-C6 alkyl substituted with one or more R 2-a, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkyl-O-, C 1-C6 alkyl-O-, substituted with one or more R 2- b, phenyl-Q-, FO 2 S-phenylene-Q-, phenyl-C (=o) NH-, -N (R 5)2、(Cl-C6 alkyl) -O- (C 1-C6 alkyl) -, (C l-C6 alkyl) -C (=o) -, Oxo (=o), (C l-C6 alkyl) -C (=o) -, -SO 2F、(Cl-C6 alkyl) -SO 2-、(Cl-C6 alkyl) -O- (C l-C6 alkyl) -O-, substituted by one or more halogens, -CH 2OC(＝O)N(R5)2、(Cl-C6 alkyl) -O-C (=o) -NHCH 2-、-CH2NHC(＝O)N(R5)2、(Cl-C6 alkyl) -C (=o) NHCH 2 -, (pyrazolyl) -CH 2-、(Cl-C6 alkyl) -SO 2-NHCH2 -, (4-10 membered heterocycloalkyl) -C (=o) -OCH 2-、(R5)2N-C(＝O)-O-、(Cl-C6 alkyl) -O- (C l-C6 alkyl) -NH-C (=o) -O-, phenyl- (C l-C6 alkyl) -NH-C (=o) -O-, (4-10 membered heterocycloalkyl) -C (=o) -O-, or (4-10 membered heterocycloalkyl) -CH 2 -; The "phenyl" in said "phenyl-C (=o) NH-" and "phenyl- (C l-C6 alkyl) -NH-C (=o) -O-" are optionally substituted by-C (=o) H, halogen, CN or OH; the "4-10 membered heterocycloalkyl" in "(4-10 membered heterocycloalkyl) -C (=o) -OCH 2 -", "(4-10 membered heterocycloalkyl) -C (=o) -O-" and "(4-10 membered heterocycloalkyl) -CH 2 -" is optionally substituted with 0,1 or 2 oxo (=o); The heteroatoms in the "(4-10 membered heterocycloalkyl) -C (=O) -OCH 2 -", "(4-10 membered heterocycloalkyl) -C (=O) -O-", and "(4-10 membered heterocycloalkyl) -CH 2 -" "4-10 membered heterocycloalkyl" are selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3;
    each Q is independently a connecting single bond or-O-;
    Each R 2-a and R 2-b is independently deuterium, -CN, halogen or-OH;
    Each R 2g、R2h and R 2i is independently halogen, -OH, -C (=o) H, C 1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkyl-O-, C 1-C6 alkyl substituted with one or more halogens or OH, or-N (R 5)2;
    R 3 is halogen, -OH, deuterium, -CN, C 1-C6 alkyl, C 1-C6 alkyl-O-, C 1-C6 alkyl-S- C 2-C6 alkenyl, C 2-C6 alkynyl, nitro 、-(CH2)n6N(R5)2、-NHC(＝NH)NH2、-(CH2)n7C(＝O)N(R5)2、-(CH2)n8C(＝O)R5、-N(R5)C(＝O)-(C6-C10 aryl), - (CH 2)n9C(＝O)O-(C1-C6 alkyl), 3-to 7-membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted with one or more R 3a, C 1-C6 alkyl-O-substituted with one or more R 3b, C, C 1-C6 alkyl-S-, substituted by one or more R 3c, C 2-C6 alkenyl substituted by one or more R 3d, C 2-C6 alkynyl substituted with one or more R 3e, 3-7 membered cycloalkyl substituted with one or more R 3f, 3-7 membered cycloalkenyl substituted with one or more R 3g, a 4-10 membered heterocycloalkyl substituted with one or more R 3h, a 4-10 membered heterocycloalkenyl substituted with one or more R 3i, a C 6-C10 aryl substituted with one or more R 3j, or a 5-to 14-membered heteroaryl substituted with one or more R 3k; The heteroatoms in the 5-to 14-membered heteroaryl groups substituted by one or more R 3k are selected from one or more of N, O and S, and the number of the heteroatoms is 1,2 or 3; the hetero atoms in the 4-10 membered heterocycloalkyl group and the 4-10 membered heterocycloalkyl group substituted by one or more R 3h are selected from one or more of N, O and S, and the number of the hetero atoms is 1,2 or 3; The hetero atoms in the 4-10 membered heterocyclic alkenyl groups and the 4-10 membered heterocyclic alkenyl groups substituted by one or more R 3i are selected from one or more of N, O and S, and the number of the hetero atoms is 1, 2 or 3;
    Each R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j and R 3k is independently deuterium, halogen, -OH, -CN, C 1-C6 alkyl, C 1-C6 alkyl-O-, deuterium, C 1-C6 alkyl-S-, C 2-C6 alkenyl-, C 2-C6 alkynyl, -N (R 5)2、-(CH2)-C(＝O)N(R5)2, 3-7 membered cycloalkyl), 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted with one or more R 3-a, C 1-C6 alkyl-O-substituted with one or more R 3-b, C, C 1-C6 alkyl-S-, substituted by one or more R 3-c, C 2-C6 alkenyl substituted by one or more R 3-d, C 2-C6 alkynyl substituted with one or more R 3-e, 3-7 membered cycloalkyl substituted with one or more R 3-f, 4-10 membered heterocycloalkyl substituted with one