CN114644631A - KRAS G12C protein mutation inhibitor, preparation method thereof, pharmaceutical composition and application thereof - Google Patents

KRAS G12C protein mutation inhibitor, preparation method thereof, pharmaceutical composition and application thereof Download PDF

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CN114644631A
CN114644631A CN202111539540.3A CN202111539540A CN114644631A CN 114644631 A CN114644631 A CN 114644631A CN 202111539540 A CN202111539540 A CN 202111539540A CN 114644631 A CN114644631 A CN 114644631A
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唐国志
马大为
黄孟炜
刘永福
陈军利
李春水
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Shanghai Weishen Pharmaceutical Co ltd
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Abstract

The invention discloses a KRAS G12C protein mutation inhibitor, a preparation method thereof, a pharmaceutical composition and application thereof. And particularly discloses a compound shown as a formula I, a solvate, a prodrug, a metabolite or a pharmaceutically acceptable salt thereofG12CProtein mutation inhibitory activity, and can be used for treating or preventing cancer.

Description

KRAS G12C protein mutation inhibitor, preparation method thereof, pharmaceutical composition and application thereof
Technical Field
The invention relates to KRASG12CProtein mutation inhibitor, preparation method thereof, pharmaceutical composition and application thereof.
Background
Ras (rat sarcoma) proteins include KRAS, HRAS and NRAS, are members of the small GTPase (GTPase) family. RAS proteins can bind to Guanine Trinucleotide Phosphate (GTP) or Guanine Dinucleotide Phosphate (GDP), and the switch between the two states is regulated by guanine nucleotide exchange factors (GEFs) and GTP hydrolase activating protein (GAP). RAS proteins are in an "inactive" state when bound to GDP; RAS proteins are in an "activated" state when bound to GTP. In the GTP-bound state, RAS proteins interact directly with a variety of downstream effector proteins and activate signaling pathways including mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K), thereby regulating cell growth, cell movement or metabolism, and interactions between cells and their extracellular environment.
Overactive mutations of the RAS gene are the most common gene mutations in cancer, with some mutated RAS genes being carried in about 30% of human tumors. Among them KRAS is the most common mutant oncogene, accounting for 86% of all RAS mutations. Mutations in most RAS genes can reduce the binding of GAP to RAS proteins, which in turn affects the ability of GAP to catalyze GTP hydrolysis, either internally or simultaneously reduce gtpase activity in RAS proteins, resulting in an increase in RAS proteins in the GTP bound state, leaving RAS proteins in an "activated" state at all times. The activated RAS protein continuously activates downstream signaling pathways, ultimately leading to the continued growth and differentiation of cells, which in turn leads to tumorigenesis. RAS mutations are genetic drivers of a variety of cancer types including colorectal cancer (CRC), Pancreatic Ductal Adenocarcinoma (PDAC), lung adenocarcinoma (LUAD; a subtype of non-small cell lung cancer (NSCLC)), melanoma, and certain hematologic cancers.
In KRAS mutant tumors, most oncogenic mutations occur within codon 12, accounting for 83%. The G12C mutation is a relatively common subtype of KRAS gene mutation. KRASG12CMutations are prevalent in lung adenocarcinomas and occur in other tumor types, pancreatic and colorectal cancers. Despite the extensive drug discovery efforts, there is currently no strategy for KRAS G12CMutated marketed drugs. KRASG12CHas been shown to be associated with a poor prognosis of cancer. Thus, for KRASG12CThe development of mutation inhibitors has an important clinical need. Covalent KRAS reported by Shokat and colleaguesG12CThe inhibitor is used for treating KRASG12CThe possibility of mutating tumors is provided (Ostrem JM., et al. Nature,2013, 548-Dada 551). Although a series of patents have been published on KRASG12C inhibitors (WO2014143659, WO2014152588, WO2015054572, WO2016049524, WO2017201161, WO2018119183, etc.), it is still very important to find more effective KRAS inhibitors with better pharmacokinetic and pharmacodynamic properties.
Disclosure of Invention
The invention aims to solve the technical problem of the prior KRASG12CThe defect that the protein mutation inhibitor has a single structure provides a KRASG12CThe compound has novel structure and better activity and selectivity.
The invention provides a compound shown as a formula I, a solvate, a prodrug, a metabolite, or a pharmaceutically acceptable salt of the compound shown as the formula I:
Figure BDA0003413556240000021
Ring A is a 4-12 membered aliphatic heterocyclic ring containing 2-4N atoms; the lipid heterocycle is monocyclic, bridged or spiro;
R1is-C (═ O) -C (R)a)＝C(Rb)(Rc)、-C(＝O)-C≡CRc、-C(＝O)-C(＝O)-O-Rdor-C (═ O) -Rd；
RaIs hydrogen, halogen or C1-6An alkyl group;
Rband RcIndependently of one another is hydrogen, C1-6Alkyl or "substituted by one or more Rb-1Substituted C1-6Alkyl groups ";
each Rb-1Independently of one another, halogen, C1-6Alkoxy or-NRb-2Rb-3；Rb-2And Rb-3Independently is hydrogen or C1-6Alkyl, or, Rb-2、Rb-3And N to which they are bonded, together form "a 4-to 10-membered heterocycloalkyl group having 1 or 2 heteroatoms N, or N and O";
Rdis C1-6An alkyl group;
n is 0, 1, 2 or 3;
each R4Independently is C1-6Alkyl or "substituted by one or more R4-1Substituted C1-6Alkyl groups ";
each R4-1Independently halogen, cyano, hydroxy or C1-6An alkoxy group;
R2is-OR2-1、-SR2-2、-C(＝O)R2-3、-S(＝O)2R2-4、-S(＝O)R2-5、-(CR1-1R1-2)mR2-6Or NR1- 3R2-7；
R1-1、R1-2And R1-3Independently is hydrogen or C1-6An alkyl group;
m is 0, 1, 2 or 3, and when m is 0, R is represented2-6Directly connected with the parent body through a single bond;
R2-1、R2-2、R2-3、R2-4and R2-5Independently is C1-6Alkyl, by one or more ReSubstituted C1-6Alkyl radical, C1-6Alkoxy, one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms, and one or more Re-1Substituted 'one or more hetero atoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', C 6-C10Aryl radicals, substituted by one or more Re-2Substituted C6-C10Aryl, 4-10 membered heterocycloalkyl with one or more heteroatoms selected from O and N, 1-3 heteroatoms, and one or more Re-3Substituted 'hetero atom selected from one or more of O and N, 4-10 membered heterocycloalkyl group having 1-3 hetero atoms', C3-10Cycloalkyl, or, by one or more Re-4Substituted C3-10A cycloalkyl group;
R2-6is hydrogen, CN, halogen, hydroxy, C1-6Alkyl, by one or more ReSubstituted C1-6Alkyl radical, C1-6Alkoxy, one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms, and one or more Re -1Substituted 'one or more hetero atoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', C6-C10Aryl radicals, substituted by one or more Re-2Substituted C6-C10Aryl, 4-10 membered heterocycloalkyl with one or more heteroatoms selected from O and N, 1-3 heteroatoms, and one or more Re-3Substituted 'hetero atom selected from one or more of O and N, 4-10 membered heterocycloalkyl group having 1-3 hetero atoms', C3-10Cycloalkyl, or, by one or more Re-4Substituted C3-10A cycloalkyl group;
R2-7is hydrogen, C1-6Alkyl, by one or more R eSubstituted C1-6Alkyl radical, C1-6Alkoxy, one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms, and one or more Re-1Substituted 'one or more hetero atoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', C6-C10Aryl radicals, substituted by one or more Re-2Substituted C6-C10Aryl, 4-10 membered heterocycloalkyl with one or more heteroatoms selected from O and N, 1-3 heteroatoms, and one or more Re-3Substituted 'hetero atom selected from one or more of O and N, 4-10 membered heterocycloalkyl group having 1-3 hetero atoms', C3-10Cycloalkyl, or, by one or more Re-4Substituted C3-10A cycloalkyl group;
each ReIndependently "one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more Re-1Substituted 'one or more hetero atoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', C6-C10Aryl radicals, substituted by one or more Re-2Substituted C6-C10Aryl, 4-10 membered heterocycloalkyl with one or more heteroatoms selected from O and N, 1-3 heteroatoms, and one or more Re-3Substituted 'hetero atom selected from one or more of O and N, 4-10 membered heterocycloalkyl group having 1-3 hetero atoms', C 3-10Cycloalkyl, or substituted by one or more Re -4Substituted C3-10A cycloalkyl group;
Re-1、Re-2and Re-4Independently of one another, halogen, C1-6Alkyl radical, C1-6Alkoxy, -C (═ O) -C (R)a)＝C(Rb)(Rc) Or NRe-5Re-6；Re-5And Re-6Independently is hydrogen or C1-6Alkyl, or, Re-5、Re-6And N to which they are bonded form together a "4-10 membered heterocycloalkyl group having 1 or 2 heteroatoms N, or N and O";
each Re-3Independently halogen, hydroxy, cyano, C1-6Alkyl, by one or more Re-7Substituted C1-6Alkyl radical, C1-6Alkoxy, by one or more Re-8Substituted C1-6Alkoxy, -C (═ O) -C (R)a)＝C(Rb)(Rc)、NRe-5Re-6、-O(C＝O)NRe-13Re-14OR-O (C ═ O) ORe-15；Re-7And Re-8Independently halogen, hydroxy, -cyano, -COOH, C1-6Alkoxy or NRe -9Re-10，Re-9And Re-10Independently of one another is hydrogen, C1-6Alkyl, -C (═ O) Re-11or-S (═ O)2Re-12；Re-11And Re-12Independently is C1-6An alkyl group;
Re-13and Re-14Independently is hydrogen or C1-6Alkyl, or, Re-13、Re-14And N to which they are bonded, together form "a 4-to 10-membered heterocycloalkyl group having 1 or 2 heteroatoms N, or N and O"; re-15Is hydrogen or C1-6An alkyl group;
R3is hydrogen, C1-6Alkyl, by one or more R3-1Substituted C1-6Alkyl, wherein each R3-1Independently is C1-6Alkyl radical, C1-6Alkoxy, CN, halogen or OH;
x and Y are independently O, NR6Or CR7R8(ii) a Each R6Independently is hydrogen or C1-6An alkyl group; each R 7And R8Independently is H or C1-6An alkyl group; z is a single bond, O, NR6Or CR7R8(ii) a X, Y and Z are not both O or NR6；
U, V, W and Q are independently N or CR5；
Each R5Independently H, halogen, hydroxy, C substituted by one or more halogens1-6Alkyl, C substituted by one or more halogens1-6Alkoxy, cyano, C3-6Cycloalkyl radical, C1-6Alkyl sulfone group, C3-6Cycloalkyl sulfone group, C1-6Alkyl or C1-6An alkoxy group;
the carbon atom with the mark is chiral carbon atom, and is in S configuration, R configuration or the mixture of the S configuration and the R configuration.
In certain preferred embodiments of the present invention, certain groups of the compounds of formula I, solvates, prodrugs, metabolites, or pharmaceutically acceptable salts thereof are defined as follows, and groups not mentioned are as described in any of the embodiments of the present invention (abbreviated as "in one of the embodiments of the present invention"),
ring A is a 4-12 membered heterocyclic ring containing 2-4N atoms; the lipid heterocycle is monocyclic, bridged or spiro;
R1is-C (═ O) -C (R)a)＝C(Rb)(Rc)、-C(＝O)-C≡CRc、-C(＝O)-C(＝O)-O-Rdor-C (═ O) -Rd；
RaIs hydrogen, halogen or C1-6An alkyl group;
Rband RcIndependently of one another is hydrogen, C1-6Alkyl or "substituted by one or more Rb-1Substituted C1-6Alkyl groups ";
each Rb-1Independently of one another, halogen, C1-6Alkoxy or-NRb-2Rb-3；Rb-2And Rb-3Independently is hydrogen or C1-6Alkyl, or, R b-2、Rb-3And N to which they are bonded, together form "a 4-to 10-membered heterocycloalkyl group having 1 or 2 heteroatoms N, or N and O";
Rdis C1-6An alkyl group;
n is 0, 1, 2 or 3;
each R4Independently is C1-6Alkyl or "substituted by one or more R4-1Substituted C1-6Alkyl groups ";
each R4-1Independently halogen, cyano, hydroxy or C1-6An alkoxy group;
R2is-OR2-1、-SR2-2、-C(＝O)R2-3、-S(＝O)2R2-4、-S(＝O)R2-5、-(CR1-1R1-2)mR2-6Or NR1- 3R2-7；
R1-1、R1-2And R1-3Independently is hydrogen or C1-6An alkyl group;
m is 0, 1, 2 or 3, and when m is 0, R is represented2-6Directly connected with the parent body through a single bond;
R2-1、R2-2、R2-3、R2-4and R2-5Independently is C1-6Alkyl, by one or more ReSubstituted C1-6Alkyl radical, C1-6Alkoxy, one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms, and one or more Re-1Substituted 'one or more hetero atoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', C6-C10Aryl radicals, substituted by one or more Re-2Substituted C6-C10Aryl, 4-10 membered heterocycloalkyl with one or more heteroatoms selected from O and N, 1-3 heteroatoms, and one or more Re-3Substituted 'hetero atom selected from one or more of O and N, 4-10 membered heterocycloalkyl group having 1-3 hetero atoms', C3-10Cycloalkyl, or, by one or more R e-4Substituted C3-10A cycloalkyl group;
R2-6is hydrogen, CN, halogen, hydroxy, C1-6Alkyl, by one or more ReSubstituted C1-6Alkyl radical, C1-6Alkoxy, one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms, and one or more Re -1Substituted 'one or more hetero atoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', C6-C10Aryl radicals, substituted by one or more Re-2Substituted C6-C10Aryl, 4-10 membered heterocycloalkyl with one or more heteroatoms selected from O and N, 1-3 heteroatoms, and one or more Re-3Substituted 'hetero atom selected from one or more of O and N, 4-10 membered heterocycloalkyl group having 1-3 hetero atoms', C3-10Cycloalkyl, or, by one or more Re-4Substituted C3-10A cycloalkyl group;
R2-7is hydrogen, C1-6Alkyl, by one or more ReSubstituted C1-6Alkyl radical, C1-6Alkoxy, one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms, and one or more Re-1Substituted 'one or more hetero atoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', C6-C10Aryl radicals, substituted by one or more Re-2Substituted C6-C10Aryl, 4-10 membered heterocycloalkyl with one or more heteroatoms selected from O and N, 1-3 heteroatoms, and one or more R e-3Substituted 'hetero atom selected from one or more of O and N, 4-10 membered heterocycloalkyl group having 1-3 hetero atoms', C3-10Cycloalkyl, or, by one or more Re-4Substituted C3-10A cycloalkyl group;
each ReIndependently "one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more Re-1Substituted 'one or more hetero atoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', C6-C10Aryl radicals, substituted by one or more Re-2Substituted C6-C10Aryl, 4-10 membered heterocycloalkyl with one or more heteroatoms selected from O and N, 1-3 heteroatoms, and one or more Re-3Substituted 'hetero atom selected from one or more of O and N, 4-10 membered heterocycloalkyl group having 1-3 hetero atoms', C3-10Cycloalkyl, or, by one or more Re -4Substituted byC3-10A cycloalkyl group;
Re-1、Re-2and Re-4Independently of one another, halogen, C1-6Alkyl radical, C1-6Alkoxy, -C (═ O) -C (R)a)＝C(Rb)(Rc) Or NRe-5Re-6；Re-5And Re-6Independently is hydrogen or C1-6Alkyl, or, Re-5、Re-6And N to which they are bonded form together a "4-10 membered heterocycloalkyl group having 1 or 2 heteroatoms N, or N and O";
each Re-3Independently halogen, hydroxy, cyano, C 1-6Alkyl, by one or more Re-7Substituted C1-6Alkyl radical, C1-6Alkoxy, by one or more Re-8Substituted C1-6Alkoxy, -C (═ O) -C (R)a)＝C(Rb)(Rc)、NRe-5Re-6、-O(C＝O)NRe-13Re-14OR-O (C ═ O) ORe-15；Re-7And Re-8Independently halogen, hydroxy, -cyano, -COOH, C1-6Alkoxy or NRe -9Re-10，Re-9And Re-10Independently of one another is hydrogen, C1-6Alkyl, -C (═ O) Re-11or-S (═ O)2Re-12；Re-11And Re-12Independently is C1-6An alkyl group;
Re-13and Re-14Independently is hydrogen or C1-6Alkyl, or, Re-13、Re-14And N to which they are bonded, together form "a 4-to 10-membered heterocycloalkyl group having 1 or 2 heteroatoms N, or N and O"; r ise-15Is hydrogen or C1-6An alkyl group;
R3is hydrogen, C1-6Alkyl, by one or more R3-1Substituted C1-6Alkyl, wherein each R3-1Independently is C1-6Alkyl radical, C1-6Alkoxy, CN, halogen or OH;
x and Y are independently O, NR6Or CH2；R6Is hydrogen or C1-6An alkyl group; z is a single bond, O, NR6Or CH2(ii) a X, Y and Z are not both O or NR6；
U, V, W and Q are independently N or CR5；
Each R5Independently H, halogen, hydroxy, C substituted by one or more halogens1-6Alkyl, C substituted by one or more halogens1-6Alkoxy, cyano, C3-6Cycloalkyl radical, C1-6Alkyl sulfone group, C3-6Cycloalkyl sulfone group, C1-6Alkyl or C1-6An alkoxy group;
the carbon atom with the mark is chiral carbon atom, and is in S configuration, R configuration or the mixture of the S configuration and the R configuration.
In one aspect of the invention, when ring A is a 4-12 membered aliphatic heterocyclic ring containing 2-4N atoms, the aliphatic heterocyclic ring is a 6-10 membered aliphatic heterocyclic ring containing 2N atoms, e.g.
Figure BDA0003413556240000051
Is composed of
Figure BDA0003413556240000052
Figure BDA0003413556240000053
In one embodiment of the present invention, when RaWhen halogen, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.
In one aspect of the invention, when RaIs C1-6When alkyl, said C1-C6Alkyl is C1-C3Alkyl groups, such as methyl.
In one aspect of the invention, when RbAnd RcIndependently is C1-6Alkyl or "substituted by one or more Rb-1Substituted C1-6When alkyl is mentioned, C is1-C6Alkyl is C1-C3Alkyl groups, such as methyl.
In one embodiment of the present invention, when each R isb-1When independently halogen, the halogen is fluorine or chlorineBromine or iodine, for example fluorine.
In one embodiment of the present invention, when each R isb-1Independently is C1-6At alkoxy, the C1-C6Alkoxy is C1-C3Alkoxy groups, such as methoxy.
In one aspect of the invention, when Rb-2And Rb-3Independently is C1-6When alkyl, said C1-C6Alkyl is C1-C3Alkyl groups, such as methyl.
In one aspect of the invention, when RdIs C1-6When alkyl, said C1-C6Alkyl is C1-C3Alkyl groups, such as methyl.
In one embodiment of the present invention, when each R is4Independently is C1-6Alkyl or "substituted by one or more R 4-1Substituted C1-6When alkyl is mentioned, C is1-C6Alkyl is C1-C3Alkyl groups, such as methyl.
In one embodiment of the present invention, when each R is4-1Independently halogen, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.
In one aspect of the invention, when R2-1、R2-2、R2-3、R2-4And R2-5Independently is C1-6Alkyl or "substituted by one or more ReSubstituted C1-6When alkyl is mentioned, C is1-C6Alkyl is C1-C3Alkyl groups, such as methyl.
In one embodiment of the present invention, when R2-1、R2-2、R2-3、R2-4And R2-5Independently is C1-6At alkoxy, the C1-C6Alkoxy is C1-C3Alkoxy groups, such as methoxy.
In one aspect of the invention, when R2-1、R2-2、R2-3、R2-4And R2-5Independently "one or more heteroatoms selected from N, O and S, the number of heteroatoms being 1-45-12 membered heteroaryl "or" substituted with one or more Re-1When the "hetero atom (S) is (are) one or more selected from N, O and S, or 5-12 membered heteroaryl having 1-4 hetero atoms", "hetero atom (S) is (are) one or more selected from N, O and S, or 5-12 membered heteroaryl having 1-4 hetero atoms" is (are) substituted
Figure BDA0003413556240000061
In one aspect of the invention, when R2-1、R2-2、R2-3、R2-4And R2-5Independently is "one or more heteroatoms selected from O and N, 4-10 membered heterocycloalkyl having 1-3 heteroatoms" or "substituted with one or more Re-3When the substituted "hetero atom is one or more selected from O and N, and 4-to 10-membered heterocycloalkyl having 1 to 3 hetero atoms", "hetero atom is one or more selected from O and N, and 4-to 10-membered heterocycloalkyl having 1 to 3 hetero atoms" is
Figure BDA0003413556240000062
In one aspect of the invention, when R2-6In the case of halogen, the halogen is fluorine, chlorine, bromine or iodine, for example chlorine.
In one aspect of the invention, when R2-6Is C1-6Alkyl or "substituted by one or more ReSubstituted C1-6When alkyl is mentioned, C is1-C6Alkyl is C1-C3Alkyl groups, such as methyl.
In one aspect of the invention, when R2-6Is C1-6At alkoxy, the C1-C6Alkoxy is C1-C3Alkoxy groups, such as methoxy.
In one aspect of the invention, when R2-6Independently is "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S" or "substituted with one or more Re-1Substituted "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S", wherein "One or more heteroatoms selected from N, O and S, and 5-12 membered heteroaryl group having 1-4 heteroatoms
Figure BDA0003413556240000063
In one aspect of the invention, when R2-6Is "one or more hetero atoms selected from O and N, 4-10 membered heterocycloalkyl having 1-3 hetero atoms" or "substituted with one or more Re-3When the substituted "hetero atom is one or more selected from O and N, and 4-to 10-membered heterocycloalkyl having 1 to 3 hetero atoms", "hetero atom is one or more selected from O and N, and 4-to 10-membered heterocycloalkyl having 1 to 3 hetero atoms" is
Figure BDA0003413556240000064
In one embodiment of the present invention, when each R iseIndependently is "one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" or "is substituted with one or more Re-1When the substituted "hetero atom is one or more selected from N, O and S, or 5-to 12-membered heteroaryl group having 1 to 4 hetero atoms", "hetero atom is one or more selected from N, O and S, or 5-to 12-membered heteroaryl group having 1 to 4 hetero atoms" is
Figure BDA0003413556240000065
In one embodiment of the present invention, when each R iseIndependently is "one or more heteroatoms selected from O and N, 4-10 membered heterocycloalkyl having 1-3 heteroatoms" or "substituted with one or more Re-3The substituted "hetero atom is selected from one or more of O and N, 4-to 10-membered heterocycloalkyl having 1 to 3 hetero atoms", the "hetero atom is selected from one or more of O and N, and 4-to 10-membered heterocycloalkyl having 1 to 3 hetero atoms" is
Figure BDA0003413556240000071
For example
Figure BDA0003413556240000072
In one aspect of the invention, when Re-1、Re-2And Re-4Independently is C1-C6When alkyl is said C1-C6Alkyl is C1-C3Alkyl groups, such as methyl.
In one embodiment of the invention, Re-3Independently halogen, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine.
In one embodiment of the invention, R e-3Independently is C1-C6Alkyl or "substituted by one or more Re-7Substituted C1-6When alkyl is mentioned, C is1-C6Alkyl is C1-C3Alkyl groups, such as methyl.
In one embodiment of the invention, Re-3Independently is C1-6At alkoxy, the C1-C6Alkoxy is C1-C3Alkoxy groups, such as methoxy.
In one aspect of the invention, when Re-5And Re-6Independently is C1-C6When alkyl is said C1-C6Alkyl is C1-C3Alkyl groups, such as methyl or ethyl.
In one aspect of the invention, when R3Is C1-C6When alkyl, said C1-C6Alkyl is C1-C3Alkyl groups, such as methyl.
In one embodiment of the present invention, when each R is5Independently halogen, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine, chlorine or bromine, further for example fluorine or chlorine.
In one embodiment of the present invention, when each R is5C independently substituted by one or more halogens1-6Alkyl, said C substituted by one or more halogens1-6Alkyl is C substituted by one or more halogens1-3Alkyl, e.g. being-CF3。
In one embodiment of the present invention, when each R is5Independently is C1-6When alkyl, said C1-C6Alkyl is C1-C3Alkyl groups, such as methyl.
In one embodiment of the present invention, when each R is5C independently substituted by one or more halogens1-6Alkoxy, said C substituted by one or more halogens 1-6Alkoxy is C substituted by one or more halogens1-3Alkoxy, e.g. being-OCF3。
In one embodiment of the present invention, when each R is7And R8Independently is C1-6When alkyl, said C1-C6Alkyl is C1-C3Alkyl groups, such as methyl.
In one embodiment of the invention, ring A is a 6-to 10-membered aliphatic heterocyclic ring containing 2N atoms, said aliphatic heterocyclic ring being monocyclic.
In one embodiment of the invention, R1is-C (═ O) -C (R)a)＝C(Rb)(Rc)、-C(＝O)-C≡CCH3、-C(＝O)-C(＝O)-OCH3or-C (═ O) -CH3(ii) a When R isaIs halogen or C1-6When alkyl, RbAnd RcIs hydrogen; when R isbOr RcIs C1-6Alkyl or "substituted by one or more Rb-1Substituted C1-6When alkyl is "or RaIs hydrogen.
In one embodiment of the invention, RaIs hydrogen or halogen.
In one embodiment of the invention, RbAnd RcIndependently of one another is hydrogen, C1-6Alkyl or "substituted by one or more Rb-1Substituted C1-6Alkyl ", and RbAnd RcAt least one is hydrogen.
In one embodiment of the invention, each Rb-1Independently a halogen.
In one embodiment of the invention, RbAnd RcIndependently hydrogen or C "substituted by one or more halogens1-6Alkyl ", and RbAnd RcAt least one is hydrogen.
In one embodiment of the invention, n is 0, 1 or 2; preferably 1 or 2.
In one embodiment of the invention, each R4Independently methyl, cyano-substituted methyl, F-substituted methyl or hydroxy-substituted methyl; preferably cyano-substituted methyl
Figure BDA0003413556240000073
In one embodiment of the invention, R2-1Is hydrogen, C1-6Alkyl, by one or more ReSubstituted C1-6Alkyl or "substituted by one or more Re-1Substituted '5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S'.
In one embodiment of the invention, R2-2Is C1-6Alkyl or "substituted by one or more ReSubstituted C1-6Alkyl groups ".
In one embodiment of the invention, R2-5Is represented by one or more ReSubstituted C1-6An alkyl group.
In one embodiment of the present invention, m is 0.
In one embodiment of the invention, R2-6Is hydrogen, halogen, substituted by one or more Re-3Substituted "heteroatom is selected from one or more of O and N, 4-10 membered heterocycloalkyl with 1-3 heteroatoms", "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", substituted with one or more Re-1The substituted heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms, or hydroxyl.
In one embodiment of the invention, each ReIndependently "one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more Re-1Substituted "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", "heteroatom selected from one or more of O and N, 4-10 membered heterocycloalkyl with 1-3 heteroatoms", or "substituted with one or more R e-3Substituted "hetero atomsOne or more selected from O and N, and a 4-to 10-membered heterocycloalkyl group "" in which the number of hetero atoms is 1 to 3; preferably, each ReIndependently is "one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" or "is substituted with one or more Re-3The substituted "hetero atom(s)" is (are) one or more selected from O and N, and the number of hetero atoms is (are) 1 to 3, and is a 4-to 10-membered heterocycloalkyl group.
In one embodiment of the invention, Re-1Independently is C1-6An alkyl group.
In one embodiment of the invention, each Re-3Independently of one another is halogen, hydroxy, C1-6Alkyl radical, C1-6Alkoxy, -C (═ O) -C (R)a)＝C(Rb)(Rc) Or NRe-5Re-6(ii) a Preferably, Ra、RbAnd RcAre all H.
In one embodiment of the invention, R2is-OR2-1、-SR2-2、-S(＝O)R2-5Or- (CR)1-1R1-2)mR2-6。
In one embodiment of the invention, R3Is hydrogen or C1-6An alkyl group.
In one embodiment of the invention, X is O or CR7R8Y is CR7R8Z is a single bond, O or CR7R8。
In one embodiment of the invention, X and Y are CH2Z is a single bond, O or CH2。
In one embodiment of the invention, U, V, W and Q are independently CR5。
In one embodiment of the invention, each R5Independently H, halogen, C substituted by one or more halogens1-6Alkyl, C substituted by one or more halogens1-6Alkoxy, cyano, C3-6Cycloalkyl radical, C 1-6Alkyl or C1-6An alkoxy group.
In one embodiment of the invention, each R5Independently is H, halogen or C1-6An alkyl group.
In the inventionIn a certain scheme, the first and second light-emitting diodes are arranged in a parallel mode,
Figure BDA0003413556240000081
is composed of
Figure BDA0003413556240000082
In one embodiment of the invention, R1Is composed of
Figure BDA0003413556240000083
Figure BDA0003413556240000091
In one embodiment of the invention, R2is-OR2-1Or- (CR)1-1R1-2)mR2-6，R2-1Is represented by one or more ReSubstituted C1-6Alkyl radical, each ReIndependently by one or more Re-3The substituted heteroatom is one or more selected from O and N, the heteroatom number is 1-3, the heterocyclic alkyl group with 4-10 members, and ReIn (1), each Re-3Independently of one another, halogen, C1-6Alkyl or C1-6An alkoxy group; m is 0, R2-6Is represented by one or more Re-3The substituted heteroatom is one or more selected from O and N, the heteroatom number is 1-3, the heterocyclic alkyl group with 4-10 members, and R2-6In (1), each Re-3Independently is NRe-5Re-6。
In one aspect of the present invention, the first and second electrodes are,
Figure BDA0003413556240000092
is composed of
Figure BDA0003413556240000093
Figure BDA0003413556240000094
In one embodiment of the invention, R2Is hydrogen, hydroxyl, chlorine,
Figure BDA0003413556240000095
-OCH3、-SCH3、
Figure BDA0003413556240000096
Figure BDA0003413556240000101
In one aspect of the present invention, the first and second electrodes are,
Figure BDA0003413556240000102
is composed of
Figure BDA0003413556240000103
Figure BDA0003413556240000104
Figure BDA0003413556240000111
Preferably, the compound shown in the formula I is any one of the following compounds:
Figure BDA0003413556240000112
Figure BDA0003413556240000121
Figure BDA0003413556240000131
Figure BDA0003413556240000141
Figure BDA0003413556240000151
Figure BDA0003413556240000161
Figure BDA0003413556240000171
Figure BDA0003413556240000181
Figure BDA0003413556240000191
preferably, the compound shown in the formula I is any one of the following compounds:
a compound having a retention time of 1.21min under the following conditions, which is
Figure BDA0003413556240000192
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO 2/MeOH＝60/40；
A compound having a retention time of 1.99min under the following conditions
Figure BDA0003413556240000193
One stereoisomer of (a): chromatographic column, Dr.mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm; column temperature is room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 0.93min under the following conditions
Figure BDA0003413556240000194
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 1.43min under the following conditions, which is
Figure BDA0003413556240000201
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 1.24min under the following conditions, which is
Figure BDA0003413556240000202
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 2.56min under the following conditions, which is
Figure BDA0003413556240000203
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 1.01min under the following conditions
Figure BDA0003413556240000204
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO 2/MeOH＝60/40；
A compound having a retention time of 2.17min under the following conditions
Figure BDA0003413556240000205
One stereoisomer of (a): chromatographic column, Dr.mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm; column temperature is room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.74min under the following conditions, which is
Figure BDA0003413556240000211
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 5.44min under the following conditions
Figure BDA0003413556240000212
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.08min under the following conditions
Figure BDA0003413556240000213
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.22min under the following conditions, which is
Figure BDA0003413556240000214
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 1.42min under the following conditions, which is
Figure BDA0003413556240000221
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO 2/MeOH＝60/40；
A compound having a retention time of 2.71min under the following conditions, which is
Figure BDA0003413556240000222
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 1.11min under the following conditions
Figure BDA0003413556240000223
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 2.21min under the following conditions, which is
Figure BDA0003413556240000224
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 3.88min under the following conditions, which is
Figure BDA0003413556240000231
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.42min under the following conditions, which is
Figure BDA0003413556240000232
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 1.254min under the following conditions
Figure BDA0003413556240000233
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO 2/MeOH＝60/40；
A compound having a retention time of 2.267min under the following conditions
Figure BDA0003413556240000234
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.473min under the following conditions
Figure BDA0003413556240000241
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.688min under the following conditions
Figure BDA0003413556240000242
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 7.008min under the following conditions
Figure BDA0003413556240000243
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 7.199min under the following conditions
Figure BDA0003413556240000244
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.735min under the following conditions
Figure BDA0003413556240000251
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO 2/MeOH＝60/40；
A compound having a retention time of 4.758min under the following conditions
Figure BDA0003413556240000252
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 7.198min under the following conditions
Figure BDA0003413556240000253
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 7.460min under the following conditions
Figure BDA0003413556240000254
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.249min under the following conditions
Figure BDA0003413556240000261
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.333min under the following conditions
Figure BDA0003413556240000262
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm;column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 6.961min under the following conditions
Figure BDA0003413556240000263
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO 2/MeOH＝60/40；
A compound having a retention time of 7.133min under the following conditions
Figure BDA0003413556240000264
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.903min under the following conditions
Figure BDA0003413556240000271
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 5.508min under the following conditions
Figure BDA0003413556240000272
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 2.174min under the following conditions, which is
Figure BDA0003413556240000273
One stereoisomer of (a): CHIRALART Cellulose SB chromatographic column of 2cm × 25cm,5 μm; mobile phase A MtBE (0.5% 2mM NH)3-MEOH), mobile phase B: MEOH: DCM ═ 1: 1;
a compound having a retention time of 2.950min under the following conditions
Figure BDA0003413556240000274
One stereoisomer of (a): CHIRALART Cellulose SB chromatographic column of 2cm × 25cm,5 μm; mobile phase A MtBE (0.5% 2mM NH)3-MEOH), mobile phase B: MEOH: DCM ═ 1: 1;
a compound having a retention time of 1.986min under the following conditions, which is
Figure BDA0003413556240000281
One stereoisomer of (a): CHIRALPAK IE chromatographic column of 2cm × 25cm,5 μm; mobile phase A MtBE (0.5% 2mM NH)3-MEOH), mobile phase B: MEOH: DCM ═ 1: 1;
a compound having a retention time of 2.919min under the following conditions
Figure BDA0003413556240000282
One stereoisomer of (a): CHIRALPAK IE,2cm × 25cm,5 μm chromatographic column; mobile phase A MtBE (0.5% 2mM NH)3-MEOH), mobile phase B: MEOH: DCM ═ 1: 1;
a compound having a retention time of 5.137min under the following conditions
Figure BDA0003413556240000283
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 5.370min under the following conditions
Figure BDA0003413556240000284
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 0.928min under the following conditions
Figure BDA0003413556240000291
One of them is differentStructure: CHIRALPAK IF chromatographic column of 2cm × 25cm,5 μm; mobile phase A MtBE (0.5% 2mM NH)3-MEOH), mobile phase B: MEOH: DCM ═ 1: 1;
a compound having a retention time of 1.411min under the following conditions
Figure BDA0003413556240000292
One stereoisomer of (a): CHIRALPAK IF chromatographic column of 2cm × 25cm,5 μm; mobile phase A MtBE (0.5% 2mM NH) 3-MEOH), mobile phase B: MEOH: DCM ═ 1: 1;
a compound having a retention time of 1.872min under the following conditions
Figure BDA0003413556240000293
One stereoisomer of (a): CHIRALPAK IF,2cm × 25cm,5 μm chromatographic column; mobile phase A is MtBE, mobile phase B is MeOH, DCM 1: 1;
a compound having a retention time of 2.467min under the following conditions
Figure BDA0003413556240000294
One stereoisomer of (a): CHIRALPAK IF chromatographic column of 2cm × 25cm,5 μm; mobile phase A is MtBE, mobile phase B is MeOH, DCM is 1: 1;
a compound having a retention time of 0.993min under the following conditions, which is
Figure BDA0003413556240000301
One stereoisomer of (a): CHIRALPAK IF chromatographic column of 2cm × 25cm,5 μm; mobile phase A MtBE (0.5% 2mM NH)3-MEOH), mobile phase B: MEOH: DCM ═ 1: 1;
a compound having a retention time of 2.596min under the following conditions
Figure BDA0003413556240000302
One stereoisomer of (a): CHIRALPAK IF chromatographic column of 2cm × 25cm,5 μm; mobile phase A MtBE (0.5% 2mM NH)3-MEOH), mobile phase B: MEOH: DCM ═ 1: 1.
The test conditions for the above retention time are not limited to compounds, and the compounds fall within the scope of the present invention as long as the retention time obtained by the measurement under the above test conditions is the same as or within the error range described above, and the compound is one stereoisomer of the above compounds limited by the retention time.
The invention also provides a preparation method of the compound shown in the formula I, which comprises the following steps:
carrying out substitution reaction on a compound shown as a formula K-X and a compound shown as a formula K-XIII to obtain a compound shown as a formula I;
Figure BDA0003413556240000303
wherein "+", n, ring A, R1、R2、R3、R4X, Y, Z, U, V, W and Q are as defined in any one of the preceding claims and L is halogen or hydroxy.
The operation and conditions of the substitution reaction may be conventional in the art and are preferably carried out under the action of a base such as DIEA and/or TEA.
The preparation method of the compound shown in the formula I can also comprise the following steps:
carrying out deprotection reaction on the compound shown as the formula K-IX to obtain a compound shown as K-X;
Figure BDA0003413556240000311
wherein "+", n, ring A, R2、R3、R4X, Y, Z, U, V, W and Q are as defined in any one of the preceding claims, PG is an amino protecting group.
In the formulae K to IX, the amino protecting group may be an amino protecting group commonly used in the art, preferably, p-tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz).
The operation and conditions of the deprotection reaction may be conventional in the art, for example under the action of an acid (e.g. trifluoroacetic acid and/or hydrochloric acid).
The invention also provides a compound shown as the formula K-X:
Figure BDA0003413556240000312
Wherein "+", n, ring A, R2、R3、R4X, Y, Z, U, V, W and Q are as defined in any of the preceding.
Preferably, the compound shown in formula K-X is any one of the following compounds:
Figure BDA0003413556240000313
Figure BDA0003413556240000321
Figure BDA0003413556240000331
Figure BDA0003413556240000341
Figure BDA0003413556240000351
the invention also provides a pharmaceutical composition, which comprises the compound shown in the formula I, a solvate, a prodrug, a metabolite or pharmaceutically acceptable salts of the compound and the solvate, the prodrug and the metabolite, and a pharmaceutical adjuvant.
The invention also provides the compound shown in the formula I, a solvate, a prodrug, a metabolite or a pharmaceutically acceptable salt thereof, or an application of the pharmaceutical composition in preparing medicines. The medicament is used for treating cancer.
Preferably, the cancer comprises one or more of lung cancer, colon cancer, pancreatic cancer, rectal cancer, lymphatic cancer, esophageal cancer, ovarian cancer, brain glioma, cervical cancer, urothelial cancer, stomach cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, leukemia and melanoma.
The invention also provides the KRAS prepared by the compound shown in the formula I, the solvate, the prodrug, the metabolite or the pharmaceutically acceptable salt thereof or the pharmaceutical composition G12CThe application of protein mutation inhibitor.
In the application, the KRASG12CInhibitors of protein mutations are useful in mammalian organisms; also useful in vitro, primarily for experimental purposes, for example: providing an alignment as a standard or control, or making a kit according to conventional methods in the art, wherein the kit is KRASG12CThe protein mutation inhibition effect provides a rapid detection.
Unless otherwise defined, the terms used in the present invention have the following meanings:
it will be understood by those skilled in the art that the "used in the structural formulae herein describing groups" means that the corresponding group is attached via this site to other fragments, groups in the compound, according to conventions used in the art. In the present invention, the term "connected to a single bond by a chemical bond" means that the bond may have a mixture of R configuration and S configuration.
The term "comprising" is open-ended, i.e. comprising what is specified in the invention, but does not exclude other aspects.
The term "plurality" means 2, 3, 4 or 5, preferably 2 or 3.
The term "room temperature" means 20 to 30 ℃.
The term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for use by the patient. The "patient" is preferably a mammal, more preferably a human.
The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in the solvate may be present in ordered or unordered arrangements. Such solvents include, but are not limited to: water, methanol, ethanol, and the like.
The term "prodrug" refers to a derivative of a compound of the invention that, when administered to a warm-blooded animal (e.g., a human), is converted to a compound of the invention (drug). Typical examples of prodrugs include compounds having biologically labile protecting groups on the functional portion of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrated, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound.
The term "metabolite" refers to a product of degradation of a compound of the invention by one or more metabolic processes, which exerts a desired biological activity.
The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, solvate thereof, prodrug thereof, or metabolite thereof, prepared with a relatively non-toxic, pharmaceutically acceptable acid or base. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat 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, and diethanolamine salt. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acids include organic acids including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4, 4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they may be converted to base addition salts or acid addition salts. See in particular 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 Camile G.Wermuth, ed., Wiley-VCH, 2002).
The terms "compound", "solvate", "prodrug", "metabolite" and "pharmaceutically acceptable salt thereof" may exist in crystalline or amorphous form. The term "crystal form" refers to a form in which ions or molecules are arranged strictly periodically in a three-dimensional space in a defined manner and have a periodic recurring pattern at a distance; due to the above described periodic arrangement, various crystal forms, i.e. polymorphism, may exist. The term "amorphous" refers to a state in which ions or molecules are distributed in a disordered manner, i.e., the ions and molecules do not have a periodic arrangement.
The terms "compound", "solvate", "prodrug", "metabolite" and "pharmaceutically acceptable salt thereof" may, if present as stereoisomers, be present as single stereoisomers or as mixtures thereof (e.g. racemates). The term "stereoisomer" refers to either a cis-trans isomer or an optical isomer. The stereoisomers can be separated, purified and enriched by an asymmetric synthesis method or a chiral separation method (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography and the like), and can also be obtained by chiral resolution in a mode of forming bonds (chemical bonding and the like) or salifying (physical bonding and the like) with other chiral compounds and the like. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound according to the invention is not less than 95% relative to all stereoisomers of the compound.
The terms "compound", "solvate", "prodrug", "metabolite" and "pharmaceutically acceptable salt thereof" when used in the context of tautomers, may exist as single tautomers or mixtures thereof, preferably predominantly as more stable tautomers.
The atoms in the terms "compound", "solvate", "prodrug", "metabolite" and "pharmaceutically acceptable salt thereof may be present in their natural or non-natural abundance. In the case of hydrogen atoms, in its natural abundance, it is understood that about 99.985% is protium and about 0.015% is deuterium; in its unnatural abundance, it is meant that about 95% thereof is deuterium. That is, one or more atoms in the terms "compound", "solvate", "prodrug", "metabolite" and "pharmaceutically acceptable salt thereof may be an atom that is present in a non-natural abundance.
When any variable (e.g., Re) occurs multiple times in a compound's definition, the definition of the variable occurring at each position is independent of the definition of the remaining positions, and their meanings are independent of each other and do not affect each other. Thus, if a group is substituted with 1, 2 or 3 Re groups, that is to say the group may be substituted with up to 3 Re, the definition of Re in this position is independent of the definition of Re in the remaining positions. In addition, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms.
The term "alkoxy" refers to the group-O-RX, wherein RX is alkyl as defined above.
The term "cycloalkyl" refers to a monovalent saturated cyclic alkyl group, examples of which are: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the like.
The term "heterocycloalkyl" refers to a saturated monocyclic or polycyclic group having a heteroatom. Examples of heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, and the like.
The term "aryl" refers to C6-C10 aryl, such as phenyl or naphthyl.
The term "heteroaryl" refers to an aromatic group containing a heteroatom, preferably an aromatic 5-6 membered monocyclic or 9-10 membered bicyclic ring containing 1, 2 or 3 members independently selected from nitrogen, oxygen and sulfur, and when bicyclic, at least one of the rings has aromatic character. Examples of heteroaryl groups are: furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, quinolyl, isoquinolyl and the like.
In some cases, standard techniques are used for chemical synthesis, chemical analysis, light emitting device performance detection.
In addition, unless otherwise explicitly indicated, the recitation of "… independently" as used herein is to be understood broadly and means that each individual species so described is independently from the others and may be independently the same or different specific groups. In more detail, the description "… is independently" can mean that the specific options expressed between the same symbols in different groups do not affect each other; it may also be indicated that the specific options expressed between the same symbols do not affect each other in the same group.
The term "pharmaceutical excipients" refers to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations, and is all substances contained in pharmaceutical preparations, except for the active ingredient. See pharmacopoeia of the people's republic of China (2015 year Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe,2009Sixth Edition)
The term "treatment" refers to therapeutic therapy. Where specific conditions are involved, treatment refers to: (1) relieving one or more biological manifestations of a disease or disorder, (2) interfering with (a) one or more points in a biological cascade that causes or contributes to 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 one or more biological manifestations of a disorder or disorder.
The term "prevention" refers to a reduced risk of acquiring or developing a disease or disorder.
The preferred compounds of the present invention can be obtained by combining the above preferred conditions in any combination without departing from the general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the present invention provides a series of novel compounds with good KRASG12CProtein mutation inhibitory activity, and can be used for treating or preventing cancer.
The compounds of the invention show strong cytotoxicity to various tumor cells, for example, all the compounds of the invention show proliferation inhibition activity to NCI-H358, MIA PaCa-2 and other cells, and the IC50 value is less than 100 mu M.
Drawings
FIG. 1 is an X-Ray diagram of intermediate A27.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples, compounds were prepared using the following procedure:
Figure BDA0003413556240000381
in the above compounds, L is halogen (e.g. chloro) or hydroxy, PG is a common amino protecting group (e.g. t-butyloxycarbonyl), and the remaining substituents are as defined in any one of the preceding.
Carrying out substitution reaction on an initial compound K-I to obtain K-II; performing halogenation reaction on the K-II to obtain K-III; K-III and K-XI undergo substitution reaction to obtain K-IV; removing protective groups from K-IV to obtain K-V; performing halogenation reaction on the K-V to obtain K-VI; K-VI and K-XII are subjected to substitution reaction to obtain K-VII; K-VII is subjected to substitution reaction to obtain K-VIII; K-VIII is subjected to reduction ammonolysis reaction (or substitution reaction) to obtain K-IX; removing protective groups from K-IX to obtain K-X; carrying out substitution or acylation reaction on the K-X and the K-XIII to obtain a compound I; and (3) carrying out SFC chiral resolution on the compound I to obtain a compound Ia and a compound Ib. The operations and conditions of each step may be conventional in the art.