or more R 3-g, A5 to 14 membered heteroaryl substituted with one or more R 3-h, a 3 to 7 membered cycloalkenyl substituted with one or more R 3-i, a 4 to 10 membered heterocyclenyl substituted with one or more R 3-j, or a C 6-C10 aryl substituted with one or more R 3-k; The hetero atoms in the 4-10 membered heterocycloalkyl group and the 4-10 membered heterocycloalkyl group substituted by one or more R 3-g are selected from one or more of N, O and S, and the number of the hetero atoms is 1,2 or 3; the hetero atoms in the 4-10 membered heterocyclic alkenyl groups and the 4-10 membered heterocyclic alkenyl groups substituted by one or more R 3-j are selected from one or more of N, O and S, and the number of the hetero atoms is 1,2 or 3; The heteroatoms in the 5-to 14-membered heteroaryl groups substituted by one or more R 3-h are selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3;
    Each R3-a、R3-b、R3-c、R3-d、R3-e、R3-f、R3-g、R3-h、R3-i、R3-j and R 3-k is independently deuterium, halogen, -CN, -OH, C 1-C6 alkyl, C 1-C6 alkyl-O-or 3-7 membered cycloalkyl;
    R 4a is deuterium, -OH, -CN, C 1-C6 alkyl, C 1-C6 alkyl-O-, C 1-C6 alkyl -S-、-(CH2)n7C(＝O)N(R5)2、-C(＝O)OR7、-C[N(R5)2](＝NR8)、C2-C6 alkenyl, C 2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted by one or more R 4-a, C 1-C6 alkyl-O-, substituted with one or more R 4-b, C 1-C6 alkyl-S-, substituted with one or more R 4-c, C 2-C6 alkenyl substituted with one or more R 4-d, C 2-C6 alkynyl substituted with one or more R 4-e, C 6-C10 aryl substituted with one or more R 4-f, 3-7 membered cycloalkyl substituted with one or more R 4-g, 3-7 membered cycloalkenyl substituted with one or more R 4-h, A 4-10 membered heterocycloalkyl substituted with one or more R 4-i, a 4-10 membered heterocycloalkenyl substituted with one or more R 4-j, or a 5-14 membered heteroaryl substituted with one or more R 4-k; The heteroatoms in the 5-to 14-membered heteroaryl groups substituted by one or more R 4-k are selected from one or more of N, O and S, and the number of the heteroatoms is 1,2 or 3; the hetero atoms in the 4-10 membered heterocycloalkyl group and the 4-10 membered heterocycloalkyl group substituted by one or more R 4-i are selected from one or more of N, O and S, and the number of the hetero atoms is 1,2 or 3; The hetero atoms in the 4-10 membered heterocyclic alkenyl groups and the 4-10 membered heterocyclic alkenyl groups substituted by one or more R 4-j are selected from one or more of N, O and S, and the number of the hetero atoms is 1, 2 or 3;
    Each R 4-a、R4-b、R4-c、R4-d、R4-e and R 4-f is independently-OH, deuterium, halogen, - (CH 2)n6N(R5)2、-CN、C1-C6 alkyl, C 1-C6 alkyl-O-), C 1-C6 alkyl-S-, C 2-C6 alkenyl-, C 2-C6 alkynyl-, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, A 5 to 14 membered heteroaryl, C 1-C6 alkyl substituted with one or more R 4-a-1, C 1-C6 alkyl-O-substituted with one or more R 4-a-2, C 1-C6 alkyl-S-, substituted by one or more R 4-a-3, C 2-C6 alkenyl substituted by one or more R 4-a-4, C 2-C6 alkynyl substituted with one or more R 4-a-5, 3-7 membered cycloalkyl substituted with one or more R 4-a-6, 3-7 membered cycloalkenyl substituted with one or more R 4-a-7, A 4-10 membered heterocycloalkyl substituted with one or more R 4-a-8, a 4-10 membered heterocycloalkenyl substituted with one or more R 4-a-9, a C 6-C10 aryl substituted with one or more R 4-a-10, or a 5-to 14-membered heteroaryl substituted with one or more R 4-a-11; The heteroatoms in the 5-to 14-membered heteroaryl groups substituted by one or more R 4-a-11 are selected from one or more of N, O and S, and the number of the heteroatoms is 1,2 or 3; the hetero atoms in the 4-10 membered heterocycloalkyl group and the 4-10 membered heterocycloalkyl group substituted by one or more R 4-a-8 are selected from one or more of N, O and S, and the number of the hetero atoms is 1,2 or 3; The hetero atoms in the 4-10 membered heterocyclic alkenyl groups and the 4-10 membered heterocyclic alkenyl groups substituted by one or more R 4-a-9 are selected from one or more of N, O and S, and the number of the hetero atoms is 1, 2 or 3;
    Each R 4-g、R4-h、R4-i、R4-j and R 4-k is independently-OH, deuterium, halogen 、-(CH2)n6N(R5)2、-CN、-(CH2)n7C(＝O)N(R5)2、C1-C6 alkyl, C 1-C6 alkyl-O- C 1-C6 alkyl-S-, C 2-C6 alkenyl, C 2-C6 alkynyl, oxo (= O), thio (= S), -C (= O) OR 7, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted by one or more R 4-g-1, C 1-C6 alkyl-O-substituted by one or more R 4-g-2, C, C 1-C6 alkyl-S-, substituted by one or more R 4-g-3, C 2-C6 alkenyl substituted by one or more R 4-g-4, C 2-C6 alkynyl substituted with one or more R 4-g-5, 3-7 membered cycloalkyl substituted with one or more R 4-g-6, 3-7 membered cycloalkenyl substituted with one or more R 4-g-7, a 4-10 membered heterocycloalkyl substituted with one or more R 4-g-8, a 4-10 membered heterocycloalkenyl substituted with one or more R 4-g-9, a C 6-C10 aryl substituted with one or more R 4-g-10, or a 5-to 14-membered heteroaryl substituted with one or more R 4-g-11; The heteroatoms in the 5-to 14-membered heteroaryl groups substituted by one or more R 4-g-11 are selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3; the hetero atoms in the 4-10 membered heterocycloalkyl group and the 4-10 membered heterocycloalkyl group substituted by one or more R 4- g-8 are selected from one or more of N, O and S, and the number of the hetero atoms is 1, 2 or 3; The hetero atoms in the 4-10 membered heterocyclic alkenyl groups and the 4-10 membered heterocyclic alkenyl groups substituted by one or more R 4-g-9 are selected from one or more of N, O and S, and the number of the hetero atoms is 1, 2 or 3;
    Each R 4-a-1～R4-a-11 and R 4-g-1～R4-g-11 is independently deuterium, halogen, -CN, -OH, C 1-C6 alkyl, C 1-C6 alkyl-O-, C 1-C6 alkyl-S-, or 3-7 membered cycloalkyl;
    R 4b is H, deuterium, -N (R 5)2, halogen, -OH, C 1-C6 alkyl, -CN, C 1-C6 alkyl substituted with one or more R 4-b-1, C 1-C6 alkyl-O-, C 2-C6 alkenyl or C 2-C6 alkynyl;
    Each R 4-b-1 is independently deuterium, halogen, -CN, or-OH;
    n1, n2, n3, n4, n5, n6, n7, n8, and n9 are each independently 0, 1, 2, 3,4, or 5;
    Each R 5 is independently H, -C (=o) OR 7 OR C 1-C6 alkyl;
    each R 6a and R 6b is independently H, deuterium, halogen, -CN, -OH, C 1-C6 alkyl or deuterated C 1-C6 alkyl;
    R 7 is independently H, deuterium, C 1-C6 alkyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, or 5-14 membered heteroaryl;
    R 8 is independently H, deuterium, -OH or C 1-C6 alkyl.
  2. The compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the compound of formula I is not any of the following:
  3. the compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1,
    R 4a is deuterium, -CN, C 1-C6 alkyl -S-、-(CH2)n7C(＝O)N(R5)2、-C(＝O)OR7、-C[N(R5)2](＝NR8)、C2-C6 alkenyl, C 2-C6 alkynyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted by one or more R 4-a, C 1-C6 alkyl-O-substituted by one or more R 4-b, C 1-C6 alkyl-S-, substituted by one or more R 4-c, C 2-C6 alkenyl substituted by one or more R 4-d, C 2-C6 alkynyl substituted with one or more R 4-e, C 6-C10 aryl substituted with one or more R 4-f, 3-7 membered cycloalkyl substituted by one or more R 4-g, 3-7 membered cycloalkenyl substituted by one or more R 4-h, 4-10 membered heterocycloalkyl substituted by one or more R 4-i, 4-10 membered heterocycloalkenyl substituted by one or more R 4-j, or 5-14 membered heteroaryl substituted by one or more R 4-k;
    Each R 4-a is independently-OH, deuterium, - (CH 2)n6N(R5)2、-CN、C1-C6 alkyl, C 1-C6 alkyl-O-, C 1-C6 alkyl-S- C 2-C6 alkenyl, C 2-C6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted with one or more R 4-a-1, C 1-C6 alkyl-O-, substituted with one or more R 4-a-2, C 1-C6 alkyl-S-, substituted with one or more R 4-a-3, C 2-C6 alkenyl substituted with one or more R 4-a-4, C 2-C6 alkynyl substituted with one or more R 4-a-5, 3-7 membered cycloalkyl substituted with one or more R 4-a-6, 3-7 membered cycloalkenyl substituted with one or more R 4-a-7, 4-10 membered heterocycloalkyl substituted with one or more R 4-a-8, 4-10 membered heterocycloalkenyl substituted with one or more R 4-a-9, A C 6-C10 aryl substituted with one or more R 4-a-10 or a 5 to 14 membered heteroaryl substituted with one or more R 4-a-11;