In the following examples, the structures of the compounds were determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
The SHIMADZU LC system (column:
Figure BDA0003413556240000391
CSHTMPrep-C18, 19 x 150mm, liquid handler LH-40, pump LC-20AP, detector SPD-20A, system controller CBM-20A, solvent system: acetonitrile and 0.05% aqueous trifluoroacetic acid).
LC/MS spectra of compounds were obtained using LC/MS (Agilent Technologies 1200 Series). LC/MS conditions were as follows (run time 10 min):
acid conditions: a: 0.05% trifluoroacetic acid in water; b: 0.05% trifluoroacetic acid in acetonitrile;
alkaline conditions: a: 0.05% NH3·H2An aqueous solution of O; b: acetonitrile
Neutral conditions are as follows: a: 10mM NH4An aqueous solution of OAC; b: acetonitrile
If not specially adaptedIn the following examples, the intermediate and the final compound were purified by silica gel column chromatography or used
Figure BDA0003413556240000392
CSHTM Prep-C18(5μm，OBDTM19 x 150mm) chromatography column or xbridge (tm) Prep Phenyl (5 μm, OBD)TM30 x 100mm) was purified by preparative HPLC on a reverse phase chromatography column.
Silica gel column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
The CombiFlash rapid preparation instrument uses CombiFlash Rf200(TELEDYNE ISCO).
The silica gel plate used in the Thin Layer Chromatography (TLC) detection product adopts a silica gel plate with the specification of 0.15 mm-0.2 mm, and the silica gel plate used in the thin layer chromatography separation and purification product adopts the specification of 0.4 mm-0.5 mm.
Unless otherwise indicated, in the following examples, intermediates or final compounds were isolated via SFC, under the following conditions: equipment: waters SFC 150 preparative chromatograph; chromatographic column CHIRAL ART Cellulose-SB,5cm × 25cm,5 μm or Dr. mail Reprosil Chiral Chiral-JM, 250 × 25mm, 10 μm; column temperature, room temperature; mobile phase of ethanol in n-hexane or CO 265/35; the flow rate is 70 g/min; the wavelength is 214 nm; the back pressure was 100 bar.
Known starting materials for the present invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc), Darri Chemicals, and the like.
The acronyms are: AcOH: acetic acid; ACN: acetonitrile; AcCl: acetyl chloride; acrylamide: prop-2-enamide; AgF: silver fluoride; ag2O: silver oxide; BH3: borane; boc2O: tert-butyloxycarbonyl carbonate; boc: a tert-butoxycarbonyl group; conc. HCl: concentrated hydrochloric acid; c2Br2Cl4:1, 2-dibromotetrachloroethane; cbz: a benzyloxycarbonyl group; CH (CH)3I: methyl iodide; cs2CO3: cesium carbonate; DAST: diethylaminosulfur trifluoride; DIEA: n, N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DCM: dichloromethane; a Dioxane: 1, 4-dioxane; DMF: dimethylformamide; DMA: dimethylacetamide; DMS: dimethyl sulfoxide; DCE: 1, 2-dichloroethane; DMF-DMA: 1, 1-dimethoxy-N, N-dimethyl-methylamine; dppf: bis diphenylphosphinoferrocene; EDCI: 1-ethyl-3 (3-dimethylpropylamine) carbodiimide; ethyl propiolate: ethyl propionate; EtOH: ethanol; et (Et) 3N: triethylamine; h2: hydrogen gas; HCOONH4: ammonium formate; LAH: aluminum lithium hydride; LiHMDS: lithium bis (trimethylsilyl) amide; LDA: lithium diisopropylamide; LiOH: lithium hydroxide; LiAlH4: lithium aluminum hydride; MeOH: methanol; MsC: methanesulfonyl chloride; MW: carrying out microwave reaction; m-CPBA: m-chloroperoxybenzoic acid; n-BuLi: n-butyl lithium; NaH: sodium hydride; NaHMDS: sodium bis (trimethylsilyl) amide; ph3PCH2OMeCl: methoxymethyl triphenyl phosphonium chloride; pd2(dba)3: tris (dibenzylideneacetone) dipalladium; pd (dppf) Cl2: [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; PPA: polyphosphoric acid; POCl3: phosphorus oxychloride; Pd/C: palladium on carbon; pyrrolidine: a pyrrolidine; SOCl2: thionyl chloride; t-BuOK: potassium tert-butoxide; t-butyl nitrate: nitrous acid tert-butyl ester; t-BuLi: tert-butyl lithium; toluene: toluene; TsOH: p-toluenesulfonic acid; THF: tetrahydrofuran; TFA: trifluoroacetic acid; TEA: triethylamine; a Urea: urea; xphos: 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl; xantphos: 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene; Zn/Cu: a zinc copper reagent; zn: zinc powder; zn (CN)2: zinc cyanide.
PREPARATION EXAMPLE 1 intermediate A1
4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000401
Step 1 preparation of 4- (2-chloro-6-methyl-5-nitropyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000402
2, 4-dichloro-6-methyl-5-nitropyrimidine (6 g, 28.8 mmol) was dissolved in anhydrous dichloromethane (30 ml) and tert-butyl piperazine-1-carboxylate (10.75 g, 57.7 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by addition of ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 4- (2-chloro-6-methyl-5-nitropyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (6 g, 58% yield). MS:358.1(M + H)+。1H NMR(400MHz,Chloroform-d)δ3.54(s,8H),2.45(s,3H),1.49(s,9H)。
Step 2 preparation of 4- (2-chloro-6-methyl-5-nitropyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000411
Tert-butyl 4- (2-chloro-6-methyl-5-nitropyrimidin-4-yl) piperazine-1-carboxylate (1.8 g, 5.03 mmol) was dissolved in anhydrous tetrahydrofuran (40 ml), LDA (6.04 mmol) was slowly added with stirring at-78 ℃ and stirring was continued for 30 minutes, and then a solution of 1, 2-dibromo-1, 1,2, 2-tetrachloroethane (1.966 g, 6.04 mmol) in tetrahydrofuran (10 ml) was added to the reaction solution. After the completion of the dropping, the reaction mixture was further stirred at-78 ℃ for 0.5 hour, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 4- (6- (bromomethyl) -2-chloro-5-nitropyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (1 g, 45% yield). 436.1 MS &438.1(M+H)+。
Step 3 preparation of tert-butyl 4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate
Figure BDA0003413556240000412
Methyl 1,2,3, 4-tetrahydronaphthalene-1-carboxylate (1.568 g, 8.24 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml), LDA (5.50 mmol) was added slowly with stirring at-78 ℃ and stirring was continued for 30 minutes at-78 ℃, then a solution of tert-butyl 4- (6- (bromomethyl) -2-chloro-5-nitropyrimidin-4-yl) piperazine-1-carboxylate (1.2 g, 2.75 mmol) in tetrahydrofuran (10 ml) was added to the reaction. After the completion of the dropping, the reaction mixture was further stirred at-78 ℃ for 0.5 hour, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give tert-butyl 4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate (300 mg, 21% yield) as a yellow solid. MS:546.1(M + H)+。
Preparation example 2 intermediate A2
(3S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000421
Step 1 preparation of (S) -4- (2-chloro-6-methyl-5-nitropyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000422
2, 4-dichloro-6-methyl-5-nitropyrimidine (5.0 g, 24.04 mmol) was dissolved in anhydrous dichloromethane (30 ml) and (S) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (9.63 g, 48.1 mmol) was added slowly with stirring at 0 deg.C). After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by adding ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (S) -4- (2-chloro-6-methyl-5-nitropyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester as a yellow solid (8 g, 90% yield). MS:372.1(M + H)+。
Step 2 preparation of (S) -4- (6- (bromomethyl) -2-chloro-5-nitropyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000431
Tert-butyl (S) -4- (2-chloro-6-methyl-5-nitropyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (4 g, 10.76 mmol) was dissolved in anhydrous tetrahydrofuran (40 ml), LDA (12.91 mmol) was slowly added with stirring at-65 ℃ and stirring was continued for 40 minutes, and then a solution of 1, 2-dibromo-1, 1,2, 2-tetrachloroethane (4.20 g, 12.91 mmol) in tetrahydrofuran (10 ml) was added to the reaction solution. After the completion of the dropping, the reaction mixture was further stirred at-65 ℃ for 0.5 hour, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (S) -tert-butyl 4- (6- (bromomethyl) -2-chloro-5-nitropyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (1.0 g, 21% yield) as a yellow solid. MS 450.1 &452.1(M+H)+。
Step 3 preparation of tert-butyl (3S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Figure BDA0003413556240000432
Methyl 1,2,3, 4-tetrahydronaphthalene-1-carboxylate (169 mg, 0.887 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml) at-78 deg.CLDA (0.887 mmol) was added slowly with stirring and stirring was continued at-78 ℃ for 30 minutes before a solution of (S) -tert-butyl 4- (6- (6-bromomethyl) -2-chloro-5-nitropyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (200 mg, 0.444 mmol) in tetrahydrofuran (10 ml) was added to the reaction. After the completion of the dropping, the reaction mixture was further stirred at-78 ℃ for 0.5 hour, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (3S) -tert-butyl 4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (140 mg, 56.3% yield) as a yellow solid. MS:561.1(M + H)+。
Preparation example 3 intermediate A3
(2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000441
Step 1 preparation of 2, 4-bis (benzyloxy) -6-methyl-5-nitropyrimidine
Figure BDA0003413556240000442
2, 4-dichloro-6-methyl-5-nitropyrimidine (20 g, 96 mmol) and phenylmethanol (52.0 g, 481 mmol) are dissolved in anhydrous tetrahydrofuran (40 ml) and potassium tert-butoxide (21.58 g, 192 mmol) is added with stirring under reflux. After the addition was complete, the reaction mixture was stirred for an additional 1 hour, then quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 2, 4-bis (benzyloxy) -6-methyl-5-nitropyrimidine (16 g, 47.4% yield) as a white solid. MS:352.1(M + H)+。
Step 2 preparation of 2, 4-bis (benzyloxy) -6- (bromomethyl) -5-nitropyrimidine
Figure BDA0003413556240000443
2, 4-bis (benzyloxy) -6-methyl-5-nitropyrimidine (15 g, 42.7 mmol) was dissolved in anhydrous tetrahydrofuran (500 ml), LiHMDS (68.3 mmol) was slowly added with stirring at-78 ℃ and stirring was continued for 40 minutes, and then a solution of 1, 2-dibromo-1, 1, 2, 2-tetrachloroethane (13.90 g, 42.7 mmol) in tetrahydrofuran (10 ml) was added to the reaction solution. After the completion of the dropping, the reaction mixture was further stirred at-78 ℃ for 0.5 hour, and then quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 2, 4-bis (benzyloxy) -6- (bromomethyl) -5-nitropyrimidine (12.8 g, 70% yield) as a yellow solid. MS 430.1 &432.1(M+H)+。
Step 3 preparation of methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate
Figure BDA0003413556240000451
Methyl 1,2,3, 4-tetrahydronaphthalene-1-carboxylate (6.63 g, 34.9 mmol) was dissolved in anhydrous tetrahydrofuran (150 ml), LDA (34.9 mmol) was added slowly with stirring at-78 ℃ and stirring at-78 ℃ was continued for 30 minutes before a solution of 2, 4-bis (benzyloxy) -6- (bromomethyl) -5-nitropyrimidine (5 g, 11.62 mmol) in tetrahydrofuran (15 ml) was added to the reaction. After the completion of the dropping, the reaction mixture was further stirred at-78 ℃ for 0.5 hour, and then quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product which was purified by silica gel column chromatography to give 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene as a white solidMethyl-1-carboxylate (4.5 g, 72% yield). MS 540.1(M + H)+。
Step 4 preparation of methyl 1- ((2, 6-dihydroxy-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate
Figure BDA0003413556240000452
Methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (1.0 g, 1.853 mmol) was dissolved in trifluoroacetic acid (5 ml). The reaction mixture was slowly warmed to 100 ℃ under nitrogen and stirred under microwave conditions for 1 hour, then the reaction mixture was concentrated and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give methyl 1- ((2, 6-dihydroxy-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (600 mg, 90% yield) as a yellow solid. MS:360.1(M + H) +。
Step 5 preparation of methyl 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate
Figure BDA0003413556240000453
Methyl 1- ((2, 6-dihydroxy-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (2.2 g, 6.12 mmol) was dissolved in phosphorus oxychloride (15 ml) and DIEA (791 mg, 6.12 mmol) was added with stirring at 0 ℃. The reaction mixture was slowly warmed to 110 ℃ under nitrogen and stirred for 6 hours, then the reaction mixture was concentrated, extracted with dichloromethane and the solution was poured into saturated sodium bicarbonate solution and stirred for 1 hour. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give methyl 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (2.2 g, 91% yield) as a yellow solid. MS:397.2(M + H)+。
Step 6 preparation of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
Figure BDA0003413556240000461
Methyl 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (1.5 g, 3.79 mmol) was dissolved in anhydrous dichloromethane (30 ml) and tert-butyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (1.71 g, 7.57 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by addition of ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (1.0 g, 45% yield). MS:586.1(M + H) +。
Preparation example 4 intermediate A4
(2R, 6S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2, 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000462
Methyl 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate a 3/step 5,0.5 g, 1.3 mmol) was dissolved in anhydrous dichloromethane (30 ml) and tert-butyl (2R, 6S) -2, 6-dimethylpiperazine-1-carboxylate (0.57 g, 2.6 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by adding ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give (2R, 6S) -4 as a yellow solidTert-butyl- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2, 6-dimethylpiperazine-1-carboxylate (0.402 g, 54% yield). MS:574.1(M + H)+。
Preparation example 5 intermediate A5
(2R, 5S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2, 5-dimethylpiperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000471
Methyl 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate a 3/step 5,0.5 g, 1.3 mmol) was dissolved in anhydrous dichloromethane (30 ml) and tert-butyl (2R, 5S) -2, 5-dimethylpiperazine-1-carboxylate (0.57 g, 2.6 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by adding ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give tert-butyl (2R, 5S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2, 5-dimethylpiperazine-1-carboxylate (0.342 g, 46% yield) as a yellow solid. MS:574.1(M + H)+。
Preparation example 6 intermediate A6
7- (2-chloro-6- (((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester
Figure BDA0003413556240000481
Methyl 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate A3/step 5,0.5 g, 1.3 mmol) was dissolved in anhydrous dichloromethane (30 ml) and 2, 7-diazaspiro [3.5] was added slowly with stirring at 0 ℃ ]Nonane-2-carboxylic acid tert-butyl ester (0.588 g)2.6 mmol). After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by addition of ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give 7- (2-chloro-6- (((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2, 7-diazaspiro [3.5 ] as a yellow solid]Nonane-2-carboxylic acid tert-butyl ester (0.388 g, 51% yield). MS:587.1(M + H)+。
Preparation example 7 intermediate A7
(1R, 5S) -3- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
Figure BDA0003413556240000482
Methyl 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate A3/step 5,0.5 g, 1.3 mmol) was dissolved in anhydrous dichloromethane (30 ml) and (1R, 5S) -3, 8-diazabicyclo [3.2.1] was added slowly with stirring at 0 ℃]Octane-8-carboxylic acid tert-butyl ester (0.551 g, 2.6 mmol). After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by adding ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give (1R, 5S) -3- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1 ]Octane-8-carboxylic acid tert-butyl ester (0.56 g, 75.1% yield). MS:573.1(M + H)+。
Preparation example 8 intermediate A8
(1R, 5S) -8- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester
Figure BDA0003413556240000491
Methyl 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate A3/step 5,0.5 g, 1.3 mmol) was dissolved in anhydrous dichloromethane (30 ml) and (1R, 5S) -3, 8-diazabicyclo [3.2.1] was added slowly with stirring at 0 ℃]Octane-3-carboxylic acid tert-butyl ester (0.551 g, 2.6 mmol). After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by adding ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give (1R, 5S) -8- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Octane-3-carboxylic acid tert-butyl ester (0.49 g, 65.9% yield). MS:573.1(M + H)+。
Preparation example 9 intermediate a9
(2R) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (fluoromethyl) piperazine-1-carboxylic acid benzyl ester
Figure BDA0003413556240000501
Step 1 preparation of (R) -3- (fluoromethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000502
Tert-butyl (R) -3- (hydroxymethyl) piperazine-1-carboxylate (2 g, 9.25 mmol) was dissolved in anhydrous dichloromethane (30 ml) and a solution of N-ethyl-N- (trifluorosulfanylamino) ethylamine (1.79 g, 11.10 mmol, 1.47 ml) in dichloromethane (2 ml) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was slowly warmed to room temperature and stirred for 3 hours, and after the completion of the reaction, the reaction solution was used directly for the next reaction.
Step 2 preparation of 4- (tert-butyl) (R) -2- (fluoromethyl) piperazine-1-benzyl-1, 4-dicarboxylate
Figure BDA0003413556240000503
N-ethyl-N-isopropyl-propan-2-amine (1.19 g, 9.21 mmol, 1.60 ml) and benzyl 2, 5-dioxopyrrolidine-1-carboxylate (3.22 g, 13.81 mmol) were slowly added to a solution of tert-butyl (R) -3- (fluoromethyl) piperazine-1-carboxylate (9.25 mmol) in dichloromethane (30 ml) with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was slowly warmed to room temperature and stirred for another 3 hours, then quenched by adding ice water and extracted by diluting with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 4- (tert-butyl) (R) -2- (fluoromethyl) piperazine-1-benzyl-1, 4-dicarboxylate (1.02 g, 31.4% yield) as a yellow solid. MS:353.1(M + H) +。1H NMR(400MHz,CDCl3)δ7.41–7.29(m,5H),5.21–5.10(m,2H),4.55–4.35(m,3H),4.19–3.82(m,3H),3.16–2.98(m,3H),2.89(s,1H),1.47(s,9H)。
Step 3 preparation of benzyl (R) -2- (fluoromethyl) piperazine-1-carboxylate
Figure BDA0003413556240000511
4- (tert-butyl) (R) -2- (fluoromethyl) piperazine-1-benzyl-1, 4-dicarboxylate (300 mg, 0.851 mmol) was dissolved in a mixed solution of dichloromethane (5 ml) and TFA (2 ml), and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate and extracted, and the organic phase was washed with saturated aqueous sodium carbonate solution, saturated brine, dried over anhydrous dried sodium sulfate, then filtered, and concentrated to give benzyl (R) -2- (fluoromethyl) piperazine-1-carboxylate (190 mg, 88% yield) as a yellow oil. MS 253.1(M + H)+。
Step 4 benzyl (2R) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (fluoromethyl) piperazine-1-carboxylate
Figure BDA0003413556240000512
Methyl 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate a 3/step 5,0.3 g, 0.757 mmol) was dissolved in anhydrous dichloromethane (10 ml) and benzyl (R) -2- (fluoromethyl) piperazine-1-carboxylate (191 mg, 0.757 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by adding ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give benzyl (2R) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (fluoromethyl) piperazine-1-carboxylate (185 mg, 39.9% yield) as a yellow solid. MS 613.1(M + H) +。
Preparation example 10 intermediate A10
(3S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -3- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000513
Figure BDA0003413556240000521
Step 1 preparation of 1-benzyl 4- (tert-butyl) (R) -2- (hydroxymethyl) piperazine-1, 4-dicarboxylate
Figure BDA0003413556240000522
(3R) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (5.2 g, 24.04 mmol) was dissolved in a mixed solution of dichloromethane (20 ml) and water (20 ml), and stirred at 0 deg.CAdding NaHCO into the mixture3(6.1 g, 72.62 mmol) followed by the slow addition of a solution of benzyl chloroformate (4.3 g, 25.21 mmol) in dichloromethane (10 ml). After the completion of the dropping, the reaction mixture was warmed to room temperature and stirred for another 18 hours, then quenched by adding ice water and extracted by diluting with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 1-benzyl 4- (tert-butyl) (R) -2- (hydroxymethyl) piperazine-1, 4-dicarboxylate (9.1 g, 108.0% yield) as a yellow solid. 351.1 MS&251.1(M+H)+。
Preparation of Step 2: 1-benzyl 4- (tert-butyl) (R) -2- (((methylsulfonyl) oxy) methyl) piperazine-1, 4-dicarboxy-late
Figure BDA0003413556240000523
1-benzyl 4- (tert-butyl) (R) -2- (hydroxymethyl) piperazine-1, 4-dicarboxylate (5.3 g, 15.13 mmol), DIEA (3.91 g, 30.25 mmol, 5.27 mL) was dissolved in anhydrous dichloromethane (30 mL) and a solution of MsCl (2.60 g, 22.69 mmol) in dichloromethane (10 mL) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by adding ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give 1-benzyl 4- (tert-butyl) (R) -2- (((methylsulfonyl) oxy) methyl) piperazine-1, 4-dicarboxylic ester as a yellow oil (5.3 g, 81.78% yield). MS 429.1 &329.1(M+H)+。
Step 3 preparation of 1-benzyl 4- (tert-butyl) (S) -2- (cyanomethyl) piperazine-1, 4-dicarboxylate
Figure BDA0003413556240000531
1-benzyl 4- (tert-butyl) (R) -2- (((methylsulfonyl) oxy) methyl) piperazine-1, 4-dicarboxylic acid ester (5.3 g, 12.37 mmol) andpotassium cyanide KCN (1.61 g, 24.72 mmol) was dissolved in DMA (40 ml). The reaction mixture was slowly raised to 80 ℃ under nitrogen and stirred for 18 hours, then diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 1-benzyl 4- (tert-butyl) (S) -2- (cyanomethyl) piperazine-1, 4-dicarboxylate (4 g, 89.9% yield) as a yellow oil. MS:360.1&304.1(M+H)+。
Step 4 preparation of tert-butyl (S) -3- (cyanomethyl) piperazine-1-carboxylate
Figure BDA0003413556240000532
1-benzyl 4- (tert-butyl) (S) -2- (cyanomethyl) piperazine-1, 4-dicarboxylate (2.4 g, 6.68 mmol) was dissolved in ethanol (5 ml) and palladium on carbon (711 mg) was added to the reaction mixture with stirring. The reaction mixture was stirred at room temperature for 1 hour under hydrogen, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give (S) -3- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (1.5 g, 100% yield) as a yellow solid. MS:226.1(M + H) +。
Step 5 preparation of tert-butyl (3S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -3- (cyanomethyl) piperazine-1-carboxylate
Figure BDA0003413556240000533
Methyl 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate a 3/step 5,600 mg, 1.514 mmol) was dissolved in anhydrous dichloromethane (10 ml) and t-butyl S) -3- (cyanomethyl) piperazine-1-carboxylate (341 mg, 1.514 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by adding ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfateDrying, followed by filtration and concentration gave a crude product which was purified by silica gel column chromatography to give tert-butyl (3S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -3- (cyanomethyl) piperazine-1-carboxylate (450 mg, 50.8% yield) as a yellow solid. MS:586.1(M + H)+。
Preparation example 11 intermediate A11
(2S) -2- (cyanomethyl) -4- (2-methoxy-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000541
Tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3,150 mg, 0.256 mmol) was dissolved in anhydrous methanol (5 ml) and sodium methoxide (27.7 mg, 0.513 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was warmed to room temperature and stirred for another 1 hour, and then quenched by adding ice water and extracted by diluting with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (2S) -2- (cyanomethyl) -4- (2-methoxy-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.12 g, 100% yield). MS:581.1(M + H) +。
Preparation example 12 intermediate A12
(2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester
Figure BDA0003413556240000542
Figure BDA0003413556240000551
Step 1 preparation of methyl 2, 3-dihydro-1H-indene-1-carboxylate
Figure BDA0003413556240000552
2, 3-dihydro-1H-indene-1-carboxylic acid (11 g, 67.8 mmol) was dissolved in anhydrous methanol (100 ml) and thionyl chloride (40.3 g, 339 mmol) was added slowly with stirring at 0 ℃. After the addition was complete, the reaction mixture was slowly raised to 70 ℃ and stirring was continued for 1 hour. After completion of the reaction, the reaction mixture was concentrated and extracted by diluting with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give methyl 2, 3-dihydro-1H-indene-1-carboxylate (11 g, 92.1% yield) as a colorless oil. MS:177.1(M + H)+。
Step 2 preparation of methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -2, 3-dihydro-1H-indene-1-carboxylate
Figure BDA0003413556240000553
Methyl 2, 3-dihydro-1H-indene-1-carboxylate (1.3 g, 6.97 mmol) was dissolved in anhydrous tetrahydrofuran (40 ml), LDA (6.97 mmol) was added slowly with stirring at-78 ℃ and stirring at-78 ℃ was continued for 30 minutes, then a solution of 2, 4-bis (benzyloxy) -6- (bromomethyl) -5-nitropyrimidine (intermediate a3-2,1.0 g, 2.32 mmol) in tetrahydrofuran (10 ml) was added to the reaction. After the completion of the dropping, the reaction mixture was further stirred at-78 ℃ for 0.5 hour, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -2, 3-dihydro-1H-indene-1-carboxylate (670 mg, 55% yield) as a yellow solid. MS 526.1(M + H) +。
Step 3 preparation of 1- ((2, 6-dihydroxy-5-nitropyrimidin-4-yl) methyl) -2, 3-dihydro-1H-indene-1-carboxylic acid methyl ester
Figure BDA0003413556240000561
Methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -2, 3-dihydro-1H-indene-1-carboxylate (2.0 g, 3.81 mmol) was dissolved in trifluoroacetic acid (5 ml). The reaction mixture was slowly warmed to 100 ℃ under nitrogen and stirred under microwave conditions for 1 hour, then the reaction mixture was concentrated and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give methyl 1- ((2, 6-dihydroxy-5-nitropyrimidin-4-yl) methyl) -2, 3-dihydro-1H-indene-1-carboxylate (1.3 g, 99% yield) as a yellow solid. MS:346.1(M + H)+。
Step 4 preparation of 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -2, 3-dihydro-1H-indene-1-carboxylic acid methyl ester
Figure BDA0003413556240000562
Methyl 1- ((2, 6-dihydroxy-5-nitropyrimidin-4-yl) methyl) -2, 3-dihydro-1H-indene-1-carboxylate (600 mg, 1.738 mmol) was dissolved in phosphorus oxychloride (15 ml) and DIEA (225 mg, 1.73 mmol) was added with stirring at 0 ℃. The reaction mixture was slowly warmed to 110 ℃ under nitrogen and stirred for 6 hours, then the reaction mixture was concentrated, extracted by dilution with dichloromethane and the solution was poured into saturated sodium bicarbonate solution and stirred for 1 hour. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give methyl 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -2, 3-dihydro-1H-indene-1-carboxylate (600 mg, 90% yield) as a yellow solid. MS:383.1(M + H) +。
Step 5 preparation of benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate
Figure BDA0003413556240000563
1-benzyl 4- (tert-butyl) (S) -2- (cyanomethyl) piperazine-1, 4-dicarboxylate (intermediate a 10/step 3,10.0 g, 27.85 mmol) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (15 ml) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness and extracted by dilution with ethyl acetate, and the organic phase was washed with saturated aqueous sodium carbonate, saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give (S) -benzyl 2- (cyanomethyl) piperazine-1-carboxylate (4.2 g, 58% yield) as a yellow solid. MS:260.1(M + H)+。
Step 6 preparation of benzyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
Figure BDA0003413556240000571
Methyl 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -2, 3-dihydro-1H-indene-1-carboxylate (600 mg, 1.570 mmol) was dissolved in anhydrous dichloromethane (10 ml) and benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (814 mg, 3.14 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by adding ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give benzyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (300 mg, 31.6% yield) as a yellow solid. MS:606.1(M + H) +。
Preparation example 13 intermediate A13
Benzyl (2S) -4- (2-chloro-6- ((4- (methoxycarbonyl) chroman-4-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000572
Step 1 preparation of methyl chroman-4-carboxylate
Figure BDA0003413556240000581
Chroman-4-carboxylic acid (1 g, 5.61 mmol) is dissolved in anhydrous methanol (10 ml) and thionyl chloride (1.335 g, 11.22 mmol) is added slowly with stirring at 0 ℃. After the addition was complete, the reaction mixture was slowly raised to 70 ℃ and stirring was continued for 1 hour. After completion of the reaction, the reaction mixture was concentrated and extracted by diluting with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give chroman-4-carboxylic acid methyl ester (0.6 g, 55.6% yield) as a colorless oil. MS:193.1(M + H)+。
Step 2 preparation of methyl 4- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) chroman-4-carboxylate
Figure BDA0003413556240000582
Methyl chromane-4-carboxylate (300 mg, 1.561 mmol) is dissolved in anhydrous tetrahydrofuran (20 ml) and LDA (1.87 mmol) is added slowly with stirring at-78 ℃ and stirring is continued for 30 minutes at-78 ℃ before a solution of 2, 4-bis (benzyloxy) -6- (bromomethyl) -5-nitropyrimidine (intermediate a3-2,672 mg, 1.561 mmol) in tetrahydrofuran (10 ml) is added to the reaction. After the completion of the dropping, the reaction mixture was further stirred at-78 ℃ for 0.5 hour, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give methyl 4- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) chroman-4-carboxylate (42) as a yellow solid 0 mg, 50% yield). MS:542.1(M + H)+。
Step 3 preparation of methyl 4- ((2, 6-dihydroxy-5-nitropyrimidin-4-yl) methyl) chroman-4-carboxylate
Figure BDA0003413556240000583
Methyl 4- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) chroman-4-carboxylate (300 mg, 0.554 mmol) was dissolved in trifluoroacetic acid (5 ml). The reaction mixture was slowly warmed to 100 ℃ under nitrogen and stirred under microwave conditions for 1 hour, then the reaction mixture was concentrated and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give methyl 4- ((2, 6-dihydroxy-5-nitropyrimidin-4-yl) methyl) chroman-4-carboxylate (194 mg, 97% yield) as a yellow solid. MS:362.1(M + H)+。
Step 4 preparation of methyl 4- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) chroman-4-carboxylate
Figure BDA0003413556240000591
Methyl 4- ((2, 6-dihydroxy-5-nitropyrimidin-4-yl) methyl) chroman-4-carboxylate (280 mg, 0.775 mmol) was dissolved in phosphorus oxychloride (5 ml) and DIEA (100 mg, 0.775 mmol) was added with stirring at 0 ℃. The reaction mixture was slowly warmed to 110 ℃ under nitrogen and stirred for 6 hours, then the reaction mixture was concentrated, extracted by dilution with dichloromethane and the solution was poured into saturated sodium bicarbonate solution and stirred for 1 hour. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give 4- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) chroman-4-carboxylic acid methyl ester as a yellow solid (309 mg, 100% yield). MS:399.1(M + H) +。
Step 5 preparation of benzyl (2S) -4- (2-chloro-6- ((4- (methoxycarbonyl) chroman-4-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000592
Methyl 4- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) chroman-4-carboxylate (309 mg, 0.776 mmol) is dissolved in anhydrous dichloromethane (10 ml) and benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a 12/step 5,402 mg, 1.55 mmol) is added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by adding ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give benzyl (2S) -4- (2-chloro-6- ((4- (methoxycarbonyl) chroman-4-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (120 mg, 24.9% yield). MS:622.1(M + H)+。
Preparation 14 intermediate A14
(2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester
Figure BDA0003413556240000593
Figure BDA0003413556240000601
Methyl 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate A3/step 5,1.5 g, 3.79 mmol) was dissolved in anhydrous dichloromethane (30 ml) and benzyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a 12/step 5,1.96 g, 7.57 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropwise addition, the reaction mixture was stirred at 0 ℃ for a further 1 hour, then quenched with ice-water and quenched with dichloro-benzene And (4) diluting and extracting methane. The organic phase was washed with saturated brine, dried over anhydrous dried sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give benzyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (1.35 g, 58% yield) as a yellow solid. MS 620.1(M + H)+。
Preparation example 15 intermediate A15
(2R) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000602
Methyl 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate a 3/step 5,200 mg, 0.51 mmol) was dissolved in anhydrous dichloromethane (5 ml) and tert-butyl (R) -2- (hydroxymethyl) piperazine-1-carboxylate (164 mg, 0.76 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by addition of ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (2R) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester as a colorless powder (180 mg, 62% yield). MS:577.1(M + H) +。
Preparation 16 intermediate A16
6- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester
Figure BDA0003413556240000611
Reacting 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylic acid methyl ester(intermediate A3/step 5,200 mg, 0.51 mmol) was dissolved in dry dichloromethane (5 ml) and 2, 6-diazaspiro [3.4] was added slowly with stirring at 0 deg.C]Octane-2-carboxylic acid tert-butyl ester (107 mg, 0.505 mmol). After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by adding ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give 6- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2, 6-diazaspiro [3.4] as a yellow oil]Octane-2-carboxylic acid tert-butyl ester (145 mg, 51.9% yield). MS:573.1(M + H)+。
Preparation of example 17 intermediate A17
7- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxylic acid tert-butyl ester
Figure BDA0003413556240000612
Figure BDA0003413556240000621
Methyl 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate A3/step 5,200 mg, 0.51 mmol) was dissolved in anhydrous dichloromethane (5 ml) and 2, 7-diazaspiro [4.4 ] was added slowly with stirring at 0 deg.C]Nonane-2-carboxylic acid tert-butyl ester (114 mg, 0.505 mmol). After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by adding ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give 7- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2, 7-diazaspiro [4.4 ] as a yellow oil]Nonane-2-carboxylic acid tert-butyl ester (145 mg, 49% yield). MS:587.1(M + H)+。
Preparation of example 18 intermediate A18
(2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitro-2- (pyridin-3-yl) pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester
Figure BDA0003413556240000622
Benzyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A14,600 mg, 0.969 mmol) was dissolved in 1, 4-dioxane (10 ml) and water (1 ml), pyridine-3-boronic acid pinacol ester (397 mg, 1.93 mmol), Pd (Ph), was added slowly with stirring at 25 ℃ 3P)4(112 mg, 0.097 mmol), K2CO3(402 mg, 2.91 mmol). After the completion of the dropping, the reaction mixture was slowly raised to 80 ℃ and stirred for 3 hours, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give benzyl (2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitro-2- (pyridin-3-yl) pyrimidin-4-yl) piperazine-1-carboxylate (500 mg, 78% yield) as a yellow solid. MS:662.1(M + H)+。
Preparation of example 19 intermediate A19
(2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (2-methylpyridin-3-yl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000631
Benzyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a14,100 mg, 0.162 mmol) was dissolved in 1, 4-dioxane (10 ml) and water (1 ml) and slowly added with stirring at 25 ℃ to the solution2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (71 mg, 0.323 mmol), Pd (Ph) 3P)4(18.7 mg, 0.016 mmol), K2CO3(67 mg, 0.485 mmol). After the completion of the dropping, the reaction mixture was slowly raised to 80 ℃ and stirred for 3 hours, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (2-methylpyridin-3-yl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (100 mg, 92% yield). MS:676.1(M + H)+。
PREPARATION EXAMPLE 20 INTERMEDIATE B1
2-fluoroacryloyl chloride
Figure BDA0003413556240000632
2-Fluoroacrylic acid (50 mg, 0.555 mmol) was dissolved in dry dichloromethane (3 ml) and oxalyl chloride (106 mg, 0.833 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was further stirred at 0 ℃ for 1 hour, and after the completion of the reaction, the reaction mixture was used directly for the next reaction.
Preparation of example 21 intermediate B2
But-2-ynoyl chloride
Figure BDA0003413556240000641
But-2-ynoic acid (300 mg, 3.57 mmol) was dissolved in anhydrous dichloromethane (3 ml) and oxalyl chloride (679 mg, 5.35 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was further stirred at 0 ℃ for 1 hour, and after the completion of the reaction, the reaction mixture was used directly for the next reaction.
PREPARATION EXAMPLE 22 INTERMEDIATE B3
(E) -4,4, 4-trifluorobut-2-enoyl chloride
Figure BDA0003413556240000642
(E) -4,4, 4-trifluorobut-2-enoic acid (200 mg, 1.428 mmol) was dissolved in anhydrous dichloromethane (3 ml) and oxalyl chloride (544 mg, 4.28 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was further stirred at 0 ℃ for 1 hour, and after the completion of the reaction, the reaction mixture was used directly for the next reaction.
Preparation of example 23 intermediate B4
(E) -4-methoxybut-2-enoyl chloride
Figure BDA0003413556240000643
(E) -4-methoxybut-2-enoic acid (200 mg, 1.722 mmol) was dissolved in anhydrous dichloromethane (3 ml) and oxalyl chloride (219 mg, 1.722 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was further stirred at 0 ℃ for 1 hour, and after the completion of the reaction, the reaction mixture was used directly for the next reaction.
Preparation of example 24 intermediate B5
(E) -4-fluorobut-2-enoyl chloride
Figure BDA0003413556240000651
Step 1 preparation of (E) -4-fluorobut-2-enoic acid methyl ester
Figure BDA0003413556240000652
Silver fluoride (4.25 g, 33.5 mmol) was dissolved in acetonitrile (20 ml) and a solution of methyl (E) -4-bromobut-2-enoate (2 g, 11.17 mmol) in acetonitrile (50 ml) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 20 ℃ for another 48 hours in the dark, and then the solvent was evaporated to dryness and extracted by dilution with dichloromethane. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give methyl (E) -4-fluorobut-2-enoate (1.2 g, 91% yield).
Step 2 preparation of (E) -4-fluorobut-2-enoic acid
Figure BDA0003413556240000653
Methyl (E) -4-fluorobut-2-enoate (1.2 g, 10.16 mmol) was dissolved in tetrahydrofuran (30 ml) and a solution of lithium hydroxide (1.217 g, 50.8 mmol) in water (30 ml) was added slowly with stirring at 0 ℃. After the end of the dropping, the reaction mixture was stirred at 20 ℃ for a further 4 hours, after which the solvent was evaporated off and the extraction diluted with dichloromethane. The organic phase was washed with dilute hydrochloric acid solution, saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give (E) -4-fluorobut-2-enoic acid (560 mg, 53% yield) as a yellow solid.
Step 3 preparation of (E) -4-fluorobut-2-enoyl chloride
Figure BDA0003413556240000654
(E) -4-Fluorobut-2-enoic acid (208 mg, 2 mmol) was dissolved in anhydrous dichloromethane (3 ml) and oxalyl chloride (219 mg, 1.722 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was further stirred at 0 ℃ for 1 hour, and after the completion of the reaction, the reaction mixture was used directly for the next reaction.
Preparation of example 25 intermediate C1
((2S, 4S) -4-fluoro-1-methylpyrrolidin-2-yl) methanol
Figure BDA0003413556240000655
1- (tert-butyl) 2-methyl (2S, 4S) -4-fluoropyrrolidine-1, 2-dicarboxylate (10 g, 40.4 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml) and LAH solution (162 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was slowly raised After 16 hours of stirring at room temperature, the reaction was quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give ((2S, 4S) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (2.2 g, 40% yield) as a yellow oil. MS:134.1(M + H)+。
Preparation of example 26 intermediate C2
((2S, 4R) -4-methoxy-1-methylpyrrolidin-2-yl) methanol
Figure BDA0003413556240000661
Step 1 preparation of 1- (tert-butyl) 2-methyl (2S, 4R) -4-methoxypyrrolidine-1, 2-dicarboxylate
Figure BDA0003413556240000662
1- (tert-butyl) 2-methyl (2S, 4R) -4-hydroxypyrrolidine-1, 2-dicarboxylate (5 g, 20.39 mmol) was dissolved in anhydrous acetonitrile (130 mL) and silver oxide (14.17 g, 61.2 mmol) and methyl iodide (28.9 g, 204 mmol) were added slowly with stirring at 0 ℃. After the addition was complete, the reaction mixture was allowed to warm slowly to room temperature and stirring was continued for 24 hours, after which the reaction was quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 1- (tert-butyl) 2-methyl (2S, 4R) -4-methoxypyrrolidine-1, 2-dicarboxylate (3.1 g, 59.6% yield) as a yellow solid. MS 260.1(M + H) +。
Step 2 preparation of ((2S, 4R) -4-methoxy-1-methylpyrrolidin-2-yl) methanol
Figure BDA0003413556240000663
1- (tert-butyl) 2-methyl (2S, 4R) -4-methoxyThe pyrrolidine-1, 2-dicarboxylate (3.2 g, 12.34 mmol) was dissolved in anhydrous tetrahydrofuran (80 ml) and the LAH solution (62 mmol) was added slowly with stirring at 0 ℃. After the addition was complete, the reaction mixture was allowed to warm slowly to room temperature and stirring was continued for 16 hours, after which the reaction was quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give a yellow oil (620 mg, 24.6% yield). MS 146.1(M + H)+。
Preparation of 27 intermediate C3
((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol
Figure BDA0003413556240000664
Figure BDA0003413556240000671
1- (tert-butyl) 2-methyl (2S, 4R) -4-fluoropyrrolidine-1, 2-dicarboxylate (10 g, 40.4 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml) and LAH solution (162 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was slowly warmed to room temperature and stirred for further 16 hours, then quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (4.3 g, 80% yield) as a yellow oil. MS:134.1(M + H) +。
Preparation of example 28 intermediate C4
(3R, 4R) -4-methoxy-1-methylpyrrolidin-3-ol
Figure BDA0003413556240000672
Reacting (3R, 4R) -3-hydroxy-4-methoxy pyrrolidine-1-carboxylic acid tert-butylButyl ester (500 mg, 2.301 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml) and the LAH solution (4.6 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was slowly warmed to room temperature and stirred for further 16 hours, then quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (3R, 4R) -4-methoxy-1-methylpyrrolidin-3-ol as a yellow oil (260 mg, 86% yield). MS:132.1(M + H)+。
Preparation of example 29 intermediate C5
(S) - (1-methylpyrrolidin-2-yl) methanethiol
Figure BDA0003413556240000673
Step 1 preparation of (S) - (1-methylpyrrolidin-2-yl) methyl methanesulfonate
Figure BDA0003413556240000674
(S) - (1-Methylpyrrolidin-2-yl) methanol (2 g, 17.36 mmol) and TEA (5.27 g, 52.1 mmol) were dissolved in anhydrous dichloromethane (100 mL) and methanesulfonyl chloride (2.387 g, 20.84 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for further 3 hours, then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give methyl (S) - (1-methylpyrrolidin-2-yl) methanesulfonate as a yellow oil (3.1 g, 92% yield). MS:194.1(M + H) +。
Step 2 preparation of (S) -S- ((1-methylpyrrolidin-2-yl) methyl) ethanethiolate
Figure BDA0003413556240000681
Methyl (S) - (1-methylpyrrolidin-2-yl) methanesulfonate (3.2 g, 16.56 mmol) was dissolved in anhydrous DMF (10 ml) and potassium thioacetate (2.08 g, 18.21 mmol) was added at 20 ℃. After the completion of the dropping, the reaction mixture was further stirred at 65 ℃ for 13 hours, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give (S) -S- ((1-methylpyrrolidin-2-yl) methyl) ethyl mercaptide (2.6 g, 91% yield) as an orange oil. MS:174.1(M + H)+。
Step 3 preparation of (S) - (1-methylpyrrolidin-2-yl) methanethiol
Figure BDA0003413556240000682
(S) -S- ((1-methylpyrrolidin-2-yl) methyl) ethanethiolate (2.6 g, 15.01 mmol) is dissolved in methanol (40 ml) and sodium hydroxide (1.8 g, 45 mmol) is added at 20 ℃. After the completion of the dropping, the reaction mixture was further stirred at 25 ℃ for 13 hours, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give (S) - (1-methylpyrrolidin-2-yl) methanethiol as a yellow oil (620 mg, 31.5% yield). MS:132.1(M + H) +。
Preparation example 30 intermediate A20
(2S, 5R) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) -5-methylpiperazine-1-carboxylic acid benzyl ester
Figure BDA0003413556240000683
Figure BDA0003413556240000691
Step 1 preparation of methyl ((benzyloxy) carbonyl) -L-serine-L-alanine
Figure BDA0003413556240000692
Methyl D-alanine (25 g, 179.11 mmol) and ((benzyloxy) carbonyl) -L-serine (42.8 g, 179.11 mmol) were dissolved in dichloromethane (780 ml) and EDCI (41.2 g, 214.93 mmol) and DIEA (109 ml, 626.89 mmol) were added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 10 ℃ for 12 hours, then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give ((benzyloxy) carbonyl) -L-serine-L-alanine methyl ester as a white solid (44.9 g, 77% yield). MS 325.1(M + H)+。
Step 2 preparation of (3S,6R) -3- (hydroxymethyl) -6-methylpiperazine-2, 5-dione
Figure BDA0003413556240000693
((benzyloxy) carbonyl) -L-serine-L-alanine methyl ester (22.4 g, 69.07 mmol) was dissolved in methanol (70 ml) and cyclohexene (45 ml), and palladium on carbon (1.15 g) was added to the reaction mixture with stirring. The reaction mixture was stirred under hydrogen at 70 ℃ for 12 hours, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give (3S,6R) -3- (hydroxymethyl) -6-methylpiperazine-2, 5-dione as a grey solid (7.9 g, 72.3% yield). 1H NMR(400MHz，DMSO)δ8.09(s，1H)，7.91(s，1H)，5.12(t，J＝5.2Hz,1H),3.92–3.87(m,1H),3.74–3.70(m,1H),3.68–3.62(m,1H),3.52–3.48(m,1H),1.23–1.19(m,3H)。
Step 3 preparation of ((2R,5R) -5-methylpiperazin-2-yl) methanol
Figure BDA0003413556240000701
(3S,6R) -3- (hydroxymethyl) -6-methylpiperazine-2, 5-dione (7.9 g, 50 mmol) was dissolved in anhydrous tetrahydrofuran (150 ml) and a borane solution in tetrahydrofuran (1M,375 ml) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was slowly raised to 70 ℃ and stirring was continued for 16 hours, then the reaction was quenched by addition of methanol, then 5M aqueous hydrochloric acid (27 ml) was added, the reaction mixture was slowly raised to 70 ℃ and stirring was continued for 2 hours, cooling was carried out to precipitate a solid, which was then filtered and dried to give ((2R,5R) -5-methylpiperazin-2-yl) methanol as a gray solid (5.2 g, 80.8% yield).1H NMR(400MHz,DMSO)δ9.90(s,2H),5.61(s,1H),3.75–3.40(m,6H),3.18–3.02(m,2H),1.31–1.28(m,3H)。
Step 4 preparation of (2R,5R) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000702
((2R,5R) -5-methylpiperazin-2-yl) methanol (6.1 g, 30.03 mmol) was dissolved in methanol (50 mL) and diethylamine (9.43 g, 93.21 mmol, 13 mL) and Boc were added slowly with stirring at 0 deg.C2O (13.8 g, 63.23 mmol). After the completion of the dropping, the reaction mixture was stirred at 50 ℃ for 12 hours, then the reaction solution was concentrated to dryness, the concentrate was dissolved in ethanol (100 ml), 1.5M aqueous NaOH solution (100 ml) was added to the above solution, and stirred at 100 ℃ for 12 hours. The reaction solution was cooled and the pH was adjusted to 9 with 2M hydrochloric acid solution and extracted by dilution with dichloromethane. The organic phase was washed with saturated aqueous sodium bicarbonate solution, saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give (2R,5R) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester as a yellow solid (6 g, 86.5% yield). MS:231.1(M + H) +。
Step 5 1-benzyl 4- (tert-butyl) (2R, 5R) -2- (hydroxymethyl) -5-methylpiperazine-1, 4-dicarboxylate
Figure BDA0003413556240000703
Tert-butyl (2R, 5R) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (7.1 g, 30.8 mmol) was dissolved in dichloromethane (80 ml) and DIEA (4.38 g, 33.91 mmol, 5.91 ml) and CbzCl (5.52 g, 32.37 mmol) were added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 10 ℃ for 12 hours, then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 1-benzyl 4- (tert-butyl) (2R, 5R) -2- (hydroxymethyl) -5-methylpiperazine-1, 4-dicarboxylate (8.9 g, 79.2% yield) as a colorless oil. MS:265.1(M + H)+。
Step 6 preparation of 1-benzyl 4- (tert-butyl) (2R, 5R) -5-methyl-2- ((methylsulfonyl) oxy) methyl) piperazine-1, 4-dicarboxylate
Figure BDA0003413556240000711
1-benzyl 4- (tert-butyl) (2R, 5R) -2- (hydroxymethyl) -5-methylpiperazine-1, 4-dicarboxylate (8.9 g, 24.42 mmol) was dissolved in dichloromethane (30 mL) and DIEA (6.31 g, 48.84 mmol, 8.51 mL) and MsCl (4.20 g, 36.63 mmol) were added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 2 hours, then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give 1-benzyl 4- (tert-butyl) (2R, 5R) -5-methyl-2- ((methylsulfonyl) oxy) methyl) piperazine-1, 4-dicarboxylate as a yellow oil (10.8 g, 100% yield).