    Each R 4-b is independently-OH, deuterium, - (CH 2)n6N(R5)2、-CN、C1-C6 alkyl, C 1-C6 alkyl-O-, C 1-C6 alkyl-S- C 2-C6 alkenyl, C 2-C6 alkynyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted with one or more R 4-a-1, C 1-C6 alkyl-O-, substituted with one or more R 4-a-2, C 1-C6 alkyl-S-, substituted with one or more R 4-a-3, C 2-C6 alkenyl substituted with one or more R 4-a-4, C 2-C6 alkynyl substituted with one or more R 4-a-5, 3-7 membered cycloalkyl substituted with one or more R 4-a-6, 3-7 membered cycloalkenyl substituted with one or more R 4-a-7, 4-10 membered heterocycloalkyl substituted with one or more R 4-a-8, 4-10 membered heterocycloalkenyl substituted with one or more R 4-a-9, A C 6-C10 aryl substituted with one or more R 4-a-10 or a 5 to 14 membered heteroaryl substituted with one or more R 4-a-11;
    Each R 4-c、R4-d、R4-e and R 4-f is independently-OH, deuterium, halogen, - (CH 2)n6N(R5)2、-CN、C1-C6 alkyl, C 1-C6 alkyl-O-), C 1-C6 alkyl-S-, C 2-C6 alkenyl-, C 2-C6 alkynyl-, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, A 5 to 14 membered heteroaryl, C 1-C6 alkyl substituted with one or more R 4-a-1, C 1-C6 alkyl-O-substituted with one or more R 4-a-2, C 1-C6 alkyl-S-, substituted by one or more R 4-a-3, C 2-C6 alkenyl substituted by one or more R 4-a-4, C 2-C6 alkynyl substituted with one or more R 4-a-5, 3-7 membered cycloalkyl substituted with one or more R 4-a-6, 3-7 membered cycloalkenyl substituted with one or more R 4-a-7, A 4-10 membered heterocycloalkyl substituted with one or more R 4-a-8, a 4-10 membered heterocycloalkenyl substituted with one or more R 4-a-9, a C 6-C10 aryl substituted with one or more R 4-a-10, or a 5-to 14-membered heteroaryl substituted with one or more R 4-a-11;
    Each R 4-g、R4-h、R4-i、R4-j and R 4-k is independently-OH, deuterium, halogen 、-(CH2)n6N(R5)2、-CN、-(CH2)n7C(＝O)N(R5)2、C1-C6 alkyl, C 1-C6 alkyl-O- C 1-C6 alkyl-S-, C 2-C6 alkenyl, C 2-C6 alkynyl, oxo (= O), thio (= S), -C (= O) OR 7, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-14 membered heteroaryl, C 1-C6 alkyl substituted by one or more R 4-g-1, C 1-C6 alkyl-O-substituted by one or more R 4-g-2, C, C 1-C6 alkyl-S-, substituted by one or more R 4-g-3, C 2-C6 alkenyl substituted by one or more R 4-g-4, C 2-C6 alkynyl substituted with one or more R 4-g-5, 3-7 membered cycloalkyl substituted with one or more R 4-g-6, 3-7 membered cycloalkenyl substituted with one or more R 4-g-7, a 4-10 membered heterocycloalkyl substituted with one or more R 4-g-8, a 4-10 membered heterocycloalkenyl substituted with one or more R 4-g-9, a C 6-C10 aryl substituted with one or more R 4-g-10, or a 5-to 14-membered heteroaryl substituted with one or more R 4-g-11;
    Preferably, R 4a is- (CH 2)n7C(＝O)N(R5)2, 4-10 membered heterocyclenyl substituted by one or more R 4-j, 5-14 membered heteroaryl substituted by one or more R 4-k, C 6-C10 aryl substituted by one or more R 4-f, C 6-C10 aryl, 5-14 membered heteroaryl or C 1-C6 alkyl substituted by one or more R 4-a;
    each R 4-a is independently-OH, -CN, - (CH 2)n6N(R5)2) or C 2-C6 alkynyl;
    Each R 4-f is independently-OH, halogen, - (CH 2)n6N(R5)2 or C 2-C6 alkynyl;
    Each R 4-j and R 4-k is independently halogen 、-(CH2)n6N(R5)2、-CN、-(CH2)n7C(＝O)N(R5)2、C1-C6 alkyl, C 1-C6 alkyl-O-, oxo (=o), 4-10 membered heterocycloalkyl, or C 1-C6 alkyl substituted with one or more R 4-g-1;
    More preferably, R 4a is a 5 to 14 membered heteroaryl substituted with one or more R 4-k, a C 6-C10 aryl substituted with one or more R 4-f, a C 6-C10 aryl, or a 5 to 14 membered heteroaryl;
    Each R 4-f is independently halogen, -OH or C 2-C6 alkynyl;
    Each R 4-k is independently halogen, C 1-C6 alkyl substituted with one or more R 4-g-1, - (CH 2)n6N(R5)2、C1-C6 alkyl or-CN.