Step 7 preparation of 1-benzyl 4- (tert-butyl) (2S,5R) -2- (cyanomethyl) -5-methylpiperazine-1, 4-dicarboxylate
Figure BDA0003413556240000712
1-benzyl 4- (tert-butyl) (2R,5R) -5-methyl-2- ((methylsulfonyl) oxy) methyl) piperazine-1, 4-dicarboxylic acidThe acid ester (10.8 g, 24.41 mmol) was dissolved in DMA (100 ml) and potassium cyanide (4.77 g, 73.22 mmol) was added slowly with stirring at 20 ℃. After the addition was completed, the reaction mixture was stirred at 80 ℃ for 12 hours, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 1-benzyl 4- (tert-butyl) (2S,5R) -2- (cyanomethyl) -5-methylpiperazine-1, 4-dicarboxylate (5.0 g, 54.8% yield) as a yellow oil. MS 374.1&318.1(M+H)+。1H NMR(400MHz,CDCl3)δ7.36(dd,J＝10.3,4.6Hz,5H),5.25–5.07(m,2H),4.69–4.05(m,2H),4.05–3.68(m,2H),3.39–3.05(m,2H),2.79–2.44(m,2H),1.48(s,9H),1.15(s,3H)。
Step 8 preparation of benzyl (2S,5R) -2- (cyanomethyl) -5-methylpiperazine-1-carboxylate
Figure BDA0003413556240000713
1-benzyl 4- (tert-butyl) (2S,5R) -2- (cyanomethyl) -5-methylpiperazine-1, 4-dicarboxylate (2.5 g, 6.69 mmol) was dissolved in dioxane (10 mL) and a solution of dioxane in hydrogen chloride (1.0M,10 mL) was added slowly with stirring at 0 ℃. After the addition was complete, the reaction mixture was stirred at 20 ℃ for 2 hours, then the reaction was concentrated to dryness and extracted by dilution with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give benzyl (2S,5R) -2- (cyanomethyl) -5-methylpiperazine-1-carboxylate (1.8 g, 100% yield) as a yellow oil. MS:274.1(M + H) +。
Step 9 preparation of benzyl (2S,5R) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) -5-methylpiperazine-1-carboxylate
Figure BDA0003413556240000721
Will 1-Methyl ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate a 3/step 5,200 mg, 0.505 mmol) was dissolved in anhydrous dichloromethane (10 ml) and benzyl (2S,5R) -2- (cyanomethyl) -5-methylpiperazine-1-carboxylate (138 mg, 0.505 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was further stirred at 0 ℃ for 1 hour, and then the reaction was quenched by adding ice water and extracted by diluting with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give benzyl (2S,5R) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) -5-methylpiperazine-1-carboxylate (200 mg, 62.6% yield) as a yellow solid. MS:633.1(M + H)+。
Preparation 31 intermediate A21
(2S) -4- (2-chloro-6- ((7-chloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000722
Figure BDA0003413556240000731
Step 1 preparation of (E) -7-chloro-1- (methoxymethylene) -1,2,3, 4-tetrahydronaphthalene
Figure BDA0003413556240000732
Ph is measured3PCH2OMeCl (83.5 g, 243.6 mmol) was dissolved in anhydrous tetrahydrofuran (400 mL) and potassium tert-butoxide (24.9 g, 221.5 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropwise addition, the reaction mixture was stirred at 0 ℃ for 1 hour, a solution of 6-chloro-3, 4-dihydronaphthalen-1 (2H) -one (20.0 g, 110.7 mmol) in tetrahydrofuran (100 ml) was added to the reaction mixture, and the reaction mixture was stirred at 20 ℃ C. for 1 hourThe reaction was quenched by addition of ice water and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (E) -7-chloro-1- (methoxymethylene) -1,2,3, 4-tetrahydronaphthalene (32 g crude) as a yellow solid.
Step 2 preparation of 7-chloro-1, 2,3, 4-tetrahydronaphthalene-1-aldehyde
Figure BDA0003413556240000733
A solution of (E) -7-chloro-1- (methoxymethylene) -1,2,3, 4-tetrahydronaphthalene (32.0 g, 153.3 mmol) in formic acid (150 ml) was stirred at 25 ℃ for 16 hours, then a saturated sodium bicarbonate solution was added to adjust the pH to 7, and the extraction was diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 7-chloro-1, 2,3, 4-tetrahydronaphthalene-1-acetaldehyde as a yellow oil (13.7 g, 63.5% yield). 1H NMR(400MHz,CHLOROFORM-d)δ9.59(d,J＝1.9Hz,1H),7.13-7.06(m,2H),7.04-6.98(m,1H),3.48(t,J＝5.5Hz,1H),2.66(t,J＝6.3Hz,2H),2.16(m,1H),1.90-1.78(m,1H),1.78-1.60(m,2H)。
Step 3 preparation of methyl 7-chloro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate
Figure BDA0003413556240000741
7-chloro-1, 2,3, 4-tetrahydronaphthalene-1-acetaldehyde (13.7 g, 70.4 mmol) was dissolved in acetonitrile (300 ml) and methanol (23.5 g, 731.9 mmol), and NIS (47.5 g, 211.1 mmol) and potassium carbonate (229.2 g, 211.1 mmol) were added slowly with stirring at 20 ℃. After the addition, the reaction mixture was stirred at 25 ℃ for a further 16 hours, then saturated sodium bicarbonate solution was added to adjust the pH to 9 and the extraction was diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatographyMethyl 7-chloro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate was obtained as a yellow oil (6.5 g, 41.0% yield).1HNMR(400MHz,CHLOROFORM-d)δ7.18(d,J＝1.8Hz,1H),7.17-7.13(m,1H),7.07-7.03(m,1H),3.81(t,J＝5.5Hz,1H),3.77-3.73(m,3H),2.87-2.68(m,2H),2.21-2.10(m,1H),2.05-1.92(m,2H),1.83-1.72(m,1H)。
Step 4 preparation of methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -7-chloro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate
Figure BDA0003413556240000742
Methyl 7-chloro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (1253 mg, 5.58 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml), LDA (6.97 mmol) was added slowly with stirring at-78 degrees and stirring was continued for 30 minutes at-78 degrees before a solution of 2, 4-bis (benzyloxy) -6- (bromomethyl) -5-nitropyrimidine (intermediate a3-2,2000 mg, 4.65 mmol) in tetrahydrofuran (15 ml) was added to the reaction. After the completion of the dropping, the reaction mixture was further stirred at-78 ℃ for 0.5 hour, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -7-chloro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (1.8 g, 68% yield) as a white solid. MS:574.1(M + H) +。
Step 5 preparation of methyl 7-chloro-1- ((2, 6-dihydroxy-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate
Figure BDA0003413556240000743
Methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -7-chloro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (1.8 g, 3.14 mmol) was dissolved in trifluoroacetic acid (5 ml). The reaction mixture was slowly raised to 100 ℃ under nitrogen and stirred under microwave conditions for 1 hour, then the reaction mixture was concentrated and diluted with ethyl acetateAnd (4) extracting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give methyl 7-chloro-1- ((2, 6-dihydroxy-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (1 g, 81% yield) as a yellow solid. MS:394.1(M + H)+。
Step 6 preparation of methyl 7-chloro-1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate
Figure BDA0003413556240000751
Methyl 7-chloro-1- ((2, 6-dihydroxy-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (2200 mg, 5.59 mmol) was dissolved in phosphorus oxychloride (15 ml) and DIEA (791 mg, 6.12 mmol) was added with stirring at 0 ℃. The reaction mixture was slowly warmed to 110 degrees under nitrogen and stirred for 6 hours, then the reaction mixture was concentrated, extracted by dilution with dichloromethane and the solution was poured into saturated sodium bicarbonate solution and stirred for 1 hour. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give methyl 7-chloro-1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (2.2 g, 91% yield) as a yellow solid. MS:397.1(M + H) +。
Step 7 preparation of tert-butyl (2S) -4- (2-chloro-6- ((7-chloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
Figure BDA0003413556240000752
Methyl 7-chloro-1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (850 mg, 1.974 mmol) was dissolved in anhydrous dichloromethane (10 ml) and tert-butyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (667 mg, 2.96 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropwise addition, the reaction mixture was further stirred at 0 ℃ for 1 hour, and then ice water was added thereto to quench the reactionThe reaction mixture was diluted with dichloromethane and extracted. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (2S) -tert-butyl 4- (2-chloro-6- ((7-chloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (0.8 g, 66.7% yield) as a yellow solid. MS:620.1(M + H)+。
Preparation of example 32 intermediate a22
(2S) -4- (2-chloro-6- ((5-chloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000753
Synthesis of intermediate a22 referring to intermediate a21, intermediate a22 was prepared by using 5-chloro-3, 4-dihydronaphthalen-1 (2H) -one instead of 7-chloro-3, 4-dihydronaphthalen-1 (2H) -one. MS:620.1(M + H) +。
Preparation of example 33 intermediate A23
(2S) -4- (2-chloro-6- ((6-chloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000761
Step 1 preparation of (E) -6-chloro-1- (methoxymethylene) -1,2,3, 4-tetrahydronaphthalene
Figure BDA0003413556240000762
Ph is measured3PCH2OMeCl (83.5 g, 243.6 mmol) was dissolved in anhydrous tetrahydrofuran (400 mL) and potassium tert-butoxide (24.9 g, 221.5 mmol) was added slowly with stirring at 0 ℃. After the addition, the reaction mixture was stirred at 0 ℃ for 1 hour, and the resulting solution was washed with 6-chloro-3, 4-dihydronaphthalen-1 (2H) -one (20.0 g, 110.7 mmol) tetrakisTetrahydrofuran (100 ml) solution was added to the above reaction solution, and the reaction mixture was further stirred at 20 ℃ for 12 hours, then quenched by adding ice water, and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (E) -6-chloro-1- (methoxymethylene) -1,2,3, 4-tetrahydronaphthalene (28.9 g, 75.1% yield) as a yellow solid. MS:208.8(M + H)+。
Step 2 preparation of 6-chloro-1, 2,3, 4-tetrahydronaphthalene-1-aldehyde
Figure BDA0003413556240000771
(E) -6-chloro-1- (methoxymethylene) -1,2,3, 4-tetrahydronaphthalene (27.3 g, 130.8 mmol) was dissolved in 1, 4-dioxane (270 ml) and water (27 ml), and concentrated hydrochloric acid (12M,10.9 ml) was slowly added with stirring at 20 ℃. After the addition, the reaction mixture was stirred at 60 ℃ for a further 16 hours, then saturated sodium bicarbonate solution was added to adjust the pH to 9 and the extraction was diluted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 6-chloro-1, 2,3, 4-tetrahydronaphthalene-1-acetaldehyde as a yellow oil (11.2 g, 39.6% yield).
Step 3 preparation of methyl 6-chloro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate
Figure BDA0003413556240000772
6-chloro-1, 2,3, 4-tetrahydronaphthalene-1-acetaldehyde (11.4 g, 58.6 mmol) was dissolved in acetonitrile (270 ml) and methanol (18.8 g, 585.7 mmol), and NIS (39.5 g, 175.7 mmol) and potassium carbonate (24.3 g, 175.7 mmol) were slowly added at 20 degrees with stirring. After the addition, the reaction mixture was stirred at 20 ℃ for a further 16 hours, then saturated sodium bicarbonate solution was added to adjust the pH to 9 and the extraction was diluted with ethyl acetate. Washing the organic phase with saturated brine, drying over anhydrous dry sodium sulfate, filtering, and concentratingTo the crude product, the crude product was purified by silica gel column chromatography to give methyl 6-chloro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (7.6 g, 56.7% yield) as a yellow solid.1H NMR(400MHz,CHLOROFORM-d)δ7.01-7.18(m,3H),3.81(t,J＝5.90Hz,1H),3.72-3.75(m,3H),2.70-2.88(m,2H),2.11-2.22(m,1H),1.91-2.06(m,2H),1.73-1.83(m,1H)。
Step 4 preparation of methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -6-chloro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate
Figure BDA0003413556240000773
Methyl 6-chloro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (1253 mg, 5.58 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml), LDA (6.97 mmol) was added slowly with stirring at-78 ℃ and stirring continued at-78 ℃ for 30 minutes, then a solution of 2, 4-bis (benzyloxy) -6- (bromomethyl) -5-nitropyrimidine (intermediate a3-2,2000 mg, 4.65 mmol) in tetrahydrofuran (15 ml) was added to the reaction. After the completion of the dropping, the reaction mixture was further stirred at-78 ℃ for 0.5 hour, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -6-chloro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (1.9 g, 73% yield) as a white solid. MS:574.1(M + H) +。
Step 5 methyl 6-chloro-1- ((2, 6-dihydroxy-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate
Figure BDA0003413556240000781
Methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -6-chloro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (1.9 g, 3.3 mmol) was dissolved in trifluoroacetic acid (5 ml). The reaction mixture was slowly raised to 100 ℃ under nitrogen and stirred for 1 hour under microwave conditions, then the reaction mixture was concentrated and diluted with ethyl acetateAnd (4) extracting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give methyl 6-chloro-1- ((2, 6-dihydroxy-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (1.1 g, 82% yield) as a yellow solid. MS:394.1(M + H)+。
Step 6 preparation of methyl 6-chloro-1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate
Figure BDA0003413556240000782
Methyl 6-chloro-1- ((2, 6-dihydroxy-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (1.1 g, 2.8 mmol) was dissolved in phosphorus oxychloride (15 ml) and DIEA (395 mg, 3.03 mmol) was added with stirring at 0 ℃. The reaction mixture was slowly warmed to 110 deg.f under nitrogen and stirred for 6 hours, then the reaction mixture was concentrated, extracted by dilution with dichloromethane and the solution poured into saturated sodium bicarbonate solution and stirred for 1 hour. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give methyl 6-chloro-1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (1 g, 90% yield) as a yellow solid. MS:397.1(M + H) +。
Step 7 preparation of (2S) -4- (2-chloro-6- ((6-chloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000783
Methyl 6-chloro-1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (1 g, 2.5 mmol) was dissolved in anhydrous dichloromethane (10 ml) and tert-butyl (S) -2- (cyanomethyl) piperazine-1-carboxylate (563 mg, 1.78 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was further stirred at 0 ℃ for 1 hour, and then the reaction was quenched by adding ice water and quenched with waterAnd (4) diluting and extracting with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (2S) -tert-butyl 4- (2-chloro-6- ((6-chloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (1.1 g, 89.2% yield) as a yellow solid. MS:620.1(M + H)+。
Preparation of example 34 intermediate A24
(2S) -4- (2-chloro-6- ((7-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000791
Synthesis of intermediate a24 referring to intermediate a21, intermediate a24 was prepared by using 7-fluoro-3, 4-dihydronaphthalen-1 (2H) -one instead of 7-chloro-3, 4-dihydronaphthalen-1 (2H) -one. MS:604.1(M + H) +。
Preparation of example 35 intermediate A25
(2S) -4- (2-chloro-6- ((6-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000792
Synthesis of intermediate a25 referring to intermediate a21, intermediate a25 was prepared by using 6-fluoro-3, 4-dihydronaphthalen-1 (2H) -one instead of 7-chloro-3, 4-dihydronaphthalen-1 (2H) -one. MS:604.1(M + H)+。
Preparation of example 36 intermediate A26
(2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -7-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000793
Synthesis of intermediate a26 referring to intermediate a21, intermediate a26 was prepared by using 7-methyl-3, 4-dihydronaphthalen-1 (2H) -one instead of 7-chloro-3, 4-dihydronaphthalen-1 (2H) -one. MS:600.1(M + H)+。
Preparation 37 intermediate a27 and intermediate a28
(S) -methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate A27) and (R) -methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate A28)
Figure BDA0003413556240000801
Methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (44 g) was resolved by SFC chirality (column model: CHIRAL ART Cellulose-SB,5cm × 25cm,5um column chromatography, mobile phase: ethanol in n-hexane) to give the first component peak intermediate a27 (retention time 3.86 min, 20 g) and the second component peak intermediate a28 (retention time 4.11 min, 19 g), both as pale yellow solids. MS:540.1(M + H) +. Intermediate a27 was identified as the (S) -configuration by X-ray crystal structure analysis and the results are shown in fig. 1.
Preparation of example 38 intermediate A29
(S) -4- (2-chloro-6- (((S) -1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000802
Synthesis of intermediate a29 referring to intermediate A3, intermediate a29 was prepared by using (S) -methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate a27) instead of methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate A3-3). MS:586.1(M + H)+。
Preparation 39 intermediate A30
(S) -4- (2-chloro-6- (((R) -1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000811
Synthesis of intermediate a30 referring to intermediate A3, intermediate a30 was prepared by using (R) -methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate a28) instead of methyl 1- ((2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate A3-3). MS:586.1(M + H)+。
Preparation example 40 intermediate A31
(2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -6-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000812
Synthesis of intermediate a31 referring to intermediate a21, intermediate a31 was prepared by using 6-methyl-3, 4-dihydronaphthalen-1 (2H) -one instead of 7-chloro-3, 4-dihydronaphthalen-1 (2H) -one. MS:600.1(M + H)+。
Preparation 41 intermediate A32
(2S) -4- (2-chloro-6- ((5-chloro-1- (methoxycarbonyl) -7-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000813
Figure BDA0003413556240000821
Step 1:4- (2-chloro-4-methylphenyl) but-3-yn-1-ol
Figure BDA0003413556240000822
2-chloro-1-iodo-4-toluene (40g,158mmol) was dissolved in tetrahydrofuran (300 mL) and but-3-yn-1-ol (167g,2376mmol), CuI (0.603g,3.17mmol), Pd (PPh) were added slowly with stirring at 0L3)2Cl2(3.34g,4.75mmol) and TEA (40.1g,396 mmol). After the completion of the dropping, the reaction mixture was stirred at 60 drops for another 12 hours, then quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 4- (2-chloro-4-methylphenyl) but-3-yn-1-ol as a yellow oil (26g, 84% yield). MS:195.2(M + H) +。
Step 2 preparation of 4- (2-chloro-4-methylphenyl) butan-1-ol
Figure BDA0003413556240000823
4- (2-chloro-4-methylphenyl) but-3-yn-1-ol (9g,45.3mmol) was dissolved in ethyl acetate (200 ml) and PtO was added to the reaction mixture with stirring2(1 g). The reaction mixture was stirred at room temperature for 12 hours under hydrogen, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give 4- (2-chloro-4-methylphenyl) butan-1-ol (9g, 98% yield) as a yellow oil. MS:199.2(M + H)+。
Step 3 preparation of 4- (2-chloro-4-methylphenyl) butyric acid
Figure BDA0003413556240000831
4- (2-chloro-4-methylphenyl) butan-1-ol (8g,40.3mmol) was dissolved in acetone (30 mL) and added to Jone's reagent (10.41g,81mmol) slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was brought to 20 deg.CThe reaction was stirred for 2 hours, then quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 4- (2-chloro-4-methylphenyl) butyric acid (3.8g, 44.4% yield) as a yellow solid. MS 213.2(M + H)+。
Step 4 preparation of 5-chloro-7-methyl-3, 4-dihydronaphthalen-1 (2H) -one
Figure BDA0003413556240000832
4- (2-chloro-4-methylphenyl) butyric acid (3.8g,17.87mmol) was dissolved in trifluoromethanesulfonic acid (10 ml), and the reaction was stirred at 0 ℃ for 3 hours, then quenched by addition of ice water, and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 5-chloro-7-methyl-3, 4-dihydronaphthalen-1 (2H) -one (2.2g, 63.3% yield) as a yellow oil. MS:195.2(M + H) +。
Step 5 preparation of (E) -5-chloro-1- (methoxymethylene) -7-methyl-1, 2,3, 4-tetrahydronaphthalene
Figure BDA0003413556240000833
Synthesis of intermediate a32-5 with reference to intermediate a 21/step 1, intermediate a32-5 was prepared by using 5-chloro-7-methyl-3, 4-dihydronaphthalen-1 (2H) -one (intermediate a32-4) instead of 7-chloro-3, 4-dihydronaphthalen-1 (2H) -one.
Step 6 preparation of 5-chloro-7-methyl-1, 2,3, 4-tetrahydronaphthalene-1-carbaldehyde
Figure BDA0003413556240000834
(E) -5-chloro-1- (methoxymethylene) -7-methyl-1, 2,3, 4-tetrahydronaphthalene (2.4g,10.78mmol) was dissolved in dichloromethane (20 ml), and stirred at-40 ℃ slowlySlow addition of BBr3(43.1 mmol). After the completion of the dropwise addition, the reaction mixture was stirred at-40 ℃ for 2 hours, then quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 5-chloro-7-methyl-1, 2,3, 4-tetrahydronaphthalene-1-carbaldehyde as a yellow oil (700mg, 31.3% yield).
Step 7 preparation of methyl 5-chloro-7-methyl-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate
Figure BDA0003413556240000841
Synthesis of intermediate a32-7 with reference to intermediate a 21/step 3, intermediate a32-7 was prepared by using 5-chloro-7-methyl-1, 2,3, 4-tetrahydronaphthalene-1-carbaldehyde (intermediate a32-6) instead of 7-chloro-1, 2,3, 4-tetrahydronaphthalene-1-carbaldehyde (intermediate a 21/step 2). MS:239.2(M + H) +。
Step 8 preparation of (2S) -4- (2-chloro-6- ((5-chloro-1- (methoxycarbonyl) -7-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000842
Synthesis of intermediate a32 referring to intermediate a21, intermediate a32 was prepared by using 5-chloro-7-methyl-1, 2,3, 4-tetrahydronaphthalene-1-carboxylic acid methyl ester (intermediate a32-7) instead of 7-chloro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylic acid methyl ester (intermediate a 21/step 3). MS:634.2(M + H)+。
Preparation of example 42 intermediate A33
(2S) -4- (2-chloro-6- ((5-chloro-1- (methoxycarbonyl) -6-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000843
Figure BDA0003413556240000851
Synthesis of intermediate a33 referring to intermediate a32, intermediate a33 was prepared by using 2-chloro-1-iodo-3-toluene instead of 2-chloro-1-iodo-4-toluene. MS:634.2(M + H)+。
Preparation 43 intermediate A34
(2S) -4- (2-chloro-6- ((5, 6-difluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000852
Step 1 preparation of 5, 6-difluoro-3, 4-dihydronaphthalen-1 (2H) -one (intermediate A34-4)
Synthesis of intermediate a34-4 with reference to intermediate a32-4, intermediate a34-4 was prepared by using 1, 2-difluoro-3-iodobenzene instead of 2-chloro-1-iodo-4-toluene. MS 183.2(M + H) +。
Step 2 preparation of (2S) -4- (2-chloro-6- ((5, 6-difluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A34)
Synthesis of intermediate a34 intermediate a34 was prepared by using 5, 6-difluoro-3, 4-dihydronaphthalen-1 (2H) -one (intermediate a34-4) instead of 6-chloro-3, 4-dihydronaphthalen-1 (2H) -one with reference to intermediate a 23. MS:622.2(M + H)+。
Preparation 44 intermediate A35
(2S) -4- (2-chloro-6- ((5-chloro-6-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000861
Step 1 preparation of 5-chloro-6-fluoro-3, 4-dihydronaphthalen-1 (2H) -one (intermediate A35-4)
Figure BDA0003413556240000862
Synthesis of intermediate a35-4 with reference to intermediate a32-4, intermediate a35-4 was prepared by using 2-chloro-1-fluoro-3-iodobenzene instead of 2-chloro-1-iodo-4-toluene. MS:199.2(M + H)+。
Step 2 preparation of 5-chloro-6-fluoro-1-methylene-1, 2,3, 4-tetrahydronaphthalene (intermediate A35-5)
Figure BDA0003413556240000863
Methyltriphenylphosphonium bromide (27.3g,77mmol) was dissolved in tetrahydrofuran (180 ml) and potassium tert-butoxide (8.59g, 77mmol) was added slowly with stirring at 0 ℃ and stirred at 0 ℃ for 1 h. Then a solution of 5-chloro-6-fluoro-3, 4-dihydronaphthalen-1 (2H) -one (intermediate a35-4, 7.6g,38.3mmol) in tetrahydrofuran (50 ml) was added to the reaction at 0 ℃. After the completion of the dropping, the reaction mixture was further stirred at 20 ℃ for 12 hours, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give 5-chloro-6-fluoro-1-methylene-1, 2,3, 4-tetrahydronaphthalene (intermediate a35-5,6.4g, 85% yield) as a colorless oil.
Step 3 preparation of (5-chloro-6-fluoro-1, 2,3, 4-tetrahydronaphthalen-1-yl) methanol (intermediate A35-6)
Figure BDA0003413556240000871
5-chloro-6-fluoro-1-methylene-1, 2,3, 4-tetrahydronaphthalene (intermediate A35-5,6.4g,32.5mmol) was dissolved in tetrahydrofuran (80 mL), borane tetrahydrofuran solution (65.1mmol) was added slowly with stirring at 0 deg.C and stirred at 0 deg.C for 1 hour. NaOH (98mmol) and H were then added2O2(521mmol) was added at 0 ℃ to the topIn the reaction solution. After the completion of the dropping, the reaction mixture was further stirred at 20 ℃ for 12 hours, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give colorless oil (5-chloro-6-fluoro-1, 2,3, 4-tetrahydronaphthalen-1-yl) methanol (intermediate a35-6,6.0g, 86% yield).
Step 4: 5-chloro-6-fluoro-1, 2,3, 4-tetrahydronaphthalene-1-carbaldehyde (intermediate A35-7)
Figure BDA0003413556240000872
(5-chloro-6-fluoro-1, 2,3, 4-tetrahydronaphthalen-1-yl) methanol (intermediate A35-6,6.0g,28.0mmol) was dissolved in dichloromethane (80 mL), and sodium bicarbonate (4.70g,55.9mmol) and dess-martinterperiodine (23.71g,55.9mmol) were added slowly with stirring at 0 ℃ and stirred at 0 ℃ for 1 hour. The reaction was then quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give 5-chloro-6-fluoro-1, 2,3, 4-tetrahydronaphthalene-1-carbaldehyde as a colorless oil (intermediate A35-7,6.0g of crude product).
Step 5 preparation of methyl 5-chloro-6-fluoro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate A35-8)
Figure BDA0003413556240000873
Synthesis of intermediate a35-8 referring to intermediate a 21/step 3, intermediate a35-8 was prepared by using 5-chloro-6-fluoro-1, 2,3, 4-tetrahydronaphthalene-1-carbaldehyde (intermediate a35-7) instead of 7-chloro-1, 2,3, 4-tetrahydronaphthalene-1-carbaldehyde (intermediate a 21/step 2). MS 243.2(M + H)+。
Step 6 (2S) -4- (2-chloro-6- ((5-chloro-6-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A35)
Figure BDA0003413556240000881
Synthesis of intermediate a35 intermediate a35 was prepared by using methyl 5-chloro-6-fluoro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate a35-8) in place of methyl 5-chloro-7-methyl-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate a32-7) with reference to intermediate a 32. MS:638.1(M + H)+。
Preparation example 45 intermediate A36
(2S) -4- (2-chloro-6- ((5-chloro-7-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000882
Step 1 preparation of (E) -4- (2-chloro-4-fluorophenyl) but-3-enoic acid
Figure BDA0003413556240000891
(2-carboxyethyl) triphenyl phosphonium bromide (79g,189mmol) is dissolved in tetrahydrofuran (300 ml) and potassium tert-butoxide (53g,473mmol) is added slowly with stirring at 0 ℃ and stirred at 0 ℃ for 10 minutes. Then a solution of 2-chloro-4-fluorobenzaldehyde (25g,158mmol) in tetrahydrofuran (50 ml) was added to the above reaction solution at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for further 5 hours, then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (E) -4- (2-chloro-4-fluorophenyl) but-3-enoic acid (20g, 59.2% yield) as a yellow oil. MS:215.2(M + H) +。
Step 2 preparation of 4- (2-chloro-4-fluorophenyl) butanoic acid
Figure BDA0003413556240000892
(E) -4- (2-chloro-4-fluorophenyl) but-3-enoic acid (15g,69.7mmol) was dissolved in ethyl acetate (200 mL) and PtO was added to the reaction mixture with stirring2(1 g). The reaction mixture was stirred at room temperature for 12 hours under hydrogen, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give 4- (2-chloro-4-fluorophenyl) butanoic acid (13.6g, 90% yield) as a yellow oil. MS 217.2(M + H)+。
Step 3 preparation of 5-chloro-7-fluoro-3, 4-dihydronaphthalen-1 (2H) -one
Figure BDA0003413556240000893
Synthesis of Intermediate a36-3 with reference to Intermediate a32-4, Intermediate a36-3 was prepared by using 4- (2-chloro-4-fluorophenyl) butanoic acid (Intermediate a36-2) instead of 4- (2-chloro-4-methylphenyl) butanoic acid (Intermediate a 32-3). MS:199.1(M + H)+。
Step 4 preparation of (2S) -4- (2-chloro-6- ((5-chloro-7-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000894
Synthesis of intermediate a36 intermediate a36 was prepared by using 5-chloro-7-fluoro-3, 4-dihydronaphthalen-1 (2H) -one (intermediate a36-3) instead of 6-chloro-3, 4-dihydronaphthalen-1 (2H) -one with reference to intermediate a 23. MS 638.2(M + H)+。
Preparation of example 46 intermediate A37
(2S) -4- (2-chloro-6- ((5, 7-dichloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000901
Synthesis of intermediate A37 reference intermediate A36 was made by using 2,4-Dichlorobenzaldehyde replaced 2-chloro-4-fluorobenzaldehyde to give intermediate a 37. MS:654.1(M + H)+。
Preparation 47 intermediate A38
(2S) -4- (2-chloro-6- ((5-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000902
Figure BDA0003413556240000911
Synthesis of intermediate a38 intermediate a38 was obtained by using 1-fluoro-2-iodobenzene instead of 1, 2-difluoro-3-iodobenzene with reference to intermediate a 34. MS:604.1(M + H)+。
Preparation of example 48 intermediate A39
(2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -5-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000912
Synthesis of intermediate a39 intermediate a39 was obtained by using 1-iodo-2-toluene instead of 1, 2-difluoro-3-iodobenzene with reference to intermediate a 34. MS:600.1(M + H)+。
Preparation 49 intermediate A40
(2S) -4- (2-chloro-6- ((7-fluoro-1- (methoxycarbonyl) -5-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000921
Synthesis of intermediate A40 reference intermediate A34 was obtained by using 1-bromo-4-fluoro-2-toluene instead of 1, 2-difluoro-3-iodobenzeneTo intermediate a 40. MS 618.1(M + H)+。
PREPARATION 50 intermediate A41
(2S) -4- (2-chloro-6- ((5-fluoro-1- (methoxycarbonyl) -6-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000922
Synthesis of intermediate a41 referring to intermediate a34, intermediate a41 was obtained by using 1-bromo-2-fluoro-3-toluene instead of 1, 2-difluoro-3-iodobenzene. MS:618.1(M + H)+。
Preparation of example 51 intermediate A42
(2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -5- (trifluoromethoxy) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000931
Step 1 preparation of 5- (trifluoromethoxy) -3, 4-dihydronaphthalen-1 (2H) -one
Figure BDA0003413556240000932
Synthesis of intermediate a42-3 intermediate a42-3 was prepared by using 2-trifluoromethoxybenzaldehyde instead of 2-chloro-4-fluorobenzaldehyde with reference to intermediate a 36-3. MS 231.1(M + H)+。
Step 2 preparation of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -5- (trifluoromethoxy) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000933
Synthesis of intermediate A42 referenceIntermediate a35 was prepared by using 5- (trifluoromethoxy) -3, 4-dihydronaphthalen-1 (2H) -one (intermediate 42-3) instead of 5-chloro-6-fluoro-3, 4-dihydronaphthalen-1 (2H) -one (intermediate a35-4) to give intermediate a 42. MS:670.1(M + H) +。
Preparation of example 52 intermediate A43
(2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -5- (trifluoromethyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000941
Synthesis of intermediate a43 referring to intermediate a34, intermediate a43 was obtained by using 1-iodo-2- (trifluoromethyl) benzene instead of 1, 2-difluoro-3-iodobenzene. MS:654.1(M + H)+。
Preparation 53 intermediate A51
(2S) -4- (2-chloro-6- ((6-chloro-5-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000942
Synthesis of intermediate a51 referring to intermediate a32, intermediate a51 was obtained by using 1-chloro-2-fluoro-3-iodobenzene instead of 2-chloro-1-iodo-4-toluene. MS 638.2(M + H)+。
Preparation 54 intermediate A44
(2S) -4- (2-chloro-6- ((5, 7-difluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000951
Synthesis of intermediate a44 referring to intermediate a35, intermediate a44 was prepared by using 2, 4-difluoro-1-iodobenzene instead of 2-chloro-1-fluoro-3-iodobenzene. MS:622.1(M + H)+。
Preparation of example 55 intermediate A46
(2S) -4- (2-chloro-6- ((5-fluoro-1- (methoxycarbonyl) -7-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid
Figure BDA0003413556240000952
Synthesis of intermediate a46 referring to intermediate a35, intermediate a46 was prepared by using 2-fluoro-1-iodo-4-toluene instead of 2-chloro-1-fluoro-3-iodobenzene. MS 618.1(M + H)+。
Preparation 56 intermediate A47
(2S) -4- (2-chloro-6- ((7-chloro-1- (methoxycarbonyl) -5-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000961
Synthesis of intermediate a47 referring to intermediate a34, intermediate a47 was prepared by using 4-chloro-1-iodo-2-toluene instead of 1, 2-difluoro-3-iodobenzene. MS:634.1(M + H)+。
Preparation 57 intermediate A48
(2S) -4- (2-chloro-6- ((6-fluoro-1- (methoxycarbonyl) -5-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000962
Synthesis of intermediate a48 referring to intermediate a34, intermediate a48 was prepared by using 1-fluoro-3-iodo-2-toluene instead of 1, 2-difluoro-3-iodobenzene. MS 618.1(M + H)+。
Preparation of 58 intermediate A45
(2S) -4- (6- ((5-bromo-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2-chloro-5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000963
Synthesis of intermediate a45 intermediate a45 was prepared by using 5-bromo-3, 4-dihydronaphthalen-1 (2H) -one instead of 5-chloro-6-fluoro-3, 4-dihydronaphthalen-1 (2H) -one (intermediate a35-4) with reference to intermediate a 35. MS 618.1(M + H) +。
Preparation of 59 intermediate A49
(2S) -4- (2-chloro-6- ((4-chloro-1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000971
Synthesis of intermediate a49 intermediate a49 was prepared by using 4-chloro-2, 3-dihydro-1H-inden-1-one instead of 5, 6-difluoro-3, 4-dihydronaphthalen-1 (2H) -one (intermediate a34-4) with reference to intermediate a 34. MS:605.4(M + H)+。
PREPARATION 60 intermediate A52
(2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -4, 4-dimethyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000972
Step 1 preparation of intermediate A52-1
2-Benzenacetonitrile (5.00 g, 42.7 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml) and sodium hydrogen (1.88 g, 47.0 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 15 ℃ for 0.5 hour, then 1-bromo-3-methyl-but-2-ene was added to the above reaction solution, and the reaction mixture was stirred at 15 ℃ for 16 hours. The reaction was then quenched by addition of ice water and extracted by dilution with ethyl acetate. Washing the organic phase with saturated brine, and drying the sulfuric acid without waterSodium was dried, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate a52-1(7.4 g) as a yellow oil. 1H NMR(400MHz,CDCl3)δ7.42-7.33(m,5H),5.25-5.18(m,1H),3.79(dd,J＝6.5,8.1Hz,1H),2.66-2.54(m,2H),1.77-1.72(m,3H),1.57(s,3H)。
Step 2 preparation of 4, 4-dimethyl-1, 2,3, 4-tetrahydronaphthalene-1-carboxylic acid (intermediate A52-2)
Intermediate a52-1(7.4 g, 39.9 mmol) was added slowly to a solution of sulfuric acid (22.9 g, 139.8 mmol, 12.4 ml, 60% pure) with stirring at 60 ℃. After the addition was complete, the reaction mixture was stirred at 130 ℃ for 16 hours. The reaction was then quenched by addition to ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give 4, 4-dimethyl-1, 2,3, 4-tetrahydronaphthalene-1-carboxylic acid (6.6 g) as a yellow oil.1HNMR(400MHz，CDCl3)δ11.45(br s，1H)，7.30(d，J＝7.9Hz，1H)，7.19-7.03(m，3H)，3.79-3.68(m，1H)2.21-1.91(m,2H),1.86-1.72(m,1H),1.55-1.48(m,1H),1.26(s,3H),1.22-1.15(m,3H)。
Step 3 preparation of methyl 4, 4-dimethyl-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate A52-3)
4, 4-dimethyl-1, 2,3, 4-tetrahydronaphthalene-1-carboxylic acid (6.6 g, 32.3 mmol) was dissolved in 3.0M methanol hydrochloride (30 ml). And the reaction mixture was stirred at 70 ℃ for 16 hours. Then concentrated and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give methyl 4, 4-dimethyl-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (5.9 g) as a colorless oil. 1H NMR(400MHz,CDCl3)δ7.40(d,J＝7.8Hz,1H),7.28-7.21(m,1H),7.18-7.11(m,2H),3.88-3.81(m,1H),3.77(s,3H),2.23-2.13(m,1H),2.12-2.01(m,1H),1.87-1.82(m,1H),1.65-1.53(m,1H),1.36(s,3H),1.30(s,3H)。
Step 4 preparation of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -4, 4-dimethyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Synthesis of intermediate a52 intermediate a52 was prepared by using methyl 4, 4-dimethyl-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate a52-3) in place of methyl 5-chloro-6-fluoro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate a35-8) with reference to intermediate a 35. MS:614.1(M + H)+。
Preparation 61 intermediate C6
(S) - (4, 4-difluoro-1-methylpyrrolidin-2-yl) methanol
Figure BDA0003413556240000981
Synthesis of intermediate C6 intermediate C6 was prepared by using 1- (tert-butyl) 2-methyl (S) -4, 4-difluoropyrrolidine-1, 2-dicarboxylate instead of 1- (tert-butyl) 2-methyl (2S, 4R) -4-fluoropyrrolidine-1, 2-dicarboxylate with reference to intermediate C3. MS:152.1(M + H)+。
Preparation of 62 intermediate A53
(2S) -4- (2-chloro-6- ((5-chloro-1- (methoxycarbonyl) isochroman-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000982
Step 1 preparation of intermediate A53-1
2- (2-chlorophenyl) ethan-1-ol (10 g, 63.9 mmol) was dissolved in TFA (40 ml) and 2, 2-dihydroxyacetic acid (8.82 g, 96 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 100 ℃ for 48 hours. Then concentrated and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was recrystallized from dichloromethane to give intermediate a53-1(3.2 g, 23.5%) as a white solid.
Step 2 preparation of intermediate A53-2
Intermediate A53-1(3.5 g, 16.46 mmol) was dissolved in methanol (10 mL) solutionSulfoxide chloride (9.79 g, 82 mmol) was added slowly with stirring at 0 ℃. After the addition was completed, the reaction mixture was stirred at 20 ℃ for 2 hours. Then concentrated and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate a53-2(2.6 g, 69.7%) as a colorless oil. MS:227.1(M + H)+。
Step 3 preparation of (2S) -4- (2-chloro-6- ((5-chloro-1- (methoxycarbonyl) isochroman-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Synthesis of intermediate a53 referring to intermediate a35, intermediate a53 was prepared by using intermediate a53-2 instead of methyl 5-chloro-6-fluoro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate a 35-8). MS 621.1(M + H)+。
Preparation of 63 intermediate C7
((2S,4R,5S) -4-fluoro-1, 5-dimethylpyrrolidin-2-yl) methanol
Figure BDA0003413556240000991
Synthesis of intermediate C7 referring to intermediate C3, intermediate C7 was prepared by using 1- (tert-butyl) 2-methyl (2S,4R,5S) -4-fluoro-5-methylpyrrolidine-1, 2-dicarboxylate instead of 1- (tert-butyl) 2-methyl (2S,4R) -4-fluoropyrrolidine-1, 2-dicarboxylate. MS:148.1(M + H) +。
Preparation 64 intermediate A54
(2S) -4- (2-chloro-6- ((4-chloro-6-fluoro-1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240000992
Step 1 preparation of 4-chloro-6-fluoro-2, 3-dihydro-1H-inden-1-one (intermediate A54-1)
Synthesis of intermediate a54-1 with reference to intermediate a32-4, intermediate a54-1 was prepared by using 3- (2-chloro-4-fluorophenyl) propionic acid instead of 4- (2-chloro-4-methylphenyl) butanoic acid (intermediate a 32-3).
Step 2 preparation of (2S) -4- (2-chloro-6- ((4-chloro-6-fluoro-1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A54)
Synthesis of intermediate a54 referring to intermediate a34, intermediate a54 was prepared by using 4-chloro-6-fluoro-2, 3-dihydro-1H-inden-1-one (intermediate a54-1) instead of 5, 6-difluoro-3, 4-dihydronaphthalen-1 (2H) -one (intermediate a 34-4). MS:623.4(M + H)+。
Preparation of 65 intermediate A55
(2S) -4- (2-chloro-6- ((5-chloro-1- (ethoxycarbonyl) -7-fluoroisochroman-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240001001
Step 1 preparation of ethyl 2- (2-chloro-4-fluorophenethoxy) -2-ethoxyacetate (intermediate A55-1)
2- (2-chloro-4-fluorophenyl) ethan-1-ol (25 g, 143 mmol) and ethyl 2, 2-diethoxyacetate (50.5 g, 286 mmol) were dissolved in a solution of DCE (300 mL) and boron trifluoride diethyl etherate (4.37 g, 14.32 mmol) was added slowly with stirring at 0 ℃. After the addition was complete, the reaction mixture was stirred at 20 ℃ for 13 hours. Then concentrated and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate a55-1(20 g, 45.8%) as a colorless oil.
Step 2 preparation of intermediate A55-2
Ethyl 2- (2-chloro-4-fluorophenethoxy) -2-ethoxyacetate (intermediate a55-1,19 g, 62.3 mmol) was dissolved in DCE (100 ml) solution and eaton's reagent (14.84 g, 62.3 mmol) was added slowly with stirring at 0 ℃. After the addition was complete, the reaction mixture was stirred at 20 ℃ for 13 hours. Then adding the reaction solution into ice water, and usingDiluting and extracting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate a55-2(9.6 g, 59.5%) as a colorless oil. MS:259.1(M + H)+。
Step 3 preparation of (2S) -4- (2-chloro-6- ((5-chloro-1- (ethoxycarbonyl) -7-fluoroisochroman-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Synthesis of intermediate a55 referring to intermediate a35, intermediate a55 was prepared by using intermediate a55-2 instead of methyl 5-chloro-6-fluoro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate a 35-8). MS:653.4(M + H)+。
Preparation 66 intermediate A56
(2S) -4- (2-chloro-6- ((5-chloro-1- (ethoxycarbonyl) -8-fluoroisochroman-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240001011
Synthesis of intermediate a56 referring to intermediate a53, intermediate a56 was prepared by using 2- (2-chloro-5-fluorophenyl) ethan-1-ol instead of 2- (2-chlorophenyl) ethan-1-ol. MS:639.4(M + H)+。
Preparation 67 intermediate A57
5-chloro-8-fluoro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylic acid methyl ester
Figure BDA0003413556240001012
Synthesis of intermediate a57 referring to intermediate a34-7, intermediate a57 was prepared by using 2-bromo-1-chloro-4-fluorobenzene instead of 1, 2-difluoro-3-iodobenzene. MS:242.4(M + H)+。
Preparation of 68 intermediate A58
(2S) -4- (5- ((tert-Butoxycarbonyl) amino) -6- ((5-chloro-8-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (methylthio) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240001021
Step 1 preparation of methyl 2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) acetate (intermediate A58-2)
2, 4-bis (benzyloxy) -6- (bromomethyl) -5-nitropyrimidine (10 g, 23.24 mmol) was dissolved in DMF (50 ml), and potassium acetate (3.42 g, 34.9 mmol) was added with stirring at 0 ℃ and stirred at 20 ℃ for 2 hours. The reaction was then quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give methyl 2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) acetate as a yellow solid (intermediate a58-2,9.0 g, 95%). MS:410.2(M + H) +。
Step 2 preparation of methyl (2, 6-dihydroxy-5-nitropyrimidin-4-yl) acetate (intermediate A58-3)
Methyl 2, 6-bis (benzyloxy) -5-nitropyrimidin-4-yl) acetate (9 g, 21.98 mmol) was dissolved in trifluoroacetic acid (50 ml). The reaction mixture was stirred at 50 ℃ under nitrogen for 12 hours, then the reaction mixture was concentrated and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give methyl (2, 6-dihydroxy-5-nitropyrimidin-4-yl) acetate (intermediate a58-3,4.2 g, 83%) as a yellow solid. MS 230.1(M + H)+。
Step 3 preparation of methyl (2, 6-dichloro-5-nitropyrimidin-4-yl) acetate (intermediate A58-4)
Methyl (2, 6-dihydroxy-5-nitropyrimidin-4-yl) acetate (intermediate a58-3,4.2 g, 18.33 mmol) was dissolved in toluene (50 ml) and phosphorus oxychloride (28.1 g, 183 mmol) and DIEA (7.11 g, 55.0 mmol) were added with stirring at 0 ℃. The reaction mixture was slowly warmed to 110 ℃ under nitrogen and stirred for 2 hours, then the reaction mixture was concentrated, extracted by dilution with dichloromethane and the solution poured into saturated sodium bicarbonate solutionAnd stirred for 1 hour. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give methyl (2, 6-dichloro-5-nitropyrimidin-4-yl) acetate as a yellow solid (intermediate a58-4,3.1 g, 63.6%). MS:266.1(M + H) +。
Step 4 preparation of tert-butyl (S) -4- (6- (acetoxymethyl) -2-chloro-5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A58-5)
Methyl (2, 6-dichloro-5-nitropyrimidin-4-yl) acetate (intermediate a58-4,3.1 g, 11.65 mmol) was dissolved in DCM (50 ml), and (S) -2- (piperazin-2-yl) acetonitrile (1.459 g, 11.65 mmol) was added to the reaction mixture with stirring at 0 ℃ and the reaction was stirred at 20 ℃ for 1 hour, and then Boc was added at 0 ℃. (Boc-a-t-b)2O (5.09 g, 23.31 mmol) and DIEA (1.506 g, 11.65 mmol) were added to the above reaction solution and reacted for 1 hour with stirring at 50 ℃. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (S) -tert-butyl 4- (6- (acetoxymethyl) -2-chloro-5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a58-5,3.3 g, 62.3%) as a yellow solid. MS:455.2(M + H)+。
Step 5 preparation of tert-butyl (S) -4- (6- (acetoxymethyl) -2- (methylthio) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A58-6)
Tert-butyl (S) -4- (6- (acetoxymethyl) -2-chloro-5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A58-5,1.6 g, 3.52 mmol) and CH 3A solution of SNa (0.493 g, 7.04 mmol) in THF (10 ml) and water (5 ml) was stirred at 20 ℃ for 2 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (S) -tert-butyl 4- (6- (acetoxymethyl) -2- (methylthio) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a58-6,1.3 g, 79%) as a yellow solid. MS:467.2(M + H)+。
Step 6 preparation of tert-butyl (S) -4- (6- (acetoxymethyl) -5-amino-2- (methylthio) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A58-7)
Tert-butyl (S) -4- (6- (acetoxymethyl) -2- (methylthio) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a58-6,1.3 g, 2.79 mmol) was dissolved in ethanol (15 ml) and iron powder (0.778 g, 13.93 mmol) and aqueous ammonium chloride solution (3 ml) were added with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 85 ℃ for another 1 hour, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (S) -tert-butyl 4- (6- (acetoxymethyl) -5-amino-2- (methylthio) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a58-7,1.0 g, 82%) as a yellow solid. MS:437.2(M + H) +。
Step 7 preparation of tert-butyl (S) -4- (6- (acetoxymethyl) -5- ((tert-butoxycarbonyl) amino) -2- (methylthio) pyrimidin-4-yl) -2- (cyano) piperazine-1-carboxylate (intermediate A58-8)
Tert-butyl (S) -4- (6- (acetoxymethyl) -5-amino-2- (methylthio) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A58-7,1.0 g, 2.291 mmol), Boc2A mixture of O (5 ml) and DIEA (0.592 g, 4.58 mmol) was stirred at 80 ℃ for an additional 12 hours, then the reaction was quenched by addition of ice water and extracted by dilution with DCM. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (S) -tert-butyl 4- (6- (acetoxymethyl) -5- ((tert-butoxycarbonyl) amino) -2- (methylthio) pyrimidin-4-yl) -2- (cyano) piperazine-1-carboxylate (intermediate a58-8,950 mg, 77%) as a yellow solid. MS:537.3(M + H)+。
Step 8 preparation of (S) -4- (5- ((tert-butoxycarbonyl) amino) -6- (hydroxymethyl) -2- (methylthio) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid (intermediate A58-9)
Reacting (S) -4- (6- (acetoxymethyl) -5- ((tert-butoxycarbonyl) amino) -2- (methylthio) pyrimidin-4-yl) -2- (cyano) piperazine-1-carboxylic acidA mixture of tert-butyl ester (intermediate a58-8,950 mg, 1.77 mmol), and lithium hydroxide (212 mg, 8.85 mmol) in THF (5 ml) and water (5 ml) was stirred at 20 ℃ for 2 h. The reaction was then quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (S) -4- (5- ((tert-butoxycarbonyl) amino) -6- (hydroxymethyl) -2- (methylthio) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid (intermediate a58-9,650 mg, 74.2%) as a yellow solid. MS:495.3(M + H) +。
Step 9 preparation of tert-butyl (S) -4- (6- (bromomethyl) -5- ((tert-butoxycarbonyl) amino) -2- (methylthio) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A58-10)
(S) -4- (5- ((tert-butoxycarbonyl) amino) -6- (hydroxymethyl) -2- (methylthio) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid (intermediate A58-9,650 mg, 1.314 mmol) was dissolved in DCM (10 mL) and Ph was added with stirring at 0 deg.C3P (517 mg, 1.971 mmol) and CBr4(654 mg, 1.971 mmol). After addition was complete, the reaction mixture was stirred at 20 ℃ for an additional 2 hours, then quenched by addition of ice water and extracted by dilution with DCM. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (S) -4- (6- (bromomethyl) -5- ((tert-butoxycarbonyl) amino) -2- (methylthio) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate a58-10,350 mg, 47.8%) as a yellow solid. MS:557.2&559.2(M+H)+。
Step 10 preparation of tert-butyl (2S) -4- (5- ((tert-butoxycarbonyl) amino) -6- ((5-chloro-8-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (methylthio) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A58)
Methyl 5-chloro-8-fluoro-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate (305 mg, 1.256 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml), LDA (1.25 mmol) was added slowly with stirring at-78 ℃ and stirring continued at-20 ℃ for 60 min, after which (S) -4- (6- (bromomethyl) -5- ((tert-butoxycarbonyl) amino) -2- (methylthio) group) Tert-butyl pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a58-10,350 mg, 0.628 mmol) was added to the reaction at-78 ℃. After the addition was complete, the reaction mixture was stirred at-78 ℃ for 1 hour, then quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dried sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (2S) -4- (5- ((tert-butoxycarbonyl) amino) -6- ((5-chloro-8-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (methylthio) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (intermediate a58,220 mg, 48.7%). MS:719.4(M + H)+。
Preparation example 69 intermediate A59
(2S) -4- (2-chloro-6- ((4-chloro-5-fluoro-1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240001041
Synthesis of intermediate a59 referring to intermediate a54, intermediate a59 was prepared by using 3- (2-chloro-3-fluorophenyl) propionic acid instead of 3- (2-chloro-4-fluorophenyl) propionic acid. MS:623.4(M + H)+。
Preparation example 70 intermediate C8
((2R) -2-Fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methanol
Figure BDA0003413556240001051
Step 1 preparation of intermediate C8-1
1- (tert-butyl) 2-methyl (2S, 4R) -4-fluoropyrrolidine-1, 2-dicarboxylate (20 g, 81 mmol) and HMPA (23.19 g, 129 mmol) were dissolved in anhydrous tetrahydrofuran (400 ml), LiHMDS (129 ml) was added slowly with stirring at-70 ℃ and stirring continued at-70 ℃ for 60 minutes, after which a solution of 1-bromo-3-chloropropane (63.7 g, 404 mmol) in tetrahydrofuran (100 ml) was added at-70 ℃ to the above trans-formShould be in solution. After the addition was complete, the reaction mixture was stirred at-70 ℃ for 2 hours and at room temperature for 2 hours. The reaction was then quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate C8-1(16 g, 61.1%) as a yellow oil. MS 323.1&267.1(M+H)+。
Step 2 preparation of intermediate C8-2
Intermediate C8-1(52 g, 161 mmol) was dissolved in acetonitrile (100 ml), a solution of hydrogen chloride in dioxane (1.0M,200 ml) was added slowly with stirring at 0 ℃, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness and extracted by dilution with ethyl acetate, and the organic phase was washed with saturated aqueous sodium carbonate, saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give intermediate C8-2(36 g, 100%) as a yellow oil. MS 224.1(M + H) +。
Step 3 preparation of intermediate C8-3
Intermediate C8-2(36 g, 161 mmol) in acetonitrile (50 mL) was added NaHCO slowly with stirring at 0 deg.C3(67.6 g, 805 mmol) and potassium iodide (2.67 g, 16.09 mmol), and the reaction mixture was then stirred at 50 ℃ for an additional 12 hours. Then cooled to room temperature, quenched with ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give intermediate C8-3(21g, 69.7%) as a yellow oil. 188.1(M + H)+。
Step 4 preparation of intermediate C8
Synthesis of intermediate C8 referring to intermediate C3, intermediate C8 was prepared by using intermediate C8-3 instead of 1- (tert-butyl) 2-methyl (2S,4R) -4-fluoropyrrolidine-1, 2-dicarboxylate. MS 160.1(M + H)+。1H NMR(400MHz,CDCl3):d 5.36-5.08(m,1H),3.51-3.29(m,3H),3.25-3.10(m,1H),3.04-2.93(m,1H),2.90-2.73(m,1H),2.71-2.59(m,1H),2.28-2.12(m,1H),1.95-1.73(m,4H),1.65-1.53(m,1H)。
Example 1
Compound I-1: 4 ' - (4-acryloylpiperazin-1-yl) -2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin-6 ' -one
Figure BDA0003413556240001061
Step 1 preparation of tert-butyl 4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate
Figure BDA0003413556240001062
(S) - (1-methylpyrrolidin-2-yl) methanol (105 mg, 0.916 mmol) and tert-butyl 4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate (intermediate A1,250 mg, 0.458 mmol) were dissolved in anhydrous tetrahydrofuran (20 ml) and cesium carbonate (448 mg, 1.374 mmol) was added slowly with stirring at 25 ℃. After the completion of the dropping, the reaction mixture was slowly raised to 50 ℃ and stirred for 11 hours, then the reaction was quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give tert-butyl 4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate (200 mg, 70% yield) as a yellow oil. MS:625.1(M + H)+。
Step 2 preparation of tert-butyl 4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazine-1-carboxylate
Figure BDA0003413556240001071
Tert-butyl 4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate (300 mg, 0.480 mmol) was dissolved in ethyl acetate (25 ml) and methanol (5 ml), and palladium on carbon (150 mg) was added to the reaction mixture with stirring. The reaction mixture was stirred at room temperature under hydrogen for 13 hours, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give 4- (5-amino-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester as a colorless oil (286 mg, 100% yield). MS:595.1(M + H) +。
Tert-butyl 4- (5-amino-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (150 mg, 0.252 mmol) was dissolved in acetic acid (2 ml) and the reaction mixture was stirred at 70 ℃ for 3 hours. After the reaction is finished, the reaction solution is filtered and concentrated to obtain a crude product, and the crude product is purified by silica gel column chromatography to obtain a white solid 4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxyl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ]]Pyrimidines]-4' -yl) piperazine-1-carboxylic acid tert-butyl ester (40 mg, 28% yield). MS:563.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.22–7.09(m,4H),4.70(t,J＝10.0Hz,1H),4.50(dt,J＝13.4,7.2Hz,1H),3.85(s,1H),3.77–3.45(m,8H),3.30(s,3H),3.12–2.92(m,4H),2.82(s,2H),2.37–2.30(m,1H),2.28–1.92(m,4H),1.83(s,3H),1.48(s,9H)。
Step 3 preparation of 2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -4' - (piperazin-1-yl) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin-6 ' -one
Figure BDA0003413556240001072
Reacting 4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ]]Pyrimidines]-4' -yl) piperazine-1-carboxylic acid methyl esterTert-butyl ester (50 mg, 0.089 mmol) was dissolved in dichloromethane (5 ml) and 6N methanol hydrochloride (5 ml) and the reaction mixture was stirred at room temperature for 1 hour. Concentrating the reaction mixture, evaporating to dryness, diluting with ethyl acetate, extracting, washing the organic phase with saturated sodium carbonate aqueous solution, saturated brine, drying with anhydrous dry sodium sulfate, filtering, and concentrating to obtain yellow oily substance 2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4' - (piperazine-1-yl) -3,4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] ]Pyrimidines]-6' -one (42 mg, 100% yield). MS:463.1(M + H)+。
Step 4 preparation of 4' - (4-acryloylpiperazin-1-yl) -2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin-6 ' -one
Figure BDA0003413556240001081
2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4' - (piperazine-1-yl) -3,4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-6' -one (40 mg, 0.086 mmol) and DIEA (33.5 mg, 0.259 mmol) were dissolved in dichloromethane (5 mL) and acryloyl chloride (7.83 mg, 0.086 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to give 4'- (4-acryloylpiperazin-1-yl) -2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] as a white solid]Pyrimidines]-6' -one (16 mg, 35.8% yield). MS:517.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.17(dd,J＝20.2,13.2Hz,4H),6.88–6.68(m,1H),6.26(d,J＝16.7Hz,1H),5.79(d,J＝10.6Hz,1H),4.61–4.57(m,3H),3.88(s,3H),3.79–3.47(m,6H),3.34–3.28(m,2H),3.13–2.95(m,4H),2.83(s,2H),2.38(s,1H),2.10–1.96(m,4H),1.84(s,3H)。
Example 2
The compound I-2 '- (4-acryloylpiperazin-1-yl) -5' -methyl-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyridin [3,2-d ] pyrimidin-6' -one
Figure BDA0003413556240001082
Figure BDA0003413556240001091
Step 1 preparation of tert-butyl 4- (5 '-methyl-2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6 '-oxy-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazine-1-carboxylate
Figure BDA0003413556240001092
4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [1,7' -pyridine [3, 2-d)]Pyrimidines]Tert-butyl (4' -yl) piperazine-1-carboxylate (compound I-1/step 2, 100 mg, 0.178 mmol) in DMF (5 ml) was added sodium hydrogen (21.32 mg, 0.533 mmol) slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and methyl iodide (25.2 mg, 0.178 mmol) was then added to the reaction solution, and stirring was continued for 1 hour. After the reaction was completed, ice water was added to quench the reaction, and the reaction solution was diluted with ethyl acetate and extracted. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give 4- (5' -methyl-2 ' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] as a yellow solid]Pyrimidines]-4' -yl) piperazine-1-carboxylic acid tert-butyl ester (80 mg, 78% yield). MS:577.1(M + H) +。
Step 2 preparation of 5 '-methyl-2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -4'- (piperazin-1-yl) -3,4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin-6' -one
Figure BDA0003413556240001093
4- (5' -methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]Tert-butyl (60 mg, 0.104 mmol) of (E) -4' -yl) piperazine-1-carboxylate was dissolved in dichloromethane (5 ml) and 6N methanol hydrochloride (5 ml) and the reaction mixture was stirred at room temperature for 1 hour. Concentrating the reaction mixture, evaporating to dryness, diluting with ethyl acetate, extracting, washing the organic phase with saturated sodium carbonate aqueous solution, saturated brine, drying with anhydrous dry sodium sulfate, filtering, and concentrating to obtain yellow oily substance 5' -methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -4' - (piperazine-1-yl) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-6' -one (50 mg, 100% yield). MS:477.1(M + H)+。
Step 3 preparation of 4'- (4-acryloylpiperazin-1-yl) -5' -methyl-2 '- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin-6' -one
Figure BDA0003413556240001101
Reacting 5' -methyl-2 ' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -4' - (piperazin-1-yl) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] ]Pyrimidines]-6' -one (40 mg, 0.084 mmol) and DIEA (33.5 mg, 0.259 mmol) were dissolved in dichloromethane (5 mL) and acryloyl chloride (7.83 mg, 0.086 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to give 4' - (4-acryloylpiperazin-1-yl) -5' -methyl-2 ' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-py-rolane as a white solid-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-6' -one (22 mg, 50% yield). MS:531.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.29–7.07(m,4H),6.81(dd,J＝16.8,10.6Hz,1H),6.26(dd,J＝16.8,1.9Hz,1H),5.80(dd,J＝10.6,1.9Hz,1H),4.83–4.67(m,1H),4.55–4.50(m,1H),3.89(s,3H),3.74–3.69(m,2H),3.65(m,2H),3.51–3.20(m,10H),3.08(s,2H),2.86–2.76(m,2H),2.40–2.37(m,1H),2.31–1.92(m,4H),1.76–1.68(m,3H)。
Example 3
Compound I-3: 4' - ((S) -4-acryloyl-2-methylpiperazin-1-yl) -2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-6 ' -one
Figure BDA0003413556240001102
Figure BDA0003413556240001111
Step 1 preparation of tert-butyl (3S) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Figure BDA0003413556240001112
(S) - (1-methylpyrrolidin-2-yl) methanol (0.339 g, 2.95 mmol) and (3S) -tert-butyl 4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (intermediate A2,1.1 g, 1.964 mmol) were dissolved in anhydrous tetrahydrofuran (20 ml) and cesium carbonate (1.280 g, 3.93 mmol) was added slowly with stirring at 25 ℃. After the completion of the dropping, the reaction mixture was slowly raised to 50 ℃ and stirred for 11 hours, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated The crude product was purified by silica gel column chromatography to give (3S) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester as a yellow solid (800 mg, 63.8% yield). MS:639.1(M + H)+。
Step 2 preparation of tert-butyl (3S) -3-methyl-4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazine-1-carboxylate
Figure BDA0003413556240001113
Tert-butyl (3S) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (50 mg, 0.078 mmol) and zinc powder (51.2 mg, 0.783 mmol) were added to a mixed solution of acetic acid (5 ml) and water (1 ml), and the reaction mixture was stirred at 75 degrees for 3 hours. After the reaction is finished, the reaction solution is filtered and concentrated to obtain a crude product, and the crude product is purified by silica gel column chromatography to obtain a yellow solid (3S) -3-methyl-4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxyl) -6' -oxyl-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyridine]Pyrimidines]-4' -yl) piperazine-1-carboxylic acid tert-butyl ester (30 mg, 66.5% yield). MS:577.6(M + H) +。
Step 3 preparation of 4' - ((S) -2-methylpiperazin-1-yl) -2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin-6 ' -one
Figure BDA0003413556240001121
Reacting (3S) -3-methyl-4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]Tert-butyl-4' -yl) piperazine-1-carboxylate (100 mg, 0.173 mmol) was dissolved in a methanol solution of hydrochloric acid (5 ml),the reaction mixture was stirred at room temperature for 12 hours, and then the reaction mixture solution was concentrated and extracted by dilution with ethyl acetate. The organic phase was washed with saturated aqueous sodium carbonate solution, saturated brine, dried over anhydrous dried sodium sulfate, filtered, and concentrated to give 4'- ((S) -2-methylpiperazin-1-yl) -2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] as a yellow oil]Pyrimidines]-6' -one (83 mg, 100% yield). MS:477.6(M + H)+。
Step 4 preparation of 4' - ((S) -4-acryloyl-2-methylpiperazin-1-yl) -2 ' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin-6 ' -one
Figure BDA0003413556240001122
4'- ((S) -2-methylpiperazin-1-yl) -2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d) ]Pyrimidines]-6' -one (100 mg, 0.210 mmol) and DIEA (81 mg, 0.629 mmol) were dissolved in dichloromethane (5 mL) and acryloyl chloride (18.99 mg, 0.210 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to give 4 '- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -2' - (((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] as a white solid]Pyrimidines]-6' -one (40 mg, 32.3% yield). MS:531.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.16–6.97(m,4H),6.92–6.69(m,1H),6.38–6.18(m,1H),5.79(d,J＝10.6Hz,1H),4.43–4.17(m,3H),4.02–3.98(m,1H),3.90–3.70(m,1H),3.65–3.29(m,4H),3.20–2.92(m,3H),2.78–2.65(m,3H),2.49(s,3H),2.36–2.29(m,1H),2.16–1.61(m,8H),1.05–0.98(m,3H)。
Compounds I-3a and I-3b
(R) -4 '- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -6 '-one and (S) -4' - ((S) -4-acryloyl-2-methylpiperazin-1-yl) -2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin-6' -ones
Figure BDA0003413556240001131
4 '- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d) ]Pyrimidines]Chiral resolution of the-6' -ketone (30 mg) by SFC (column model: Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide) gave the first component peak compound I-3a (retention time 1.21 min, 8 mg) and the second component peak compound I-3b (retention time 1.99 min, 9 mg) both as white solids. MS:531.1(M + H)+。
Compound I-3a (1.21 min retention time, 8 mg):1H NMR(400MHz,Methanol-d4)δ7.16–6.96(m,4H),6.92–6.69(m,1H),6.38–6.18(m,1H),5.79(d,J＝10.6Hz,1H),4.43–4.17(m,3H),4.02–3.96(m,1H),3.90–3.70(m,1H),3.65–3.29(m,4H),3.20–2.92(m,3H),2.78–2.64(m,3H),2.49(s,3H),2.36–2.26(m,1H),2.16–1.61(m,8H),1.05–0.98(m,3H)。
compound I-3b (retention time 1.99 min, 9 mg):1H NMR(400MHz,Methanol-d4)δ7.16–6.90(m,4H),6.92–6.69(m,1H),6.38–6.18(m,1H),5.79(d,J＝10.6Hz,1H),4.43–4.17(m,3H),4.02–3.91(m,1H),3.90–3.75(m,1H),3.65–3.29(m,4H),3.20–2.91(m,3H),2.79–2.66(m,3H),2.49(s,3H),2.36–2.28(m,1H),2.16–1.61(m,8H),1.05–0.96(m,3H)。
example 4
Compound I-4: 4 ' - ((S) -4- (2-fluoroacryloyl) -2-methylpiperazin-1-yl) -2 ' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-6 ' -one
Figure BDA0003413556240001141
4 '- ((S) -2-methylpiperazin-1-yl) -2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d)]Pyrimidines]-6' -one (100 mg, 0.210 mmol) and DIEA (81 mg, 0.629 mmol) were dissolved in dichloromethane (5 mL) and 2-fluoroacryloyl chloride (intermediate B1,22.76 mg, 0.210 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to give 4 '- ((S) -4- (2-fluoroacryloyl) -2-methylpiperazin-1-yl) -2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] as a white solid ]Pyrimidines]-6' -one (50 mg, 43.5% yield). MS:549.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.14–6.90(m,4H),5.44–5.08(m,2H),4.32–4.26(m,2H),4.08–3.97(m,2H),3.84–3.31(m,5H),3.18–2.92(m,2H),2.80–2.71(m,3H),2.50(s,3H),2.37–2.29(m,1H),2.06–1.89(m,2H),1.77–1.69(m,6H),1.29–1.19(m,4H)。
Compounds I-4a and I-4b
(R) -4'- ((S) -4- (2-Fluoroacryloyl) -2-methylpiperazin-1-yl) -2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -6 '-one and (S) -4' - ((S) -4- (2-Fluoroacryloyl) -2-methylpiperazin-1-yl) -2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin-6' -one
Figure BDA0003413556240001142
4’-((S)-4- (2-Fluoroacryloyl) -2-methylpiperazin-1-yl) -2 ' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d)]Pyrimidines]Chiral resolution of the-6' -ketone (40 mg) by SFC (column model: Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide) gave the first component peak compound I-4a (retention time 0.93 min, 12 mg) and the second component peak compound I-4b (retention time 1.43 min, 10 mg) both as white solids. MS:549.1(M + H)+。
Compound I-4a (retention time 0.93 min, 12 mg):1H NMR(400MHz，Methanol-d4)δ7.14–6.90(m4H),5.44–5.08(m,2H),4.32–4.26(m,2H),4.08–3.97(m,2H),3.84–3.31(m,5H),3.18–2.92(m,2H),2.80–2.71(m,3H),2.50(s,3H),2.37–2.29(m,1H),2.06–1.89(m,2H),1.77–1.69(m,6H),1.29–1.19(m,4H)。
compound I-4b (retention time 1.43 min, 10 mg):1H NMR(400MHz,Methanol-d4)δ7.14–6.90(m,4H),5.44–5.08(m,2H),4.32–4.26(m,2H),4.08–3.97(m,2H),3.84–3.31(m,5H),3.18–2.92(m,2H),2.80–2.71(m,3H),2.50(s,3H),2.37–2.29(m,1H),2.06–1.89(m,2H),1.77–1.69(m,6H),1.29–1.19(m,4H)。
example 5
Compound I-5: 2- ((2S) -1-acryloyl-4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001151
Step 1 preparation of tert-butyl (2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate
Figure BDA0003413556240001161
(S) - (1-methylpyrrolidin-2-yl) methanol (413 mg, 3.59 mmol) and (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3,700 mg, 1.196 mmol) were dissolved in anhydrous tetrahydrofuran (2 mL) and cesium carbonate (780 mg, 2.393 mmol) was added slowly with stirring at 25 ℃. After the completion of the dropping, the reaction mixture was slowly raised to 50 ℃ and stirred for 11 hours, then the reaction was quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (700 mg, 88% yield). MS:664.1(M + H)+。
Step 2 preparation of tert-butyl (2S) -2- (cyanomethyl) -4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazine-1-carboxylate
Figure BDA0003413556240001162
Tert-butyl (2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate (700 mg, 1.055 mmol) and zinc powder (207 mg, 3.16 mmol) were added to a mixed solution of acetic acid (5 ml) and water (1 ml), and the reaction mixture was stirred at 75 ℃ for 3 hours. After the reaction is finished, the reaction solution is filtered and concentrated to obtain a crude product, and the crude product is purified by silica gel column chromatography to obtain a yellow solid (2S) -2- (cyanomethyl) -4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxyl) -6' -oxyl-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d)]Pyrimidines]-4' -yl) piperazine-1-carboxylic acid tert-butyl ester (500 mg, 78.7% yield). MS:602.3(M + H)+。
Step 3 preparation of 2- ((2S) -4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001163
Mixing (2S) -2- (cyanomethyl) -4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]Tert-butyl (350 mg, 0.582 mmol) of (E) -4' -yl) piperazine-1-carboxylate was dissolved in dichloromethane (5 ml) and 6N methanol hydrochloride (5 ml) and the reaction mixture was stirred at room temperature for 1 hour. Concentrating the reaction mixture, evaporating to dryness, diluting with ethyl acetate, extracting, washing the organic phase with saturated sodium carbonate aqueous solution, saturated brine, drying with anhydrous dry sodium sulfate, filtering, and concentrating to obtain yellow oily substance 2- ((2S) -4- (2'- ((((S) -1-methylpyrrolidin-2-yl) methoxyl) -6' -oxyl-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] ]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (292 mg, 100% yield). MS 502.3(M + H)+。
Step 4 preparation of 2- ((2S) -1-acryloyl-4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001171
2- ((2S) -4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d)]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (100 mg, 0.199 mmol) and TEA (60.5 mg, 0.598 mmol) were dissolved in dichloromethane (5 ml) and acryloyl chloride (18.04 mg, 0.199 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, then quenched by adding ice water, and extracted by diluting with ethyl acetate. Washing the organic phase with saturated brine, and drying the sulfuric acid without waterSodium drying, then filtration, concentration to give crude product, which was prepared by Pre-HPLC to give 2- ((2S) -1-acryloyl-4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] as a white solid]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (55 mg, 50% yield). MS 556.1. (M + H) +。1H NMR(400MHz,Methanol-d4)δ7.17–6.99(m,4H),6.79(s,1H),6.27(d,J＝16.7Hz,1H),5.81(d,J＝10.6Hz,1H),4.39–4.22(m,2H),4.20–3.68(m,3H),3.59–3.32(m,3H),3.15–2.67(m,8H),2.49(s,3H),2.37–2.34(m,1H),2.15–1.60(m,8H),1.29(s,1H)。
Compound I-5a and Compound I-5b
2- ((S) -1-acryloyl-4- ((R) -2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile and 2- ((S) -1-acryloyl-4- ((S) -2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001172
Figure BDA0003413556240001181
2- ((2S) -1-acryloyl-4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d)]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (50 mg) was purified by SFC chiral resolution (column type: mail Reprosil Chiral-JM, 250x25mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide) to give the first component peak compound I-5a (retention time 1.24 min, 11 mg) and the second component peak compound I-5b (retention time 2.56 min, 8 mg) both as white solids. MS 556.1(M + H)+。
Compound I-5a (retention time 1.24 min, 11 mg).1H NMR(400MHz,Methanol-d4)δ7.17–6.99(m,4H),6.79(s,1H),6.27(d,J＝16.7Hz,1H),5.81(d,J＝10.6Hz,1H),4.39–4.22(m,2H),4.20–3.68(m,3H),3.59–3.32(m,3H),3.15–2.67(m,8H),2.49(s,3H),2.37–2.34(m,1H),2.15–1.60(m,8H),1.29(s,1H)。
Compound I-5b (retention time 2.56 min, 8 mg).1H NMR(400MHz,Methanol-d4)δ7.17–6.99(m,4H),6.79(s,1H),6.27(d,J＝16.7Hz,1H),5.81(d,J＝10.6Hz,1H),4.39–4.22(m,2H),4.20–3.68(m,3H),3.59–3.32(m,3H),3.15–2.67(m,8H),2.49(s,3H),2.37–2.34(m,1H),2.15–1.60(m,8H),1.29(s,1H)。
Example 6
Compound I-6 (481): 2- ((2S) -1- (2-fluoropropenyl) -4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001182
2- ((2S) -4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d)]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (100 mg, 0.199 mmol) and TEA (60.5 mg, 0.598 mmol) were dissolved in dichloromethane (5 ml) and 2-fluoroacryloyl chloride (intermediate B1,21.63 mg, 0.199 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to give 2- ((2S) -1- (2-fluoroacryloyl) -4- (2'- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] as a white solid]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (55 mg, 50% yield). MS:574.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.26–7.06(m,4H),5.30–5.20(m,2H),4.48–4.27(m,2H),3.93–3.69(m,2H),3.52–3.41(m,1H),3.37–3.21(m,1H),3.17–2.67(m,9H),2.49(s,3H),2.35(m,1H),2.18–1.58(m,8H),1.29(s,2H)。
Compound I-6a and Compound I-6b
2- ((S) -1- (2-Fluoroacryloyl) -4- ((R) -2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile and 2- ((S) -1- (2-Fluoroacryloyl) -4- ((S) -2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001191
2- ((2S) -1- (2-fluoropropenyl) -4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d)]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (50 mg) was resolved by SFC chirality (column model: mail Reprosil Chiral-JM, 250x25mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide) gave the first component peak compound I-6a (retention time 1.01 min, 13 mg) and the second component peak compound I-6b (retention time 2.17 min, 9 mg) both as white solids. MS:574.1(M + H)+。
Compound I-6a (retention time 1.01 min, 13 mg).1H NMR(400MHz,Methanol-d4)δ7.26–7.06(m,4H),5.30–5.20(m,2H),4.48–4.27(m,2H),3.93–3.69(m,2H),3.52–3.41(m,1H),3.37–3.21(m,1H),3.17–2.67(m,9H),2.49(s,3H),2.35(m,1H),2.18–1.58(m,8H),1.29(s,2H)。
Compound I-6b (retention time 2.17 min, 9 mg).1H NMR(400MHz,Methanol-d4)δ7.26–7.06(m,4H),5.30–5.20(m,2H),4.48–4.27(m,2H),3.93–3.69(m,2H),3.52–3.41(m,1H),3.37–3.21(m,1H),3.17–2.67(m,9H),2.49(s,3H),2.35(m,1H),2.18–1.58(m,8H),1.29(s,2H)。
Example 7
Compound I-7: 4' - ((2S, 5R) -4-acryloyl-2, 5-dimethylpiperazin-1-yl) -2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidin-6 ' -one
Figure BDA0003413556240001201
Synthesis of compound I-7 with reference to compound I-5, compound I-7 was prepared by using tert-butyl (2R, 5S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2, 5-dimethylpiperazine-1-carboxylate (intermediate a5) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3).
Compound I-7(11.6 mg). MS:545.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.29–7.06(m,4H),6.80(s,1H),6.15–6.98(m,1H),5.71–5.65(m,1H),4.78(s,1H),4.52–4.49(m,1H),4.46–4.28(m,2H),4.00–3.87(m,1H),3.76–3.65(m,2H),3.52-3.41(m,3H),3.21–3.02(m,2H),2.90–2.85(m,2H),2.81(s,1H),2.73(s,1H),2.41(s,3H),2.19(s,1H),2.02(s,1H),1.93–1.77(m,3H),1.74–1.67(m,1H),1.18–1.09(m,3H),1.00–0.89(m,3H)。
Example 8
Compound I-8: 4' - (2-acryloyl-2, 7-diazaspiro [3.5] non-7-yl) -2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidine ] -6' -one
Figure BDA0003413556240001202
Synthesis of Compound I-8 with reference to Compound I-5, Compound I-8 was prepared by using tert-butyl 7- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2, 7-diazaspiro [3.5] nonane-2-carboxylate (intermediate A6) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3).
Compound I-8(10.6 mg). MS:557.1(M + H)+。1H NMR(400MHz,DMSO-d6)7.13–7.02(m,4H),6.32(dd,J＝17.0,10.3Hz,1H),6.10(d,J＝17.0Hz,1H),5.66–5.59(m,1H),4.58–4.36(m,2H),4.09–3.83(m,10H),3.68(s,1H),3.57(s,1H),3.43–3.38(m,3H),3.25(s,2H),3.15–3.05(m,1H),2.92–2.71(m,5H),2.21–2.16(m,1H),1.94(s,1H),1.86(s,1H),1.71(s,4H)。
Example 9
Compound I-9: 2- ((2S) -1- (but-2-ynoyl) -4- (2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001211
2- ((2S) -4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d)]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (50 mg, 0.100 mmol) and TEA (60.5 mg, 0.598 mmol) were dissolved in dichloromethane (5 ml) and but-2-alkynylchloride (intermediate B2,10.63 mg, 0.100 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to give 2- ((2S) -1- (but-2-ynoyl) -4- (2'- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] as a white solid ]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (5 mg, 10% yield). MS 568.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.17–6.98(m,4H),4.64–4.56(m,3H),4.41–4.30(m,3H),4.19–3.70(m,2H),3.60–3.33(m,1H),3.17–2.74(m,7H),2.54–2.45(m,4H),2.32–1.60(m,9H),1.30–1.15(m,3H)。
Example 10
Compounds I-10a and I-10 b: 2- ((S) -1-acryloyl-4- ((S) -2 '-methoxy-6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4 '-yl) piperazin-2-yl) acetonitrile and 2- ((S) -1-acryloyl-4- ((R) -2' -methoxy-6 '-oxy-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile.
Figure BDA0003413556240001212
Synthesis of Compounds I-10a and I-10b reference was made to Compound I-5 by using (2S) -2- (cyanomethyl) -4- (2-methoxy-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A11) in place of (2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) piperazine- Tert-butyl 1-carboxylate (Compound I-5/step 1) to give Compound I-10a and Compound I-10 b.
Compound I-10a (retention time 4.74 min, 7.6 mg). MS:473.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.15–6.97(m，4H)，6.80(s，1H)，6.28–6.01(m，1H)，5.83–5.71(m，1H)，5.24–4.86(m，1H)，4.68–4.30(m,1H),4.03–3.88(m,4H),3.66–3.28(m,6H),3.13–2.88(m,2H),2.83–2.74(m,2H),2.20–1.72(m,4H)。
Compound I-10b (retention time 5.44 min, 11.6 mg). MS:473.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.15–6.97(m,4H),6.80(s,1H),6.28–6.01(m,1H),5.83–5.71(m,1H),5.24–4.86(m,1H),4.68–4.30(m,1H),4.03–3.88(m,4H),3.66–3.28(m,6H),3.13–2.88(m,2H),2.83–2.74(m,2H),2.20–1.72(m,4H)。
Example 11
Compound I-11: 2- ((2S) -4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidine ] -4' -yl) -1- ((E) -4,4, 4-trifluoro-2-enyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001221
Synthesis of Compound I-11 with reference to Compound I-6, Compound I-11 was prepared by using (E) -4,4, 4-trifluoro-2-enoyl chloride (intermediate B3) in place of 2-fluoroacryloyl chloride (intermediate B1).
Compound I-11(25.4 mg). MS:625.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.54–7.35(m,1H),7.27–7.02(m,4H),6.84(dd,J＝15.6,7.6Hz,1H),5.05(s,1H),4.80(s,1H),4.58–4.48(m,1H),4.43(s,1H),3.75(s,2H),3.59–3.41(m,4H),3.36–3.20(m,1H),3.13(s,2H),2.99–2.95(m,1H),2.92–2.85(m,5H),2.76–2.53(m,2H),2.23(s,1H),2.04(s,2H),1.74–1.54(m,6H)。
Example 12
Compound I-12: 4' - ((R) -4-acryloyl-3- (fluoromethyl) piperazin-1-yl) -2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-6 ' -one
Figure BDA0003413556240001222
Synthesis of compound I-12 was prepared with reference to compound I-5 by using (2R) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (fluoromethyl) piperazine-1-carboxylic acid benzyl ester (intermediate a9) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) to afford compound I-12.
Compound I-12(10.6 mg). MS:549.1(M + H)+。1H NMR(400MHz，DMSO-d6)δ7.27–7.04(m，4H)6.81(dd,J＝16.4,10.6Hz,1H),6.15(d,J＝16.2Hz,1H),5.72–5.54(m,1H),4.92(s,1H),4.63(s,2H),4.40–4.13(m,2H),4.08–3.98(m,1H),3.89–3.66(m,2H),3.58–3.45(m,1H),3.16–3.08(m,2H),2.97–2.92(m,1H),2.89–2.61(m,4H),2.55(s,1H),2.34(s,3H),2.18(s,1H),2.01–1.48(m,8H)。
Example 13
Compound I-13: 4' - ((3R, 5S) -4-acryloyl-3, 5-dimethylpiperazin-1-yl) -2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-6 ' -one
Figure BDA0003413556240001231
Synthesis of compound I-13 with reference to compound I-5, compound I-13 was prepared by using tert-butyl (2R, 6S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2, 6-dimethylpiperazine-1-carboxylate (intermediate a4) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3).
Compound I-13(9.1 mg). MS:545.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.18–7.06(m,4H),6.77(dd,J＝16.5,10.5Hz,1H),6.16(d,J＝16.6Hz,1H),5.73–5.68(m,1H),4.48–4.35(m,4H),4.19–3.99(m,1H),3.86(s,1H),3.42–3.26(m,2H),3.18–3.09(m,2H),2.91–2.85(m,3H),2.83–2.78(m 1H),2.74(s,3H),2.42(s,1H),2.23(s,1H),2.03(s,1H),1.89(s,3H),1.71(s,3H),1.32–1.25(m,3H),1.14–1.10(m,3H)。
Example 14
Compound I-14: 2- ((2S) -1-acryloyl-4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-2, 3,5',8' -tetrahydro-6 ' H-spiro [ indene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001232
Figure BDA0003413556240001241
Step 1 preparation of benzyl (2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate
Figure BDA0003413556240001242
(S) - (1-methylpyrrolidin-2-yl) methanol (114 mg, 0.992 mmol) and benzyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A12,200 mg, 0.331 mmol) were dissolved in anhydrous tetrahydrofuran (5 ml) and cesium carbonate (215 mg, 0.661 mmol) was added slowly with stirring at 25 ℃. After the completion of the dropping, the reaction mixture was slowly raised to 50 ℃ and stirred for 11 hours, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester as a yellow solid (113 mg, 50% yield). MS:684.1(M + H) +。
Step 2 preparation of benzyl (2S) -2- (cyanomethyl) -4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-2, 3,5',8' -tetrahydro-6 ' H-spiro [ indene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazine-1-carboxylate
Figure BDA0003413556240001243
(2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) benzyl piperazine-1-carboxylate (226 mg, 0.331 mmol) and zinc powder (103 mg, 1.18 mmol) were added to a mixed solution of acetic acid (5 ml) and water (1 ml), the reaction mixture was stirred at 75 ℃ for 3 hours, after completion of the reaction, the reaction solution was filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give a yellow solid(2S) -2- (cyanomethyl) -4- (2'- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-2, 3,5',8' -tetrahydro-6 'H-spiro [ indene-1, 7' -pyridine [3,2-d ])]Pyrimidines]-4' -yl) piperazine-1-carboxylic acid benzyl ester (120 mg, 58.4% yield). MS:622.1(M + H)+。
Step 3 preparation of 2- ((2S) -4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-2, 3,5',8' -tetrahydro-6 ' H-spiro [ indene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001251
Mixing (2S) -2- (cyanomethyl) -4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-2, 3,5',8' -tetrahydro-6 'H-spiro [ indene-1, 7' -pyridine [3,2-d ] ]Pyrimidines]Benzyl-4' -yl) piperazine-1-carboxylate (210 mg, 0.338 mmol) was dissolved in ethanolic alcohol (5 ml) and palladium on carbon (711 mg) was added to the reaction mixture with stirring. The reaction mixture was stirred at room temperature for 2 hours under hydrogen, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give 2- ((2S) -4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-2, 3,5',8' -tetrahydro-6 'H-spiro [ indene-1, 7' -pyridine [3,2-d ] as a yellow oil]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (160 mg, 97% yield). MS:488.1(M + H)+。
Step 4 preparation of 2- ((2S) -1-acryloyl-4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-2, 3,5',8' -tetrahydro-6 ' H-spiro [ indene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001252
2- ((2S) -4- (2'- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-2, 3,5',8' -tetrahydro-6 'H-spiro [ indene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (90 mg, 0.185 mmol) and TEA (56.0 mg, 0.554 mmol) were dissolved in dichloromethane (5 ml) and acryloyl chloride (16.7 mg, 0.185 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction was mixedThe mixture was stirred at 0 ℃ for 1 hour, then quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to give 2- ((2S) -1-acryloyl-4- (2'- ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-2, 3,5',8' -tetrahydro-6 'H-spiro [ indene-1, 7' -pyridine [3,2-d ] as a white solid ]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (50 mg, 50% yield). MS:542.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.42–6.65(m,5H),6.28–6.15(m,1H),5.82–5.73(m,1H),5.06(s,1H),4.71–4.64(m,1H),4.52(s,1H),4.04–3.95(m,3H),3.78–3.67(m,2H),3.37–3.35(m,1H),3.34–2.69(m,13H),2.43–2.31(m,1H),2.11–1.96(m,5H)。
Example 15
Compound I-15: 2- ((2S) -4-acryloyl-1- (2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5', 8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001261
Synthesis of compound I-15 was prepared by using (3S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -3- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate a10) instead of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) with reference to compound I-5.
Compound I-15(2.1 mg). MS 556.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.13–7.02(m,4H),6.81–6.71(m,1H),6.45–6.07(m,1H),5.82–5.45(m,1H),4.57–4.21m,6H),3.89–3.32(m,6H),3.09–2.58(m,5H),2.34–1.67(m,8H),1.30–1.21(m,4H)。
Example 16
Compound I-16: 4' - ((1R, 5S) -8-acryloyl-3, 8-diazabicyclo [3.2.1] octane-3-yl) -2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5', 8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidine ] -6' -one
Figure BDA0003413556240001262
Synthesis of Compound I-16 with reference to Compound I-5, Compound I-16 was prepared by using tert-butyl (1R, 5S) -3- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (intermediate A7) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3).
Compound I-16(11.6 mg). MS:543.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.14–6.95(m,4H),6.75(dd,J＝16.8,10.4Hz,1H),6.34(d,J＝16.7Hz,1H),5.80–5.45(m,1H),4.77–4.68(m,1H),4.61(s,1H),4.45–4.38(m,1H),4.32–4.13(m,2H),3.72–3.69(m,1H),3.66–3.50(m,1H),3.44–3.34(m,1H),3.23–3.05(m,2H),2.94–2.87(m,1H),2.81–2.61(m,3H),2.51(s,3H),2.38–2.34(m,1H),2.32–2.15(m,2H),2.13–1.63(m,8H)。
Example 17
Compound I-17: 4' - ((1R, 5S) -3-acryloyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) -2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5', 8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidine ] -6' -one
Figure BDA0003413556240001271
Synthesis of Compound I-17 with reference to Compound I-5, Compound I-17 was prepared by using tert-butyl (1R, 5S) -8- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate A8) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3).
Compound I-17(15.7 mg). MS:543.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.15–6.98(m,4H),6.81–6.63(m,1H),6.23–6.10(m,1H),5.76–5.65(m,1H),4.69(s,1H),4.55–4.49(m,1H),4.32–4.15(m,3H),4.02–3.42(m,3H),3.35–3.19(m,2H),3.11–2.99(m,1H),2.93–2.87(m 1H),2.80–2.75(m,3H),2.51(s,3H),2.39–2.34(m,1H),2.29–1.61(m,9H)。
Example 18
Compound I-18: 2- ((2S) -1- ((E) -4-methoxy-2-enyl) -4- (2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5', 8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001272
Synthesis of Compound I-18 with reference to Compound I-6, Compound I-18 was prepared by using (E) -4-methoxy-2-enoyl chloride (intermediate B4) in place of 2-fluoroacryloyl chloride (intermediate B1).