  4. The compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, meets one or more of the following conditions:
    (1) Ring A is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkenyl;
    (2) n is 0 or 1;
    (3) Each R 1 is independently halogen, -CN, -OH, -N (R 5)2、C1-C6 alkyl or C 1-C6 alkyl substituted with one or more R 1a;
    (4) Each R 1a、R1b、R1c and R 1d is independently-CN, halogen or-OH;
    (5) L is-O- (CR 6aR6b)n2 -representing the end attached to R 2;
    (6) R 2 is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl substituted by one or more R 2e;
    (7) Each R 2a、R2b、R2c、R2d、R2e、R2f and R 2j is independently halogen or C 1-C6 alkyl;
    (8) R 3 is halogen, C 6-C10 aryl, 5 to 14 membered heteroaryl, C 6-C10 aryl substituted with one or more R 3j, or 5 to 14 membered heteroaryl substituted with one or more R 3k;
    (9) Each R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j and R 3k is independently halogen, -OH, -N (R 5)2、C1-C6 alkyl, C 1-C6 alkyl substituted with one or more R 3-a, or C 2-C6 alkynyl;
    (10) Each R3-a、R3-b、R3-c、R3-d、R3-e、R3-f、R3-g、R3-h、R3-i、R3-j and R 3-k is independently halogen, -CN or-OH;
    (11) R 4a is C 1-C6 alkyl, - (CH 2)n7C(＝O)N(R5)2, 4-10 membered heterocycloalkenyl, C 6-C10 aryl, 5-to 14-membered heteroaryl, C 1-C6 alkyl substituted by one or more R 4-a, C 6-C10 aryl substituted by one or more R 4-f, 4-10 membered heterocycloalkenyl substituted by one or more R 4-j, or 5-to 14-membered heteroaryl substituted by one or more R 4-k;
    Preferably, R 4a is 4-10 membered heterocycloalkenyl substituted with one or more R 4-j, 5-14 membered heteroaryl substituted with one or more R 4-k, C 6-C10 aryl substituted with one or more R 4-f, C 6-C10 aryl, or 5-14 membered heteroaryl;
    More preferably, R 4a is a 5 to 14 membered heteroaryl substituted with one or more R 4-k, a C 6-C10 aryl substituted with one or more R 4-f, a C 6-C10 aryl, or a 5 to 14 membered heteroaryl;
    (12) Each R 4-a、R4-b、R4-c、R4-d、R4-e and R 4-f is independently-OH, halogen, - (CH 2)n6N(R5)2, -CN, or C 2-C6 alkynyl;
    Preferably, each R 4-a can be independently-OH, - (CH 2)n6N(R5)2, -CN, or C 2-C6 alkynyl, each R 4-b、R4-c、R4-d、R4-e and R 4-f can be independently-OH, halogen, - (CH 2)n6N(R5)2, or C 2-C6 alkynyl;
    More preferably, each R 4-a can be independently-OH, - (CH 2)n6N(R5)2) or-CN, further preferably-OH, each R 4-b、R4- c、R4-d、R4-e and R 4-f can be independently halogen, -OH or C 2-C6 alkynyl;
    (13) Each R 4-g、R4-h、R4-i、R4-j and R 4-k is independently halogen 、-(CH2)n6N(R5)2、-CN、-(CH2)n7C(＝O)N(R5)2、C1-C6 alkyl, C 1-C6 alkyl-O-, oxo (=o), 4-10 membered heterocycloalkyl, or C 1-C6 alkyl substituted with one or more R 4-g-1;
    (14) Each R 4-a-1～R4-a-11 and R 4-g-1～R4-g-11 is independently halogen;
    (15) R 4b is halogen;
    (16) n1, n2, n3, n4, n5, n6, n7, n8 and n9 are each independently 0 or 1;
    (17) Each R 6a and R 6b is independently H.
  5. The compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, meets one or more of the following conditions:
    (1) Ring A is 4-10 membered heterocycloalkyl;
    (2) n is 0;
    (3) R 2 is 4-10 membered heterocycloalkyl substituted with one or more R 2e;
    (4) Each R 2a、R2b、R2c、R2d、R2e、R2f and R 2j is independently halogen;
    (5) R 3 is halogen or C 6-C10 aryl substituted with one or more R 3j;
    (6) Each R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j and R 3k is independently halogen, -OH or C 2-C6 alkynyl;
    (7) R 4a is a 5-to 14-membered heteroaryl substituted with one or more R 4-k, a C 6-C10 aryl substituted with one or more R 4-f, a C 6-C10 aryl, a 5-to 14-membered heteroaryl, or a C 1-C6 alkyl substituted with one or more R 4-a;
    (8) Each R 4-a、R4-b、R4-c、R4-d、R4-e and R 4-f is independently OH, halogen or C 2-C6 alkynyl;
    (9) Each R 4-g、R4-h、R4-i、R4-j and R 4-k is independently halogen, C 1-C6 alkyl substituted with one or more R 4-g-1, - (CH 2)n6N(R5)2、C1-C6 alkyl or-CN), preferably halogen, C 1-C6 alkyl substituted with one or more R 4-g-1, - (CH 2)n6N(R5)2 or C 1-C6 alkyl;
    (10) n2 is 1;
    (11) n1, n3, n4, n5, n6, n7, n8 and n9 are each independently 0.