Compound I-18(20.4 mg). MS:600.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.30–7.00(m,4H),6.67–6.45(m,2H),5.06(s,1H),4.62–4.24(m,4H),4.08(s,2H),3.72–3.59(m,6H),3.37(s,1H),3.30–3.27(m,3H),3.10–3.05(m,3H),2.97–2.94(m,1H),2.91(s,3H),2.75–2.69(m,3H),2.22(s,1H),2.04–1.95(m,2H),1.79–1.68(m,5H)。
Example 19
Compound I-19: 4 ' - ((R) -4-acryloyl-2- (hydroxymethyl) piperazin-1-yl) -2 ' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5', 8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-6 ' -one
Figure BDA0003413556240001281
Step 1 preparation of (R) -4-acryloyl-2- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester
Figure BDA0003413556240001282
Tert-butyl (R) -2- (hydroxymethyl) piperazine-1-carboxylate (2.0 g, 9.26 mmol) and TEA (1.87 g, 18.52 mmol) were dissolved in dichloromethane (25 ml) and acryloyl chloride (922 mg, 10.19 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (R) -4-acryloyl-2- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester as a colorless oil (1.8 g, 72% yield). MS:271.3(M + H)+。
Step 2 preparation of (R) -1- (3- (hydroxymethyl) piperazin-1-yl) prop-2-en-1-one
Figure BDA0003413556240001283
Tert-butyl (R) -4-acryloyl-2- (hydroxymethyl) piperazine-1-carboxylate (1.8 g, 6.67 mmol) was dissolved in dichloromethane (15 ml) and trifluoroacetic acid (10 ml), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness and extracted by dilution with ethyl acetate, the organic phase was washed with saturated aqueous sodium carbonate, saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give (R) -1- (3- (hydroxymethyl) piperazin-1-yl) prop-2-en-1-one (1.7 g, 100% yield) as a yellow oil. MS 171.3(M + H) +。
Step 3 preparation of methyl 1- ((6- ((R) -4-acryloyl-2- (hydroxymethyl) piperazin-1-yl) -2-chloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate
Figure BDA0003413556240001291
The (R) -1- (3- (hydroxymethyl) piperazine-1-Yl) prop-2-en-1-one (120 mg, 0.51 mmol) and methyl 1- ((2, 6-dichloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (intermediate a3-5,200 mg, 0.51 mmol) were dissolved in anhydrous dichloromethane (5 ml) and TEA (78 mg, 0.76 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred for another 1 hour, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give methyl 1- ((6- ((R) -4-acryloyl-2- (hydroxymethyl) piperazin-1-yl) -2-chloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (150 mg, 42% yield) as a colorless oil. MS:530.2(M + H)+。
Step 4 preparation of methyl 1- ((6- ((R) -4-acryloyl-2- (hydroxymethyl) piperazin-1-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate
Figure BDA0003413556240001292
(S) - (1-methylpyrrolidin-2-yl) methanol (54 mg, 0.47 mmol) and methyl 1- ((6- ((R) -4-acryloyl-2- (hydroxymethyl) piperazin-1-yl) -2-chloro-5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (150 mg, 0.28 mmol) were dissolved in anhydrous tetrahydrofuran (10 ml) and cesium carbonate (153 mg, 0.47 mmol) was added slowly with stirring at 25 ℃. After the completion of the dropping, the reaction mixture was slowly raised to 50 ℃ and stirred for 11 hours, then the reaction was quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by silica gel column chromatography to give a colorless oil, methyl 1- ((6- ((R) -4-acryloyl-2- (hydroxymethyl) piperazin-1-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (120 mg, 70% yield). MS:609.3(M + H)+。
Step 5 preparation of 4 ' - ((R) -4-acryloyl-2- (hydroxymethyl) piperazin-1-yl) -2 ' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5', 8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-6 ' -one
Figure BDA0003413556240001301
Methyl 1- ((6- ((R) -4-acryloyl-2- (hydroxymethyl) piperazin-1-yl) -2- ((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) methyl) -1,2,3, 4-tetrahydronaphthalene-1-carboxylate (120 mg, 0.20 mmol) and zinc powder (30 mg, 0.46 mmol) were added to a mixed solution of acetic acid (5 ml) and water (1 ml), and the reaction mixture was stirred at 50 degrees for 3 hours. After the reaction is finished, the reaction solution is filtered and concentrated to obtain a crude product, and the crude product is purified by silica gel column chromatography to obtain a yellow white solid 4 '- ((R) -4-acryloyl-2- (hydroxymethyl) piperazine-1-yl) -2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5', 8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] ]Pyrimidines]-6' -one (20 mg, 18.7% yield). MS:547.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.14–6.95(m,4H),6.81(dd,J＝16.7,10.5Hz,1H),6.30(d,J＝16.7Hz,1H),5.94–5.79(m,1H),4.79–4.50(m,6H),4.05–3.45(m,8H),3.28–2.65(m,9H),2.49–1.78(m,6H)。
Example 20
Compound I-20a and compound I-20 b: 2- ((S) -1-acryloyl-4- ((R) -2' - ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6' -oxo-3, 4,5', 8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile and 2- ((S) -1-acryloyl-4- ((S) -2' - ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6' -oxo-3, 4,5', 8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001302
Figure BDA0003413556240001311
Step 1 preparation of tert-butyl (2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate
Figure BDA0003413556240001312
Tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3,200 mg, 0.342 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml) and 2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-ol (55.8 mg, 0.342 mmol) and sodium hydroxide (13.67 mg, 0.342 mmol) were slowly added with stirring at 25 ℃. After the completion of the dropping, the reaction mixture was slowly raised to 50 ℃ and stirred for 4 hours, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered, concentrated to give a crude product, which was purified by silica gel column chromatography to give (2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -5-nitropyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (197 mg, 91% yield). MS:712.1(M + H) +。
Step 2 preparation of tert-butyl (2S) -2- (cyanomethyl) -4- (2' - ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6' -oxo-3, 4,5', 8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazine-1-carboxylate
Figure BDA0003413556240001321
(2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -5-nitropyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (190 mg, 0.267 mmol) and zinc powder (87 mg, 1.335 mmol) were added to acetic acid (5 mL) andto the mixed solution of water (1 ml), the reaction mixture was stirred at 75 ℃ for 3 hours. After the reaction is finished, the reaction solution is filtered and concentrated to obtain a crude product, and the crude product is purified by silica gel column chromatography to obtain a yellow solid (2S) -2- (cyanomethyl) -4- (2'- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6' -oxo-3, 4,5', 8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazine-1-carboxylic acid tert-butyl ester (200 mg, 115% yield). MS:550.1(M + H)+。
Step 3 preparation of 2- ((2S) -4- (2' - ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6' -oxo-3, 4,5', 8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001322
Reacting (2S) -2- (cyanomethyl) -4- (2'- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6' -oxo-3, 4,5', 8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]Tert-butyl-4' -yl) piperazine-1-carboxylate (200 mg, 0.308 mmol) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (5 ml) and the reaction mixture was stirred at room temperature for 2 hours. Concentrating the reaction mixture, evaporating to dryness, diluting with ethyl acetate, extracting, washing the organic phase with saturated sodium carbonate aqueous solution, saturated brine, drying with anhydrous dry sodium sulfate, filtering, and concentrating to obtain yellow oily substance 2- ((2S) -4- (2'- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6' -oxo-3, 4,5', 8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyridine]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (175 mg, 103% yield). MS 550.1(M + H)+。
Step 4:2- ((S) -1-acryloyl-4- ((R) -2' - ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6' -oxo-3, 4,5', 8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile and 2- ((S) -1-acryloyl-4- ((S) -2' - ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6' -oxo-3, preparation of 4,5', 8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001331
2- ((2S) -4- (2'- ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6' -oxo-3, 4,5', 8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d)]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (175 mg, 0.318 mmol) and DIEA (82 mg, 0.637 mmol) were dissolved in dichloromethane (5 ml) and acryloyl chloride (43.2 mg, 0.478 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to give compound I-20a (retention time 4.08 min, 3 mg) and compound I-20b (retention time 4.22 min, 4 mg) as both white solids. MS:604.1(M + H)+。
Compound I-20a (retention time 4.08 min, 3 mg).1H NMR(400MHz,DMSO-d6)δ7.12–6.98(m,5H),6.92–6.89(m,2H),6.81(s,1H),6.15–6.09(m,1H),5.73–5.61(m,1H),4.93(s,1H),4.65(s,1H),4.30(s,1H),3.65(s,2H),3.54-3.51(m,3H),3.41-3.25(m,2H),3.15(s,1H),2.90–2.79(m,3H),2.75–2.68(m,2H),2.32(s,3H),2.04–1.95(m,2H),1.76(s,3H),1.22(s,2H)。
Compound I-20b (retention time 4.22 min, 4 mg).1H NMR(400MHz,DMSO-d6)δ7.12–6.98(m,5H),6.92–6.89(m,2H),6.81(s,1H),6.15–6.09(m,1H),5.73–5.61(m,1H),4.93(s,1H),4.65(s,1H),4.30(s,1H),3.65(s,2H),3.54-3.51(m,3H),3.41-3.25(m,2H),3.15(s,1H),2.90–2.79(m,3H),2.75–2.68(m,2H),2.32(s,3H),2.04–1.95(m,2H),1.76(s,3H),1.22(s,2H)。
Example 21
Compound I-21- ((2S) -1- (2-Fluoroacryloyl) -4- (2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-2, 3,5',8' -tetrahydro-6 ' H-spiro [ indene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001332
Synthesis of Compound I-21 with reference to Compound I-14, Compound I-21 was prepared by using 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride.
Compound I-21(46.5 mg). MS:560.1(M + H)+。1H NMR(400MHz，Methanol-d4)δ7.34–6.88(m，4H)5.32–5.18(m,2H),4.73–4.61(m,1H),4.53(s,1H),4.08–3.99(m,3H),3.79–3.64(m,2H),3.49–2.90(m,13H),2.43–2.21(m 1H),2.13–2.09(m,6H)。
Example 22
Compound I-22- ((2S) -1-acryloyl-4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-5 ', 8' -dihydro-6 ' H-spiro [ chroman-4, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001341
Synthesis of Compound I-22 was prepared by substituting benzyl (2S) -4- (2-chloro-6- ((4- (methoxycarbonyl) chroman-4-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A13) for (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A12) with reference to Compound I-14.
Compound I-22(4.6 mg). MS 558.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.20–7.10(m,2H),7.01–6.69(m,2H),6.29–6.11(m,1H),5.83–5.76(m,1H),5.09(s,1H),4.58(s,3H),4.41–3.81(m,6H),3.64–3.51(m,1H),3.48–2.76(m,8H),2.49–1.66(m,6H),1.31–1.20(m,3H)。
Example 23
Compound I-23: 2- ((2S) -1- (2-fluoropropenyl) -4- (2' - ((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) oxy) -6' -oxo-3, 4,5', 8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001342
Synthesis of Compound I-23 with reference to Compound I-20, Compound I-23 was prepared by using 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride.
Compound I-23(14.83 mg). MS:622.1(M + H) +。1H NMR(400MHz,DMSO-d6)δ7.39–7.19(m,2H),7.11(dq,J＝14.1,8.2,7.6Hz,5H),5.44–5.11(m,2H),4.54(d,J＝14.2Hz,1H),4.45–4.25(m,1H),4.02–3.43(m,6H),3.31–2.53(m,14H),2.14–1.57(m,4H)。
Example 24
Compound I-24: 4' - ((R) -4-acryloyl-3- (hydroxymethyl) piperazin-1-yl) -2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-6 ' -one
Figure BDA0003413556240001351
Synthesis of compound I-24 was prepared with reference to compound I-5 by using (2R) -tert-butyl 4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (hydroxymethyl) piperazine-1-carboxylate (intermediate a15) instead of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3) to afford compound I-24.
Compound I-24(10.67 mg). MS:547.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.15–6.96(m,4H),6.80(s,1H),6.25–6.01(m,1H),5.94–5.59(m,1H),4.82–4.41(m,3H),4.40–3.97(m,2H),3.95–3.36(m,3H),3.33–2.67(m,10H),2.51–1.77(m,9H),1.31–1.20(m,2H)。
Example 25
Compound I-25: 2- ((2S) -1-acetyl-4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-2, 3,5',8' -tetrahydro-6 ' H-spiro [ indene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001352
Synthesis of Compound I-25 was prepared by using acetyl chloride instead of acryloyl chloride with reference to Compound I-14.
Compound I-25(20 mg). MS:530.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.34–6.86(m,4H),5.00–4.86(m,1H),4.61–4.43(m,4H),4.21–3.57(m,5H),3.43–2.84(m,11H),2.55–1.93(m,9H)。
Example 26
Compound I-26: 2- ((2S) -4- (2' - (((2S, 4S) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001361
Synthesis of Compound I-26 reference is made to Compound I-14 by using (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A14) in place of ((2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A12), ((2S, 4S) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C1) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride gave compound I-26.
Compound I-26(4.6 mg). MS:592.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.29–7.02(m,4H),5.42–5.03(m,3H),4.26–4.19(m,1H),4.17–4.02(m,1H),3.81–3.47(m,2H),3.34–2.54(m,17H),2.31(s,4H),2.13–1.57(m,2H)。
Example 27
Compound I-27: 2- ((2S) -1- (2-fluoroacryloyl) -4- (2' - ((((2S, 4R) -4-methoxy-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001362
Synthesis of Compound I-27 reference is made to Compound I-14 by using (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A14) in place of ((2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A12), ((2S, 4R) -4-methoxy-1-methylpyrrolidin-2-yl) methanol (intermediate C2) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride gave compound I-27.
Compound I-27(14.6 mg). MS:604.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.31–7.04(m,4H),5.45–5.13(m,2H),4.64–4.38(m,2H),4.09(s,1H),3.89(s,1H),3.82–3.61(m,2H),3.59–2.65(m,19H),2.32(s,1H),2.07–1.59(m,5H)。
Example 28
Compound I-28: 2- ((2S) -1-acryloyl-4- (2' - (((2S, 4S) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001371
Synthesis of Compound I-28 reference is made to Compound I-14 by using (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A14) in place of ((2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A12), ((2S, 4S) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C1) instead of (S) - (1-methylpyrrolidin-2-yl) methanol gave compound I-28.
Compound I-28(14.6 mg). MS:574.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.32–7.03(m,4H),6.84(s,1H),6.18(d,J＝16.7Hz,1H),5.77(d,J＝10.3Hz,1H),5.46(m,1H),5.16–4.68(m,1H),4.65–4.32(m,2H),4.20–3.44(m,9H),3.33–2.61(m,11H),2.21–1.60(m,5H)。
Example 29
Compound I-29: 2- ((2S) -1-acryloyl-4- (2' - (((2S, 4R) -4-methoxy-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001372
Synthesis of Compound I-29 reference is made to Compound I-14 by using (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A14) in place of ((2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A12), ((2S, 4R) -4-methoxy-1-methylpyrrolidin-2-yl) methanol (intermediate C2) instead of (S) - (1-methylpyrrolidin-2-yl) methanol gave compound I-29.
Compound I-29(11.6 mg). MS:586.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.33–7.05(m,4H),6.84(s,1H),6.18(d,J＝16.7Hz,1H),5.77(d,J＝10.4Hz,1H),4.94–4.81(mz,1H),4.67–4.30(m,2H),4.16–3.42(m,9H),3.32–2.60(m,13H),2.39–1.59(m,6H)。
Example 30
Compound I-30: 2- ((2S) -4- (2' - (((2S, 4R) -4-methoxy-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- ((E) -4-methoxy-2-enyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001381
Synthesis of Compound I-30 reference is made to Compound I-14 by using (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A14) in place of ((2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A12), ((2S, 4R) -4-methoxy-1-methylpyrrolidin-2-yl) methanol (intermediate C2) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and (E) -4-methoxy-2-enoyl chloride (intermediate B4) instead of acryloyl chloride gave compound I-30.
Compound I-30(8.4 mg). MS:630.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.26–7.04(m,4H),6.66–6.21(m,1H),5.06(s,1H),4.43–3.93(m,3H),3.89–3.43(m,9H),3.35–3.19(m,6H),3.16–3.14(m,3H),3.12–2.52(m,5H),2.29–2.21(m,3H),2.19–1.92(m,2H),1.92–1.64(m,5H)。
Example 31
Compound I-31: 2- ((2S) -1-acryloyl-4- (2' - ((2-ethylpyridin-3-yl) oxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001382
Figure BDA0003413556240001391
Step 1 preparation of benzyl (2S) -2- (cyanomethyl) -4- (2- ((2-ethylpyridin-3-yl) oxy) -6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate
Figure BDA0003413556240001392
Benzyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a14,600 mg, 0.969 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml) and 2-ethylpyridin-3-ol (239 mg, 1.938 mmol) and sodium hydroxide (116 mg, 2.91 mmol) were added slowly with stirring at 25 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 4 hours, then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (2S) -benzyl 2- (cyanomethyl) -4- (2- ((2-ethylpyridin-3-yl) oxy) -6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate (580 mg, 85% yield) as a yellow solid. MS:706.1(M + H)+。
Step 2 preparation of benzyl (2S) -2- (cyanomethyl) -4- (2' - ((2-ethylpyridin-3-yl) oxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazine-1-carboxylate
Figure BDA0003413556240001393
To a mixed solution of acetic acid (5 ml) and water (1 ml) were added (2S) -benzyl 2- (cyanomethyl) -4- (2- ((2-ethylpyridin-3-yl) oxy) -6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate (580 mg, 0.822 mmol) and zinc powder (161 mg, 2.46 mmol), and the reaction mixture was stirred at 75 degrees for 3 hours. After the reaction is finished, the reaction solution is filtered and concentrated to obtain a crude product, and the crude product is purified by silica gel column chromatography to obtain a yellow solid (2S) -2- (cyanomethyl) -4- (2'- ((2-ethylpyridin-3-yl) oxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazine-1-carboxylic acid benzyl ester (280 mg, 52.9% yield). MS:644.1(M + H)+。
Step 3 preparation of 2- ((2S) -4- (2' - ((2-ethylpyridin-3-yl) oxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001401
Mixing (2S) -2- (cyanomethyl) -4- (2'- ((2-ethylpyridin-3-yl) oxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]Benzyl (4' -yl) piperazine-1-carboxylate (280 mg, 0.435 mmol) was dissolved in ethanol (15 ml) and palladium on carbon (231 mg) was added to the reaction mixture with stirring. The reaction mixture was stirred at room temperature for 12 hours under hydrogen, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give 2- ((2S) -4- (2'- ((2-ethylpyridin-3-yl) oxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d) as a yellow oil ]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (222 mg, 100% yield). MS 510.1(M + H)+。
Step 4 preparation of 2- ((2S) -1-acryloyl-4- (2' - ((2-ethylpyridin-3-yl) oxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001402
2- ((2S) -4- (2'- ((2-ethylpyridin-3-yl) oxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (100 mg, 0.196 mmol) and TEA (19.86 mg, 0.196 mmol) were dissolved in dichloromethane (5 ml) and acryloyl chloride (17.76 mg, 0.196 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to a white solidThe isomer 2- ((2S) -1-acryloyl-4- (2'- ((2-ethylpyridin-3-yl) oxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (14 mg, 7.3% yield). MS:564.1(M + H) +。1H NMR(400MHz,Methanol-d4)δ8.36–8.15(m,1H),7.61–7.57(m,1H),7.36–7.21(m,1H),7.17–7.89(m,5H),6.76(s,1H),6.25–6.10(m，1H)，5.80–5.54(m，1H)，4.69(s，4H)，3.69(m，3H)，3.24–2.94(m，2H)，2.78(m，5H)，2.15–1.78(m4H),1.42–1.15(m,4H)。
Example 32
Compound I-32: 2- ((2S) -4- (2' - ((2-ethylpyridin-3-yl) oxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001411
Synthesis of Compound I-32 with reference to Compound I-31, Compound I-32 was prepared by using 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride.
Compound I-32(9.6 mg). MS:582.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ8.52(d,J＝5.0Hz,1H),8.24–8.16(m,1H),7.75(dd,J＝8.4,5.7Hz,1H),7.26–7.07(m,4H),5.39–5.16(m,2H),4.82–4.58(m,3H),4.21–3.90(m,2H),3.78–3.61(m,1H),3.54–3.39(m,1H),3.23–3.18(m,1H),3.10–2.58(m,7H),2.15–1.76(m,4H),1.44–1.24(m,3H)。
Example 33
Compound I-33: 2- ((2S) -1-acetyl-4- (2' - ((2-ethylpyridin-3-yl) oxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001412
Synthesis of Compound I-33 with reference to Compound I-31, Compound I-33 was prepared by using acetyl chloride instead of acryloyl chloride.
Compound I-33(9.6 mg). MS:552.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ8.52(d,J＝5.6Hz,1H),8.27–8.10(m,1H),7.85–7.67(m,1H),7.28–7.04(m,4H),4.62–4.31(m,1H),3.88–3.79(m,2H),3.76–3.33(m,3H),3.25–2.47(m,9H),2.33–1.76(m,6H),1.31–1.21(m,4H)。
Example 34
Compound I-34: 2- ((2S) -1- (2-fluoropropenyl) -4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-5 ',8' -dihydro-6 ' H-spiro [ chroman-4, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001421
Synthesis of Compound I-34 with reference to Compound I-22, Compound I-34 was prepared by using 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride.
Compound I-34(14.6 mg). MS:576.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.28–7.11(m,2H),6.97–6.74(m,2H),5.32–5.09(m,2H),4.82–4.42(m,3H),4.36–3.55(m,9H),3.51–3.22(m,3H),3.15–2.81(m,5H),2.45–1.86(m,7H)。
Example 35
Compound I-35: 2- ((2S) -1- ((E) -4- (dimethylamino) but-2-enyl) -4- (2' - ((2S, 4S) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001422
2- ((2S) -4- (2'- ((((2S, 4S) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d)]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (Compound I-28/step 3,150 mg, 0.289 mmol) and DIEA (112 mg, 0.866 mmol) is dissolved in dichloromethane (5 ml) and (E) -4-bromo-2-enoic acid (47.6 mg, 0.289 mmol) and 2- (3H- [1,2,3 mmol) are added slowly with stirring at 0 deg.C]Triazole [4,5-b ]]Pyridin-3-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate (V) (110 mg, 0.289 mmol). After dropping, the reaction mixture was stirred at 20 ℃ for 1 hour, and then dimethylamine (0.866 mmol) was added to the above reaction solution and the reaction was further stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and extracted. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to give 2- ((2S) -1- ((E) -4- (dimethylamino) but-2-enyl) -4- (2'- ((2S, 4S) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] as a white solid ]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (7.52 mg, 4.3% yield). MS:576.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.33–7.02(m,4H),6.65(s,2H),5.11–4.98(m,1H),4.42–4.21(m,1H),4.19–4.01(m,2H),3.83–3.42(m,10H),3.23–2.51(m,10H),2.45–2.13(m,10H),2.07–1.60(m,2H)。
Example 36
Compound I-36: 2- ((2S) -4- (2' - (((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001431
Synthesis of Compound I-36 reference is made to Compound I-14 by using (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A14) in place of ((2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A12), ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride gave compound I-36.
Compound I-36(33 mg). MS:592.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.30–7.02(m,4H),5.61–5.21(m,3H),4.75–4.50(m,2H),4.38–3.83(m,3H),3.82–3.24(m,8H),3.24–2.59(m,9H),2.52–1.74(m,5H)。
Example 37
Compound I-37
2- ((2S) -1-acryloyl-4- (2' - (((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001432
Synthesis of Compound I-37 reference is made to Compound I-14 by using (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A14) in place of ((2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A12), ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) in place of (S) - (1-methylpyrrolidin-2-yl) methanol to afford compound I-37.
Compound I-37(19.6 mg). MS:574.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.17–6.98m,4H),6.81(s,1H),6.30–6.21(m,1H),5.84–5.76(m,1H),5.48–5.38(m,1H),4.72–3.83(m,8H),3.82–3.39(m,5H),3.24–2.59(m,9H),2.52–1.77(m,5H)。
Example 38
Compound I-38: 2- ((2S) -4- (2' - (((2S, 4S) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- ((E) -4-fluoro-2-enyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001441
Synthesis of Compound I-38 reference is made to Compound I-14 by using (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A14) in place of ((2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A12), compound I-38 was prepared from ((2S, 4S) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C1) instead of (S) - (1-methylpyrrolidin-2-yl) methanol, and (E) -4-fluoro-2-enoyl chloride (intermediate B5) instead of acryloyl chloride.
Compound I-38(10.1 mg). MS:606.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.29–7.01(m,4H),6.80–6.66(m,1H),5.45–5.35(m,1H),5.26–4.90(m,1H),4.46–4.21(m,2H),3.98–3.44(m,8H),3.30–2.61(m,13H),2.31–1.58(m,6H)。
Example 39
Compound II-1: 2- ((2S) -1-acryloyl-4- (2' - (3- (dimethylamino) azepin-1-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001442
Figure BDA0003413556240001451
Step 1 preparation of tert-butyl (2S) -2- (cyanomethyl) -4- (2- (3- (dimethylamino) azetidin-1-yl) -6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate
Figure BDA0003413556240001452
Mixing (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1, 2)Tert-butyl 3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3,600 mg, 1.026 mmol) and DIEA (1.4 ml, 8.2 mmol) were dissolved in anhydrous dichloromethane (10 ml) and N, N-dimethylazacyclobutylamine hydrochloride (355 mg, 2.05 mmol) was added slowly with stirring at 25 ℃. After the completion of the dropping, the reaction mixture was slowly raised to 50 ℃ and stirred for 11 hours, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (2S) -tert-butyl 2- (cyanomethyl) -4- (2- (3- (dimethylamino) azetidin-1-yl) -6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate (600 mg, 90.2% yield) as a yellow solid. MS:649.1(M + H) +。
Step 2 preparation of tert-butyl (2S) -2- (cyanomethyl) -4- (2' - (3- (dimethylamino) azetidin-1-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazine-1-carboxylate
Figure BDA0003413556240001453
Tert-butyl (2S) -2- (cyanomethyl) -4- (2- (3- (dimethylamino) azetidin-1-yl) -6- ((1- (methoxycarbonyl) -1, 2, 3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate (600 mg, 0.925 mmol) and zinc powder (181 mg, 2.77 mmol) were added to a mixed solution of acetic acid (10 ml) and water (1 ml), and the reaction mixture was stirred at 75 ℃ for 3 hours. After the reaction is finished, the reaction solution is filtered and concentrated to obtain a crude product, and the crude product is purified by silica gel column chromatography to obtain a yellow oily substance (2S) -2- (cyanomethyl) -4- (2'- (3- (dimethylamino) azetidin-1-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazine-1-carboxylic acid tert-butyl ester (480 mg, 88% yield). MS:587.1(M + H)+。
Step 3 preparation of 2- ((2S) -4- (2' - (3- (dimethylamino) azetidin-1-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001461
Reacting (2S) -2- (cyanomethyl) -4- (2'- (3- (dimethylamino) azetidin-1-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]Tert-butyl (300 mg, 0.511 mmol) of (4' -yl) piperazine-1-carboxylate was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (5 ml), and the reaction mixture was stirred at room temperature for 1 hour. Concentrating the reaction mixture, evaporating to dryness, diluting with ethyl acetate, extracting, washing the organic phase with saturated sodium carbonate aqueous solution, saturated brine, drying with anhydrous dry sodium sulfate, filtering, and concentrating to obtain yellow oily substance 2- ((2S) -4- (2'- (3- (dimethylamino) azetidin-1-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (250 mg, 100% yield). MS:487.1(M + H)+。
Step 4 preparation of 2- ((2S) -1-acryloyl-4- (2' - (3- (dimethylamino) azepin-1-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001462
2- ((2S) -4- (2'- (3- (dimethylamino) azetidin-1-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (100 mg, 0.205 mmol) and TEA (20.79 mg, 0.205 mmol) were dissolved in dichloromethane (5 ml) and acryloyl chloride (18.60 mg, 0.205 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, then quenched by adding ice water, and extracted by diluting with ethyl acetate. Washing the organic phase with saturated brine, drying over anhydrous dry sodium sulfate, filtering, concentrating to obtain crude product, and subjecting the crude product to Pre-HPLC to obtain white pigment 2- ((2S) -1-acryloyl-4- (2'- (3- (dimethylamino) azepin-1-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] as a colored solid]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (26 mg, 24.8% yield). MS:541.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.21–7.03(m,4H),6.79(s,1H),6.27(d,J＝16.6Hz,1H),5.81(d,J＝10.6Hz,1H),4.19–3.96(m,3H),3.97–3.68(m,4H),3.35–3.29(m,2H),3.24–2.92(m,7H),2.82–2.65(m,2H),2.21(s，6H)，2.12–1.98(m，1H)，1.87–1.71(m，3H)。
Compounds II-1a and II-1b 2- ((S) -1-acryloyl-4- ((R) -2' - (3- (dimethylamino) azetidin-1-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile and 2- ((S) -1-acryloyl-4- ((S) -2' - (3- (dimethylamino) azetidin-1-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001471
2- ((2S) -1-acryloyl-4- (2'- (3- (dimethylamino) azepin-1-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (20 mg) was purified by SFC chiral resolution (column type: mail Reprosil Chiral-JM, 250x25mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide) to give the first component peak compound II-1a (retention time of 1.42 minutes, 5 mg) and the second component peak compound II-1b (retention time of 2.71 minutes, 7 mg) both as white solids. MS:541.1(M + H) +。
Compound II-1a (retention time 1.42 min, mg).1H NMR(400MHz,Methanol-d4)δ7.21–7.03(m,4H),6.79(s,1H),6.27(d,J＝16.6Hz,1H),5.81(d,J＝10.6Hz,1H),4.19–3.96(m,3H),3.97–3.68(m,4H),3.35–3.29(m,2H),3.24–2.92(m,7H),2.82–2.65(m,2H),2.21(s,6H),2.12–1.98(m,1H),1.87–1.65(m,3H)。
Compound II-1b (retention time 2.71 min, 7 mg))。1H NMR(400MHz,Methanol-d4)δ7.21–7.03(m,4H),6.79(s,1H),6.27(d,J＝16.6Hz,1H),5.81(d,J＝10.6Hz,1H),4.19–3.96(m,3H),3.97–3.68(m,4H),3.35–3.29(m,2H),3.24–2.92(m,7H),2.82–2.65(m,2H),2.21(s,6H),2.12–1.98(m,1H),1.87–1.65(m,3H)。
Example 40
Compound II-2: 2- ((2S) -4- (2' - (3- (dimethylamino) azetidin-1-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) -1-methacryloylpiperazin-2-yl) acetonitrile
Figure BDA0003413556240001472
Synthesis of Compound II-2 with reference to Compound II-1, Compound II-2 was prepared by using 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride.
Compound II-2(34.3 mg). MS:559.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.12–6.91(m,4H),5.29–5.19(m,2H),4.23–3.96(m,3H),3.96–3.65(m,3H),3.42–2.91(m,11H),2.81(s,2H),2.20–2.15(m,6H),2.10–1.78(m,5H)。
Compounds II-2a and II-2 b: 2- ((S) -4- ((R) -2'- (3- (dimethylamino) azetidin-1-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4 '-yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile and 2- ((S) -4- ((S) -2' - (3- (dimethylamino) azetidin-1-yl) -6 '-oxo-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin-4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001481
2- ((2S) -4- (2'- (3- (dimethylamino) azetidin-1-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) -1-methacryloylpiperazin-2-yl) acetonitrile (30 mg) was purified by SFC chiral resolution (column type: main Repr osil Chiral-JM, 250x25mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide) to give the first component peak compound II-2a (retention time 1.11 min, 10 mg) and the second component peak compound II-2b (retention time 2.21 min, 9 mg) both as white solids. MS:559.1(M + H)+。
Compound II-2a (1.11 min retention time, 10 mg).1H NMR(400MHz,Methanol-d4)δ7.12–6.90(m,4H),5.29–4.99(m,2H),4.23–3.96(m,3H),3.96–3.65(m,3H),3.42–2.91(m,11H),2.81(s,2H),2.20–2.12(m,6H),2.10–1.78(m,5H)。
Compound II-2b (retention time 2.21 min, 9 mg).1H NMR(400MHz,Methanol-d4)δ7.12–6.90(m,4H),5.29–4.99(m,2H),4.23–3.96(m,3H),3.96–3.65(m,3H),3.42–2.91(m,11H),2.81(s,2H),2.20–2.12(m,6H),2.10–1.78(m,5H)。
EXAMPLE 41
Compound II-3: 2- ((2S) -1-acryloyl-4- (2' -chloro-6 ' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001491
Step 1 preparation of tert-butyl (2S) -4- (2' -chloro-6 ' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) -2- (cyanomethyl) piperazine-1-carboxylate
Figure BDA0003413556240001492
Tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3,250 mg, 0.427 mmol) and zinc powder (84 mg, 1.28 mmol) were added to a mixed solution of acetic acid (5 ml) and water (1 ml), and the reaction mixture was stirred at 75 ℃ for 3 hours. After the reaction is finished, filtering and concentrating the reaction solution to obtain a crude product, and treating the crude product with silicon Purifying by gel column chromatography to obtain yellow solid (2S) -4- (2 '-chloro-6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (130 mg, 58.2% yield). MS 524.1(M + H)+。
Step 2 preparation of 2- ((2S) -4- (2' -chloro-6 ' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001501
Mixing (2S) -4- (2 '-chloro-6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]Tert-butyl (4' -yl) -2- (cyanomethyl) piperazine-1-carboxylate (130 mg, 0.248 mmol) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (5 ml) and the reaction mixture was stirred at room temperature for 11 hours. Concentrating the reaction mixture, evaporating to dryness, diluting with ethyl acetate, extracting, washing the organic phase with saturated sodium carbonate aqueous solution, saturated brine, drying with anhydrous dry sodium sulfate, filtering, and concentrating to obtain yellow oily substance 2- ((2S) -4- (2 '-chloro-6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (106 mg, 100% yield). MS:424.1(M + H)+。
Step 3 preparation of 2- ((2S) -1-acryloyl-4- (2' -chloro-6 ' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001502
2- ((2S) -4- (2 '-chloro-6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (106 mg, 0.205 mmol) and TEA (20.79 mg, 0.205 mmol) were dissolved in dichloromethane (5 ml) and acryloyl chloride (18.60 mg, 0.205 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, then quenched by adding ice water and quenched with acetic acidAnd (5) diluting and extracting with ethyl ester. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to give 2- ((2S) -1-acryloyl-4- (2 '-chloro-6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] -as a white solid]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (29.6 mg, 24.8% yield). MS:477.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.17–6.95(m,4H),6.80(s,1H),6.28–6.12(m,1H),5.83–5.69(m,1H),5.09(s,1H),4.81–4.44(m,1H),4.21–3.72(m,3H),3.55–3.49(m,1H),3.42–3.22(m,4H),3.18–2.96(m,1H),2.82–2.67(m,3H),2.13–1.70(m,3H)。
Example 42
Compound II-4: 2- ((2S) -1-acryloyl-4- (2' -hydroxy-6 ' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001511
Step 1 preparation of tert-butyl (2S) -2- (cyanomethyl) -4- (2' -hydroxy-6 ' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazine-1-carboxylate
Figure BDA0003413556240001512
Tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3,250 mg, 0.427 mmol) and zinc powder (84 mg, 1.28 mmol) were added to a mixed solution of acetic acid (5 ml) and water (1 ml), and the reaction mixture was stirred at 75 ℃ for 3 hours. After the reaction is finished, the reaction solution is filtered and concentrated to obtain a crude product, and the crude product is purified by silica gel column chromatography to obtain a yellow solid (2S) -2- (cyanomethyl) -4- (2 '-hydroxy-6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazine-1-carboxylic acid tert-butyl ester (60 mg, 27.8% yield). MS:505.1(M + H)+。
Step 2 preparation of 2- ((2S) -4- (2' -hydroxy-6 ' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001521
Mixing (2S) -2- (cyanomethyl) -4- (2 '-hydroxy-6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]Tert-butyl (60 mg, 0.119 mmol) of (E) -4' -yl) piperazine-1-carboxylate was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (5 ml), and the reaction mixture was stirred at room temperature for 1 hour. Concentrating the reaction mixture, evaporating to dryness, diluting and extracting with ethyl acetate, washing the organic phase with saturated sodium carbonate aqueous solution, saturated brine, drying with anhydrous dry sodium sulfate, filtering, and concentrating to obtain yellow oily substance 2- ((2S) -4- (2 '-hydroxy-6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] ]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (50 mg, 100% yield). MS 405.1(M + H)+。
Step 3 preparation of 2- ((2S) -1-acryloyl-4- (2' -hydroxy-6 ' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001522
2- ((2S) -4- (2 '-hydroxy-6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (48 mg, 0.119 mmol) and DIEA (33.5 mg, 0.259 mmol) were dissolved in dichloromethane (5 ml) and acryloyl chloride (10.74 mg, 0.119 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to give 2- ((2S) -1-acryloyl-4- (2 '-hydroxy-6' -oxy-3) as a white solid,4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (13.6 mg, 25.1% yield). MS:459.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.15–6.92(m,4H),6.80(s,1H),6.27–6.04(m,1H),5.82–5.65(m,1H),4.13–3.99(m,2H),3.42–3.20(m,4H),3.16–2.69(m,5H),2.17–1.75(m,5H),1.28(s,1H)。
Example 43
Compound II-5a and Compound II-5 b: 2- ((S) -1-acryloyl-4- ((S) -6 '-oxo-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile and 2- ((S) -1-acryloyl-4- ((R) -6 '-oxo-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001531
Step 1 preparation of tert-butyl (2S) -4- (5-amino-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
Figure BDA0003413556240001532
Tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3,180 mg, 0.308 mmol) was dissolved in methanol (5 ml), and palladium on carbon (150 mg) was added to the reaction mixture with stirring. The reaction mixture was stirred at room temperature for 5 hours under hydrogen, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give (2S) -4- (5-amino-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester as a colorless oil (130 mg, 48.7% yield). MS:522.1(M + H)+。
Step 2 preparation of tert-butyl (2S) -2- (cyanomethyl) -4- (6 '-oxo-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazine-1-carboxylate
Figure BDA0003413556240001541
Tert-butyl (2S) -4- (5-amino-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (113 mg, 0.065 mmol) and sodium methoxide (0.436 mmol) were dissolved in DMF (2 ml) and the reaction mixture was stirred at 50 ℃ for 1 hour. After the reaction was completed, the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give (2S) -2- (cyanomethyl) -4- (6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] as a yellow solid ]Pyrimidines]-4' -yl) piperazine-1-carboxylic acid tert-butyl ester (100 mg, 94% yield). MS:489.1(M + H)+。
Step 3 preparation of 2- ((2S) -4- (6 '-oxo-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001542
Mixing (2S) -2- (cyanomethyl) -4- (6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]Tert-butyl (4' -yl) piperazine-1-carboxylate (100 mg, 0.205 mmol) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (5 ml) and the reaction mixture was stirred at room temperature for 1 hour. Concentrating the reaction mixture, evaporating to dryness, diluting with ethyl acetate, extracting, washing the organic phase with saturated sodium carbonate aqueous solution, saturated brine, drying with anhydrous dry sodium sulfate, filtering, and concentrating to obtain yellow oily substance 2- ((2S) -4- (6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (80 mg, 100% yield). MS:389.1(M + H)+。
Step 4 preparation of 2- ((S) -1-acryloyl-4- ((S) -6 '-oxo-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile and 2- ((S) -1-acryloyl-4- ((R) -6 '-oxo-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001543
2- ((2S) -4- (6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (150 mg, 0.193 mmol) and DIEA (49.9 mg, 0.386 mmol) were dissolved in dichloromethane (5 ml) and acryloyl chloride (26.2 mg, 0.290 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, and then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was prepared by Pre-HPLC to give compound II-5a (retention time 3.88 min, 5 mg) and compound II-5b (retention time 4.42 min, 8 mg) as both white solids. MS:443.1(M + H)+。
Compound II-5a (retention time 3.88 min, 5 mg).1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),7.11–6.90(m,4H),6.86(s,1H),6.22–6.13(m,1H),5.76–5.56(m,1H),5.06(s,1H),4.80(s,1H),4.36(s,1H),4.03(s,1H),3.59–3.49(m,2H),3.47–3.23(m,2H),3.06–2.99(m,2H),2.95(s,2H),2.77(s,2H),2.32(s,1H),1.77–1.56(m,2H)。
Compound II-5b (retention time 4.42 min, 8 mg).1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),7.11–6.90(m,4H),6.86(s,1H),6.22–6.13(m,1H),5.76–5.56(m,1H),5.06(s,1H),4.80(s,1H),4.36(s,1H),4.03(s,1H),3.59–3.49(m,2H),3.47–3.23(m,2H),3.06–2.99(m,2H),2.95(s,2H),2.77(s,2H),2.32(s,1H),1.77–1.56(m,2H)。
Example 44
Compound II-6: 2- ((2S) -1-acryloyl-4- (2' - (3- (diethylamino) azepin-1-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001551
Synthesis of Compound II-6 with reference to Compound II-1, Compound II-6 was prepared by using N, N-diethylazetidine hydrochloride instead of N, N-dimethylazacyclobutylamine hydrochloride.
Compound II-6(27.6 mg). MS:570.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.24–7.01(m,4H),6.18–5.98(m,1H),5.76–5.69(m,1H),5.06(s,1H),4.78(s,1H),4.36–4.07(m,8H),3.69–3.45(m,5H),3.13–3.07(m,4H),2.96–2.86(m,2H),2.74–2.56(m,2H),1.74–1.56(m,3H),1.28–1.11(m,6H)。
Example 45
Compound I-94- ((2S) -4- (6-chloro-5-fluoro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001561
Synthesis of Compound I-94 reference is made to Compound I-5 by using (2S) -4- (2-chloro-6- ((6-chloro-5-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A51) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoropropenylchloride (intermediate B1) instead of acryloyl chloride to afford compound I-94.
Compound I-94(35 mg). MS:626.2(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),7.38(s,1H),7.21–7.10(d,J＝8.6Hz,1H),5.43–5.10(m,2H),4.53–4.41(m,3H),3.78–3.65(m,3H),3.61–3.54(m,2H),3.46(s,1H),3.13(d,J＝11.8Hz,2H),3.05–2.93(m,2H),2.91(d,J＝4.7Hz,3H),2.86–2.77(m,1H),2.75–2.69(m,2H),2.28–2.17(m,1H),2.06–2.01(m,1H),1.74–1.57(m,8H)。
Example 46
Compound I-39 ' - (2-acryloyl-2, 6-diazaspiro [3.4] octan-6-yl) -2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-6 ' -one
Figure BDA0003413556240001562
Synthesis of Compound I-39 with reference to Compound I-5, Compound I-39 was prepared by using tert-butyl 6- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylate (intermediate A16) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3).
Compound I-39(9.6 mg). MS:543.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.16–6.90(m,4H),6.43–6.17(m,2H),5.75–5.65(m,1H),4.95–4.84(m,3H),4.65–4.50(m,1H),4.31–4.21(m,2H),4.18–3.66(m,7H),3.51–3.41(m,1H),3.23(s,1H),3.04(s,3H),2.94–2.87(m,1H),2.81–2.65(m,2H),2.47–2.28(m,1H),2.26–1.74(m,8H)。
Example 47
The compound I-40 ' - (7-acryloyl-2, 7-diazaspiro [4.4] non-2-yl) -2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidin-6 ' -one
Figure BDA0003413556240001571
Synthesis of Compound I-40 with reference to Compound I-5, Compound I-40 was prepared by using tert-butyl 7- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxylate (intermediate A17) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3).
Compound I-40(12.1 mg). MS:557.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.14–6.90(m,4H),6.59–6.41(m,1H),6.27–6.15(m,1H),5.76–5.45(m,1H),4.77–4.51(m,2H),4.10(s,1H),3.99–3.40(m,10H),3.01–2.85(m,4H),2.81–2.64(m,2H),2.47–1.71(m,13H)。
Example 48
Compound I-41:2- ((2S) -1-acryloyl-4- (2' - ((3R, 4R) -3-hydroxy-4-methoxypyrrolidin-1-yl) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001572
Synthesis of Compound I-41 reference is made to Compound I-14 by using (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A14) in place of ((2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A12), preparation of (3R, 4R) -4-methoxy-1-methylpyrrolidin-3-ol (intermediate C4) instead of (S) - (1-methylpyrrolidin-2-yl) methanol gave compound I-41.
Compound I-41(14.6 mg). MS 558.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.28–7.05(m,4H),6.80(s,1H),6.38–6.24(m,1H),5.83(d,J＝10.2Hz,1H),5.19–4.61(m,2H),4.50–4.00(m,3H),3.99–3.43(m,5H),3.41(s,3H),3.37–2.74(m,9H),2.22–1.78(m,4H)。
Example 49
Compound I-42- ((2S) -1-acryloyl-4- (6' -oxy-2 ' - (pyridin-3-yl) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001581
Synthesis of Compound I-42 reference is made to Compound I-14 by using (2S) -benzyl 2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitro-2- (pyridin-3-yl) pyrimidin-4-yl) piperazine-1-carboxylate (intermediate A18) in place of (2S) -4- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) piperazine- Benzyl 1-carboxylate (intermediate A12/step 1) to afford compound I-42.
Compound I-42(19.1 mg). MS 520.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ9.57(s,1H),9.18(s,1H),8.76(s,1H),7.91(d,J＝7.9Hz,1H),7.36–7.05(m,4H),6.83(s,1H),6.30(d,J＝16.6Hz,1H),5.84(d,J＝10.8Hz,1H),5.18–4.51(m,2H),3.94–3.87(m,3H),3.79–3.16(m,4H),3.16–2.73(m,4H),2.14–1.77(m,4H)。
Example 50
Compound I-43- ((2S) -1-acryloyl-4- (2' - (2-methylpyridin-3-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001582
Synthesis of Compound I-43 reference is made to Compound I-14 by using benzyl 2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (2-methylpyridin-3-yl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate (intermediate A19) in place of (2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) ) Benzyl piperazine-1-carboxylate (intermediate A12/step 1) affords compound I-43.
Compound I-43(16.1 mg). MS:534.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ9.14–8.98(m,1H),8.69(d,J＝4.5Hz,1H),7.91(d,J＝7.6Hz,1H),7.19–6.94(m,4H),6.82(s,1H),6.29–6.15(m,1H),5.84–5.64(m,1H),5.26–4.87(m,2H),4.26–3.35(m,4H),3.27–2.71(m,9H),2.16–1.78(m,5H)。
Example 51
Compound I-44- ((2S) -1- (2-Fluoroacryloyl) -4- (2' - (2-methylpyridin-3-yl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001591
Synthesis of Compound I-44 reference is made to Compound I-14 by using benzyl 2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (2-methylpyridin-3-yl) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate (intermediate A19) in place of (2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) ) Compound I-44 was prepared from benzyl piperazine-1-carboxylate (intermediate A12/step 1) and 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride.