  6. The compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the compound of formula I satisfies any one of the following:
    Scheme one: ring A is 4-10 membered heterocycloalkyl;
    n is 0;
    L is-O- (CR 6aR6b)n2 -representing the end attached to R 2;
    R 2 is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl substituted by one or more R 2e;
    Each R 2e is independently halogen;
    R 3 is halogen or C 6-C10 aryl substituted with one or more R 3j;
    Each R 3j is independently halogen, -OH or C 2-C6 alkynyl;
    R 4a is a 5-to 14-membered heteroaryl substituted with one or more R 4-k, a C 6-C10 aryl substituted with one or more R 4-f, a C 6-C10 aryl, a 5-to 14-membered heteroaryl, or a C 1-C6 alkyl substituted with one or more R 4-a;
    Each R 4-a and R 4-f is independently OH, halogen or C 2-C6 alkynyl;
    Each R 4-k is independently halogen, C 1-C6 alkyl substituted with one or more R 4-g-1, - (CH 2)n6N(R5)2 or C 1-C6 alkyl;
    Each R 4-g-1 is independently halogen;
    R 4b is halogen;
    Each R 5 is independently H or C 1-C6 alkyl;
    n2 is 1;
    n6 is 0;
    Each R 6a and R 6b is independently H
    Scheme II: ring A is 4-10 membered heterocycloalkyl;
    n is 0;
    L is-O- (CR 6aR6b)n2 -representing the end attached to R 2;
    R 2 is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl substituted by one or more R 2e;
    Each R 2e is independently halogen;
    R 3 is halogen or C 6-C10 aryl substituted with one or more R 3j;
    Each R 3j is independently halogen, -OH or C 2-C6 alkynyl;
    R 4a is a 5-to 14-membered heteroaryl substituted with one or more R 4-k, a C 6-C10 aryl substituted with one or more R 4-f, a C 6-C10 aryl, a 5-to 14-membered heteroaryl, or a C 1-C6 alkyl substituted with one or more R 4-a;
    Each R 4-a is independently-OH;
    Each R 4-f is independently-OH, halogen, or C 2-C6 alkynyl;
    Each R 4-k is independently halogen, -CN, C 1-C6 alkyl substituted with one or more R 4-g-1, - (CH 2)n6N(R5)2 or C 1-C6 alkyl;
    Each R 4-g-1 is independently halogen;
    R 4b is halogen;
    Each R 5 is independently H or C 1-C6 alkyl;
    n2 is 1;
    n6 is 0;
    Each R 6a and R 6b is independently H;
    Scheme III: ring A is 4-10 membered heterocycloalkyl;
    n is 0;
    L is-O- (CR 6aR6b)n2 -representing the end attached to R 2;
    R 2 is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl substituted by one or more R 2e;
    Each R 2e is independently halogen or C 1-C6 alkyl;
    R 3 is halogen, C 6-C10 aryl, 5 to 14 membered heteroaryl, C 6-C10 aryl substituted with one or more R 3j, or 5 to 14 membered heteroaryl substituted with one or more R 3k;
    Each R 3j and R 3k is independently halogen, -OH, -N (R 5)2、C1-C6 alkyl, C 1-C6 alkyl substituted with one or more R 3-a, or C 2-C6 alkynyl;
    Each R 3-a is independently halogen, -CN or-OH;
    R 4a is- (CH 2)n7C(＝O)N(R5)2, 4-10 membered heterocycloalkenyl substituted by one or more R 4-j, 4-10 membered heterocycloalkenyl, 5-14 membered heteroaryl substituted by one or more R 4-k, C 6-C10 aryl substituted by one or more R 4-f, C 6-C10 aryl, 5-14 membered heteroaryl or C 1-C6 alkyl substituted by one or more R 4-a;
    Each R 4-a is independently-OH, - (CH 2)n6N(R5)2) or-CN;
    Each R 4-f is independently-OH, halogen, or C 2-C6 alkynyl;
    Each R 4-k is independently halogen, 4-10 membered heterocycloalkyl, - (CH 2)n7C(＝O)N(R5)2), C 1-C6 alkyl substituted by one or more R 4-g-1, C 1-C6 alkyl-O-, - (CH 2)n6N(R5)2、C1-C6 alkyl or-CN;
    Each R 4-g-1 is independently halogen;
    Each R 4-j is oxo (=o);
    R 4b is halogen;
    Each R 5 is independently H or C 1-C6 alkyl;
    n2 is 1;
    n6 is 0;
    n7 is 0;
    each R 6a and R 6b is independently H.
  7. The compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 6, wherein the compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, meets one or more of the following conditions:
    (1) Each of said "4-10 membered heterocycloalkyl" is independently a 5-8 membered heterocycloalkyl, for example
    (2) Each of the halogens is independently fluorine, chlorine, bromine or iodine;
    (3) Each of said "C 6-C10 aryl" is independently phenyl or naphthyl;
    (4) Each said "C 1-C6 alkyl" is independently a C 1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    (5) Each said "C 2-C6 alkynyl" is independently a C 2-C3 alkynyl, such as ethynyl, propynyl or propargyl;
    (6) Each of the "5-to 14-membered heteroaryl" is independently "a 5-to 10-membered heteroaryl having a heteroatom of 1 or 2, such as pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, quinazolinyl, indolyl, indazolyl, pyrazolopyridyl, pyrimidinyl or benzothienyl;
    (7) Each of the "4-10 membered heterocycloalkenyl" is independently a 5-8 membered heterocycloalkenyl, e.g
    (8) Each of the "3-7 membered cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
    (9) Each of said "3-7 membered cycloalkenyl" is independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl;
    (10) Each of the "C 2-C6 alkenyl" groups is independently vinyl, 1-propenyl, n-allyl, but-1-enyl, but-2-enyl, pent-1-enyl or pent-1, 4-dienyl.
  8. The compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 6, wherein the compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, meets one or more of the following conditions:
    (1) In the rings A, R 2、R4-g、R4-h、R4-i、R4-j and R 4-k, "4-10 membered heterocycloalkyl" in the "4-10 membered heterocycloalkyl" and "4-10 membered heterocycloalkyl substituted with one or more R 2e" are each independently 5-8 membered heterocycloalkyl, for example
    (2)R2a、R2b、R2c、R2d、R2e、R2f、R2j、R3、R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j、R3k、R4-a、R4-b、R4-c、R4-d、R4-e、R4-f、R4-g、R4-h、R4-i、R4-j、R4-k、R4-a-1～R4-a-11、R4-g-1～R4-g-11 And R 4b, each of said "halogen" is independently fluorine, chlorine, bromine or iodine;
    (3) In R 3 and R 4a, "C 6-C10 aryl" in the "C 6-C10 aryl substituted with one or more R 3j", "C 6-C10 aryl", and "C 6-C10 aryl substituted with one or more R 4-f" are each independently phenyl or naphthyl;
    (4)R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j、R3k、R4a、R4-g、R4-h、R4-i、R4-j、R4-k And in R 5, "C 1-C6 alkyl" in the "C 1-C6 alkyl", "C 1-C6 alkyl substituted with one or more R 4-a", "C 1-C6 alkyl-O-" and "C 1-C6 alkyl substituted with one or more R 4-g-1" are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    (5)R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j、R3k、R4-a、R4-b、R4-c、R4-d、R4-e And R 4- f, the "C 2-C6 alkynyl" groups are each independently a C 2-C3 alkynyl group, such as ethynyl, propynyl, or propargyl;
    (6) In R 4a, the "5-to 14-membered heteroaryl" and "5-to 14-membered heteroaryl" in "5-to 14-membered heteroaryl substituted with one or more R 4-k" are each independently "5-to 10-membered heteroaryl having 1 or 2 heteroatoms in N or S", such as pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, indolyl, indazolyl, pyrazolopyridinyl, pyrimidinyl or benzothienyl;
    (7) In R 4a, "4-10 membered heterocycloalkenyl" in "4-10 membered heterocycloalkenyl substituted with one or more R 4-j" are each independently 5-8 membered heterocycloalkenyl, e.g.
  9. The compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 7, wherein the compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, meets one or more of the following conditions:
    (1) Each of the "4-10 membered heterocycloalkyl" is independently Wherein saidIs that
    (2) Each of the halogens is independently fluorine or chlorine;
    (3) Each said "C 1-C6 alkyl" is independently methyl or ethyl;
    (4) Each said "C 2-C6 alkynyl" is independently an ethynyl group;
    (5) Each said "5-to 14-membered heteroaryl" is independently
  10. The compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, meets one or more of the following conditions:
    (1) Ring A is
    (2) N is 0;
    (3) L is-O-CH 2 -represents the end attached to R 2;
    (4) R 2 is
    (5) R 4b is F;
    (6) R 3 is Or Cl;
    (7) R 4a is
  11. The compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 10, wherein the compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, meets one or more of the following conditions:
    (1) R 2 is
    (2) R 4a is Preferably
  12. The compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the compound of formula I is any one of the following:
    Or the pharmaceutically acceptable salt of the compound shown in the formula I is any one of the following compounds: Is a trifluoroacetate salt of (a).
  13. A compound as follows:
    Or a hydrochloride salt of any one of the following compounds:
  14. a process for the preparation of a compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12 which is the following route:
    Route one:
    wherein P 1 is an amino protecting group, e.g., boc, PMB, bn, cbz, fmoc,
    L, R 2、R3 and R 4a are as defined in any one of claims 1 to 12;
    Step 1: in a solvent, carrying out Suzuki reaction on a compound shown as a formula SM-1 in the presence of alkali and a catalyst to obtain a compound shown as a formula SM-2;
    Step 2: in a solvent, carrying out Suzuki reaction on a compound shown as a formula SM-2 in the presence of alkali and a catalyst to obtain a compound shown as a formula SM-3;
    Step 3: deprotection reaction [ R 3 wherein the substituent R 3a、R3b (e.g., -OH, -NH 2、C2-C6 alkynyl) is protected with a protecting group, may be carried out to give a compound of formula I ];
    the deprotection reaction in step 3 satisfies one or more of the following conditions:
    (1) Under acidic conditions, deamination protecting groups and dehydroxylation protecting groups are reacted;
    (2) Removing TIPS protection in the presence of tetrabutylammonium fluoride, tetramethylammonium fluoride or cesium fluoride;
    Route two:
    Wherein P 1 is an amino protecting group, such as Boc, PMB, bn, cbz or Fmoc,
    L, R 2 and R 4a are as defined in any one of claims 1 to 12;
    Step 1: in a solvent, carrying out Suzuki reaction on a compound shown as a formula SM-1 in the presence of alkali and a catalyst to obtain a compound shown as a formula SM-4;
    step 2: under acidic conditions, the compound shown as the formula SM-4 is subjected to deamination protecting group reaction.
  15. A pharmaceutical composition comprising substance a and a pharmaceutical adjuvant; the compound shown in the formula I, stereoisomer or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12.
  16. Use of a substance a for the preparation of an RAS inhibitor, wherein said substance a is a compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 12;
    The RAS is KRAS or KRAS mutation; such as KRAS G12D, KRAS G12V.
  17. The application of the substance A in preparing medicines is characterized in that,
    The substance A is a compound shown in the formula I, a stereoisomer or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12; the substance a may be in a therapeutically effective amount; the medicament may be a medicament for the treatment and/or prophylaxis of RAS-mediated diseases; alternatively, the medicament may be a medicament for the treatment and/or prophylaxis of cancer.
  18. The use of claim 17, wherein the use satisfies one or more of the following conditions:
    (1) The RAS is KRAS or KRAS mutation; such as KRAS G12D, KRAS G12V;
    (2) The RAS mediated disease is cancer;
    (3) The cancer is selected from one or more of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, colorectal cancer, non-small cell lung cancer, esophagus cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.