Compound I-44(10.1 mg). MS:552.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ9.09(dd,J＝15.4,8.1Hz,1H),8.70(d,J＝5.6Hz,1H),7.93(t,J＝7.1Hz,1H),7.37–7.11(m,4H),5.32–5.09(m,2H),4.12–4.09(m,1H),4.05–3.35(m,5H),3.30–2.74(m,9H),2.24–1.76(m,5H)。
Example 52
Compound I-45- ((2S) -1- (2-Fluoroacryloyl) -4- (6' -oxy-2 ' - (pyridin-3-yl) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001592
Synthesis of Compound I-45 reference was made to Compound I-14 by using (2S) -benzyl 2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitro-2- (pyridin-3-yl) pyrimidin-4-yl) piperazine-1-carboxylate (intermediate A18) in place of (2S) -4- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5-nitropyrimidin-4-yl) piperazine- Benzyl 1-carboxylate (intermediate A12/step 1) and 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride gave compound I-45.
Compound I-45(11.1 mg). MS:538.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ9.45(s,1H),8.74(d,J＝8.1Hz,1H),8.59(d,J＝4.9Hz,1H),7.54(d,J＝7.1Hz,1H),7.30–7.07(m,4H),5.32–5.12(m,2H),4.41–3.33(m,6H),3.27–2.69(m,6H),2.30–1.74(m,5H)。
Example 53
Compound I-46 2- ((2S) -1-acryloyl-4- (2' - ((((((S) -1-methylpyrrolidin-2-yl) methyl) thio) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001601
Synthesis of Compound I-46 with reference to Compound I-5, Compound I-46 was prepared by using (S) - (1-methylpyrrolidin-2-yl) methanethiol (intermediate C5) in place of (S) - (1-methylpyrrolidin-2-yl) methanol.
Compound I-46(11.7 mg). MS:572.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.30–7.11(m,4H),6.81(s,1H),6.28–6.10(m,1H),5.83–5.65(m,1H),5.09(s,1H),4.21–3.43(m,6H),3.28–2.75(m,9H),2.54–2.37(m,1H),2.01–1.69(m,10H),1.29(s,2H)
Example 53
Compound I-47, 2- ((2S) -4- (2' - ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1-methacryloylpiperazin-2-yl) acetonitrile
Figure BDA0003413556240001602
Synthesis of Compound I-47 reference is made to Compound I-14 by using (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A14) in place of ((2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A12), ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and methacryloyl chloride instead of acryloyl chloride gave compound I-47.
Compound I-47(19.6 mg). MS:588.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.17(s,4H),5.37–5.01(m,3H),4.67–4.51(m,1H),4.35–3.82(m,4H),3.77–3.44(m,1H),2.92–2.57(m,14H),2.51–1.75(m,8H),1.38–1.24(m,2H)。
Example 54
Compound I-48:2- ((2S) -1- ((E) -but-2-enyl) -4- (2' - (((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001611
Synthesis of Compound I-48 reference is made to Compound I-14 by using (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A14) in place of ((2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A12), ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and (E) -but-2-enoyl chloride instead of acryloyl chloride.
Compound I-48(11.6 mg). MS:588.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.34–7.11(m,4H),6.91(s,1H),6.51(s,1H),5.48–5.31(m,1H),4.82–4.53(m,3H),4.34–3.85(m,3H),3.54(m,3H),3.21–2.76(m,8H),2.65(s,1H),2.50–1.73(m,9H),1.33–1.24(m,2H)。
Example 55
Compound I-49 methyl 2- ((2S) -2- (cyanomethyl) -4- (2' - ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-1-yl) -2-oxoacetate
Figure BDA0003413556240001612
Synthesis of Compound I-49 reference is made to Compound I-14 by using (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A14) in place of ((2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A12), ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and methyl 2-chloro-2-oxoacetate instead of acryloyl chloride gave compound I-49.
Compound I-49(21.6 mg). MS:606.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.30–7.10(m,4H),5.47–5.31(m,1H),4.94(s,1H),4.77–4.69(m,1H),4.65–4.51(m,1H),4.47–4.17(m,2H),4.06–3.85(m,4H),3.77–3.33(m,3H),3.22–2.76(m,8H),2.65–2.54(m,1H),2.37–2.25(m,1H),2.15(s,3H),2.12–1.73(m,4H),1.29–1.23(m,2H)。
Example 56
Compound I-50:2- ((2S) -1-acryloyl-4- (2' - (methylthio) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001621
Step 1 preparation of benzyl (2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (methylthio) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate
Figure BDA0003413556240001622
Benzyl 4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a14,300 mg, 0.485 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml) and sodium methyl mercaptide (67.9 mg, 0.969 mmol) was added slowly with stirring at 25 ℃. After the completion of the dropping, the reaction mixture was slowly raised to 50 ℃ and stirred for 4 hours, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give benzyl (2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (methylthio) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate (320 mg, 105% yield) as a yellow solid. MS:631.1(M + H) +。
Step 2 preparation of benzyl (2S) -2- (cyanomethyl) -4- (2' - (methylthio) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazine-1-carboxylate
Figure BDA0003413556240001631
Benzyl (2S) -2- (cyanomethyl) -4- (6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (methylthio) -5-nitropyrimidin-4-yl) piperazine-1-carboxylate (300 mg, 0.476 mmol) and zinc powder (155 mg, 2.378 mmol) were added to a mixed solution of acetic acid (5 ml) and water (1 ml), and the reaction mixture was stirred at 65 ℃ for 3 hours. After the reaction is finished, the reaction solution is filtered and concentrated to obtain a crude product, and the crude product is purified by silica gel column chromatography to obtain yellow solid (2S) -2- (cyanomethyl) -4- (2'- (methylthio) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazine-1-carboxylic acid benzyl ester(180 mg, 66.5% yield). MS:569.1(M + H)+。
Step 3 preparation of 2- ((2S) -4- (2' - (methylthio) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001632
Mixing (2S) -2- (cyanomethyl) -4- (2'- (methylthio) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]Benzyl (4' -yl) piperazine-1-carboxylate (100 mg, 0.176 mmol) acetic acid (5 ml) and 40% hydrobromic acid in acetic acid (1 ml) and the reaction mixture was stirred at 50 ℃ for 13 h. After the reaction is finished, the reaction solution is concentrated to obtain a crude product, and the crude product is purified by silica gel column chromatography to obtain a yellow solid 2- ((2S) -4- (2'- (methylthio) -6' -oxyl-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] ]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (80 mg, 105% yield). MS:435.1(M + H)+。
Step 4 preparation of 2- ((2S) -1-acryloyl-4- (2' - (methylthio) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001633
2- ((2S) -4- (2'- (methylthio) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (80 mg, 0.184 mmol) and DIEA (23.79 mg, 0.184 mmol) were dissolved in dichloromethane (5 ml) and acryloyl chloride (24.99 mg, 0.276 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to white solid 2- ((2S) -1-acryloyl-4- (2'- (methylthio) -6' -Oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (10.72 mg, 11.9% yield). MS:489.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.29–6.77(m,6H),6.17–5.98(m,1H),5.75–5.54(m 1H),4.93–4.87(m,1H),4.44–3.92(m,1H),3.76–3.44(m,6H),3.34–2.61(m,7H),1.88–1.64(m,4H)。
Example 57
Compound I-51:2- ((2S) -1-acryloyl-4- (2'- ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -5' -methyl-6 '-oxo-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001641
Step 1 preparation of benzyl (2S) -2- (cyanomethyl) -4- (5 '-methyl-2' - (methylthio) -6 '-oxy-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazine-1-carboxylate
Figure BDA0003413556240001651
Mixing (2S) -2- (cyanomethyl) -4- (2'- (methylthio) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]Benzyl (4' -yl) piperazine-1-carboxylate (compound I-50/step 2,400 mg, 0.703 mmol) was dissolved in tetrahydrofuran (10 ml) and sodium hydrogen (16.88 mg, 0.703 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 15 minutes, methyl iodide (300 mg, 2.110 mmol) was added to the above reaction solution at 0 ℃ and stirring was continued at 0 ℃ for 3 hours. The reaction was then quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC as a yellow oil (2S) -2- (cyanomethyl) -4- (5' -methyl-2 ' - (methylthio) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d)]Pyrimidines]-4' -yl) piperazineBenzyl oxazine-1-carboxylate (350 mg, 85% yield). MS:583.1(M + H)+。
Step 2 preparation of benzyl (2S) -2- (cyanomethyl) -4- (5 '-methyl-2' - (methylsulfinyl) -6 '-oxo-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin-4' -yl) piperazine-1-carboxylate
Figure BDA0003413556240001652
Mixing (2S) -2- (cyanomethyl) -4- (5' -methyl-2 ' - (methylthio) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) piperazine-1-carboxylic acid benzyl ester (400 mg, 0.686 mmol) was dissolved in dichloromethane (5 ml) and m-CPBA (118 mg, 0.686 mmol) was added slowly with stirring at 0 ℃. After the addition was complete, the reaction mixture was stirred at 0 ℃ for 15 minutes and then at room temperature for a further 3 hours. The reaction was then quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give (2S) -2- (cyanomethyl) -4- (5' -methyl-2 ' - (methylsulfinyl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] -as a yellow oil]Pyrimidines]-4' -yl) piperazine-1-carboxylic acid benzyl ester (411 mg, 100% yield), used in the next reaction without purification. MS:599.1(M + H)+。
Step 3 preparation of benzyl (2S) -2- (cyanomethyl) -4- (2'- ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -5' -methyl-6 '-oxy-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazine-1-carboxylate
Figure BDA0003413556240001653
Mixing (2S) -2- (cyanomethyl) -4- (5' -methyl-2 ' - (methylsulfinyl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] ]Pyrimidines]Benzyl (350 mg, 0.585 mmol) of (4' -yl) piperazine-1-carboxylate and ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (156 mg, 1.17 mmol) were dissolved in anhydrous tetra-ethyl acetateTo tetrahydrofuran (5 ml), cesium carbonate (571 mg, 1.75 mmol) was added slowly with stirring at 25 ℃. After the completion of the dropping, the reaction mixture was slowly raised to 50 ℃ and stirred for 11 hours, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give (2S) -2- (cyanomethyl) -4- (2' - ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -5' -methyl-6 ' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] as a yellow solid]Pyrimidines]-4' -yl) piperazine-1-carboxylic acid benzyl ester (260 mg, 66.6% yield). MS:668.1(M + H)+。
Step 4 preparation of 2- ((2S) -4- (2'- (((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -5' -methyl-6 '-oxy-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyridin [3,2-d ] pyrimidin-4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001661
Reacting (2S) -2- (cyanomethyl) -4- (2' - ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -5' -methyl-6 ' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] ]Pyrimidines]Benzyl-4' -yl) piperazine-1-carboxylate (260 mg, 0.389 mmol) was dissolved in ethanolic alcohol (5 ml) and palladium on carbon (71 mg) was added to the reaction mixture with stirring. The reaction mixture was stirred at room temperature for 2 hours under hydrogen, and then the mixture solution was filtered. The filtrate was concentrated in vacuo to give 2- ((2S) -4- (2' - (((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -5' -methyl-6 ' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] as a yellow oil]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (120 mg, 57.7% yield). MS:534.1(M + H)+。
Step 5 preparation of 2- ((2S) -1-acryloyl-4- (2'- ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -5' -methyl-6 '-oxo-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001662
2- ((2S) -4- (2' - ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -5' -methyl-6 ' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d)]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (120 mg, 0.225 mmol) and DIEA (0.12 ml, 0.675 mmol) were dissolved in dichloromethane (5 ml) and acryloyl chloride (20.35 mg, 0.225 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 1 hour, then quenched by adding ice water, and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to a yellow solid, 2- ((2S) -1-acryloyl-4- (2' - ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -5' -methyl-6 ' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] ]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (40 mg, 30.3% yield). MS:588.1(M + H)+。1H NMR(400MHz，Methanol-d4)δ7.29–7.10(m，4H)，6.79(s，1H)，6.27–6.11(m,1H),5.82–5.67(m,1H),5.48–5.21(m,1H),4.60(m,2H),4.12(m,2H),3.84–3.32(m,4H),3.22–2.22(m,14H),2.14–2.10(m,1H),2.08–1.63(m,4H),1.29–1.19(m,3H)。
Example 58
Compound I-52- ((2S) -1-acryloyl-4- (6' -oxy-2 ' - (pyridin-2-ylmethoxy) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001671
Synthesis of Compound I-52 reference is made to Compound I-14 by using (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A14) in place of ((2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A12), pyridin-2-ylmethanol instead of (S) - (1-methylpyrrolidin-2-yl) methanol gave compound I-52.
Compound I-52(20.6 mg). MS 550.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ8.66(d,J＝5.2Hz,1H),8.19(d,J＝8.8Hz,1H),7.83(t,J＝8.3Hz,1H),7.65(d,J＝6.7Hz,1H),7.31–7.06(m,5H),6.79(s,1H),6.28–6.15(m,1H),5.82–5.71(m,1H),5.60(s,2H),5.01(s,1H),4.26–3.43(m,2H),3.28–2.61(m,5H),2.26–1.68(m,6H),1.28–1.13(m,2H)。
Example 59
Compound I-53- ((2S) -1-acryloyl-4- (2' - (((((S) -1-methylpyrrolidin-2-yl) methyl) sulfinyl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001672
Figure BDA0003413556240001681
Step 1 preparation of tert-butyl (2S) -2- (cyanomethyl) -4- (2' - (((((S) -1-methylpyrrolidin-2-yl) methyl) sulfinyl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazine-1-carboxylate
Figure BDA0003413556240001682
Reacting (2S) -2- (cyanomethyl) -4- (2'- (((((S) -1-methylpyrrolidin-2-yl) methyl) thio) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]Tert-butyl (4' -yl) piperazine-1-carboxylate (compound I-46/step 2,300 mg, 0.486 mmol) was dissolved in anhydrous dichloromethane (10 ml) and m-CPBA (94 mg, 0.461 mmol) was added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was stirred at 0 ℃ for 15 minutes, and then quenched with ice waterThe reaction was quenched and extracted by dilution with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give (2S) -2- (cyanomethyl) -4- (2'- ((((((S) -1-methylpyrrolidin-2-yl) methyl) sulfinyl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] as a yellow solid]Pyrimidines]-4' -yl) piperazine-1-carboxylic acid tert-butyl ester (210 mg, 68.2% yield). MS:634.1(M + H)+。
Step 2 preparation of 2- ((2S) -4- (2' - (((((S) -1-methylpyrrolidin-2-yl) methyl) sulfinyl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001683
Reacting (2S) -2- (cyanomethyl) -4- (2'- (((((S) -1-methylpyrrolidin-2-yl) methyl) sulfinyl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] ]Pyrimidines]Tert-butyl (210 mg, 0.331 mmol) of (E) -4' -yl) piperazine-1-carboxylate was dissolved in dichloromethane (5 ml) and 1, 4-dioxane solution of hydrochloric acid (4.0M,1 ml), and the reaction mixture was stirred at room temperature for 1 hour. Concentrating the reaction mixture, evaporating to dryness, diluting with ethyl acetate, extracting, washing the organic phase with saturated sodium carbonate aqueous solution, saturated brine, drying with anhydrous dry sodium sulfate, filtering, and concentrating to obtain yellow solid 2- ((2S) -4- (2'- ((((((S) -1-methylpyrrolidin-2-yl) methyl) sulfinyl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] -pyridine]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (160 mg, 90% yield). MS:543.3(M + H)+。
Step 3 preparation of 2- ((2S) -1-acryloyl-4- (2' - (((((S) -1-methylpyrrolidin-2-yl) methyl) sulfinyl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001691
2- ((2S) -4- (2'- (((((S) -1-methylpyrrolidin-2-yl) methyl) sulfinyl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d)]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (160 mg, 0.300 mmol) was dissolved in dichloromethane (5 ml) and sodium carbonate (95 mg, 0.899 mmol) and acryloyl chloride (27.1 mg, 0.300 mmol) were added slowly with stirring at-50 ℃. After the completion of the dropping, the reaction mixture was stirred at-50 ℃ for 5 minutes, then quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was prepared by Pre-HPLC to give 2- ((2S) -1-acryloyl-4- (2'- ((((((((S) -1-methylpyrrolidin-2-yl) methyl) sulfinyl) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] -as a yellow solid ]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (11.65 mg, 5.8% yield). MS:576.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.27–7.04(m,4H),6.81(s,1H),6.36–6.20(m,1H),5.83–5.69(m,1H),5.19–4.92(m,1H),4.22–3.74(m,3H),3.66–3.45(m,8H),3.11–2.76(m,5H),2.54–2.47(m,1H),2.15(s,9H),1.29(s,2H)。
Example 60
Compound I-54- ((2S, 5R) -1-acryloyl-5-methyl-4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001692
Synthesis of Compound I-54 was prepared by using (2S, 5R) -benzyl 4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) -5-methylpiperazine-1-carboxylate (intermediate A20) in place of benzyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A12) with reference to Compound I-14.
Compound I-54(14.6 mg). MS:570.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.28–7.02(m,4H),6.97–6.72(m,1H),6.30(d,J＝16.6Hz,1H),5.83(d,J＝10.7Hz,1H),4.78–4.25(m,2H),4.01–3.35(m,7H),3.24–2.72(m,9H),2.49–1.73(m,10H),1.26–0.89(m,3H)。
Example 61
Compound I-55- ((2S, 5R) -1- (2-Fluoroacryloyl) -5-methyl-4- (2' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001701
Synthesis of Compound I-55 reference is made to Compound I-14 by using (2S, 5R) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) -5-methylpiperazine-1-carboxylic acid benzyl ester (intermediate A20) instead of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A12) and 2-fluoropropenyl chloride instead of (2S, 5R) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester (intermediate A12) Acryloyl chloride to afford compound I-55.
Compound I-55(20.6 mg). MS:588.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.32–6.99(m,4H),5.31–5.21(m,2H),4.74–4.19(m,2H),3.95–3.36(m,7H),3.26–2.76(m,9H),2.45–1.75(m,10H),1.26–0.99(m,3H)。
Example 62
Compound I-56- ((2S) -1-acryloyl-4- (7-chloro-2 ' - ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001702
Synthesis of compound I-56 reference was made to compound I-5 by using (2S) -4- (2-chloro-6- ((7-chloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate a21) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and ((2S, preparation of 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol gave compound I-56.
Compound I-56(20.6 mg). MS:608.1(M + H)+。1H NMR(400MHz，Methanol-d4)δ7.34–7.09(m，3H)6.81(s,1H),6.29–6.09(m,1H),5.83–5.69(m,1H),5.48–5.35(m,1H),4.68–3.86(m,8H),3.80–3.36(m,6H),3.24–2.76(m,6H),2.64–2.51(m,1H),2.38–2.28(m,1H),2.15(s,1H),2.11–1.96(m,1H),1.96–1.75(m,3H)。
Example 63
Compound I-57 2- ((2S) -1-acryloyl-4- (5-chloro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001711
Synthesis of compound I-57 was prepared with reference to compound I-5 by using tert-butyl ((2S) -4- (2-chloro-6- ((5-chloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a22) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3) to afford compound I-57.
Compound I-57(10.6 mg). MS:590.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.40–7.14(m,3H),6.82(s,1H),6.29(d,J＝16.8Hz,1H),5.84(d,J＝10.9Hz,1H),4.79–4.43(m,1H),4.39–3.38(m,5H),3.28–2.61(m,10H),2.52–1.78(m,11H),1.35–1.30(m,2H)。
Example 63
Compound I-58:2- ((2S) -1-acryloyl-4- (6-chloro-2 ' - (((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001712
Synthesis of compound I-58 compound I-5 was referenced by using tert-butyl ((2S) -4- (2-chloro-6- ((6-chloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a23) instead of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3) and ((2S, preparation of 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol gave compound I-58.
Compound I-58(12.6 mg). MS:608.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.31–7.10(m,3H),6.81(s,1H),6.29(d,J＝16.6Hz,1H),5.83(d,J＝10.5Hz,1H),5.48–5.34(m,1H),4.78–3.40(m,8H),3.22–2.56(m,10H),2.45–2.15(m,5H),2.08–1.68(m,4H)。
Example 64
Compound I-59:2- ((2S) -4- (5-chloro-2 ' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001721
Synthesis of Compound I-59 with reference to Compound I-5, tert-butyl ((2S) -4- (2-chloro-6- ((5-chloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A22) was used in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3) and 2-fluoropropenyl chloride in place of acryloyl chloride To obtain the compound I-59.
Compound I-59(21.6 mg). MS:608.2(M + H)+.1H NMR(400MHz,Methanol-d4)δ7.36–7.14(m,3H),5.32–5.21(m,2H),4.78–4.45(m,2H),4.35–3.38(m,7H),3.28–2.64(m,8H),2.56–1.79(m,9H),1.37–1.31(m,3H)。
Compounds I-59a and 59b 2- ((S) -4- ((S) -5-chloro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile and 2- ((S) -4- ((R) -5-chloro-2 ' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001722
2- ((2S) -4- (5-chloro-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridine [3, 2-d)]Pyrimidines]-4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile (180 mg) was resolved by SFC chiral resolution (column type: mail Reprosil Chiral-JM, 250x25mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide) to give the first component peak compound I-59a (retention time of 1.254 min, 60 mg) and the second component peak compound I-59b (retention time of 2.267 min, 80 mg) both as white solids. MS:608.2(M + H)+。
Compound I-59a (retention time 1.254 min) MS 608.2(M + H)+.1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),7.40–7.18(m,3H),7.05–7.01(m,2H),5.55–5.10(m,2H),4.60–4.36(m,2H),3.84–3.47(m,6H),3.12(d,J＝13.0Hz,3H),3.03–2.83(m,6H),2.80–2.58(m,2H),2.22–2.15(m,1H),2.04–2.01(m,1H),1.95–1.61(m,6H)。
Compound I-59b (retention time 2.267 min) MS:608.2(M + H) +.1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),7.40–7.18(m,3H),7.05–7.01(m,2H),5.55–5.10(m,2H),4.60–4.36(m,2H),3.84–3.47(m,6H),3.12(d,J＝13.0Hz,3H),3.03–2.83(m,6H),2.80–2.58(m,2H),2.22–2.15(m,1H),2.04–2.01(m,1H),1.95–1.61(m,6H)。
Example 65
Compound I-60- ((2S) -4- (6-chloro-2 ' - ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001731
Synthesis of compound I-60 reference was made to compound I-5 by using tert-butyl ((2S) -4- (2-chloro-6- ((6-chloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a23) instead of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3) and ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride instead of acryloyl chloride gave compound I-60.
Compound I-60(50.1 mg). MS:626.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.32–7.14(m,3H),5.63–5.22(m,3H),4.82–4.54(m,2H),4.38–3.86(m,5H),3.80–3.45(m,5H),3.22–2.58(m,9H),2.53–1.77(m,6H)。
Example 66
Compound I-61 2- ((S) -4- ((S) -7-chloro-2 ' - ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001741
Synthesis of compound I-61 with reference to compound I-5, by using (2S) -4- (2-chloro-6- ((7-chloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate a21) instead of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and ((2S, preparation of 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride gave compound I-61.
Compound I-61(51.1 mg). MS:626.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.28–7.07(m,3H),5.59–5.22(m,3H),4.81–4.76(m,2H),4.57–4.45(m,1H),4.36–3.86(m,5H),3.79–3.33(m,7H),3.24–2.96(m,5H),2.81–2.71(m,2H),2.65–2.51(m,1H),2.38–2.19(m,1H),2.11–1.98(m,1H),1.96–1.78(m,3H)。
Example 67
Compound I-62- ((S) -1-acryloyl-4- ((S) -2' - (((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001742
Synthesis of compound I-62 reference was made to compound I-5 by using (S) -tert-butyl 4- (2-chloro-6- (((S) -1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a29) instead of (2S) -tert-butyl 4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3) and ((2S, preparation of 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol gave compound I-62.
Compound I-62(21.1 mg). MS:574.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.23–7.06(m,4H),6.82(s,1H),6.29(d,J＝16.7Hz,1H),5.83(d,J＝10.6Hz,1H),5.17–5.01(m,2H),4.57(s,1H),4.36–4.29(m,2H),4.25–4.01(m,2H),3.85–3.70(m,1H),3.65–3.42(m,3H),3.29–2.97(m,5H),2.92–2.79(m,2H),2.67–2.58(m,1H),2.54(s,3H),2.26–2.18(m,1H),2.14–1.82(m,5H)。
Example 68
Compound I-63- ((S) -1-acryloyl-4- ((R) -2' - ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001751
Synthesis of compound I-63 reference was made to compound I-5 by using (S) -tert-butyl 4- (2-chloro-6- (((R) -1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a30) instead of (2S) -tert-butyl 4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3) and ((2S, preparation of 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol gave compound I-63.
Compound I-63(31.1 mg). MS:574.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.32–7.05(m,4H),6.80(s,1H),6.27(d,J＝16.7Hz,1H),5.82(d,J＝10.6Hz,1H),5.16–4.98(m,2H),4.80–4.28(m,3H),4.15–3.74(m,3H),3.66–3.34(m,4H),3.17–2.58(m,7H),2.52(s,3H),2.25–2.20(m,1H),2.10–1.74(m,5H)。
Example 69
Compound I-64- ((S) -4- ((R) -2' - ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001752
Synthesis of Compound I-64 reference is made to Compound I-5 by using (S) -tert-butyl 4- (2-chloro-6- (((R) -1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A30) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3), ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride gave compound I-64.
Compound I-64(17.1 mg). MS:592.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.17–6.90(m,4H),5.51–5.07(m,3H),4.37–4.24(m,2H),4.12–4.02(m,1H),3.87–3.71(m,1H),3.68–3.52(m,3H),3.40–2.99(m,8H),2.92–2.80(m,2H),2.76–2.61(m,1H),2.51(s,3H),2.26–2.15(m,1H),2.11–1.81(m,5H)。
Example 70
Compound I-65- ((S) -4- ((S) -2' - ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001761
Synthesis of Compound I-65 reference was made to Compound I-5 by using (S) -tert-butyl 4- (2-chloro-6- (((S) -1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A29) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3), ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride gave compound I-65.
Compound I-65(19.1 mg). MS:592.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.15–6.97(m,4H),5.49–5.05(m,3H),4.36–4.21(m,2H),4.14–4.01(m,1H),3.85–3.75(m,1H),3.61–3.42(m,3H),3.30–2.96(m,8H),2.90–2.83(m,2H),2.78–2.68(m,1H),2.54(s,3H),2.27–2.17(m,1H),2.12–1.80(m,5H)。
Example 71
Compound I-66 2- ((2S) -1-acryloyl-4- (7-fluoro-2 ' - (((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001762
Synthesis of compound I-66 reference was made to compound I-5 by using (2S) -4- (2-chloro-6- ((7-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate a24) instead of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and ((2S, preparation of 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol gave compound I-66.
Compound I-66(18.1 mg). MS:592.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.15(dd,J＝8.6,6.0Hz,1H),7.06–6.89(m,2H),6.80(s,1H),6.28(dt,J＝16.8,1.9Hz,1H),5.83(d,J＝10.7Hz,1H),5.47–5.31(m,1H),4.82–4.74(m,3H),4.60–4.51(m,1H),4.37–3.84(m,4H),3.82–3.34(m,5H),3.22–2.75(m,8H),2.65–2.51(m,1H),2.36–2.21(m,1H),2.09–1.74(m,4H)。
Example 72
Compound I-67, 2- ((2S) -4- (7-fluoro-2 ' - ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001771
Synthesis of Compound I-67 with reference to Compound I-5, by using tert-butyl (2S) -4- (2-chloro-6- ((7-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A24) instead of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3), ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride gave compound I-67.
Compound I-67(30.1 mg). MS 610.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.15(s,1H),7.05–6.85(m,2H),5.67–5.14(m,3H),4.81–4.50(m,4H),4.36–3.86(m,5H),3.81–3.32(m,5H),3.22–2.58(m,8H),2.53–2.25(m,1H),2.11–1.73(m,4H)。
Example 73
Compound I-68- ((2S) -1-acryloyl-4- (7-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001772
Synthesis of compound I-68 referring to compound I-5, compound I-68 was prepared by using tert-butyl 2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -7-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a26) instead of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3).
Compound I-68(18.1 mg). MS:570.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.80–9.76(m,1H),7.21–6.58(m,4H),6.18–6.09(m,1H),5.96–5.64(m,1H),4.93–4.68(m,1H),4.09–3.98(m,2H),3.81–3.44(m,6H),3.22–2.56(m,9H),2.32(s,3H),2.24(s,1H),2.15(s,3H),2.05–1.49(m,7H)。
Example 74
Compound I-69:2- ((2S) -1- (2-Fluoroacryloyl) -4- (7-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001781
Synthesis of Compound I-69 reference was made to Compound I-5 by using tert-butyl 2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -7-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A26) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3) and 2-fluoropropenyl chloride (intermediate B1) Acryloyl chloride to afford compound I-69.
Compound I-69(30.1 mg). MS:588.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.81–9.75(m,1H),7.25–6.60(m,3H),5.76–5.15(m,2H),4.31–3.46(m,9H),3.20–2.57(m,9H),2.32(s,3H),2.24(s,1H),2.15(s,3H),2.07–1.48(m,7H)。
Example 75
Compound I-70:2- ((2S) -1-acryloyl-4- (6-fluoro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001782
Synthesis of Compound I-70 with reference to Compound I-5, Compound I-70 was prepared by using tert-butyl (2S) -4- (2-chloro-6- ((6-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A25) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3).
Compound I-70(18.1 mg). MS:574.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.84–9.76(m,1H),7.38–6.70(m,4H),6.18–6.06(m,1H),5.87–5.64(m,1H),4.91–4.86(m,1H),4.50–3.44(m,8H),3.24–2.53(m,8H),2.34(s,3H),2.00–1.58(m,9H)。
Example 76
Compound I-71:2- ((2S) -4- (6-fluoro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001791
Synthesis of Compound I-71 reference is made to Compound I-5 by using (2S) -4- (2-chloro-6- ((6-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A25) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoropropenylchloride (intermediate B1) Acryloyl chloride to afford compound I-71.
Compound I-71(19 mg). MS:592.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.81–9.76(m,1H),7.45–6.79(m,4H),5.53–5.07(m,3H),4.31–3.37(m,6H),3.19–2.60(m,8H),2.31(s,3H),2.15–2.10(m,1H),2.03–1.50(m,10H)。
Example 77
Compound I-72- ((2S) -1- (2-Fluoroacryloyl) -4- (6-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001792
Synthesis of Compound I-72 reference is made to Compound I-5 by using tert-butyl 2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -6-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A31) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3) and 2-fluoropropenyl chloride (intermediate B1) Acryloyl chloride was prepared to provide compound I-72.
Compound I-72(30.9 mg). MS:588.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.90-9.80(m,1H),9.62(s,1H),7.13-6.85(m,3H),5.42-5.35(m,1H),5.32-5.15(m,1H),4.55-4.45(m,1H),4.44-4.36(m,1H),3.80-3.69(m,2H),3.55-3.25(m,6H),3.17-3.07(m,2H),3.05-2.87(m,5H),2.83-2.80(m,1H),2.75-2.65(m,3H),2.25-2.18(m,3H),2.08-1.98(m,2H),1.92-1.63(m,6H)。
Example 78
Compound I-73:2- ((2S) -1- (2-Fluoroacryloyl) -4- (5-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001801
Synthesis of Compound I-73 reference was made to Compound I-5 by substituting (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -5-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A39) for (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoropropenylchloride (intermediate B1) for Compound I-5 The compound I-73 is obtained by substituting acryloyl chloride.
Compound I-73(40.1 mM)Grams). MS:588.1(M + H)+。1H NMR(400MHz,CD3OD)δ7.09-7.03(m,3H),5.40-5.32(m,1H),5.30-5.22(m,1H),4.40-4.21(m,3H),4.11-4.08(m,1H),3.97-3.92(m,1H),3.86-3.78(m,1H),3.59-3.45(m,2H),3.34-3.30(m,1H),3.27-3.16(m,1H),3.14-3.04(m,2H),3.04-2.95(m,1H),2.89-2.82(m,1H),2.75-2.62(m,4H),2.48(s,3H),2.36-2.32(m,1H),2.26-2.23(m,3H),2.12-1.97(m,2H),1.92-1.77(m,5H),1.75-1.66(m,1H)。
Example 79
Compound I-74 acetonitrile 2- ((2S) -1-acryloyl-4- (5-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001802
Synthesis of compound I-74 was prepared with reference to compound I-5 by using (2S) -tert-butyl 4- (2-chloro-6- ((1- (methoxycarbonyl) -5-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a39) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3) to afford compound I-74.
Compound I-74(2.1 mg). MS:570.1(M + H)+。
Example 80
Compound I-75:2- ((2S) -4- (5, 6-difluoro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001811
Synthesis of Compound I-75 reference was made to Compound I-5 by using (2S) -4- (2-chloro-6- ((5, 6-difluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A34) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoropropenylchloride (intermediate B1) ) Compound I-75 was prepared instead of acryloyl chloride.
Compound I-75(40 mg). MS 610.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.34–6.92(m,2H),5.51–5.12(m,2H),4.78–4.40(m,2H),4.31–4.12(m,1H),4.01(dt,J＝11.2,6.2Hz,1H),3.89–3.35(m,5H),3.28–2.55(m,8H),2.31(s,3H),2.15(q,J＝8.6Hz,1H),2.06–1.30(m,8H)。
Example 81
Compound I-76- ((2S) -4- (5-chloro-7-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001812
Synthesis of Compound I-76 reference was made to Compound I-5 by using (2S) -4- (2-chloro-6- ((5-chloro-1- (methoxycarbonyl) -7-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A32) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoroacryloyl-oyl Chloro (intermediate B1) substituted for acryloyl chloride to afford compound I-76.
Compound I-76(34 mg). MS 622.3(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.33–6.77(m,2H),5.54–5.15(m,2H),4.65–4.35(m,2H),4.14–3.36(m,5H),3.23–2.61(m,11H),2.42–2.31(m,6H),2.23–2.17m,4H),2.09–1.57(m,4H)。
Example 82
Compound I-77:2- ((2S) -1-acryloyl-4- (5-chloro-7-fluoro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001821
Synthesis of Compound I-77 Compound I-5 was prepared by using (2S) -4- (2-chloro-6- ((5-chloro-7-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A36) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) to give Compound I- 77.
Compound I-77(28 mg). MS:608.2(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),7.34(d,J＝7.9Hz,1H),7.33–7.11(m,1H),6.82(d,14.3Hz,1H),6.17(d,J＝16.7Hz,1H),5.76(s,1H),5.20–4.68(m,1H),4.44–3.96(m,4H),3.79–3.27(m,4H),3.12–2.54(m,9H),2.44–2.22(m,2H),2.05–1.44(m,9H)。
Example 83
Compound I-78:2- ((2S) -4- (5-chloro-7-fluoro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001822
Synthesis of Compound I-78 reference was made to Compound I-5 by using (2S) -4- (2-chloro-6- ((5-chloro-7-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A36) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoropropenylchloride (intermediate B1) instead of acryloyl chloride, compound I-78 was prepared.
Compound I-78(56 mg). MS:626.2(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),7.34(dt,J＝8.4,1.9Hz,2H),7.28(dd,J＝10.5,2.7Hz,1H),7.15(dd,J＝10.3,2.6Hz,1H),5.48–5.11(m,2H),4.12–3.95(m,2H),3.89–3.47(m,2H),3.19–2.60(m,9H),2.33(s,3H),2.18–1.39(m,11H)。
Example 84
Compound I-79- ((2S) -1-acryloyl-4- (7-fluoro-5-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spirochete [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001831
Synthesis of Compound I-79 Compound I-5 was prepared by using (2S) -4- (2-chloro-6- ((7-fluoro-1- (methoxycarbonyl) -5-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A40) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) to give Compound I- 79.
Compound I-79(21 mg). MS:588.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.09–6.63(m,2H),6.29–5.63(m,2H),5.10-4.70(m,1H),4.48–3.95(m,4H),3.92–3.45(m,6H),3.14–2.74(m,6H),2.67–2.52(m,1H),2.32(s,3H),2.27–2.10(m,4H),1.97–1.51(m,8H)。
Example 85
Compound I-80- ((2S) -1- (2-Fluoroacryloyl) -4- (2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-5- (trifluoromethoxy) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001832
Synthesis of Compound I-80 reference was made to Compound I-5 by using (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -5- (trifluoromethoxy) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A42) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoropropenylchloride (F Intermediate B1) instead of acryloyl chloride to afford compound I-80.
Compound I-80(21 mg). MS:658.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),7.39–7.30(m,1H),7.29–7.17(m,2H),5.42–5.18(m,2H),4.59–4.36(m,2H),3.88–3.68(m,5H),3.48–3.40(m,2H),3.23–3.06(m,3H),3.06–2.93(m,2H),2.91–2.80(m,3H),2.78–2.60(m,3H),2.23–2.15(m,1H),2.05(m,1H),1.97–1.64(m,7H)。
Example 86
Compound I-81:2- ((2S) -4- (5-chloro-6-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl-1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001841
Synthesis of Compound I-81 reference was made to Compound I-5 by using (2S) -4- (2-chloro-6- ((5-chloro-1- (methoxycarbonyl) -6-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A33) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoroacryloyl-oyloxy Chloro (intermediate B1) substituted for acryloyl chloride to afford compound I-81.
Compound I-81(26 mg). MS 622.3(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),7.20(s,1H),7.15–7.03(m,1H),5.42–5.30(m,2H),5.19(s,1H),4.61–4.35(m,4H),3.73(d,J＝10.9Hz,2H),3.42(m,1H),3.13–3.09(m,3H),3.07–2.94(m,2H),2.92–2.90(m,3H),2.82–2.68(m,3H),2.31–2.29(m,3H),2.27–2.18(m,1H),2.09–2.00–1.94(m,1H),1.90(s,1H),1.83–1.79(m,3H),1.77–1.63(m,4H)。
Example 87
Compound I-82 2- ((2S) -1-acryloyl-4- (5-chloro-6-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001851
Synthesis of Compound I-82 with reference to Compound I-5, Compound I-5 was prepared by using (2S) -4- (2-chloro-6- ((5-chloro-1- (methoxycarbonyl) -6-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A33) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) 82.
Compound I-82(23 mg). MS:604.2(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),7.20(s,1H),7.15–7.03(m,1H),6.88(s,1H),6.24–6.11(m,1H),5.83–5.70(m,1H),4.94(s,1H),4.58–4.39(m,3H),3.79–3.38(m,7H),3.10(d,J＝11.5Hz,2H),2.96(s,1H),2.93–2.89(m,3H),2.85–2.64(m,3H),2.31–2.24(m,3H),2.22–2.17(m,1H),2.12–1.99(m,1H),1.95–1.63(m,6H)。
Example 88
Compound I-83, 2- ((2S) -4- (5-fluoro-2 ' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidine ] -4' -1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001852
Synthesis of Compound I-83 reference is made to Compound I-5 by using (2S) -4- (2-chloro-6- ((5-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A38) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoropropenylchloride (intermediate B1) Acryloyl chloride to afford compound I-83.
Compound I-83(46 mg). MS:592.1(M + H)+。1H NMR(400MHz,CD3OD)δ7.25-7.16(m,1H),7.13-7.06(m,1H),7.00-6.94(m,1H),5.39-5.34(m,1H),5.33-5.28(m,1H),4.81-4.72(m,1H),4.55-4.36(m,1H),4.09-3.83(m,3H),3.76-3.53(m,3H),3.48-3.32(m,4H),3.27-3.20(m,1H),3.15-3.02(m,6H),3.01-2.90(m,1H),2.87-2.70(m,1H),2.42-2.38(m,1H),2.25-2.15(m,1H),2.12-1.98(m,3H),1.96-1.78(m,3H)。
Example 89
Compound I-84:2- ((2S) -1-acryloyl-4- (5-fluoro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001861
Synthesis of Compound I-84 reference is made to Compound I-5 by using (2S) -4- (2-chloro-6- ((5-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A38) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoropropenylchloride (intermediate B1) Acryloyl chloride to afford compound I-84.
Compound I-84(49 mg). MS:574.1(M + H)+。1H NMR(400MHz,CD3OD)δ7.25-7.15(m,1H),7.12-7.05(m,1H),7.00-6.93(m,1H),6.85-6.75(m,1H),6.29(d,J＝16.6Hz,1H),5.84(d,J＝10.6Hz,1H),4.76-4.68(m,1H),4.56-4.49(m,1H),4.36-4.28(m,1H),4.08-4.00(m,1H),3.95-3.82(m,2H),3.76-3.68(m,1H),3.64-3.50(m,1H),3.45-3.41(m,1H),3.35-3.30(m,2H),3.27-3.19(m,1H),3.10-3.03(m,4H),3.01-2.88(m,2H),2.82-2.74(m,2H),2.42-2.33(m,1H),2.25-2.15(m,1H),2.12-1.97(m,3H),1.90-1.80(m,3H)。
Example 90
Compound I-85:2- ((2S) -1-acryloyl-4- (5, 6-difluoro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001862
Synthesis of compound I-85 was prepared by using (2S) -tert-butyl 4- (2-chloro-6- ((5, 6-difluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a34) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3) with reference to compound I-5.
Compound I-85(30.3 mg). MS:592.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.32–6.99(m,2H),6.97-6.75(m,1H),6.18(d,J＝16.6Hz,1H),5.77(d,J＝10.3Hz,1H),5.17–4.26(m,4H),4.12–3.69(m,3H),3.68-3.59(m,3H),3.50–3.26(m,3H),3.23-3.06(m,2H),3.05–2.80(m,4H),2.80–2.52(m,3H),2.30-2.15(m,1H),2.11–1.56(m,6H)。
Example 91
Compound I-86- ((2S) -4- (7-fluoro-5-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001871
Synthesis of Compound I-86 reference was made to Compound I-5 by using (2S) -4- (2-chloro-6- ((7-fluoro-1- (methoxycarbonyl) -5-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A40) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoroacryloyl-oyloxy Chloro (intermediate B1) substituted for acryloyl chloride to afford compound I-86.
Compound I-86(21 mg). MS:606.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.06–6.78(m,2H),5.45–5.15(m,2H),5.05-4.60(m,2H),4.58–4.35(m,2H),3.70–3.43(m,6H),3.20-2.70(m,8H),2.65-2.53(m,2H),2.30-2.15(m,4H),2.13–1.59(m,8H)。
Example 92
Compound I-87:2- ((2S) -4- (5-fluoro-6-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001872
Synthesis of Compound I-87 reference was made to Compound I-5 by using (2S) -4- (2-chloro-6- ((5-fluoro-1- (methoxycarbonyl) -6-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A41) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoroacryloyl-oyloxy Chloro (intermediate B1) substituted for acryloyl chloride to afford compound I-87.
Compound I-87(91 mg). MS:606.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.14–6.89(m,3H),5.45–5.21(m,3H),4.79–4.66(m,2H),4.53(t,J＝10.0Hz,1H),4.28(d,J＝13.9Hz,1H),4.07–3.81(m,3H),3.83–3.65(m,1H),3.56–3.49(m,1H),3.44–3.19(m,3H),3.17–2.61(m,9H),2.49–1.95(m,8H),1.92–1.71(m,1H)。
Example 93
Compound I-88 2- ((2S) -1-acryloyl-4- (5-fluoro-6-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001881
Synthesis of Compound I-88 reference was made to Compound I-5 by using (2S) -4- (2-chloro-6- ((5-fluoro-1- (methoxycarbonyl) -6-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A41) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoroacryloyl-oyl Chloro (intermediate B1) substituted for acryloyl chloride to afford compound I-88.
Compound I-88(71 mg). MS:588.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.19–6.98(m,2H),6.85(d,J＝8.0Hz,1H),6.18(s,1H),5.77(d,J＝10.7Hz,1H),5.08(s,1H),4.68–4.37(m,2H),4.22–3.88(m,5H),3.74–3.05(m,14H),2.94–1.61(m,10H)。
Example 94
Compound I-89:2- ((2S) -1-acryloyl-4- (5-chloro-6-fluoro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001882
Synthesis of Compound I-89 Compound I-5 was prepared by using (2S) -4- (2-chloro-6- ((5-chloro-6-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A35) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) to give Compound I- 89.
Compound I-89(7 mg). MS:608.2(M + H)+。1H NMR(400MHz，DMSO-d6)δ7.47–7.17(m 2H)，6.97-6.6.75(m,1H),6.18(d,J＝16.6Hz,1H),5.76(t,J＝7.5Hz,1H),5.15–4.27(m,4H),4.12–3.60(m,6H),3.44–3.24(m,3H),3.22-3.05(m,2H),3.05–2.87(m,4H),2.86–2.56(m,3H),2.30-2.12(m,1H),2.11–1.98(m,1H),1.95-1.62(m,5H)。
Example 95
Compound I-90:2- ((2S) -4- (5-chloro-6-fluoro-2 ' - (((S) -1-methylpyrrolidin-2-ylmethoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001891
Synthesis of Compound I-90 reference was made to Compound I-5 by using (2S) -4- (2-chloro-6- ((5-chloro-6-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A35) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoropropenylchloride (intermediate B1) instead of acryloyl chloride to afford compound I-90.
Compound I-90(97 mg). MS:626.2(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.45–7.14(m,2H),5.50–5.09(m,2H),5.05–4.10(m,4H),3.79(4.05-3.70,4H),3.59–3.31(m,5H),3.25-3.02(m,2H),3.01-2.95(m,1H),2.94–2.82(m,3H),2.81–2.54(m,3H),2.30-2.15(m,1H),2.10-1.97(m,1H),1.95-1.60(m,5H)。
Example 96
Compound I-91- ((2S) -4- (5, 7-dichloro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001892
Synthesis of Compound I-91 with reference to Compound I-5, tert-butyl (2S) -4- (2-chloro-6- ((5, 7-dichloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A37) was used in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3) and 2-fluoropropenylchloride (intermediate B1) ) Compound I-91 was prepared instead of acryloyl chloride.
Compound I-91(91 mg). MS:642.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),7.67–7.19(m,2H),5.58–5.16(m,2H),4.62–4.30(m,2H),3.97–3.47(m,5H),3.31–2.83(m,7H),2.79–2.57(m,5H),2.31–1.98(m,2H),1.99–1.62(m,8H)。
Example 97
Compound I-92- ((2S) -1-acryloyl-4- (5, 7-dichloro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001901
Synthesis of compound I-92 was prepared with reference to compound I-5 by using (2S) -tert-butyl 4- (2-chloro-6- ((5, 7-dichloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a37) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3).
Compound I-92(23 mg). MS:624.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),7.54–7.33(m,2H),6.86–6.56(m,1H),6.18(dd,J＝16.4,2.5Hz,1H),5.77(d,J＝10.4Hz,1H),4.94–4.16(m,6H),3.81–3.48(m,5H),3.11(q,J＝9.2,7.9Hz,2H),3.03–2.83(m,4H),2.72–2.56(m,2H),2.14–2.06(m,2H),1.98–1.62(m,8H)。
Example 98
Compound I-93:2- ((2S) -1- (2-Fluoroacryloyl) -4- (2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-5- (trifluoromethyl) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001902
Synthesis of Compound I-93 reference was made to Compound I-5 by using (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -5- (trifluoromethyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A43) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoropropenylchloride (intermediate A3) Body B1) instead of acryloyl chloride to afford compound I-93.
Compound I-93(45 mg). MS:642.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),7.56(dd,J＝31.0,8.1Hz,2H),7.38(dt,J＝16.0,7.8Hz,1H),5.52–5.11(m,2H),4.47–4.15(m,4H),3.95–3.35(m,5H),3.25–2.74(m,10H),2.31–1.64(m,10H)。
Example 99
Compound I-94- ((2S) -4- (6-chloro-5-fluoro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropy-l) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001911
Synthesis of Compound I-94 reference is made to Compound I-5 by using (2S) -4- (2-chloro-6- ((6-chloro-5-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A51) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoropropenylchloride (intermediate B1) instead of acryloyl chloride, compound I-94 was prepared.
Compound I-94(35 mg). MS:626.2(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),7.38(s,1H),7.21–7.10(d,J＝8.6Hz,1H),5.43–5.10(m,2H),4.53–4.41(m,3H),3.78–3.65(m,3H),3.61–3.54(m,2H),3.46(s,1H),3.13(d,J＝11.8Hz,2H),3.05–2.93(m,2H),2.91(d,J＝4.7Hz,3H),2.86–2.77(m,1H),2.75–2.69(m,2H),2.28–2.17(m,1H),2.06–2.01(m,1H),1.74–1.57(m,8H)。
Example 100
Compound I-95:2- ((2S) -1-acryloyl-4- (2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-5- (trifluoromethyl) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001912
Synthesis of compound I-95 was prepared by using (2S) -tert-butyl 4- (2-chloro-6- ((1- (methoxycarbonyl) -5- (trifluoromethyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a43) instead of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3) with reference to compound I-5.
Compound I-95(35 mg). MS:624.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),7.68–7.49(m,2H),7.39(dt,J＝16.4,7.9Hz,1H),7.03–6.73(m,1H),6.18(d,J＝16.7Hz,1H),5.77(d,J＝10.4Hz,1H),4.61–4.38(m,2H),3.99–3.44(m,9H),3.22–2.75(m,9H),2.34–1.66(m,9H)。
Example 101
Compound I-96:2- ((2S) -4- (5-fluoro-7-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001921
Synthesis of Compound I-96 reference was made to Compound I-5 by using (2S) -4- (2-chloro-6- ((5-fluoro-1- (methoxycarbonyl) -7-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A46) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoroacryloyl-oyloxy Chloro (intermediate B1) substituted for acryloyl chloride to afford compound I-96.
Compound I-96(55 mg). MS:606.2(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),6.87(dd,J＝10.5,6.5Hz,1H),6.78(s,1H),5.37–5.28(m,2H),5.19(s,1H),4.54–4.48(m,1H),4.40(dd,J＝12.4,6.7Hz,1H),3.75(s,3H),3.57(d,J＝12.9Hz,2H),3.39–3.29(m,1H),3.13–3.01(m,2H),2.99(d,J＝4.9Hz,1H),2.90(d,J＝4.4Hz,4H),2.64–2.58(m,2H),2.26(s,1H),2.19(s,3H),2.09–1.91(m,3H),1.86–1.64(m,7H)。
Example 102
Compound I-97:2- ((2S) -4- (5-fluoro-2 ' - ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -7-methyl-6 ' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001931
Synthesis of Compound I-97 with reference to Compound I-5, by using (2S) -4- (2-chloro-6- ((5-fluoro-1- (methoxycarbonyl) -7-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A46) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3), ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride gave compound I-97.
Compound I-97(58 mg). MS:624.4(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),6.90–6.85(m,1H),6.78(s,1H),5.55–5.16(m,2H),4.61–4.45(m,3H),4.07–3.90(m,4H),3.73(d,J＝13.6Hz,2H),3.53–3.42m,3H),3.12–3.01(m,1H),2.99(d,J＝4.5Hz,4H),2.84–2.76(m,1H),2.61–2.50(m,2H),2.26(s,2H),2.19(s,3H),1.85–1.60(m,6H)。
Example 103
Compounds I-98a and I-98b 2- ((S) -1-acryloyl-4- ((S) -5, 7-difluoro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile and 2- ((S) -1-acryloyl-4- ((R) -5, 7-difluoro-2 ' - ((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001932
Synthesis of Compounds I-98a and I-98b with reference to Compound I-5, tert-butyl (2S) -4- (2-chloro-6- ((5, 7-difluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A44) was used instead of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3), and subjected to SFC Chiral resolution (column model: Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide) to obtain compound I-98a and compound I-98 b.
Compound I-98a (retention time 4.473 min, 65 mg). MS:592.1(M + H) +。1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),7.09(dd,J＝10.4,8.1Hz,1H),6.97(d,J＝10.2Hz,1H),6.93-6.77(m,1H),6.17(d,J＝16.6Hz,1H),5.76(d,J＝10.4Hz,1H),5.01–4.78(m,1H),4.21(dd,J＝10.8,5.2Hz,1H),4.12–3.94(m,2H),3.88-3.69(m,1H),3.67–3.56(m,1H),3.56–3.38(m,3H),3.31–3.17(m,2H),3.07(d,J＝13.1Hz,1H),3.02-2.85(m,3H),2.84-2.55(m,3H),2.33(s,3H),2.16(d,J＝7.7Hz,1H),1.91–1.87(m,2H),1.81–1.49(m,5H)。
Compound I-98b (retention time 4.688 min, 55 mg). MS:592.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),7.18–7.02(m,2H),6.95-6.75(m,1H),6.17(s,J＝16.6Hz,1H),5.75(d,J＝10.4Hz,1H),5.08–4.86(m,1H),4.33–4.29(m,1H),4.26–4.16(m,1H),4.01(d,J＝11.7Hz,2H),3.74–3.63(m,2H),3.63–3.40(m,2H),3.05(t,J＝16.0Hz,1H),2.98-2.86(m,2H),2.81(d,J＝17.4Hz,1H),2.68-2.56(m,3H),2.32(s,3H),2.15(q,J＝8.8Hz,1H),1.95–1.79(m,2H),1.79–1.49(m,7H)。
Example 104
The compound I-99:2- ((2S) -4- (5, 7-difluoro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001941
Synthesis of Compound I-99 reference was made to Compound I-5 by using (2S) -4- (2-chloro-6- ((5, 7-difluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A44) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoroacryloyl chloride (intermediate B1) ) PreHPLC preparation instead of acryloyl chloride afforded compound I-99.
Compound I-99(35 mg). MS 610.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),7.15–6.93(m,2H),5.49–5.06(m,2H),4.20–4.16(m,2H),4.11–3.96(m,2H),3.82–3.46(m,4H),3.14–2.76(m,6H),2.61(s,2H),2.32(s,3H),2.23–2.11(m,1H),2.01–1.49(m,9H)。
Example 105
Compounds I-100a and I-100b 2- ((S) -4- ((S) -2' - ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-5- (trifluoromethyl) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile and 2- ((S) -4- ((R) -2' - ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxy -5- (trifluoromethyl) -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001951
Synthesis of Compounds I-100a and I-100b reference was made to Compound I-5 by using (2S) -tert-butyl 4- (2-chloro-6- ((1- (methoxycarbonyl) -5- (trifluoromethyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A43) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3), ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride, and compound I-100a and compound I-100B were prepared via SFC Chiral resolution (column model: Dr. mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide).
Compound I-100a (Retention time 7.008 min, 15 mg). MS:660.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.60(d,J＝7.7Hz,1H),7.55(d,J＝8.0Hz,1H),7.37(t,J＝7.8Hz,1H),5.45–5.05(m,3H),4.44–4.28(m,2H),4.00–3.88(m,2H),3.62–3.35(m,5H),3.19–2.84(m,6H),2.65–2.58(m,1H),2.53(s,3H),2.26–2.19(m,1H),2.11–1.74(m,6H)。
Compound I-100b (retention time 7.199 min, 25 mg). MS:660.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.60(d,J＝7.7Hz,1H),7.55(d,J＝8.0Hz,1H),7.37(t,J＝7.8Hz,1H),5.45–5.05(m,3H),4.44–4.28(m,2H),4.00–3.88(m,2H),3.62–3.35(m,5H),3.19–2.84(m,6H),2.65–2.58(m,1H),2.53(s,3H),2.26–2.19(m,1H),2.11–1.74(m,6H)。
Example 106
Compound I-101: 2- ((2S) -4- (7-chloro-5-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropy-l) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001952
Synthesis of Compound I-101 reference is made to Compound I-5 by using (2S) -4- (2-chloro-6- ((7-chloro-1- (methoxycarbonyl) -5-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A47) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoroacryloyl-oyloxy Chloro (intermediate B1) substituted for acryloyl chloride to afford compound I-101.
Compound I-101(61 mg). MS 622.4(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),7.14(t,J＝2.7Hz,1H),7.07(d,J＝2.2Hz,1H),5.44–5.27(m,2H),5.20(s,1H),4.56–4.39(m,2H),3.86–3.53(m,6H),3.46(s,1H),3.13–3.1(m,2H),3.07–2.93(m,2H),2.91(d,J＝4.6Hz,3H),2.87–2.71(m,1H),2.64–2.52(m,3H),2.20(d,J＝3.5Hz,3H),2.09–1.99(m,1H),1.93–1.65(m,6H)。
Example 107
Compound I-102: 2- ((2S) -1-acryloyl-4- (7-chloro-5-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001961
Synthesis of Compounds I-102 Compounds I-5 were prepared by using (2S) -4- (2-chloro-6- ((7-chloro-1- (methoxycarbonyl) -5-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A47) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) to give compounds I- 102.
Compound I-102(13 mg). MS:604.2(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),7.22(d,J＝2.2Hz,1H),7.14(t,J＝2.7Hz,1H),7.06(d,J＝2.1Hz,1H),6.19(dd,J＝16.6,2.8Hz,1H),5.77(d,J＝10.0Hz,1H),5.04(s,1H),4.80(s,1H),4.57–4.27(m,3H),4.03(s,1H),3.69–3.27(m,5H),3.14–3.05(m,2H),2.91(d,J＝4.7Hz,4H),2.87–2.75(m,1H),2.55(s,2H),2.20(d,J＝3.9Hz,4H),2.08–1.62(m,8H)。
Example 108
Compounds I-103a and I-103b 2- ((S) -4- ((S) -6-fluoro-5-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoroacryl) piperazin-2-yl) acetonitrile and 2- ((S) -4- ((R) -6-fluoro-5-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy- 3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001971
Synthesis of Compounds I-103a and I-103b reference was made to Compound I-5 by using (2S) -tert-butyl 4- (2-chloro-6- ((6-fluoro-1- (methoxycarbonyl) -5-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A48) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3) ) And 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride, and subjected to SFC chiral resolution (column type: mail Reprosil Chiral-JM, 250x25mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide) to yield compound I-103a and compound I-103 b.
Compound I-103a (retention time 4.735 min, 41 mg). MS:606.4(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),7.02–6.85(m,2H),5.45–5.15(m,2H),4.77(s,2H),4.19(dd,J＝10.7,5.0Hz,1H),4.00(dd,J＝10.7,6.1Hz,1H),3.68–3.52(m,3H),3.10–3.07(m,1H),3.04–2.77(m,4H),2.74–2.54(m,2H),2.32(s,3H),2.24–1.98(m,4H),1.92–1.88(m,2H),1.80–1.79(s,2H),1.77–1.42(m,7H)。
Compound I-103b (retention time 4.758 min, 50 mg). MS:606.4(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),7.02–6.85(m,2H),5.45–5.15(m,2H),4.77(s,2H),4.19(dd,J＝10.7,5.0Hz,1H),4.00(dd,J＝10.7,6.1Hz,1H),3.68–3.52(m,3H),3.10–3.07(m,1H),3.04–2.77(m,4H),2.74–2.54(m,2H),2.32(s,3H),2.24–1.98(m,4H),1.92–1.88(m,2H),1.80–1.79(s,2H),1.77–1.42(m,7H)。
Example 109
Compounds I-104a and I-104b 2- ((2S) -4- ((1S) -7-chloro-2 '- ((2S) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -5-methyl-6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4 '-yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile and 2- ((2S) -4- ((1R) -7-chloro-2' - ((2S) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -5-methyl-6 '-oxo-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin-4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001972
Figure BDA0003413556240001981
Synthesis of Compounds I-104a and I-104b with reference to Compound I-5, tert-butyl (2S) -4- (2-chloro-6- ((7-chloro-1- (methoxycarbonyl) -5-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A47) was used instead of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3) ) ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride, and chiral resolution by SFC (column model: mail Reprosil Chiral-JM, 250x25mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide) to yield compound I-104a and compound I-104 b.
Compound I-104a (retention time 7.198 min, 11 mg). MS:640.4(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),7.13(s,1H),7.05(s,1H),5.43–5.28(m,2H),5.21–5.18(m,2H),4.24–4.18(m,1H),4.11–4.07(m,1H),3.70–3.58(m,3H),3.44–3.28(m,3H),3.12–3.08(m,2H),3.03–2.79(m,5H),2.36(s,3H),2.19(s,3H),2.14–1.98(m,2H),1.96–1.67(m,6H)。
Compound I-104b (retention time 7.46 min, 20 mg). MS:640.4(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),7.13(s,1H),7.05(s,1H),5.43–5.28(m,2H),5.21–5.18(m,2H),4.24–4.18(m,1H),4.11–4.07(m,1H),3.70–3.58(m,3H),3.44–3.28(m,3H),3.12–3.08(m,2H),3.03–2.79(m,5H),2.36(s,3H),2.19(s,3H),2.14–1.98(m,2H),1.96–1.67(m,6H)。
Example 110
Compounds I-105a and I-105b 2- ((S) -1-acryloyl-4- ((S) -6-fluoro-5-methyl-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy-3, 4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile and 2- ((S) -1-acryloyl-4- ((R) -6-fluoro-5-methyl-2 ' - ((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxy -3,4,5',8' -tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001982
Synthesis of Compounds I-105a and I-105b reference was made to Compound I-5 by using (2S) -tert-butyl 4- (2-chloro-6- ((6-fluoro-1- (methoxycarbonyl) -5-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A48) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3) ) And subjected to SFC chiral resolution (column type: mail Reprosil Chiral-JM, 250x25mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide) to yield compound I-105a and compound I-105 b.
Compound I-105a (retention time 4.249 min, 6 mg). MS:588.5(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),7.15(dd,J＝8.9,5.8Hz,1H),6.99(t,J＝9.0Hz,1H),6.94–6.73(m,1H),6.17(d,J＝16.3Hz,1H),5.75(d,J＝9.9Hz,1H),5.08(s,1H),4.46–4.12(m,2H),4.05–3.98(m,1H),3.86–3.80(m,1H),3.73–3.44(m,4H),3.11–2.85(m,3H),2.79–2.74(m,1H),2.60–2.54(m,2H),2.52(s,1H),2.32(s,3H),2.16–2.14(m,1H),2.10(d,J＝1.9Hz,3H),1.91(m,1H),1.85–1.48(m,7H)。
Compound I-105b (retention time 4.333 min, 9 mg). MS:588.5(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),7.15(dd,J＝8.9,5.8Hz,1H),6.99(t,J＝9.0Hz,1H),6.94–6.73(m,1H),6.17(d,J＝16.3Hz,1H),5.75(d,J＝9.9Hz,1H),5.08(s,1H),4.46–4.12(m,2H),4.05–3.98(m,1H),3.86–3.80(m,1H),3.73–3.44(m,4H),3.11–2.85(m,3H),2.79–2.74(m,1H),2.60–2.54(m,2H),2.52(s,1H),2.32(s,3H),2.16–2.14(m,1H),2.10(d,J＝1.9Hz,3H),1.91(m,1H),1.85–1.48(m,7H)。
Example 111
Compound I-106a and compound I-106 b: 2- ((S) -4- ((S) -5-bromo-2 ' - ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile and 2- ((S) -4- ((R) -5-bromo-2 ' - ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240001991
Figure BDA0003413556240002001
Synthesis of Compounds I-106a and I-106b with reference to Compound I-5, tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2-chloro-5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A45) was used instead of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3), ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride, and compound I-106a and compound I-106B were prepared via SFC Chiral resolution (column model: Dr. mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide).
Compound I-106a (retention time 6.961 min, 16 mg). MS:670.2(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.51(d,J＝7.8Hz,1H),7.20(d,J＝7.8Hz,1H),7.09(t,J＝7.8Hz,1H),5.56–5.35(m,2H),5.34-5.17(m,1H),4.97–4.38(m,4H),4.24–3.77(m,5H),3.70–3.57(m,2H),3.44–3.37(m,1H),3.19–3.02(m,2H),3.01-2.87(m,4H),2.86–2.60(m,3H),2.37–2.03(m,2H),2.02-1.89(m,2H),1.86–1.66(m,3H)。
Compound I-106b (retention time 7.133 min, 18 mg). MS:670.2(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.52(d,J＝7.8Hz,1H),7.35(d,J＝7.9Hz,1H),7.16(t,J＝7.9Hz,1H),5.58–5.23(m,2H),5.21-4.89(m,1H),4.70-4.43(m,2H),4.32–3.80(m,4H),3.77–3.64(m,3H),3.54-3.28(m,3H),3.21–3.08(m,1H),3.07–2.77(m,4H),2.74-2.56(m,2H),2.32-2.11(m,2H),1.90–1.56(m,6H)。
Example 112
Compound I-107: 4' - ((S) -3- (cyanomethyl) -4- (2-fluoroacryloyl) piperazin-1-yl) -2' - ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidine ] -5-carbanitrile
Figure BDA0003413556240002011
Step 1 preparation of tert-butyl (2S) -4- (5-cyano-2 ' - (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate I-107-1)
Mixing (2S) -4- (5-bromo-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 '-H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]-4' -yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate I-106-2,300 mg, 0.220 mmol), zinc cyanide (129 mg, 1.102 mmol), Pd2dba3A solution of (40.4 mg, 0.044 mmol) and dppf (24.44 mg, 0.044 mmol) in DMF (5 ml) was stirred at 100 ℃ and the reaction was retarded for 1.5 hours. The reaction was then quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dried sodium sulfate, then filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give (2S) -4- (5-cyano-2 '- ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 '-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] as a yellow oil ]Pyrimidines]-4' -yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (290 mg, 84% yield). MS:638.2(M + H)+。
Step 2 preparation of 4' - ((S) -3- (cyanomethyl) -4- (2-fluoroacryloyl) piperazin-1-yl) -2' - ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidine ] -5-carbo-nitrile
Synthesis of Compound I-107 reference was made to Compound I-5 by using (2S) -4- (5-cyano-2 ' - (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate I-107-1) in place of (2S) -2- (cyanomethyl) -4- (2' - ((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, tert-butyl 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl ] piperazine-1-carboxylate (intermediate I-5/step 2), ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride gave compound I-107.
Compound I-107(10 mg). MS:617.3(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.74–7.49(m,2H),7.44-7.29(m,1H),5.45–5.20(m,2H),5.19-5.05(m,1H),5.03-4.45(m,2H),4.32-4.20(m,1H),4.17-4.07(m,1H),4.05–3.74(m,2H),3.75–3.57(m,3H),3.47-3.43(m,2H),3.16–3.00(m,2H),2.99-2.91(m,2H),2.90-2.79(m,3H),2.42-2.32(m,3H),2.17–2.02(m,1H),1.97–1.64(m,5H)。
Example 113
Compound I-108: 2- ((2S) -4- (5-cyclopropyl-2 ' - (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002021
Step 1 preparation of tert-butyl (2S) -2- (cyanomethyl) -4- (5-cyclopropyl-2 ' - (((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl ] piperazine-1-carboxylate (intermediate I-108-1)
Reacting (2S) -4- (5-bromo-2 '- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 '-H-spiro [ naphthalene-1, 7' -pyridine [3,2-d ]]Pyrimidines]Tert-butyl (4' -yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate I-106. sup. sodium acetate 2,200 mg, 0.147 mmol),Cs2CO3(144 mg, 0.44 mmol), PdCl2A solution of (dppf) (21.50 mg, 0.029 mmol) and cyclopropylboronic acid (76 mg, 0.882 mmol) in DMF (5 ml) was stirred at 100 ℃ and the reaction was retarded for 1.5 h. The reaction was then quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (2S) -2- (cyanomethyl) -4- (5-cyclopropyl-2 '- ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 '-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] as a yellow oil]Pyrimidines]-4' -yl]Piperazine-1-carboxylic acid tert-butyl ester (200 mg, 85% yield). MS:638.0(M + H) +。
Step 2 preparation of 2- ((2S) -4- (5-cyclopropyl-2 ' - (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Synthesis of Compound I-108 reference is made to Compound I-5 by using (2S) -2- (cyanomethyl) -4- (5-cyclopropyl-2 ' - (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl ] piperazine-1-carboxylic acid tert-butyl ester (intermediate I-108-1) in place of (2S) -2- (cyanomethyl) -4- (2' - (((((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, tert-butyl 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl ] piperazine-1-carboxylate (intermediate I-5/step 2) ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride to afford compound I-108.
Compound I-108(30 mg). MS:632.3(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.11-7.03(m,1H),7.03–6.84(m,2H),5.45-5.26(m,2H),5.22-5.08(m,1H),4.96-4.60(m,2H),4.28-4.22(m,1H),4.14-4.07(m,1H),3.71–3.55(m,5H),3.32(m,1H),3.11(m,1H),3.03-2.90(m,2H),2.89-2.69(m,4H),2.43-2.31(m,3H),2.16–1.98(m,2H),1.97-1.78(m,4H),1.77-1.61(m,2H),0.95–0.79(m,2H),0.66–0.48(m,2H)。
Example 114
Compound I-109a and compound I-109b 2- ((S) -4- ((S) -5-chloro-7-fluoro-2 '- (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 '-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4 '-yl) -1- (2-fluoroacryl oyl) piperazin-2-yl) acetonitrile and 2- ((S) -4- ((R) -5-chloro-7-fluoro-2' - (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6 '-oxo-3, 4,5',8 '-tetrahydro-2H, 6' -spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidine ] -4' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002031
Synthesis of Compounds I-109a and I-109b reference was made to Compound I-5 by using (2S) -tert-butyl 4- (2-chloro-6- ((5-chloro-7-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A36) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3), ((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride, and Compound I-109a and Compound I-109B were prepared by SFC Chiral resolution (column model: Dr. mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide).
Compound I-109a (retention time 4.903 min, 36 mg). MS:644.3(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.17(dd,J＝8.2,2.5Hz,1H),7.06(dd,J＝10.0,2.6Hz,1H),5.61–5.19(m,4H),4.85–4.48(m,4H),4.43–3.83(m,4H),3.80–3.33(m,3H),3.23–2.95(m,7H),2.89–2.58(m,3H),2.01(q,J＝7.7Hz,1H),1.87(d,J＝7.6Hz,4H)。
Compound I-109b (retention time 5.508 min, 38 mg). MS:644.3(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.17(dd,J＝8.2,2.5Hz,1H),7.10(dd,J＝10.0,2.6Hz,1H),5.43–5.19(m,3H),5.17–4.92(m,2H),4.47–4.34(m,2H),3.94–3.84(m,2H),3.66–3.35(m,4H),3.10–3.07(m,1H),3.05–2.57(m,6H),2.53(s,3H),2.26–2.19(m,1H),2.12–1.73(m,6H)。
Example 115
Compound I-110- ((2S) -4- (2' - (((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -4, 4-dimethyl-6 ' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002041
Synthesis of Compound I-110 reference is made to Compound I-5 by using (2S) -tert-butyl 4- (2-chloro-6- ((1- (methoxycarbonyl) -4, 4-dimethyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A52) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3), compound I-110 was prepared from ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride.
Compound I-110(43 mg). MS 620.1(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.43(d,J＝7.8Hz,1H),7.28–7.10(m,3H),5.60–5.22(m,3H),4.86–4.74(m,3H),4.59–4.49(m,1H),4.37–4.18(m,2H),3.97–3.87(m,2H),3.54–3.42(m,3H),3.22–2.83(m,7H),2.77–2.54(m,1H),2.38(m,1H),2.26–2.02(m,1H),1.98–1.63(m,4H),1.32–1.22(m,6H)。
Example 116
Compound I-111: 2- ((2S) -4- (4-chloro-2 ' - (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-2, 3,5',8' -tetrahydro-6 ' H-spiro [ indene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002042
Synthesis of Compound I-111 with reference to Compound I-5, by using (2S) -4- (2-chloro-6- ((4-chloro-1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A49) instead of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3), ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride gave compound I-111.
Compound I-111(49 mg). MS:612.4(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.31–7.18(m,2H),7.18–6.90(m,2H),5.61–5.19(m,4H),4.87–4.73(m,2H),4.59(m,1H),4.35–3.91(m,5H),3.51–3.34(m,2H),3.26–2.91(m,8H),2.82–2.58(m,2H),2.56–2.29(m,2H),2.12(m,1H)。
Compound I-111a and Compound I-111b
2- ((S) -4- ((S) -4-chloro-2 ' - (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-2, 3,5',8' -tetrahydro-6 ' H-spiro [ indene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoroacryl) piperazin-2-yl) acetonitrile and 2- ((S) -4- ((R) -4-chloro-2 ' - (((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-2, 3,5',8' -tetrahydro-6 ' H-spiro [ indene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002051
2- ((2S) -4- (4-chloro-2 ' - (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-2, 3,5',8' -tetrahydro-6 ' H-spiro [ indene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (50 mg) was subjected to SFC chiral resolution (CHIRALART Cellulose SB,2 cm. times.25 cm,5um column, mobile phase A: MtBE (0.5% 2mM NH3-MEOH), mobile phase B: MeOH: DCM ═ 1:1) to give the first component peak compound I-111a as a white solid (retention time of 2.174 min, 13 mg) and the second component peak compound I-111b (retention time 2.95 min, 20 mg).
Compound I-111a (retention time 2.174 min, 13 mg) MS:612.4(M + H) +。1H NMR(400MHz,Methanol-d4)δ7.31–7.18(m,2H),7.18–6.90(m,2H),5.61–5.19(m,4H),4.87–4.73(m,2H),4.59(m,1H),4.35–3.91(m,5H),3.51–3.34(m,2H),3.26–2.91(m,8H),2.82–2.58(m,2H),2.56–2.29(m,2H),2.12(m,1H)。
Compound I-111b (retention time 2.95 min, 20 mg) MS 612.4(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.31–7.18(m,2H),7.18–6.90(m,2H),5.61–5.19(m,4H),4.87–4.73(m,2H),4.59(m,1H),4.35–3.91(m,5H),3.51–3.34(m,2H),3.26–2.91(m,8H),2.82–2.58(m,2H),2.56–2.29(m,2H),2.12(m,1H)。
Example 117
Compound I-112: 2- ((2S) -4- (5-chloro-2 ' - (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002052
Synthesis of Compound I-112 reference is made to Compound I-5 by using (2S) -4- (2-chloro-6- ((5-chloro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A22) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3), ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride gave compound I-112.
Compound I-112(79 mg). MS:626.4(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.96–9.93(m,1H),7.38–7.13(m,3H),5.58–5.13(m,4H),4.68–4.44(m,4H),4.14–3.38(m,6H),3.26–2.62(m,10H),2.32–1.91(m,2H),1.91–1.60(m,4H)。
Compound I-112a and Compound I-112b
2- ((S) -4- ((R) -5-chloro-2 ' - (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile and 2- ((S) -4- ((S) -5-chloro-2 ' - ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002061
2- ((2S) -4- (5-chloro-2 '- (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 '-spiro [ naphthalene-1, 7' -pyridine [3, 2-d)]Pyrimidines]-4' -yl) -1- (2-Fluoroacryloyl) piperazin-2-yl) acetonitrile (90 mg) was resolved by SFC chiral resolution (CHIRALPAK IE,2 cm. times.25 cm,5um column, mobile phase A: MtBE (0.5% 2mM NH)3-MEOH), mobile phase B: MEOH: DCM ═ 1:1) to give the first component peak compound I-112a (retention time 1.986 min, 30 mg) and the second component peak compound I-112B (retention time 2.919 min, 25 mg) both as white solids.
Compound I-112a (retention time 1.986 min, 30 mg) MS:626.4(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.96–9.93(m,1H),7.38–7.13(m,3H),5.58–5.13(m,4H),4.68–4.44(m,4H),4.14–3.38(m,6H),3.26–2.62(m,10H),2.32–1.91(m,2H),1.91–1.60(m,4H)。
Compound I-112b (retention time 2.919 min, 25 mg) MS:626.4(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.96–9.93(m,1H),7.38–7.13(m,3H),5.58–5.13(m,4H),4.68–4.44(m,4H),4.14–3.38(m,6H),3.26–2.62(m,10H),2.32–1.91(m,2H),1.91–1.60(m,4H)。
Example 118
Compound I-113: 2- ((2S) -4- (6-fluoro-2 ' - (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -5-methyl-6 ' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002071
Synthesis of Compound I-113 reference is made to Compound I-5 by using (2S) -4- (2-chloro-6- ((6-fluoro-1- (methoxycarbonyl) -5-methyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A48) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3), ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride gave compound I-113.
Compound I-113(72 mg). MS:624.1(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.20–6.86(m,2H),5.57–5.12(m,3H),5.05-4.75(m,1H),4.67–4.45(m,2H),4.13-3.76(m,8H),3.63–3.34(m,5H),3.13–3.09(m,1H),3.04–2.79(m,5H),2.70-2.59(m,2H),2.13-2.06(m,3H),1.86–1.59(m,3H)。
Example 119
Compound I-114:2- ((2S) -4- (5-chloro-2 ' - ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-5 ',8' -dihydro-6 ' H-spiro [ isochroman-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoroacryl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002072
Synthesis of compound I-114 referring to compound I-5, by using tert-butyl (2S) -4- (2-chloro-6- ((5-chloro-1- (methoxycarbonyl) isochroman-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate a53) instead of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3), ((2S, preparation of 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride afforded Compound I-114.
Compound I-114(7 mg). MS:628.1(M + H)+。
Example 120
Compounds I-115a and I-115b 2- ((S) -4- ((S) -5-chloro-2 '- (((S) -4, 4-difluoro-1-methylpyrrolidin-2-yl) methoxy) -7-fluoro-6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 'H-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4 '-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile and 2- ((S) -4- ((R) -5-chloro-2' - (((S) -4, 4-difluoro-1-methylpyrrolidin-2-yl) methoxy) -7-fluoro-6 '-oxo-3, 4,5',8 '-tetrahydro-2H, 6' H-spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin-4' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002081
Synthesis of Compounds I-115a and I-115b reference is made to Compound I-5 by using (2S) -tert-butyl 4- (2-chloro-6- ((5-chloro-7-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A36) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3), (S) - (4, 4-difluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C6) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride, and compound I-115a and compound I-115B were prepared by SFC Chiral resolution (column model: Dr. mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm column, mobile phase: 40% methanol in carbon dioxide).
Compound I-115a (retention time 5.137 min, 6 mg). MS 622.3(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),7.35(dd,J＝8.5,2.5Hz,1H),7.17(dd,J＝10.2,2.6Hz,1H),5.38–5.31(m,1H),5.25–5.19(m,1H),4.82(s,2H),4.45–4.34(m,2H),3.87–3.74(m,2H),3.66–363(m,2H),3.60-3.54(m,5H),3.13–3.04(m,1H),3.01–2.97(m,2H),2.91–2.89(m,1H),2.84–2.59(m,6H),1.94–1.66(m,4H)。
Compound I-115b (retention time 5.37 min, 2 mg). MS 622.3(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),7.35(dd,J＝8.5,2.5Hz,1H),7.17(dd,J＝10.2,2.6Hz,1H),5.38–5.31(m,1H),5.25–5.19(m,1H),4.82(s,2H),4.45–4.34(m,2H),3.87–3.74(m,2H),3.66–363(m,2H),3.60-3.54(m,5H),3.13–3.04(m,1H),3.01–2.97(m,2H),2.91–2.89(m,1H),2.84–2.59(m,6H),1.94–1.66(m,4H)。
Example 121
Compound I-116- ((2S) -4- (5-chloro-7-fluoro-2 ' - (((2S,4R,5S) -4-fluoro-1, 5-dimethylpyrrolidin-2-yl) methoxy) -6 ' -oxo-3, 4,5 ', 8 ' -tetrahydro-2H, 6 ' -spiro [ naphthalene-1, 7 ' -pyridin [3,2-d ] pyrimidin ] -4 ' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002091
Synthesis of Compound I-116 reference is made to Compound I-5 by using (2S) -4- (2-chloro-6- ((5-chloro-7-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A36) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3), ((2S,4R,5S) -4-fluoro-1, 5-dimethylpyrrolidin-2-yl) methanol (intermediate C7) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride gave compound I-116.
Compound I-116(3.6 mg). MS:658.3(M + H)+。
Example 122
Compound I-117, 2- ((2S) -4- (4-chloro-6-fluoro-2 ' - ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-2, 3,5',8' -tetrahydro-6 ' H-spiro [ indene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002092
Synthesis of Compound I-117 reference is made to Compound I-5 by using (2S) -tert-butyl 4- (2-chloro-6- ((4-chloro-6-fluoro-1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A54) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3), ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride gave compound I-117.
Compound I-117(76 mg). MS:630.2(M + H)+。1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),7.33(d,J＝8.9Hz,1H),7.24(dd,J＝8.8,2.3Hz,1H),5.54–5.28(m,3H),4.66–4.43(m,4H),4.17–3.72(m,7H),3.52–4.38(m,2H),3.27–3.10(m,2H),3.00(s,3H),2.98–2.93(m,2H),2.83–2.78(m,2H),2.73–2.68(m,1H),2.32–2.22(m,1H),2.10–1.98(m,1H)。
Example 123
Compound I-118 2- ((2S) -4- (5-chloro-7-fluoro-2 ' - (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-5 ',8' -dihydro-6 ' H-spiro [ isochroman-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002101
Synthesis of Compound I-118 reference is made to Compound I-5 by using (2S) -4- (2-chloro-6- ((5-chloro-1- (ethoxycarbonyl) -7-fluoroisochroman-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A55) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3), ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride gave compound I-118.
Compound I-118(22 mg). MS:646.3(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.46(dd,J＝8.5,2.5Hz,1H),7.36(dt,J＝9.8,2.6Hz,1H),5.57–5.15(m,4H),4.61–4.43(m,2H),4.06–3.68(m,7H),3.66-3.53(m,2H),3.18–3.05(m,2H),3.05–2.89(m,5H),2.83–2.59(m,4H),2.21-2.01(m,2H)。
Example 124
Compound I-119:2- ((2S) -4- (5-chloro-7-fluoro-2 ' - ((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-5 ',8' -dihydro-6 ' H-spiro [ isochroman-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002102
Synthesis of Compound I-119 reference Compound I-5 was prepared by using (2S) -4- (2-chloro-6- ((5-chloro-1- (ethoxycarbonyl) -7-fluoroisochroman-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A55) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride Compound I-119 is obtained.
Compound I-119(12 mg). MS:628.4(M + H)+。1H NMR(400MHz,DMSO-d6)δ7.45(dd,J＝8.8,2.4Hz,1H),7.35(d,J＝10.1Hz,1H),5.41–5.24(m,2H),5.17-4.92(m,2H),4.55–4.49(m,1H),4.41-4.17(m,1H)，3.96-3.87(m，2H)，3.72-3.67(m，3H)，3.62-3.47(m，4H)，3.15-3.05(m，2H)，3.01–2.87(m，4H)，2.74–2.58(m,3H),2.26–2.16(m,1H),2.08–1.75(m,4H)。
Example 125
Compound I-120- ((2S) -4- (5-chloro-8-fluoro-2 ' - ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-5 ',8' -dihydro-6 ' H-spiro [ isochroman-1, 7' -pyridin [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002111
Synthesis of Compound I-120 with reference to Compound I-5, by using tert-butyl (2S) -4- (2-chloro-6- ((5-chloro-1- (ethoxycarbonyl) -8-fluoroisochroman-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A56) in place of tert-butyl (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (intermediate A3), ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride gave compound I-120.
Compound I-120(62 mg). MS:646.3(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.48(dd,J＝8.9,4.7Hz,1H),7.08(td,J＝9.5,8.6,1H),5.60–5.17(m,3H),4.90–4.79(m,2H),4.64–4.58(m,1H),4.45–4.16(m,2H),4.11–4.05(mz,3H),3.93–3.79(m,4H),3.76–3.37(m,3H),3.21–3.08(m,5H),3.01–2.77(m,3H),2.70–2.65(m,1H),2.46–2.38(m,1H)。
Compound I-120a and compound I-120b
2- ((S) -4- ((S) -5-chloro-8-fluoro-2 '- ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-5 ',8' -dihydro-6 'H-spiro [ isochroman-1, 7' -pyridin [3,2-d ] pyrimidin ] -4 '-yl) -1- (2-fluoroacryl) piperazin-2-yl) acetonitrile and 2- ((S) -4- (((R) -5-chloro-8-fluoro-2' - ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6 '-oxo-5', 8 '-dihydro-6' H-spiro [ isochroman-1, 7 '-pyrido [3,2-d ] pyrimidin-4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002112
2- ((2S) -4- (5-chloro-8-fluoro-2 ' - ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-5 ',8' -dihydro-6 ' H-spiro [ isochroman-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoroacryl) piperazin-2-yl) acetonitrile (50 mg) was subjected to SFC chiral resolution (CHIRALPAK IF,2 cm. times.25 cm,5um column, mobile phase A: MTBE, mobile phase B: MeOH: DCM:. times.1: 1) to give the first component peak compound I-120a as a white solid (retention time 0.928 min, 16 mg) and the second component peak compound I-120b (retention time 1.411 min, 20 mg).
Compound I-120a (retention time 0.928 min, 16 mg). MS:646.2(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.48(dd,J＝8.9,4.7Hz,1H),7.08(td,J＝9.5,8.6,1H),5.60–5.17(m,3H),4.90–4.79(m,2H),4.64–4.58(m,1H),4.45–4.16(m,2H),4.11–4.05(mz,3H),3.93–3.79(m,4H),3.76–3.37(m,3H),3.21–3.08(m,5H),3.01–2.77(m,3H),2.70–2.65(m,1H),2.46–2.38(m,1H)。
Compound I-120b (1.411 min retention time, 20 mg). MS:646.2(M + H) +。1H NMR(400MHz,Methanol-d4)δ7.48(dd,J＝8.9,4.7Hz,1H),7.08(td,J＝9.5,8.6,1H),5.60–5.17(m,3H),4.90–4.79(m,2H),4.64–4.58(m,1H),4.45–4.16(m,2H),4.11–4.05(mz,3H),3.93–3.79(m,4H),3.76–3.37(m,3H),3.21–3.08(m,5H),3.01–2.77(m,3H),2.70–2.65(m,1H),2.46–2.38(m,1H)。
Example 126
Compound I-121, 2- ((2S) -4- (5-chloro-8-fluoro-2 ' - (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002121
Step 1 preparation of (2S) -4- (5- ((tert-butoxycarbonyl) amino) -6- ((5-chloro-8-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (methylsulfonyl) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester
Will (a) to2S) -4- (5- ((tert-butoxycarbonyl) amino) -6- ((5-chloro-8-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (methylthio) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A58,220 mg, 0.306 mmol) was dissolved in DCM (5 mL) and mCPBA (63.3 mg, 0.367 mmol) was added slowly with stirring at 0 ℃. After the addition was completed, the reaction mixture was stirred at 20 ℃ for 2 hours. The reaction was then quenched by addition of ice water and extracted by dilution with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (2S) -4- (5- ((tert-butoxycarbonyl) amino) -6- ((5-chloro-8-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (methylsulfonyl) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (225 mg, 98%). MS:735.4(M + H) +。
Step 2 preparation of tert-butyl (2S) -4- (5- ((tert-butoxycarbonyl) amino) -6- ((5-chloro-8-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate
(2S) -4- (5- ((tert-butoxycarbonyl) amino) -6- ((5-chloro-8-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- (methylsulfonyl) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (220 mg, 0.299 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and cesium carbonate (146 mg, 0.449 mmol) and ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (80 mg, 0.598 mmol) were added slowly with stirring at 25 ℃. After the completion of the dropping, the reaction mixture was slowly raised to 60 ℃ and stirred for 12 hours, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give (2S) -4- (5- ((tert-butoxycarbonyl) amino) -6- ((5-chloro-8-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (150 mg, 62.3%). MS:804.4(M + H) +。
Step 3 preparation of 2- ((2S) -4- (5-chloro-8-fluoro-2 ' - ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6 ' -oxo-3, 4,5 ', 8 ' -tetrahydro-2H, 6 ' -spiro [ naphthalene-1, 7 ' -pyridin [3,2-d ] pyrimidin ] -4 ' -yl) piperazin-2-yl) acetonitrile
A solution of tert-butyl (2S) -4- (5- ((tert-butoxycarbonyl) amino) -6- ((5-chloro-8-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -2- ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylate (150 mg, 0.186 mmol) in TFA (2 ml) was reacted at 20 ℃ for 2 hours with stirring. The reaction solution was concentrated to give a crude product, and the crude product was reacted with a solution of sodium methoxide (30.2 mg, 0.559 mmol) in DMF (2 ml) at 60 ℃ for 0.5 hour with stirring, followed by quenching the reaction with ice water and dilution extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dried sodium sulfate, then filtered and concentrated to give a crude product which was purified by silica gel column chromatography to give 2- ((2S) -4- (5-chloro-8-fluoro-2 '- ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5 ', 8' -tetrahydro-2H, 6 '-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] as a yellow solid]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (50 mg, 46.9%). MS:572.3(M + H) +。
Step 4 preparation of 2- ((2S) -4- (5-chloro-8-fluoro-2 ' - ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile
2- ((2S) -4- (5-chloro-8-fluoro-2 '- (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 '-spiro [ naphthalene-1, 7' -pyridine [3,2-d ] is]Pyrimidines]-4' -yl) piperazin-2-yl) acetonitrile (50 mg, 0.087 mmol) and 2-fluoroacrylic acid (11.81 mg, 0.131 mmol) were dissolved in DMF (2 ml) and HATU (49.9 mg, 0.131 mmol) and DIEA (22.59 mg, 0.175 mmol) were added slowly with stirring at 0 ℃. After the completion of the dropping, the reaction mixture was slowly raised to 20 ℃ and stirred for 2 hours, and then the reaction was quenched by adding ice water and extracted by diluting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous dry sodium sulfate, then filtered and concentrated to give the crude product which was purified by Pre-HPLC to give white2- ((2S) -4- (5-chloro-8-fluoro-2 '- (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6 '-spiro [ naphthalene-1, 7' -pyridine [3, 2-d) as a colored solid]Pyrimidines]-4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile (30 mg, 35.5%). MS 644.3(M + H) +。1H NMR(400MHz，DMSO-d6)δ10.09(s,1H),9.71(s,1H),7.48-7.42(m,1H),7.17-7.07(m,1H),5.53-5.37(m,1H),5.37-5.18(m,1H),4.62-4.58(m,1H),4.52-4.48(m,1H),4.12-3.81(m,3H),3.71-3.68(m,1H),3.62-3.55(m,3H),3.35-3.30(m,2H),3.13-3.08(m,1H),3.05-2.95(m,7H),2.87-2.80(m,2H),2.69-2.56(m,2H),2.30-2.15(m,1H),1.92-1.85(m,1H),1.77-1.15(m,3H)。
Example 127
Compound I-122: 2- ((2S) -4- (5-chloro-8-fluoro-2 ' - (((S) -1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-5 ',8' -dihydro-6 ' H-spiro [ isochroman-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002141
Synthesis of Compounds I-122 reference Compound I-5 was prepared by using (2S) -4- (2-chloro-6- ((5-chloro-1- (ethoxycarbonyl) -8-fluoroisochroman-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A56) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3) and 2-fluoroacryloyl chloride (intermediate B1) in place of acryloyl chloride Compound I-122 is obtained.
Compound I-122(22 mg). MS:628.3(M + H)+。1H NMR(400MHz,Methanol-d4)δ7.47(dd,J＝8.8,4.7Hz,1H),7.07(t,J＝9.7Hz,1H),5.48–5.23(m,2H),4.79–4.68(m,1H),4.54–4.48(m,1H),4.33–4.28(m,1H),4.04–3.98(m,2H),3.95–3.65(m,5H),3.41–3.38(m,2H),3.27–3.01(m,7H),2.91–2.88(m,3H),2.50–2.33(m,1H),2.30–1.96(m,4H)。
Example 128
Compound I-123 2- ((2S) -4- (4-chloro-5-fluoro-2 ' - ((((2S, 4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-2, 3,5',8' -tetrahydro-6 ' H-spiro [ indene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002142
Synthesis of Compounds I-123 reference is made to compound I-5 by using (2S) -4- (2-chloro-6- ((4-chloro-5-fluoro-1- (methoxycarbonyl) -2, 3-dihydro-1H-inden-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A59) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3), compound I-123 was prepared from ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (intermediate C3) instead of (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) instead of acryloyl chloride.
Compound I-123(112 mg). MS:630.3(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.95–9.88(m,1H),7.28–7.18(m,2H),7.07–6.98(m,1H),6.82–6.68(m,1H),5.37–5.28(m,2H),5.26–5.06(m,3H),4.23–4.18(m,2H),4.11–4.08(m,2H),4.00–3.37(m,5H),3.24–2.59(m,8H),2.35–2.18(m,2H),2.18–1.98(m,3H),1.96–1.74(m,2H)。
Compound I-123a and compound I-123b 2- ((S) -4- ((R) -4-chloro-5-fluoro-2 '- (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-2, 3,5',8' -tetrahydro-6 'H-spiro [ indene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4 '-yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile and 2- ((S) -4-chloro-5-fluoro-2' - (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6 '-oxo-2, 3,5',8 '-tetrahydro-6' H-spiro [ indene-1, 7 '-pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002151
2- ((2S) -4- (4-chloro-5-fluoro-2 ' - (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -6' -oxo-2, 3,5',8' -tetrahydro-6 ' H-spiro [ indene-1, 7' -pyridin [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile (110 mg) was subjected to SFC chiral resolution (CHIRALPAK IF,2 cm. times.25 cm,5um column, mobile phase A: MTBE, mobile phase B: MeOH: DCM ═ 1:1) to give the first component, peak compound I-123a, which was a white solid (retention time 1.872 minutes, 40 mg) and a second component, compound I-123b (retention time 2.467 min, 25 mg).
Compound I-123a (retention time 1.872 min, 40 mg). MS:630.3(M + H)+。1H NMR(400MHz,DMSO-d6)δ9.95–9.88(m,1H),7.28–7.18(m,2H),7.07–6.98(m,1H),6.82–6.68(m,1H),5.37–5.28(m,2H),5.26–5.06(m,3H),4.23–4.18(m,2H),4.11–4.08(m,2H),4.00–3.37(m,5H),3.24–2.59(m,8H),2.35–2.18(m,2H),2.18–1.98(m,3H),1.96–1.74(m,2H)。
Compound I-123b (retention time 2.467 min, 25 mg). MS:630.3(M + H) +。1H NMR(400MHz,DMSO-d6)δ9.95–9.88(m,1H),7.28–7.18(m,2H),7.07–6.98(m,1H),6.82–6.68(m,1H),5.37–5.28(m,2H),5.26–5.06(m,3H),4.23–4.18(m,2H),4.11–4.08(m,2H),4.00–3.37(m,5H),3.24–2.59(m,8H),2.35–2.18(m,2H),2.18–1.98(m,3H),1.96–1.74(m,2H)。
Example 129
Compound I-124: 2- ((2S) -4- (5-chloro-7-fluoro-2 ' - (((2R) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -6' -oxo-3, 4,5', 8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyridine [3,2-d ] pyrimidin-4 ' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002161
Compound I-124
Synthesis of Compound I-124 reference is made to Compound I-5 by using (2S) -4- (2-chloro-6- ((5-chloro-7-fluoro-1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A36) in place of (2S) -4- (2-chloro-6- ((1- (methoxycarbonyl) -1,2,3, 4-tetrahydronaphthalen-1-yl) methyl) -5-nitropyrimidin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A3), intermediate C8 was substituted for (S) - (1-methylpyrrolidin-2-yl) methanol and 2-fluoroacryloyl chloride (intermediate B1) was substituted for acryloyl chloride to afford compounds I-124.
Compound I-124(36 mg). MS:670.3(M + H)+。1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),7.40–7.13(m,2H),5.64–5.14(m,3H),4.55–4.26(m,2H),4.18–3.22(m,14H),3.22–2.82(m,3H),2.79–2.54(m,2H),2.44–1.95(m,5H),1.92–1.59(m,3H)。
Compounds I-124a and I-124b 2- ((2S) -4- ((1R) -5-chloro-7-fluoro-2 '- (((2R) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -6' -oxo-3, 4,5', 8' -tetrahydro-2H, 6 '-spiro [ naphthalene-1, 7' -pyridin [3,2-d ] pyrimidin-4 '-yl) -1- (2-fluoroacryl) piperazin-2-yl) acetonitrile and 2- ((2S) -4- ((1S) -5-chloro-7-fluoro-2' - ((2R) -2-fluorotetrahydro-1H-pyrrol-e Lin-7 a (5H) -yl) methoxy) -6 '-oxo-3, 4,5', 8 '-tetrahydro-2H, 6' -spiro [ naphthalene-1, 7 '-pyrido [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile
Figure BDA0003413556240002162
2- ((2S) -4- (5-chloro-7-fluoro-2 ' - (((2R) -2-fluorotetrahydro-1H-pyrrolin-7 a (5H) -yl) methoxy) -6' -oxo-3, 4,5',8' -tetrahydro-2H, 6' -spiro [ naphthalene-1, 7' -pyrido [3,2-d ] pyrimidin ] -4' -yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile (90 mg) was subjected to SFC chiral resolution (CHIRALPAK IE,2cm × 25cm,5um column, mobile phase a: MtBE (0.5% 2mM NH3-MEOH), mobile phase B: MEOH: DCM ═ 1:1) to give the first component peak compound I-124a as a white solid (retention time 0.993 min, 30 mg) and the second component, peak compound I-124b (retention time 2.596 minutes, 25 mg).
Compound I-124a (retention time 0.993 min, 30 mg). MS:670.3(M + H)+.1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),7.40–7.13(m,2H),5.64–5.14(m,3H),4.55–4.26(m,2H),4.18–3.22(m,14H),3.22–2.82(m,3H),2.79–2.54(m,2H),2.44–1.95(m,5H),1.92–1.59(m,3H)。
Compound I-124b (retention time 2.596 min, 25 mg). MS:670.3(M + H)+.1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),7.40–7.13(m,2H),5.64–5.14(m,3H),4.55–4.26(m,2H),4.18–3.22(m,14H),3.22–2.82(m,3H),2.79–2.54(m,2H),2.44–1.95(m,5H),1.92–1.59(m,3H)。
Effect example 1 evaluation of drug efficacy at cellular level
This experiment was conducted to verify that the compound of the present invention is on KRASG12CMutated NCI-H358 human non-small cell lung carcinoma cells and KRASG12CInhibitory effects on proliferation of mutant MIA PaCa-2 human pancreatic cancer cells.
1. Main experimental materials and instruments:
DMEM Cell culture medium + GlutaMAXTM-I (Invitrogen), RPMI 1640 Cell culture medium + L-Glutamine (Invitrogen), fetal bovine serum (Corning), dimethyl sulfoxide DMSO (Sigma), penicillin streptomycin (Gibico), Du's phosphate buffer DPBS (Corning), pancreatic enzyme TryPLETM Express (Gibco), 96-well Cell culture plate (Corning), Cell titer
Figure BDA0003413556240002172
(Promega), TC-20 cytometer (Bio-rad), multifunction microplate reader Bio Synergy NEO2 (Bio-tek).
Human non-small cell lung carcinoma cells NCI-H358(ATCC) were cultured in RPMI 1640 medium cultured in 10% fetal bovine serum, 100U penicillin, and 100. mu.g/mL streptomycin.
Human pancreatic cancer cells MIA PaCa-2(ATCC) were cultured in DMEM medium with 10% fetal bovine serum, 100U penicillin and 100. mu.g/mL streptomycin.
2. Experimental procedure
NCI-H358 and MIA PaCa-2 cells were plated into 96-well cell culture plates (about 800 cells per well for NCI-H358 and about 1200 cells per well for MIA PaCa-2), and the well-plated 96-well plates were transferred to 37 ℃ with 5% CO2The culture was carried out overnight in an incubator. Test compounds were formulated in DMSO as 10mM stock. The compounds to be tested were diluted in DMSO in 3.16-fold gradients for a total of 9 concentration gradients, and the mostThe high concentration was 1mM, and the DMSO control was set after the ninth concentration. The test compound and the positive compound which are diluted in a gradient manner are diluted by 33.3 times by using a cell culture solution, mixed evenly and then transferred into a cell culture plate with the volume of 40 mu L to 96 holes. Transfer 96 well cell culture plates to 37 ℃ 5% CO2Incubate in incubator for 5 days. The cell culture plate was removed and equilibrated at room temperature for 30 minutes. 60ul of celltiter Glo reagent was added to a 96 well cell culture plate containing 120ul of cell culture reagent. The cells were lysed thoroughly by shaking on a shaker at 350rpm for 20 min. The luminescence signal values of the compounds were read using Bio-TeK SYNERGY NEO 2. Chemiluminescence values (Luminescent) of different cell numbers are measured by a microplate reader, the cytotoxicity percentage of a compound to be detected is calculated according to DMSO control and culture medium control, the concentration of the compound is used as a horizontal coordinate, the cytotoxicity percentage of the compound is used as a vertical coordinate, and GraphPad Prism is used for fitting (fit) the half inhibition concentration IC50 of the drug, and the result is shown in Table 1.
Table 1: determination of the cytotoxicity of the Compounds of the invention on NCI-H358 and MIA PaCa-2 IC50Value of
Figure BDA0003413556240002171
Figure BDA0003413556240002181
Figure BDA0003413556240002191
Figure BDA0003413556240002201
Figure BDA0003413556240002211
And (4) conclusion: the compound has good inhibitory activity on NCI-H358 and MIA PaCa-2 cells.

Claims (17)

1. A compound of formula I, a solvate thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0003413556230000011
ring A is a 4-12 membered aliphatic heterocyclic ring containing 2-4N atoms; the lipid heterocycle is monocyclic, bridged or spiro;
R1is-C (═ O) -C (R)a)＝C(Rb)(Rc)、-C(＝O)-C≡CRc、-C(＝O)-C(＝O)-O-Rdor-C (═ O) -Rd；
RaIs hydrogen, halogen or C1-6An alkyl group;
Rband RcIndependently of one another is hydrogen, C1-6Alkyl or "substituted by one or more Rb-1Substituted C1-6Alkyl groups ";
each Rb-1Independently of one another, halogen, C1-6Alkoxy or-NRb-2Rb-3；Rb-2And Rb-3Independently is hydrogen or C1-6Alkyl, or, Rb -2、Rb-3And N to which they are bonded, together form "a 4-to 10-membered heterocycloalkyl group having 1 or 2 heteroatoms N, or N and O";
Rdis C1-6An alkyl group;
n is 0, 1, 2 or 3;
each R4Independently is C1-6Alkyl or "substituted by one or more R4-1Substituted C1-6Alkyl groups ";
each R4-1Independently halogen, cyano, hydroxy or C1-6An alkoxy group;
R2is-OR2-1、-SR2-2、-C(＝O)R2-3、-S(＝O)2R2-4、-S(＝O)R2-5、-(CR1-1R1-2)mR2-6Or NR1-3R2-7；
R1-1、R1-2And R1-3Independently is hydrogen or C1-6An alkyl group;
m is 0, 1, 2 or 3, and when m is 0, R is represented2-6Directly connected with the parent body through a single bond;
R2-1、R2-2、R2-3、R2-4And R2-5Independently is C1-6Alkyl, by one or more ReSubstituted C1-6Alkyl radical, C1-6Alkoxy, one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms, and one or more Re -1Substituted 'one or more hetero atoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', C6-C10Aryl radical, by one or more Re-2Substituted C6-C10Aryl, 4-10 membered heterocycloalkyl with one or more heteroatoms selected from O and N, 1-3 heteroatoms, and one or more Re-3Substituted 'hetero atom selected from one or more of O and N, 4-10 membered heterocycloalkyl group having 1-3 hetero atoms', C3-10Cycloalkyl, or, by one or more Re-4Substituted C3-10A cycloalkyl group;
R2-6is hydrogen, CN, halogen, hydroxy, C1-6Alkyl, by one or more ReSubstituted C1-6Alkyl radical, C1-6Alkoxy, one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms, and one or more Re-1Substituted 'one or more hetero atoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', C6-C10Aryl radicals, substituted by one or more Re-2Substituted C6-C10Aryl, 4-10 membered heterocycloalkyl with one or more heteroatoms selected from O and N, 1-3 heteroatoms, and one or more R e-3Substituted "4-to 10-membered heterocycloalkyl having 1 to 3 hetero atoms, and one or more hetero atoms selected from O and N"、C3-10Cycloalkyl, or substituted by one or more Re-4Substituted C3-10A cycloalkyl group;
R2-7is hydrogen, C1-6Alkyl, by one or more ReSubstituted C1-6Alkyl radical, C1-6Alkoxy, one or more of 'hetero atom selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', one or more Re-1The substituted 'hetero atom is one or more selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', C6-C10Aryl radicals, substituted by one or more Re-2Substituted C6-C10Aryl, 4-10 membered heterocycloalkyl with one or more heteroatoms selected from O and N, 1-3 heteroatoms, and one or more Re-3Substituted 'hetero atom selected from one or more of O and N, 4-10 membered heterocycloalkyl group having 1-3 hetero atoms', C3-10Cycloalkyl, or, by one or more Re-4Substituted C3-10A cycloalkyl group;
each ReIndependently "one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more Re-1Substituted 'one or more hetero atoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', C 6-C10Aryl radical, by one or more Re-2Substituted C6-C10An aryl group, a 4-to 10-membered heterocycloalkyl group containing one or more heteroatoms selected from O and N and having 1 to 3 heteroatoms, and a substituted or unsubstituted heteroaryl groupe-3The substituted heteroatom is one or more selected from O and N, 4-10 membered heterocycloalkyl with 1-3 heteroatoms, and C3-10Cycloalkyl, or substituted by one or more Re-4Substituted C3-10A cycloalkyl group;
Re-1、Re-2and Re-4Independently of one another is halogen, C1-6Alkyl radical, C1-6Alkoxy, -C (═ O) -C (R)a)＝C(Rb)(Rc) Or NRe- 5Re-6；Re-5And Re-6Independently is hydrogen or C1-6Alkyl, or, Re-5、Re-6And N to which they are bonded form together a "4-10 membered heterocycloalkyl group having 1 or 2 heteroatoms N, or N and O";
each Re-3Independently halogen, hydroxy, cyano, C1-6Alkyl, by one or more Re-7Substituted C1-6Alkyl radical, C1-6Alkoxy, by one or more Re-8Substituted C1-6Alkoxy, -C (═ O) -C (R)a)＝C(Rb)(Rc)、NRe-5Re-6、-O(C＝O)NRe -13Re-14OR-O (C ═ O) ORe-15；Re-7And Re-8Independently halogen, hydroxy, -cyano, -COOH, C1-6Alkoxy or NRe-9Re -10，Re-9And Re-10Independently of one another is hydrogen, C1-6Alkyl, -C (═ O) Re-11or-S (═ O)2Re-12；Re-11And Re-12Independently is C1-6An alkyl group;
Re-13and Re-14Independently is hydrogen or C1-6Alkyl, or, Re-13、Re-14And N to which they are bonded, together form "a 4-to 10-membered heterocycloalkyl group having 1 or 2 heteroatoms N, or N and O"; r e-15Is hydrogen or C1-6An alkyl group;
R3is hydrogen, C1-6Alkyl, by one or more R3-1Substituted C1-6Alkyl, wherein each R3-1Independently is C1-6Alkyl radical, C1-6Alkoxy, CN, halogen or OH;
x and Y are independently O, NR6Or CR7R8(ii) a Each R6Independently is hydrogen or C1-6An alkyl group; each R7And R8Independently is H or C1-6An alkyl group; z is a single bond, O, NR6Or CR7R8(ii) a X, Y and Z are not both O or NR6；
U, V, W and Q are independently N or CR5；
Each R5Independently H, halogen, hydroxy, C substituted by one or more halogens1-6Alkyl, C substituted by one or more halogens1-6Alkoxy, cyano, C3-6Cycloalkyl radical, C1-6Alkyl sulfone group, C3-6Cycloalkyl sulfone group, C1-6Alkyl or C1-6An alkoxy group;
the carbon atom with the mark is chiral carbon atom, and is in S configuration, R configuration or the mixture of the S configuration and the R configuration.
2. The compound of formula I, its solvates, its prodrugs, its metabolites, or their pharmaceutically acceptable salts according to claim 1, wherein ring a is a 4-12 membered heterocyclic aliphatic ring containing 2-4N atoms; the lipid heterocycle is monocyclic, bridged or spiro;
R1is-C (═ O) -C (R)a)＝C(Rb)(Rc)、-C(＝O)-C≡CRc、-C(＝O)-C(＝O)-O-Rdor-C (═ O) -Rd；
RaIs hydrogen, halogen or C1-6An alkyl group;
Rband RcIndependently of one another is hydrogen, C1-6Alkyl or "substituted by one or more R b-1Substituted C1-6Alkyl ";
each Rb-1Independently of one another is halogen, C1-6Alkoxy or-NRb-2Rb-3；Rb-2And Rb-3Independently hydrogen or C1-6Alkyl, or, Rb -2、Rb-3And N to which they are bonded, together form "a 4-to 10-membered heterocycloalkyl group having 1 or 2 heteroatoms N, or N and O";
Rdis C1-6An alkyl group;
n is 0, 1, 2 or 3;
each R4Independently is C1-6Alkyl or "substituted by one or more R4-1Substituted C1-6Alkyl groups ";
each R4-1Independently halogen, cyano, hydroxy or C1-6An alkoxy group;
R2is-OR2-1、-SR2-2、-C(＝O)R2-3、-S(＝O)2R2-4、-S(＝O)R2-5、-(CR1-1R1-2)mR2-6Or NR1-3R2-7；
R1-1、R1-2And R1-3Independently is hydrogen or C1-6An alkyl group;
m is 0, 1, 2 or 3, and when m is 0, R is represented2-6Directly connected with the parent body through a single bond;
R2-1、R2-2、R2-3、R2-4and R2-5Independently is C1-6Alkyl, by one or more ReSubstituted C1-6Alkyl radical, C1-6Alkoxy, one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms, and one or more Re -1Substituted 'one or more hetero atoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', C6-C10Aryl radicals, substituted by one or more Re-2Substituted C6-C10Aryl, 4-10 membered heterocycloalkyl with one or more heteroatoms selected from O and N, 1-3 heteroatoms, and one or more Re-3Substituted 'hetero atom selected from one or more of O and N, 4-10 membered heterocycloalkyl group having 1-3 hetero atoms', C 3-10Cycloalkyl, or substituted by one or more Re-4Substituted C3-10A cycloalkyl group;
R2-6is hydrogen, CN, halogen, hydroxy, C1-6Alkyl, by one or more ReSubstituted C1-6Alkyl radical, C1-6Alkoxy, one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms, and one or more Re-1Substituted 'one or more hetero atoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', C6-C10Aryl radical, by one or more Re-2Substituted C6-C10Aryl, a "heteroatom selected from O and NOne or more of 4-to 10-membered heterocycloalkyl having 1 to 3 hetero atoms, with one or more Re-3Substituted 'hetero atom selected from one or more of O and N, 4-10 membered heterocycloalkyl group having 1-3 hetero atoms', C3-10Cycloalkyl, or, by one or more Re-4Substituted C3-10A cycloalkyl group;
R2-7is hydrogen, C1-6Alkyl, by one or more ReSubstituted C1-6Alkyl radical, C1-6Alkoxy, one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms, and one or more Re-1Substituted 'one or more hetero atoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', C6-C10Aryl radicals, substituted by one or more R e-2Substituted C6-C10An aryl group, a 4-to 10-membered heterocycloalkyl group containing one or more heteroatoms selected from O and N and having 1 to 3 heteroatoms, and a substituted or unsubstituted heteroaryl groupe-3The substituted heteroatom is one or more selected from O and N, 4-10 membered heterocycloalkyl with 1-3 heteroatoms, and C3-10Cycloalkyl, or substituted by one or more Re-4Substituted C3-10A cycloalkyl group;
each ReIndependently "one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more Re-1The substituted 'hetero atom is one or more selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms', C6-C10Aryl radicals, substituted by one or more Re-2Substituted C6-C10Aryl, 4-10 membered heterocycloalkyl with one or more heteroatoms selected from O and N, 1-3 heteroatoms, and one or more Re-3Substituted 'hetero atom selected from one or more of O and N, 4-10 membered heterocycloalkyl group having 1-3 hetero atoms', C3-10Cycloalkyl, or, by one or more Re-4Substituted C3-10A cycloalkyl group;
Re-1、Re-2and Re-4Independently of one another, halogen, C1-6Alkyl radical, C1-6Alkoxy, -C (═ O) -C (R)a)＝C(Rb)(Rc) Or NRe- 5Re-6；Re-5And Re-6Independently is hydrogen or C1-6Alkyl, or, Re-5、Re-6And N to which they are bonded form together a "4-10 membered heterocycloalkyl group having 1 or 2 heteroatoms N, or N and O";
Each Re-3Independently halogen, hydroxy, cyano, C1-6Alkyl, by one or more Re-7Substituted C1-6Alkyl radical, C1-6Alkoxy, by one or more Re-8Substituted C1-6Alkoxy, -C (═ O) -C (R)a)＝C(Rb)(Rc)、NRe-5Re-6、-O(C＝O)NRe -13Re-14OR-O (C ═ O) ORe-15；Re-7And Re-8Independently halogen, hydroxy, -cyano, -COOH, C1-6Alkoxy or NRe-9Re -10，Re-9And Re-10Independently of one another is hydrogen, C1-6Alkyl, -C (═ O) Re-11or-S (═ O)2Re-12；Re-11And Re-12Independently is C1-6An alkyl group;
Re-13and Re-14Independently is hydrogen or C1-6Alkyl, or, Re-13、Re-14And N to which they are bonded, together form "a 4-to 10-membered heterocycloalkyl group having 1 or 2 heteroatoms N, or N and O"; re-15Is hydrogen or C1-6An alkyl group;
R3is hydrogen, C1-6Alkyl, by one or more R3-1Substituted C1-6Alkyl, wherein each R3-1Independently is C1-6Alkyl radical, C1-6Alkoxy, CN, halogen or OH;
x and Y are independently O, NR6Or CH2；R6Is hydrogen or C1-6An alkyl group; z is a single bond, O, NR6Or CH2(ii) a X, Y and Z are not both O or NR6；
U, V, W and Q are independently N or CR5；
Each R5Independently H, halogen, hydroxy, C substituted by one or more halogens1-6Alkyl, C substituted by one or more halogens1-6Alkoxy, cyano, C3-6Cycloalkyl radical, C1-6Alkyl sulfone group, C3-6Cycloalkyl sulfone group, C1-6Alkyl or C1-6An alkoxy group;
the carbon atom with the mark is chiral carbon atom, and is in S configuration, R configuration or the mixture of the S configuration and the R configuration.
3. The compound of formula I, its solvate, its prodrug, its metabolite, or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2, wherein when ring a is a 4-12 membered aliphatic heterocycle containing 2-4N atoms, the aliphatic heterocycle is a 6-10 membered aliphatic heterocycle containing 2N atoms;
and/or when RaWhen halogen, the halogen is fluorine, chlorine, bromine or iodine;
and/or when RaIs C1-6When alkyl, said C1-C6Alkyl is C1-C3An alkyl group;
and/or when RbAnd RcIndependently is C1-6Alkyl or "substituted by one or more Rb-1Substituted C1-6When alkyl is mentioned, C is1-C6Alkyl is C1-C3An alkyl group;
and/or, when each R isb-1When independently halogen, the halogen is fluorine, chlorine, bromine or iodine;
and/or, when each R isb-1Independently is C1-6At alkoxy, the C1-C6Alkoxy is C1-C3An alkoxy group;
and/or when Rb-2And Rb-3Independently is C1-6When alkyl, said C1-C6Alkyl is C1-C3An alkyl group;
and/or when RdIs C1-6When it is alkylSaid C is1-C6Alkyl is C1-C3An alkyl group;
and/or, when each R is4Independently is C1-6Alkyl or "substituted by one or more R4-1Substituted C1-6When alkyl is mentioned, C is1-C6Alkyl is C1-C3An alkyl group;
and/or, when each R is4-1When independently halogen, the halogen is fluorine, chlorine, bromine or iodine;
and/or when R 2-1、R2-2、R2-3、R2-4And R2-5Independently is C1-6Alkyl or "substituted by one or more ReSubstituted C1-6When it is alkyl ", said C1-C6Alkyl is C1-C3An alkyl group;
and/or when R2-1、R2-2、R2-3、R2-4And R2-5Independently is C1-6At alkoxy, the C1-C6Alkoxy is C1-C3An alkoxy group;
and/or when R2-1、R2-2、R2-3、R2-4And R2-5Independently is "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S" or "substituted with one or more Re-1When the "hetero atom (S) is (are) one or more selected from N, O and S, or 5-12 membered heteroaryl having 1-4 hetero atoms", "hetero atom (S) is (are) one or more selected from N, O and S, or 5-12 membered heteroaryl having 1-4 hetero atoms" is (are) substituted
Figure FDA0003413556230000041
And/or when R2-1、R2-2、R2-3、R2-4And R2-5Independently is "one or more heteroatoms selected from O and N, 4-10 membered heterocycloalkyl having 1-3 heteroatoms" or "substituted with one or more Re-3The substituted heteroatom is one or more selected from O and N, and the number of the heteroatoms is 1-3, and the heteroatom number is 4-10-memberedWhen the "cycloalkyl group", "the" hetero atom(s) is (are) selected from one or more of O and N, and the 4-to 10-membered heterocycloalkyl group having 1 to 3 hetero atoms "is
Figure FDA0003413556230000051
And/or when R2-6When halogen, the halogen is fluorine, chlorine, bromine or iodine;
and/or when R2-6Is C1-6Alkyl or "substituted by one or more R eSubstituted C1-6When it is alkyl ", said C1-C6Alkyl is C1-C3An alkyl group;
and/or when R2-6Is C1-6At alkoxy radical, the C1-C6Alkoxy is C1-C3An alkoxy group;
and/or when R2-6Independently is "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S" or "substituted with one or more Re-1When the "hetero atom (S) is (are) one or more selected from N, O and S, or 5-12 membered heteroaryl having 1-4 hetero atoms", "hetero atom (S) is (are) one or more selected from N, O and S, or 5-12 membered heteroaryl having 1-4 hetero atoms" is (are) substituted
Figure FDA0003413556230000052
And/or when R2-6Is "one or more hetero atoms selected from O and N, 4-10 membered heterocycloalkyl having 1-3 hetero atoms" or "substituted with one or more Re-3When the substituted "hetero atom is one or more selected from O and N, and 4-to 10-membered heterocycloalkyl having 1 to 3 hetero atoms", "hetero atom is one or more selected from O and N, and 4-to 10-membered heterocycloalkyl having 1 to 3 hetero atoms" is
Figure FDA0003413556230000053
Figure FDA0003413556230000054
And/or, when each R iseIndependently is "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S" or "substituted with one or more Re-1When the "hetero atom (S) is (are) one or more selected from N, O and S, or 5-12 membered heteroaryl having 1-4 hetero atoms", "hetero atom (S) is (are) one or more selected from N, O and S, or 5-12 membered heteroaryl having 1-4 hetero atoms" is (are) substituted
Figure FDA0003413556230000055
And/or, when each R iseIndependently is "one or more heteroatoms selected from O and N, 4-to 10-membered heterocycloalkyl having 1 to 3 heteroatoms" or "substituted with one or more Re-3The substituted "hetero atom is one or more selected from O and N, 4-to 10-membered heterocycloalkyl having 1 to 3 hetero atoms" ", the" hetero atom is one or more selected from O and N, and 4-to 10-membered heterocycloalkyl having 1 to 3 hetero atoms "is
Figure FDA0003413556230000056
And/or when Re-1、Re-2And Re-4Independently is C1-C6When alkyl is said to be C1-C6Alkyl is C1-C3An alkyl group;
and/or, Re-3When independently halogen, the halogen is fluorine, chlorine, bromine or iodine;
and/or, Re-3Independently is C1-C6Alkyl or "substituted by one or more Re-7Substituted C1-6When alkyl is mentioned, C is1-C6Alkyl is C1-C3An alkyl group;
and/or, Re-3Independently is C1-6At alkoxy, the C1-C6Alkoxy is C1-C3An alkoxy group;
and/or when Re-5And Re-6Independently is C1-C6When alkyl is said C1-C6Alkyl is C1-C3An alkyl group;
and/or when R3Is C1-C6When alkyl, said C1-C6Alkyl is C1-C3An alkyl group;
and/or, when each R is5When independently halogen, the halogen is fluorine, chlorine, bromine or iodine;
and/or, when each R is5C independently substituted by one or more halogens1-6Alkyl, said C substituted by one or more halogens 1-6Alkyl is C substituted by one or more halogens1-3An alkyl group;
and/or, when each R is5Independently is C1-6When alkyl, said C1-C6Alkyl is C1-C3An alkyl group;
and/or, when each R is5C independently substituted by one or more halogens1-6Alkoxy, said C substituted by one or more halogens1-6Alkoxy is C substituted by one or more halogens1-3An alkoxy group;
and/or, when each R is7And R8Independently is C1-6When alkyl, said C1-C6Alkyl is C1-C3An alkyl group.
4. A compound of formula I, a solvate thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt thereof, according to claim 3,
Figure FDA0003413556230000061
is composed of
Figure FDA0003413556230000062
Figure FDA0003413556230000063
And/or the presence of a gas in the gas,when R isaWhen halogen, the halogen is fluorine;
and/or when RaIs C1-6When alkyl, said C1-C6Alkyl is methyl;
and/or when RbAnd RcIndependently is C1-6Alkyl or "substituted by one or more Rb-1Substituted C1-6When alkyl is mentioned, C is1-C6Alkyl is methyl;
and/or, when each R isb-1When independently halogen, the halogen is fluorine;
and/or, when each R isb-1Independently is C1-6At alkoxy, the C1-C6Alkoxy is methoxy;
and/or when Rb-2And Rb-3Independently is C1-6When alkyl, said C1-C6Alkyl is methyl;
and/or when RdIs C1-6When alkyl, said C 1-C6Alkyl is methyl;
and/or, when each R is4Independently is C1-6Alkyl or "substituted by one or more R4-1Substituted C1-6When it is alkyl ", said C1-C6Alkyl is methyl;
and/or, when each R is4-1When independently halogen, the halogen is fluorine;
and/or when R2-1、R2-2、R2-3、R2-4And R2-5Independently is C1-6Alkyl or "substituted by one or more ReSubstituted C1-6When alkyl is mentioned, C is1-C6Alkyl is methyl;
and/or when R2-1、R2-2、R2-3、R2-4And R2-5Independently is C1-6At alkoxy, the C1-C6Alkoxy is methoxy;
and/or when R2-6When halogen, the halogen is chlorine;
and/or when R2-6Is C1-6Alkyl or "substituted by one or more ReSubstituted C1-6When alkyl is mentioned, C is1-C6Alkyl is methyl;
and/or when R2-6Is C1-6At alkoxy, the C1-C6Alkoxy is methoxy;
and/or when Re-1、Re-2And Re-4Independently is C1-C6When alkyl is said C1-C6Alkyl is methyl;
and/or, Re-3When independently halogen, the halogen is fluorine;
and/or, Re-3Independently is C1-C6Alkyl or "substituted by one or more Re-7Substituted C1-6When alkyl is mentioned, C is1-C6Alkyl is methyl;
and/or, Re-3Independently is C1-6At alkoxy, the C1-C6Alkoxy is methoxy;
and/or when Re-5And Re-6Independently is C1-C6When alkyl is said C1-C6Alkyl is methyl or ethyl;
And/or when R3Is C1-C6When alkyl, said C1-C6Alkyl is methyl;
and/or, when each R is5When independently halogen, the halogen is fluorine, chlorine or bromine;
and/or, when each R is5C independently substituted by one or more halogens1-6Alkyl, said C substituted by one or more halogens1-6Alkyl is-CF3；
And/or, when each R is5Independently is C1-6When alkyl, said C1-C6Alkyl is methyl;
and/or, when each R is5C independently substituted by one or more halogens1-6Alkoxy, said C substituted by one or more halogens1-6Alkoxy is-OCF3；
And/or, when each R is7And R8Independently is C1-6When alkyl, said C1-C6The alkyl group is a methyl group.
5. The compound of formula I, its solvate, its prodrug, its metabolite, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein ring a is a 6-10 membered aliphatic heterocyclic ring containing 2N atoms, said aliphatic heterocyclic ring being a monocyclic ring;
and/or, R1is-C (═ O) -C (R)a)＝C(Rb)(Rc)、-C(＝O)-C≡CCH3、-C(＝O)-C(＝O)-OCH3or-C (═ O) -CH3(ii) a When R isaIs halogen or C1-6When alkyl, RbAnd RcIs hydrogen; when R isbOr RcIs C1-6Alkyl or "substituted by one or more Rb-1Substituted C1-6When alkyl is "or RaIs hydrogen;
and/or, RaIs hydrogen or halogen;
and/or, RbAnd RcIndependently of one another is hydrogen, C1-6Alkyl or "substituted by one or more R b-1Substituted C1-6Alkyl ", and RbAnd RcAt least one is hydrogen;
and/or each Rb-1Independently is halogen;
and/or n is 0, 1 or 2;
and/or each R4Independently methyl, cyano-substituted methyl, F-substituted methyl or hydroxy-substituted methyl;
and/or, R2-1Is hydrogen, C1-6Alkyl, by one or more ReSubstituted C1-6Alkyl or "substituted by one or more Re-1Substituted "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S";
and/or, R2-2Is C1-6Alkyl or "substituted by one or more ReSubstituted C1-6Alkyl groups ";
and/or, R2-5Is represented by one or more ReSubstituted C1-6An alkyl group;
and/or, m is 0;
and/or, R2-6Is hydrogen, halogen, substituted by one or more Re-3Substituted "heteroatom is selected from one or more of O and N, 4-10 membered heterocycloalkyl with 1-3 heteroatoms", "heteroatom is selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", substituted with one or more Re-1Substituted "heteroatom selected from one or more of N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms" or hydroxy;
and/or, each ReIndependently "one or more heteroatoms selected from N, O and S, 5-12 membered heteroaryl with 1-4 heteroatoms", one or more R e-1The substituted "hetero atom is one or more selected from N, O and S, 5-12 membered heteroaryl with 1-4 hetero atoms", "hetero atom is one or more selected from O and N, 4-10 membered heterocycloalkyl with 1-3 hetero atoms", or "substituted with one or more Re-3Substituted "hetero atom is one or more selected from O and N, hetero atom number is 4-10 membered heterocycloalkyl of 1-3";
and/or, Re-1Independently is C1-6An alkyl group;
and/or each Re-3Independently of one another is halogen, hydroxy, C1-6Alkyl radical, C1-6Alkoxy, -C (═ O) -C (R)a)＝C(Rb)(Rc) Or NRe-5Re-6；
And/or, R2is-OR2-1、-SR2-2、-S(＝O)R2-5Or- (CR)1-1R1-2)mR2-6；
And/or, R3Is hydrogen or C1-6An alkyl group;
and/or X is O or CR7R8Y is CR7R8Z is a single bond, O or CR7R8；
And/or, U, V, W and Q are independently CR5；
And/or, each R5Independently H, halogen, C substituted by one or more halogens1-6Alkyl, C substituted by one or more halogens1-6Alkoxy, cyano, C3-6Cycloalkyl radical, C1-6Alkyl or C1-6An alkoxy group.
6. A compound of formula I, its solvates, its prodrugs, its metabolites, or their pharmaceutically acceptable salts according to claim 1 or 2, wherein R isbAnd RcIndependently hydrogen or C "substituted by one or more halogens1-6Alkyl ", and R bAnd RcAt least one is hydrogen;
and/or, n is 1 or 2;
and/or each R4Independently a cyano-substituted methyl group;
and/or each Re-3Independently of one another is halogen, hydroxy, C1-6Alkyl radical, C1-6Alkoxy, -C (═ O) -CH ═ CH2Or NRe-5Re-6；
And/or, each ReIndependently is "5-12 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S" or "substituted with one or more Re-3Substituted' 4-10 membered heterocycloalkyl with 1-3 heteroatoms selected from one or more of O and N;
and/or X and Y are CH2Z is a single bond, O or CH2；
And/or, each R5Independently is H, halogen or C1-6An alkyl group.
7. The compound of formula I, its solvates, its prodrugs, its metabolites, or their pharmaceutically acceptable salts according to claim 1 or 2,
Figure FDA0003413556230000081
is composed of
Figure FDA0003413556230000082
And/or, R1Is composed of
Figure FDA0003413556230000083
Figure FDA0003413556230000084
And/or, R2is-OR2-1Or- (CR)1-1R1-2)mR2-6，R2-1Is represented by one or more ReSubstituted C1-6Alkyl radical, each ReIndependently by one or more Re-3The substituted heteroatom is one or more selected from O and N, the heteroatom number is 1-3, the heterocyclic alkyl group with 4-10 members, and ReIn (1), each Re-3Independently of one another, halogen, C1-6Alkyl or C1-6An alkoxy group; m is 0, R2-6Is represented by one or more R e-3The substituted 'hetero atom is one or more selected from O and N, and the hetero atom number is 1-3, 4-10 membered heterocyclic alkyl', R2-6In each Re-3Independently of one another is NRe-5Re-6。
8. The compound of formula I, its solvate, its prodrug, its metabolite, or a pharmaceutically acceptable salt thereof according to claim 1 or 2,
Figure FDA0003413556230000091
is composed of
Figure FDA0003413556230000092
Figure FDA0003413556230000093
And/or, R2Is hydrogen, hydroxyl, chlorine,
Figure FDA0003413556230000094
-OCH3、-SCH3、
Figure FDA0003413556230000095
Figure FDA0003413556230000101
And/or the presence of a gas in the atmosphere,
Figure FDA0003413556230000102
is composed of
Figure FDA0003413556230000103
Figure FDA0003413556230000104
Figure FDA0003413556230000111
9. The compound of formula I, its solvates, its prodrugs, its metabolites, or their pharmaceutically acceptable salts according to claim 1 or 2, wherein the compound of formula I is any one of the following compounds:
Figure FDA0003413556230000112
Figure FDA0003413556230000121
Figure FDA0003413556230000131
Figure FDA0003413556230000141
Figure FDA0003413556230000151
Figure FDA0003413556230000161
Figure FDA0003413556230000171
Figure FDA0003413556230000181
Figure FDA0003413556230000191
Figure FDA0003413556230000201
Figure FDA0003413556230000211
Figure FDA0003413556230000221
Figure FDA0003413556230000231
Figure FDA0003413556230000241
Figure FDA0003413556230000251
10. the compound of formula I, its solvates, its prodrugs, its metabolites, or their pharmaceutically acceptable salts according to claim 1 or 2, wherein the compound of formula I is any one of the following compounds:
a compound having a retention time of 1.21min under the following conditions, which is
Figure FDA0003413556230000261
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 1.99min under the following conditions
Figure FDA0003413556230000262
One stereoisomer of (a): chromatographic column, Dr.mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm; column temperature is room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 0.93min under the following conditions
Figure FDA0003413556230000263
One stereoisomer of (a): chromatographic column, Dr.mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm; column temperature is room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 1.43min under the following conditions, which is
Figure FDA0003413556230000271
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 1.24min under the following conditions, which is
Figure FDA0003413556230000272
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 2.56min under the following conditions, which is
Figure FDA0003413556230000273
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 1.01min under the following conditions
Figure FDA0003413556230000281
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 2.17min under the following conditions, which is
Figure FDA0003413556230000282
One stereoisomer of (a): chromatographic column, Dr.mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm; column temperature is room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.74min under the following conditions
Figure FDA0003413556230000283
One stereoisomer of (a): chromatographic column, Dr.mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm; column temperature is room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 5.44min under the following conditions
Figure FDA0003413556230000291
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.08min under the following conditions
Figure FDA0003413556230000292
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.22min under the following conditions, which is
Figure FDA0003413556230000293
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 1.42min under the following conditions, which is
Figure FDA0003413556230000301
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 2.71min under the following conditions, which is
Figure FDA0003413556230000302
In (1)The individual stereoisomers: chromatographic column, Dr.mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm; column temperature is room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 1.11min under the following conditions
Figure FDA0003413556230000303
One stereoisomer of (a): chromatographic column, Dr.mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm; column temperature is room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 2.21min under the following conditions, which is
Figure FDA0003413556230000311
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 3.88min under the following conditions, which is
Figure FDA0003413556230000312
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.42min under the following conditions, which is
Figure FDA0003413556230000313
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 1.254min under the following conditions
Figure FDA0003413556230000314
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 2.267min under the following conditions
Figure FDA0003413556230000321
One stereoisomer of (a): chromatographic column, Dr.mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm; column temperature is room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.473min under the following conditions
Figure FDA0003413556230000322
One stereoisomer of (a): chromatographic column, Dr.mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm; column temperature is room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.688min under the following conditions
Figure FDA0003413556230000323
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 7.008min under the following conditions
Figure FDA0003413556230000331
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 7.199min under the following conditions
Figure FDA0003413556230000332
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.735min under the following conditions, whichIs composed of
Figure FDA0003413556230000333
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.758min under the following conditions
Figure FDA0003413556230000341
One stereoisomer of (a): chromatographic column, Dr.mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm; column temperature is room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 7.198min under the following conditions
Figure FDA0003413556230000342
One stereoisomer of (a): chromatographic column, Dr.mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm; column temperature is room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 7.460min under the following conditions
Figure FDA0003413556230000343
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.249min under the following conditions
Figure FDA0003413556230000351
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.333min under the following conditions
Figure FDA0003413556230000352
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 6.961min under the following conditions
Figure FDA0003413556230000353
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 7.133min under the following conditions, which is
Figure FDA0003413556230000361
One stereoisomer of (a): chromatographic column, Dr.mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm; column temperature is room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 4.903min under the following conditions
Figure FDA0003413556230000362
One stereoisomer of (a): chromatographic column, Dr.mail Reprosil Chiral Chiral-JM, 250X25mm, 10 μm; column temperature is room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 5.508min under the following conditions
Figure FDA0003413556230000363
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 2.174min under the following conditions, which is
Figure FDA0003413556230000371
One stereoisomer of (a): chromatographic column CHIRALART Cellulose SB,2cm × 25cm,5 μm; mobile phase A MtBE (0.5% 2mM NH)3-MEOH), mobile phase B: MEOH: DCM ═ 1: 1;
a compound having a retention time of 2.950min under the following conditions
Figure FDA0003413556230000372
One stereoisomer of (a): CHIRALART Cellulose SB chromatographic column of 2cm × 25cm,5 μm; mobile phase A MtBE (0.5% 2mM NH)3-MEOH), mobile phase B: MEOH: DCM ═ 1: 1;
a compound having a retention time of 1.986min under the following conditions, which is
Figure FDA0003413556230000373
One stereoisomer of (a): CHIRALPAK IE chromatographic column of 2cm × 25cm,5 μm; mobile phase A MtBE (0.5% 2mM NH) 3-MEOH), mobile phase B: MEOH: DCM ═ 1: 1;
a compound having a retention time of 2.919min under the following conditions
Figure FDA0003413556230000381
One stereoisomer of (a): CHIRALPAK IE,2cm × 25cm,5 μm chromatographic column; mobile phase A MtBE (0.5% 2mM NH)3-MEOH), mobile phase B: MEOH: DCM ═ 1: 1;
a compound having a retention time of 5.137min under the following conditions
Figure FDA0003413556230000382
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature is room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 5.370min under the following conditions
Figure FDA0003413556230000383
One stereoisomer of (a): chromatographic column, Dr. mail Reprosil Chiral-JM, 250X25mm, 10 μm; column temperature, room temperature; mobile phase of CO2/MeOH＝60/40；
A compound having a retention time of 0.928min under the following conditions
Figure FDA0003413556230000391
One stereoisomer of (a): CHIRALPAK IF chromatographic column of 2cm × 25cm,5 μm; mobile phase A MtBE (0.5% 2mM NH)3-MEOH), mobile phase B: MEOH: DCM ═ 1: 1;
a compound having a retention time of 1.411min under the following conditions
Figure FDA0003413556230000392
One stereoisomer of (a): CHIRALPAK IF chromatographic column of 2cm × 25cm,5 μm; mobile phase A MtBE (0.5% 2mM NH)3-MEOH), mobile phase B: MEOH: DCM ═ 1: 1;
a compound having a retention time of 1.872min under the following conditions
Figure FDA0003413556230000393
One stereoisomer of (a): CHIRALPAK IF,2cm × 25cm,5 μm chromatographic column; mobile phase A is MtBE, mobile phase B is MeOH, DCM 1: 1;
a compound having a retention time of 2.467min under the following conditions
Figure FDA0003413556230000401
One stereoisomer of (a): CHIRALPAK IF,2cm × 25cm,5 μm chromatographic column; mobile phase A is MtBE, mobile phase B is MeOH, DCM 1: 1;
a compound having a retention time of 0.993min under the following conditions, which is
Figure FDA0003413556230000402
One stereoisomer of (a): CHIRALPAK IF,2cm × 25cm,5 μm chromatographic column; mobile phase A MtBE (0.5% 2mM NH)3-MEOH), mobile phase B: MEOH: DCM ═ 1: 1;
a compound having a retention time of 2.596min under the following conditions
Figure FDA0003413556230000403
One stereoisomer of (a): CHIRALPAK IF chromatographic column of 2cm × 25cm,5 μm; mobile phase A MtBE (0.5% 2mM NH)3-MEOH), mobile phase B: MEOH: DCM ═ 1: 1.
11. A process for the preparation of a compound of formula I as claimed in any one of claims 1 to 10, comprising the steps of:
carrying out substitution reaction on a compound shown as a formula K-X and a compound shown as a formula K-XIII to obtain a compound shown as a formula I;
Figure FDA0003413556230000411
wherein ". x", n, ring A, R1、R2、R3、R4X, Y, Z, U, V, W and Q are as defined in any one of claims 1 to 10, L is halogen or hydroxy;
Preferably, the preparation method of the compound shown in the formula I further comprises the following steps:
carrying out deprotection reaction on the compound shown as the formula K-IX to obtain a compound shown as K-X;
Figure FDA0003413556230000412
wherein "+", n, ring A, R2、R3、R4X, Y, Z, U, V, W and Q are as defined in any one of claims 1 to 9, PG is an amino protecting group.
12. A compound of the formula K-X:
Figure FDA0003413556230000413
wherein "+", n, ring A, R2、R3、R4X, Y, Z, U, V, W and Q are as defined in any one of claims 1 to 10.
13. The compound of formula K-X according to claim 12, wherein the compound of formula K-X is any one of the following compounds:
Figure FDA0003413556230000421
Figure FDA0003413556230000431
Figure FDA0003413556230000441
Figure FDA0003413556230000451
Figure FDA0003413556230000461
Figure FDA0003413556230000471
Figure FDA0003413556230000481
14. a pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 10, a solvate, prodrug, metabolite, or pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.
15. Use of a compound of formula I, a solvate thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 10, or a pharmaceutical composition as claimed in claim 14, in the manufacture of a medicament.
16. The use according to claim 15, wherein the medicament is for the treatment of cancer; preferably, the cancer comprises one or more of lung cancer, colon cancer, pancreatic cancer, rectal cancer, lymphatic cancer, esophageal cancer, ovarian cancer, brain glioma, cervical cancer, urothelial cancer, stomach cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, leukemia and melanoma.
17. Use of a compound of formula I, a solvate, a prodrug, a metabolite, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 10, or a pharmaceutical composition of claim 14 in the preparation of KRASG12CThe application of protein mutation inhibitor.
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