CN202380019027.2A 2022-01-28 2023-01-18 Nitrogen-containing heterocyclic compound, and preparation method and application thereof Pending CN118679170A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN2022101085764 2022-01-28
CN202210108576 2022-01-28
PCT/CN2023/072929 WO2023143312A1 (en) 2022-01-28 2023-01-18 Nitrogen-containing heterocyclic compound, and preparation method therefor and use thereof

Publications (1)

Publication Number Publication Date
CN118679170A true CN118679170A (en) 2024-09-20

Family

ID=87470740

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202380019027.2A Pending CN118679170A (en) 2022-01-28 2023-01-18 Nitrogen-containing heterocyclic compound, and preparation method and application thereof

Country Status (2)

Country Link
CN (1) CN118679170A (en)
WO (1) WO2023143312A1 (en)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7713603B2 (en) 2022-02-09 2025-07-25 クアンタ セラピューティクス， インコーポレイテッド KRAS MODULATORS AND USES THEREOF
EP4532494A1 (en) 2022-05-25 2025-04-09 Quanta Therapeutics, Inc. Pyrimidine based modulators and uses thereof
CN119855815A (en) * 2022-09-21 2025-04-18 甘李药业股份有限公司 KRAS mutant protein inhibitor, and preparation method and application thereof
AU2024234154A1 (en) 2023-03-15 2025-09-25 Quanta Therapeutics, Inc. Kras modulators and uses thereof
KR20250164828A (en) 2023-03-30 2025-11-25 레볼루션 메디슨즈, 인크. Composition for inducing RAS GTP hydrolysis and use thereof
AU2024265078A1 (en) 2023-05-04 2025-12-11 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
US20250049810A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder
WO2025054530A1 (en) 2023-09-08 2025-03-13 Gilead Sciences, Inc. Pyrimidine-containing polycyclic derivatives as kras g12d modulating compounds
US20250114346A1 (en) 2023-10-09 2025-04-10 Incyte Corporation Combination therapy using a kras g12d inhibitor and pd-1 inhibitor or pd-l1 inhibitor
US20250114339A1 (en) 2023-10-09 2025-04-10 Incyte Corporation Combination therapy comprising a kras g12d inhibitor and an egfr inhibitor
US20250120981A1 (en) * 2023-10-12 2025-04-17 Mirati Therapeutics, Inc. Mrtx1133 pharmaceutical compositions
WO2025080946A2 (en) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Ras inhibitors
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11453683B1 (en) * 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
EP4182313A4 (en) * 2020-07-16 2024-10-09 Mirati Therapeutics, Inc. KRAS G12D INHIBITORS
US20230357233A1 (en) * 2020-08-26 2023-11-09 InventisBio Co., Ltd. Heteroaryl compounds, preparation methods and uses thereof

Also Published As

Publication number Publication date
WO2023143312A1 (en) 2023-08-03

Similar Documents

Publication Publication Date Title
CN118679170A (en) Nitrogen-containing heterocyclic compound, and preparation method and application thereof
JP2024524524A (en) Nitrogen-containing heterocyclic compounds, their preparation, intermediates and uses
WO2023001123A1 (en) New pyridopyrimidine derivative
AU2022200478B2 (en) Inhibitors of KEAP1-Nrf2 protein-protein interaction
CN118434747A (en) A nitrogen-containing heterocyclic compound, preparation method, intermediate and application thereof
WO2023056951A1 (en) Aryl-substituted heterocyclic compound
KR102412035B1 (en) α,β-unsaturated amide compounds derived from benzotriazole, a TGF-βRI inhibitor
CA2974784A1 (en) Inhibitors of trka kinase
CN113966336B (en) Tricyclic compounds and uses thereof
CN116390923B (en) Heterocyclic derivatives and their preparation methods and uses
TW202309029A (en) Heterocyclic compounds as triggering receptor expressed on myeloid cells 2 agonists and methods of use
CN113286796A (en) Camptothecin derivative, water-soluble prodrug thereof, pharmaceutical composition containing camptothecin derivative, preparation method and application of camptothecin derivative and water-soluble prodrug
CN108349989B (en) Pyranodipyridine compounds
CN120500487A (en) Heterocyclic compound, pharmaceutical composition and application thereof
CN113387962A (en) Pyrazolo [3,4-d ] pyrimidine-3-one derivative, pharmaceutical composition and application thereof
WO2022227987A1 (en) Heterocyclic derivative and preparation method therefor and use thereof
CN110272425B (en) Pyridinyl octahydropyrrolo[3,4-c]pyrrole derivatives and uses thereof
CA3231988A1 (en) Azaindazole macrocycle compound and use thereof
WO2024149389A1 (en) Substituted bridge ring inhibitor, preparation method therefor, and application thereof
JP7546780B2 (en) Azaheteroaryl compounds, methods for their preparation and uses
CN104822658B (en) Fused Tricyclic Amides as Multiple Kinase Inhibitors
CN118369323A (en) Heterocyclic compounds as SHP2 inhibitors, compositions comprising the same, and methods of use thereof
JP2023542789A (en) Pyrazole compounds and their preparation and use
CN120441596A (en) Pyrimidoheterocyclic compound, pharmaceutical composition and use thereof
CN118239947A (en) A compound, its intermediate, preparation method, pharmaceutical composition and application

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination