CN115433184A - HPK1 inhibitor and application thereof - Google Patents

HPK1 inhibitor and application thereof Download PDF

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Publication number
CN115433184A
CN115433184A CN202210626210.6A CN202210626210A CN115433184A CN 115433184 A CN115433184 A CN 115433184A CN 202210626210 A CN202210626210 A CN 202210626210A CN 115433184 A CN115433184 A CN 115433184A
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substituted
alkyl
methyl
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halogen
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Inventor
张学军
常少华
李学强
井真中
王洪强
蔡立波
刘勇
赵心
李禹琼
徐清
倪萍
李莉娥
杨俊�
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Humanwell Healthcare Group Co ltd
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Humanwell Healthcare Group Co ltd
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention provides an HPK1 inhibitor and application thereof, and particularly provides a compound shown as a formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, a preparation method thereof, and application thereof in preparing medicines.

Description

HPK1 inhibitor and application thereof
Technical Field
The invention belongs to the field of medical chemistry, particularly relates to an HPK1 inhibitor and application thereof, and more particularly relates to a pyrrolopyridine compound, a preparation method thereof and application thereof in preparing medicaments.
Background
Hematopoietic progenitor kinase (Hematopoietic progenitor kinase I) HPK1, also known as MAP4K1, gene ID:11184 located: 19q13.1-q13.4, MAP kinase kinase kinase kinases (MAP 4K) belonging to the mammalian Ste 20-like serine/threonine kinase family.
HPK1 is a negative regulator of TCR (T cell receptor) signaling and T cell mediated immune responses. Upon TCR activation, cytoplasmic HPK1 is recruited to the plasma membrane and is fully activated by its phosphorylation of Y381, S171 and T165, and activated HPK1 phosphorylates adaptor protein SLP76, providing a binding site for negative regulator 14-3-3, ultimately disrupting the stabilization of the TCR signaling complex (Lat-Gads-SLP 76), blocking downstream mitogen-activated protein (MAP) kinase (MAPK) signaling required for T Cell activation and proliferation (Hernandez S et al, cell Reports,2018,25 (1): 80-94.). In HPK1 overexpression and gene knock-out studies, HPK1 negatively regulates the T-cell MAPK signaling pathway and AP-1 (activin-1) transcription (Liou J et al. Immunity,2000,12 (4): 399-408.). HPK1 -/- Mice show effects such as enhanced T cell proliferative capacity, increased secretion of IL-2, IL-4 and Interferon (IFN) - γ, decreased sensitivity to inhibitory effects of prostaglandins, decreased threshold of T cell activation, and the like (Shui, JW., boomer, j., han, j.et al. Nat Immunol 8,84-91 (2007)).
Similar to the T cell mechanism, HPK1 also negatively regulates BCR (B cell receptor) signaling, HPK1 -/- Mouse B cells showed a high response to a range of stimuli and loss of HPK1 activity was associated with higher titers of IgG1 and IgG2B produced in the immune response. In addition, HPK1 also exerts multiple effects such as an inhibitory action on NK (natural killer) cell-mediated release of a novel antigen and inhibition of Lipopolysaccharide (LPS) -stimulated Dendritic Cell (DC) maturation (Liu J et al plos ONE,2019,14 (3): e 0212670.). HPK1 negatively regulates T cell function, negatively regulates multiple immune cells, inhibits activity of the immune cells, and promotes immune response from multiple nodes.
Based on the negative regulation and control effect of HPK1 on immune response, the inhibition of the activity of HPK1 has obvious anti-tumor effect. Wild type and HPK1 -/- When mice were administered with Lewis lung cancer tumor cell line (3 LL) by intravenous injection, HPK1 was observed in comparison with wild-type mice -/- The number and size of tumors in mice are small, and this tumor suppression is mediated by T cells; when HPK1 -/- When the mouse spleen cells and the 3LL cells are co-cultured, the killing effect on the 3LL cells is 5 times that of wild spleen cells; intravenous injection of wild type or HPK1 into T cell deficient mice -/- After T cells of (3), HPK1 is injected -/- Number and size of tumors in lungs of T cell mice
Significantly less than mice injected with wild type T cells (Si J, shi X, sun S, et al cancer Cell,2020,38 (4)). The test results show that the reduction of the HPK1 level can enhance the anti-tumor response of T cells, and the inhibitor of the HPK1 has the potential of being used as an anti-tumor drug.
In addition, MAP4K1 expression and signal molecules related to T cell exhaustion (such as PD-1, TIGIT, CTLA4, LAG3 and the like) show strong positive correlation, and patients showing low MAP4K1 expression in tumors such as low-grade glioma (LGG) and invasive breast cancer (BRAC) have longer survival period. Protein expression of HPK1 with immunosuppressive molecules was measured in T cells in clinical multiple myeloma tissue biopsies and expression of HPK1 was found to be upregulated in depleted T cells. These results indicate that HPK1 is also an important kinase in humans to regulate T cell depletion and to inhibit anti-tumor immune responses (Sawasdkosol S et al immunological Research,2012,54 (1-3): 262-265.) and that small molecule inhibitors thereof may be useful in the treatment of tumors.
The immunosuppressive pathway regulated by HPK1 is different from PD-1/L1 (programmed death receptor 1/programmed death receptor-ligand 1), suggesting that small molecule inhibitors of HPK1 can be used in combination with inhibitors/antibodies to PD-1/L1. While the combination of an inhibitor of HPK1 and an anti-PD-1/L1 antibody enhances antiviral and antitumor activity, an inhibitor of HPK1 inhibits tumor growth and enhances the efficacy of PD-L1, another study has shown that combined blockade of HPK1 and PD-L1 enhances anti-tumor T Cell responses (Hernandez S et al, cell Reports,2018,25 (1): 80-94.). These all demonstrate that small molecule inhibitors of HPK1 can be used in combination with anti-PD-1/L1 antibodies to achieve superior antiviral and antitumor efficacy.
MAP4K includes, in addition to MAP4K1/HPK1, MAP4K2/GCK, MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS and MAP4K6/MINK, for 6 structurally similar subtypes (Chuang H C et al. Advances in Immunology,2016, 129. Research shows that obvious toxic and side effects exist in the inhibition of subtypes such as MAP4K3, MAP4K5 and the like, so that the selective HPK1 inhibitor has better safety; in addition, northern blot analysis of HPK1 shows that except for embryonic stage, HPK1 is mainly expressed in hematopoietic-related cells, such as hematopoietic progenitor cells, T cells, B cells, macrophages, dendritic cells, neutrophils and mast cells (Kiefer F et al the EMBO Journal,1996,15 (24): 7013-7025), and the expression of other tissue organs is rather limited, which reduces their safety risk.
Currently some HPK1 inhibitors (CFI-402411, BGB-15025) have entered clinical stage and HPK1 inhibition may be a promising tumor immunotherapy.
Disclosure of Invention
The invention aims to provide a novel HPK1 inhibitor which can be used for preparing a medicament for treating HPK1 related diseases.
In a first aspect of the present invention, the present invention provides a compound, which is a compound represented by formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof:
Figure BDA0003677664240000031
wherein the content of the first and second substances,
R 1 independently H, cyano, halogen, C substituted by 1-5 same or different halogens 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl or-O- (C) 1 -C 6 Alkyl groups);
ring A is independently 6-10 membered aryl, 5-8 membered heteroaryl, 4-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl or C 3 -C 10 A cycloalkenyl group;
R 2 independently is
Figure BDA0003677664240000032
R 21 And R 22 Each independently of the others being unsubstituted orBy R 211 Substituted C 1 -C 6 Alkyl, or, unsubstituted or substituted by R 211 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 211 Substituted C 1 -C 6 Alkyl or by R 211 Substituted C 3 -C 6 In the cycloalkyl group, said R 211 The substitution may be one or more, and R is 211 Each independently is the following substituent: hydroxy, halogen, -O- (C) 1 -C 6 Alkyl group), C 1 -C 6 Alkylamino or C 3 -C 6 A cycloalkyl group; when the number of the substituents is plural, the substituents may be the same or different; the R is 21 And R 22 At least one is represented by R 211 Substituted C 1 -C 6 Alkyl or by R 211 Substituted C 3 -C 6 A cycloalkyl group;
ring B is independently unsubstituted or substituted with R 23 Substituted 4-8 membered heterocycloalkyl, or, unsubstituted or substituted by R 23 A substituted 6-11 membered hetero spirocycloalkyl group; the quilt R 23 Substituted 4-8 membered heterocycloalkyl or by R 23 In a substituted 6-11 membered hetero spiro cycloalkyl group, said R 23 The substitution may be one or more, R 23 Each independently is the following substituent: hydroxy, cyano, halogen, C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group; when the number of the substituents is plural, the substituents may be the same or different;
R 24 independently is unsubstituted or substituted by R 241 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 241 Substituted C 3 -C 6 In the cycloalkyl group, the R is 241 The substitution may be one or more, R 241 Each independently is the following substituent: cyano, halogen, C substituted by 1-5 identical or different halogens 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group; when the substituent is plural, the substituents are the same or different;
R 3 independently halogen, CN, C substituted by 1-5 same or different halogens 1 -C 6 Alkyl or C 1 -C 6 An alkyl group;
n is 0,1, 2 or 3;
R 4 and R 5 Each independently being C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl or C 1 -C 6 An alkyl group; or R 4 And R 5 The carbon atoms to which they are commonly attached may form a 4-8 membered cycloalkyl or 4-8 membered heterocycloalkyl group.
In some embodiments of the present invention, the present invention provides a compound of formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof:
Figure BDA0003677664240000041
wherein the content of the first and second substances,
R 1 independently H, cyano, halogen, C substituted by 1-5 same or different halogens 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl or-O- (C) 1 -C 6 Alkyl groups);
ring A is independently 6-10 membered aryl, 5-8 membered heteroaryl, 4-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl or C 3 -C 10 A cycloalkenyl group;
R 2 independently is
Figure BDA0003677664240000042
R 21 And R 22 Each independently of the other being unsubstituted or substituted by R 211 Substituted C 1 -C 6 Alkyl, or, unsubstituted or substituted by R 211 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 211 Substituted C 1 -C 6 Alkyl or by R 211 Substituted C 3 -C 6 In the cycloalkyl group, the R is 211 Can substituteTo be one or more substitutions, said R 211 Each independently is the following substituent: hydroxy, halogen, -O- (C) 1 -C 6 Alkyl group), C 1 -C 6 Alkylamino or C 3 -C 6 A cycloalkyl group; when the substituent is plural, the substituents are the same or different; the R is 21 And R 22 At least one is represented by R 211 Substituted C 1 -C 6 Alkyl or by R 211 Substituted C 3 -C 6 A cycloalkyl group;
ring B is independently unsubstituted or substituted with R 23 Substituted 4-8 membered heterocycloalkyl, or, unsubstituted or substituted by R 23 A substituted 6-11 membered hetero spirocycloalkyl group; the quilt R 23 Substituted 4-8 membered heterocycloalkyl or by R 23 In the substituted 6-to 11-membered heterospirocycloalkyl group, said R 23 The substitution may be one or more, R 23 Each independently is the following substituent: hydroxy, cyano, halogen, C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group; when the number of the substituents is plural, the substituents may be the same or different;
R 24 independently is unsubstituted or substituted by R 241 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 241 Substituted C 3 -C 6 In the cycloalkyl group, the R is 241 The substitution may be one or more, R 241 Each independently is the following substituent: cyano, halogen, C substituted by 1-5 halogen, the same or different 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group; when the substituent is plural, the substituents are the same or different;
R 3 independently halogen, C substituted by 1-5 same or different halogens 1 -C 6 Alkyl or C 1 -C 6 An alkyl group;
n is 0,1, 2 or 3;
R 4 and R 5 Each independently of the other being substituted by 1 to 5 identical or different halogensSubstituted C 1 -C 6 Alkyl or C 1 -C 6 An alkyl group; or R 4 And R 5 The carbon atoms to which they are commonly attached may form a 4-8 membered heterocycloalkyl group.
In some embodiments of the invention, R 3 Is CN.
In some embodiments of the invention, R 4 And R 5 The carbon atoms to which they are commonly attached may form a 4-8 membered cycloalkyl group.
In a preferred embodiment of the present invention, the compound has a structure as shown in formula II, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof.
Figure BDA0003677664240000051
Wherein R is 2 、R 4 、R 5 And ring A are as defined herein.
In a preferred embodiment of the present invention, the compound is represented by formula III or IV, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof.
Figure BDA0003677664240000052
Wherein R is 2 、R 24 、R 4 And R 5 As defined herein;
ring C is independently 5-8 membered heteroaryl, 4-8 membered heterocycloalkyl, or 4-8 membered heterocycloalkenyl.
In a preferred embodiment of the present invention, the compound is represented by formula (V) or formula (VI), a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof.
Figure BDA0003677664240000061
Wherein ring D is 6-10 membered aryl or C 3 -C 10 Cycloalkenyl radical, R 2 Is composed of
Figure BDA0003677664240000062
Ring B, R 4 、R 5 、R 21 、R 22 And R 24 Is defined as described in the present invention.
In a preferred embodiment of the present invention, when ring A is a 6-10 membered aryl group, said 6-10 membered aryl group is benzene or naphthalene, preferably benzene.
In a preferred embodiment of the invention, when ring a is a 5-8 membered heteroaryl, said 5-8 membered heteroaryl is pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl or triazinyl, preferably pyrrolyl, oxazolyl, thiazolyl or pyridyl.
In a preferred embodiment of the invention, when ring a is a 4-8 membered heterocycloalkyl, said 4-8 membered heterocycloalkyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, morpholinyl or piperazinyl, preferably azetidinyl, morpholinyl or morpholinyl.
In a preferred embodiment of the invention, when ring A is a 4-8 membered heterocycloalkenyl, said 4-8 membered heterocycloalkenyl is 4H-pyranyl, 2H-pyranyl, tetrahydropyridinyl, 2,5-dihydro-1H-pyrrolyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothienyl, 2,3-dihydrothienyl or 4,5-dihydrooxazolyl, preferably tetrahydropyridinyl.
In a preferred embodiment of the invention, when ring A is C 3 -C 10 Cycloalkenyl group, the C 3 -C 10 Cycloalkenyl is cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, preferably cyclohexenyl.
In a preferred embodiment of the invention, R 2 Is composed of
Figure BDA0003677664240000063
In a preferred embodiment of the invention, R 2 Is composed of
Figure BDA0003677664240000064
In a preferred embodiment of the invention, when R is 21 And R 22 Is unsubstituted or substituted by R 211 Substituted C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl, preferably methyl, ethyl, n-propyl or isobutyl.
In a preferred embodiment of the invention, when R is 21 And R 22 Is unsubstituted or substituted by R 211 Substituted C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl.
In a preferred embodiment of the invention, R 21 And R 22 Is as a quilt R 211 Substituted C 1 -C 6 Alkyl or by R 211 Substituted C 3 -C 6 When cycloalkyl is present, said R 211 The number of substitutions is 1,2,3,4 or 5, preferably 1 or 2.
In a preferred embodiment of the invention, R 211 Is a hydroxyl group.
In a preferred embodiment of the invention, when R is 211 When halogen is used, the halogen is F, cl, br or I, preferably F or Cl.
In a preferred embodiment of the invention, when R 211 is-O- (C) 1 -C 6 Alkyl) of said C 1 -C 6 The alkyl group is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, preferably a methyl group, an ethyl group, an n-propyl group or an isopropyl group.
In a preferred embodiment of the invention, when R is 211 is-O- (C) 1 -C 6 Alkyl radical) When said is-O- (C) 1 -C 6 Alkyl) is-O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl-O-n-butyl, -O-isobutyl, -O-sec-butyl or-O-tert-butyl, preferably-O-methyl, -O-ethyl, -O-n-propyl or-O-isopropyl.
In a preferred embodiment of the invention, when R is 211 Is C 1 -C 6 When there is an alkylamino group, C 1 -C 6 Alkylamino is-NHCH 3 、-N(CH 3 ) 2 、-NHCH 2 CH 3 、-N(CH 3 )CH 2 CH 3 、-NHCH 2 CH 2 CH 3 or-NHCH 2 (CH 3 ) 2 preferably-NHCH 3 、-N(CH 3 ) 2 or-NHCH 2 CH 3 。
In a preferred embodiment of the invention, when R is 211 Is C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl.
In a preferred embodiment of the invention, R 2 Is composed of
Figure BDA0003677664240000071
In a preferred embodiment of the invention, when ring B is unsubstituted or substituted with R 23 Substituted 4-8 membered heterocycloalkyl, said 4-8 membered heterocycloalkyl is aziridinyl, azetidinyl, azepinyl, azacyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl, preferably azetidinyl, azepinyl or morpholinyl.
In a preferred embodiment of the invention, when ring B is a 4-8 membered heterocycloalkyl, said 4-8 membered heterocycloalkyl is aziridinyl, azetidinyl, azepinyl, azacyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl, preferably azetidinyl, azepinyl or morpholinyl.
In a preferred embodiment of the invention, when ring B is unsubstituted or substituted with R 23 When substituted 6-11 membered hetero spiro cycloalkyl, the 6-11 membered hetero spiro cycloalkyl is preferably azaspiro [3.3]]Heptyl, oxaazaspiro [3.3]Heptyl, thiaazaspiro [3.3]]Heptyl or oxaspiro [5.3]]Nonyl, more preferably oxaazaspiro [3.3]]And a heptyl radical.
In a preferred embodiment of the present invention, when ring B is a 6-11 membered heterospirocycloalkyl group, said 6-11 membered heterospirocycloalkyl group is preferably an azaspiro [3.3] heptyl group, an oxaazaspiro [3.3] heptyl group, a thiaazaspiro [3.3] heptyl group or an oxaazaspiro [5.3] nonyl group, more preferably an oxaazaspiro [3.3] heptyl group.
In a preferred embodiment of the invention, ring B is substituted with R 23 Substituted 4-8 membered heterocycloalkyl or by R 23 When substituted 6-11 membered heterospirocycloalkyl, said R 23 The number of substitutions is 1,2,3,4 or 5, preferably 1 or 2.
In a preferred embodiment of the invention, R 23 Is a hydroxyl group.
In a preferred embodiment of the invention, R 23 Is a cyano group.
In a preferred embodiment of the invention, when R 23 When halogen is used, the halogen is F, cl, br or I, preferably F or Cl.
In a preferred embodiment of the invention, when R is 23 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl.
In a preferred embodiment of the invention, when R is 23 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 When alkyl, the halogen is F, cl, br or I, preferably F or Cl.
In a preferred embodiment of the invention, when R is 23 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 In the case of alkyl, the number of said halogen is 1,2,3,4 or 5, preferably 1,2Or 3.
In a preferred embodiment of the invention, when R is 23 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl.
In a preferred embodiment of the invention, when R is 23 Is C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl.
In a preferred embodiment of the invention, R 2 Is composed of
Figure BDA0003677664240000081
In a preferred embodiment of the invention, when R 24 Is unsubstituted or substituted by R 241 Substituted C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl.
In a preferred embodiment of the invention, when R is 24 Is unsubstituted or substituted by R 241 Substituted C 3 -C 6 When cycloalkyl is present, said R 241 The number of substitutions is 1,2,3,4 or 5, preferably 1 or 2.
In a preferred embodiment of the invention, R 241 Is cyano.
In a preferred embodiment of the invention, when R is 241 When halogen is present, the halogen is F, cl, br or I, preferably F or Cl.
In a preferred embodiment of the invention, when R 241 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl.
In a preferred embodiment of the invention, when R is 241 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 When the alkyl group is used, the alkyl group,the halogen is F, cl, br or I, preferably F or Cl.
In a preferred embodiment of the invention, when R is 241 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 In the case of alkyl, the number of the halogen is 1,2,3,4 or 5, preferably 1,2 or 3.
In a preferred embodiment of the invention, when R is 241 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl.
In a preferred embodiment of the invention, when R is 241 Is C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl.
In a preferred embodiment of the invention, n is 0,1 or 2.
In a preferred embodiment of the invention, when R is 3 When halogen is used, the halogen is F, cl, br or I, preferably F or Cl.
In a preferred embodiment of the invention, when R is 3 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl.
In a preferred embodiment of the invention, when R is 3 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 When alkyl, the halogen is F, cl, br or I, preferably F or Cl.
In a preferred embodiment of the invention, when R is 3 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 In the case of alkyl, the number of the halogen is 1,2,3,4 or 5, preferably 1,2 or 3.
In a preferred embodiment of the invention, when R is 3 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl isMethyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl.
In a preferred embodiment of the invention, when R is 4 And R 5 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl.
In a preferred embodiment of the invention, when R is 4 And R 5 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl.
In a preferred embodiment of the invention, when R is 4 And R 5 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 When alkyl, the halogen is F, cl, br or I, preferably F or Cl.
In a preferred embodiment of the invention, when R is 4 And R 5 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 In the case of alkyl, the number of the halogen is 1,2,3,4 or 5, preferably 1,2 or 3.
In a preferred embodiment of the invention, R 4 And R 5 When the carbon atoms to which they are both attached form a 4-8 membered heterocycloalkyl, said 4-8 membered heterocycloalkyl is aziridinyl, oxetanyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, preferably oxetanyl.
In a preferred embodiment of the present invention,
Figure BDA0003677664240000101
is composed of
Figure BDA0003677664240000102
Figure BDA0003677664240000103
Preferably is
Figure BDA0003677664240000104
Figure BDA0003677664240000105
In a preferred embodiment of the present invention,
Figure BDA0003677664240000106
is composed of
Figure BDA0003677664240000107
Figure BDA0003677664240000108
Preferably is
Figure BDA0003677664240000109
Figure BDA00036776642400001010
In a preferred embodiment of the present invention,
Figure BDA00036776642400001011
is composed of
Figure BDA00036776642400001012
Figure BDA00036776642400001013
Preferably is
Figure BDA00036776642400001014
In a preferred embodiment of the invention, R 1 Is H.
In a preferred embodiment of the present invention,
Figure BDA0003677664240000111
is composed of
Figure BDA0003677664240000112
In a preferred embodiment of the invention, R 2 Is composed of
Figure BDA0003677664240000113
In a preferred embodiment of the invention, when R is 2 Is composed of
Figure BDA0003677664240000114
When it is in use, the
Figure BDA0003677664240000115
Is composed of
Figure BDA0003677664240000116
Figure BDA0003677664240000117
In a preferred embodiment of the invention, when R is 2 Is composed of
Figure BDA0003677664240000118
When is in use, the
Figure BDA0003677664240000119
Is composed of
Figure BDA00036776642400001110
Figure BDA00036776642400001111
In a preferred embodiment of the invention, when R is 2 Is composed of
Figure BDA00036776642400001112
When is in use, the
Figure BDA00036776642400001113
Is composed of
Figure BDA00036776642400001114
Figure BDA00036776642400001115
In a preferred embodiment of the invention, when R is 2 Is composed of
Figure BDA0003677664240000121
When is in use, the
Figure BDA0003677664240000122
Is composed of
Figure BDA0003677664240000123
In a preferred embodiment of the invention, when R 2 Is composed of
Figure BDA0003677664240000124
When is in use, the
Figure BDA0003677664240000125
Is composed of
Figure BDA0003677664240000126
In a preferred embodiment of the invention, when R is 2 Is composed of
Figure BDA0003677664240000127
When is in use, the
Figure BDA0003677664240000128
Is composed of
Figure BDA0003677664240000129
In a preferred embodiment of the invention, R 4 And R 5 Is methyl.
In a preferred embodiment of the invention, R 4 And R 5 The heterocyclic ring formed by the carbon atoms to which they are both attached is
Figure BDA00036776642400001210
In a preferred embodiment of the present invention, the compound has a structure as shown in formula III, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:
Figure BDA00036776642400001211
R 2 independently is
Figure BDA00036776642400001212
R 21 And R 22 Each independently of the other being unsubstituted or substituted by R 211 Substituted C 1 -C 6 Alkyl, or, unsubstituted or substituted by R 211 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 211 Substituted C 1 -C 6 Alkyl or by R 211 Substituted C 3 -C 6 In the cycloalkyl group, the R is 211 The substitution may be one or more, and R is 211 Each independently is the following substituent: hydroxy, halogen, -O- (C) 1 -C 6 Alkyl group), C 1 -C 6 Alkylamino or C 3 -C 6 A cycloalkyl group; when the number of the substituents is plural, the substituents may be the same or different; the R is 21 And R 22 At least one is represented by R 211 Substituted C 1 -C 6 Alkyl or by R 211 Substituted C 3 -C 6 A cycloalkyl group;
ring B is independently unsubstituted or substituted with R 23 Substituted 4-8 membered heterocycloalkyl, or, unsubstituted or substituted by R 23 A substituted 6-11 membered hetero spirocycloalkyl group; the quilt R 23 Substituted 4-8 membered heterocycloalkyl or by R 23 In the substituted 6-to 11-membered heterospirocycloalkyl group, said R 23 The substitution may be one or more, R 23 Each independently is the following substituent: hydroxy, cyano, halogen, C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group; when the number of the substituents is plural, the substituents may be the same or different;
R 4 and R 5 Each independently being C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl or C 1 -C 6 An alkyl group; or R 4 And R 5 The carbon atoms to which they are commonly attached may form a 4-8 membered heterocyclic ring.
In a preferred embodiment of the present invention, the compound has a structure shown in formula IV, and the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof is:
Figure BDA0003677664240000131
ring C is independently 4-8 membered heterocycloalkenyl;
R 24 independently is unsubstituted or substituted by R 241 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 241 Substituted C 3 -C 6 In the cycloalkyl group, the R is 241 The substitution may be one or more, R 241 Each independently is the following substituent: cyano, halogen, C substituted by 1-5 halogen, the same or different 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group; when the number of the substituents is plural, the substituents may be the same or different;
R 4 and R 5 Each independently being C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl or C 1 -C 6 An alkyl group; or R 4 And R 5 The carbon atoms to which they are commonly attached may form a 4-8 membered heterocyclic ring.
In a preferred embodiment of the present invention, the compound has a structure shown in formula II, and the tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof is:
Figure BDA0003677664240000132
ring A is independently C 3 -C 10 A cycloalkenyl group;
R 2 independently is
Figure BDA0003677664240000133
R 21 And R 22 Each independently of the other is unsubstituted or substituted by R 211 Substituted C 1 -C 6 Alkyl, or, unsubstituted or substituted by R 211 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 211 Substituted C 1 -C 6 Alkyl or by R 211 Substituted C 3 -C 6 In the cycloalkyl group, the R is 211 The substitution may be one or more, and R is 211 Each independently is the following substituent: hydroxy, halogen, -O- (C) 1 -C 6 Alkyl group), C 1 -C 6 Alkylamino or C 3 -C 6 A cycloalkyl group; when the number of the substituents is plural, the substituents may be the same or different; the R is 21 And R 22 At least one is represented by R 211 Substituted C 1 -C 6 Alkyl or by R 211 Substituted C 3 -C 6 A cycloalkyl group;
ring B is independently unsubstituted or substituted with R 23 Substituted 4-8 membered heterocycloalkyl, or, unsubstituted or substituted by R 23 A substituted 6-11 membered hetero spirocycloalkyl group; the quilt R 23 Substituted 4-8 membered heterocycloalkyl or by R 23 In the substituted 6-to 11-membered heterospirocycloalkyl group, said R 23 The substitution may be one or more, R 23 Each independently is the following substituent: hydroxy, cyano, halogen, C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group; when the number of the substituents is plural, the substituents may be the same or different;
R 4 and R 5 Each independently of the other is C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl or C 1 -C 6 An alkyl group; or R 4 And R 5 The carbon atoms to which they are commonly attached may form a 4-8 membered heterocyclic ring.
In a preferred embodiment of the invention, the compound is represented by formula V, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof,
Figure BDA0003677664240000141
wherein ring D is 6-10 membered aryl or C 3 -C 10 Cycloalkenyl radical, R 2 Is composed of
Figure BDA0003677664240000142
Ring B is independently unsubstituted or substituted with R 23 Substituted 4-8 membered heterocycloalkyl, or, unsubstituted or substituted by R 23 A substituted 6-11 membered hetero spirocycloalkyl group; the quilt R 23 Substituted 4-8 membered heterocycloalkyl or by R 23 In the substituted 6-to 11-membered heterospirocycloalkyl group, said R 23 The substitution may be one or more, R 23 Each independently is the following substituent: hydroxy, cyano, halogen, C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group; when the number of the substituents is plural, the substituents may be the same or different;
R 21 and R 22 Each independently of the other being unsubstituted or substituted by R 211 Substituted C 1 -C 6 Alkyl, or unsubstituted or substituted by R 211 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 211 Substituted C 1 -C 6 Alkyl or by R 211 Substituted C 3 -C 6 In the cycloalkyl group, said R 211 The substitution can be one or more, and R is 211 Each independently is the following substituent:hydroxy, halogen, -O- (C) 1 -C 6 Alkyl group), C 1 -C 6 Alkylamino or C 3 -C 6 A cycloalkyl group; when the number of the substituents is plural, the substituents may be the same or different; the R is 21 And R 22 At least one is represented by R 211 Substituted C 1 -C 6 Alkyl or by R 211 Substituted C 3 -C 6 A cycloalkyl group;
R 24 independently is unsubstituted or substituted by R 241 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 241 Substituted C 3 -C 6 In the cycloalkyl group, the R is 241 The substitution may be one or more, R 241 Each independently is the following substituent: cyano, halogen, C substituted by 1-5 identical or different halogens 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group; when the number of the substituents is plural, the substituents may be the same or different;
R 4 and R 5 Each independently being C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl or C 1 -C 6 An alkyl group; or R 4 And R 5 The carbon atoms to which they are commonly attached may form a 4-8 membered cycloalkyl or 4-8 membered heterocycloalkyl group.
In a preferred embodiment of the invention, the compound is represented by formula VI, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug,
Figure BDA0003677664240000151
R 4 and R 5 Each independently being C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl or C 1 -C 6 An alkyl group; or R 4 And R 5 The carbon atoms to which they are commonly attached may form a 4-8 membered cycloalkyl or 4-8 membered heterocycloalkyl group.
In a preferred embodiment of the invention, the compound is a compound having a structure shown in formula V-1 or V-2, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof,
Figure BDA0003677664240000152
wherein R is 21 And R 22 Each independently of the other being unsubstituted or substituted by R 211 Substituted C 1 -C 6 An alkyl group;
ring D is 6-10 membered aryl or C 3 -C 10 A cycloalkenyl group;
ring B is independently unsubstituted or substituted with R 23 Substituted 4-8 membered heterocycloalkyl, or, unsubstituted or substituted by R 23 A substituted 6-11 membered hetero spirocycloalkyl group; the quilt R 23 Substituted 4-8 membered heterocycloalkyl or by R 23 In the substituted 6-to 11-membered heterospirocycloalkyl group, said R 23 The substitution may be one or more, R 23 Each independently is the following substituent: hydroxy, cyano, halogen, C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group; when the number of the substituents is plural, the substituents may be the same or different;
R 4 and R 5 Each independently being C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl or C 1 -C 6 An alkyl group; or R 4 And R 5 The carbon atoms to which they are commonly attached may form a 4-8 membered cycloalkyl group or a 4-8 membered heterocycloalkyl group.
In a preferred embodiment of the invention, the compound is of the formula V-1a, V-1b, V-2a or V-2b, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0003677664240000161
wherein, the first and the second end of the pipe are connected with each other,R 21 and R 22 Each independently of the other being unsubstituted or substituted by R 211 Substituted C 1 -C 6 An alkyl group;
R 41 and R 51 Each independently being C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl or C 1 -C 6 An alkyl group;
ring E is 4-8 membered cycloalkyl or 4-8 membered heterocycloalkyl;
ring D is 6-10 membered aryl or C 3 -C 10 A cycloalkenyl group;
ring B is independently unsubstituted or substituted with R 23 Substituted 4-8 membered heterocycloalkyl, or unsubstituted or substituted by R 23 A substituted 6-11 membered hetero spirocycloalkyl group; the quilt R 23 Substituted 4-8 membered heterocycloalkyl or by R 23 In the substituted 6-to 11-membered heterospirocycloalkyl group, said R 23 The substitution may be one or more, R 23 Each independently is the following substituent: hydroxy, cyano, halogen, C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group; when the substituent is plural, the substituents may be the same or different.
In a preferred embodiment of the present invention, the compound has the structure shown below, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:
Figure BDA0003677664240000171
in a second aspect of the present invention, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable excipient.
According to a specific embodiment of the present invention, the pharmaceutical composition of the present invention may include a therapeutically effective amount of the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier, diluent or excipient mixed to prepare a pharmaceutical preparation suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulations may be administered by any route, for example by infusion or bolus injection, by a route of absorption through epithelial or cutaneous mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of the formulation for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulation.
In a third aspect of the present invention, the present invention provides the use of the above compound, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, in combination with an antibody against PD-1/PD-L1/CTLA-4 or an inhibitor of PD-1/PD-L1/CTLA-4, for the manufacture of a medicament for the treatment or prevention of diseases associated with HPK1, which medicament is useful for the treatment or prevention of solid tumors, hematological cancers, non-small cell lung cancer, cutaneous melanoma, merkel cell carcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the anal canal or skin, urothelial carcinoma, clear cell or non-clear cell renal cell carcinoma, triple negative breast cancer, endometrial cancer, cervical cancer, gastroesophageal cancer or hepatocellular carcinoma.
In a fourth aspect of the present invention, the present invention provides a use of the above compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the above pharmaceutical composition for preparing a medicament for treating or preventing HPK 1-related diseases.
According to a specific embodiment of the present invention, the above compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the above pharmaceutical composition is used for preparing a medicament for treating or preventing diseases related to HPK1, wherein the medicament is used for treating solid tumors, hematological cancers, non-small cell lung cancer, skin melanoma, merkel cell carcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the anal canal or skin, urothelial cancer, clear cell or non-clear cell renal cell carcinoma, triple negative breast cancer, endometrial cancer, cervical cancer, gastroesophageal cancer or hepatocellular carcinoma.
Terms and definitions
Unless otherwise indicated, the terms and definitions used in the present application, including in the specification and claims of the present application, are as follows.
It will be understood by those skilled in the art that, according to the convention used in the art, in the structural formulae of the present application,
Figure BDA0003677664240000181
for delineation of chemical bonds, which are the points where moieties or substituents are attached to the core structure or the backbone structure.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
In addition to pharmaceutically acceptable salts, other salts are also contemplated by the present invention. They may serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the invention.
The term "pharmaceutical composition" denotes a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.
The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of classes of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients enhance the handling characteristics of the pharmaceutical formulation, i.e., make the formulation more amenable to direct compression by increasing flowability and/or cohesiveness.
The term "prodrug" refers to a compound of the invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds, which modifications may be routinely made or removed in vivo to provide the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy or amino group is attached to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxy or a free amino group, respectively.
The term "stereoisomer" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformers.
Depending on the choice of starting materials and process, the compounds according to the invention may be present as one of the possible isomers or as a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, for example as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50. Many geometric isomers of olefins, C = N double bonds, and the like, may also be present in the compounds described herein, and all such stable isomers are contemplated herein. When compounds described herein contain olefinic double bonds, such double bonds include both E and Z geometric isomers, unless otherwise specified. If the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may be in the cis or trans (cis-or trans-) configuration.
When the bond to a chiral carbon in the formula of the invention is depicted as a direct line, it is to be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are encompassed within the formula. The illustrations of racemic or enantiomerically pure compounds herein are from Maehr, j.chem.ed.1985, 62. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by wedge bonds and dashed bonds.
Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. The compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active salt-forming organic acids. Suitable resolving agents for use in the fractional recrystallization process are, for example, the D and L forms of optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids, such as β -camphorsulfonic acid. Other resolving agents suitable for fractional crystallization processes include stereoisomerically pure forms of α -methyl-benzylamine (e.g., S and R forms or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of the racemic mixture can also be carried out by elution on a chromatographic column packed with an optically active resolving agent (e.g. dinitrobenzoylphenylglycine). The method can be performed by High Performance Liquid Chromatography (HPLC) or Supercritical Fluid Chromatography (SFC). The choice of the particular method and the conditions of elution, the choice of the chromatography column can be selected by the person skilled in the art according to the structure of the compound and the results of the test. Further, any enantiomer or diastereomer of the compounds described herein may also be obtained by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.
The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in a molecule at two positions. The compounds of the invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; whereas in phenol the enol type predominates. The present invention encompasses all tautomeric forms of the compounds.
The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioisotopes, such as deuterium (g) ((R)) 2 H) Tritium (A) 3 H) Iodine-125 ( 125 I) Or C-14 ( 14 C) In that respect All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, including deuterium and hydrogen variants, so long as the valency of the particular atom is normal and the substituted compound is stable. When the substituent is keto (i.e = O), it means that two hydrogen atoms are substituted. The keto substitution does not occur on the aromatic group. The term "optionally substituted" means that it may or may not be substituted and, unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical feasibility.
Prefix "C u- C v "means that the following groups have from u to v carbon atoms. For example, "C 1- C 6 Alkyl "means that the alkyl has 1 to 6 carbon atoms.
The term "C 1 -C 6 Alkyl "is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1,2,3,4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof. In particular, the radicals have 1,2 or 3 carbon atoms ("C) 1 -C 3 Alkyl groups) such as methyl, ethyl, n-propyl or isopropyl.
The term "-O- (C) 1 -C 6 Alkyl) "is understood to mean that the alkyl radical is bonded to the rest of the molecule via an oxygen atom, where" C "is 1 -C 6 Alkyl "has the above definition. Such as-O- (methyl), -O- (ethyl).
The term "C 1 -C 6 Alkylamino "refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an amino group. Said C is 1 -C 6 Examples of alkylamino include, but are not limited to, -NHCH 3 、-N(CH 3 ) 2 、-NHCH 2 CH 3 、-N(CH 3 )CH 2 CH 3 、-N(CH 2 CH 3 )(CH 2 CH 3 )、-NHCH 2 CH 2 CH 3 、-NHCH 2 (CH 3 ) 2 、-NHCH 2 CH 2 CH 2 CH 3 And the like.
The term "C 3 -C 6 Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
The term "C 3 -C 10 Cycloalkenyl refers to a monovalent monocyclic hydrocarbon ring which contains one double bond and which contains 3,4, 5,6, 7, 8, 9 or 10 carbon atoms ("C) 3 -C 10 -cycloalkenyl "). Said C is 3 -C 10 Cycloalkenyl is, for example, a monocyclic hydrocarbon ring, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl. In particular, the cycloalkenyl group contains 5,6 or 7 carbon atoms ("C) 5 -C 7 -cycloalkenyl ") and is, for example, cyclopentenyl, cyclohexenyl or cycloheptenyl.
The terms "4-8 membered heterocyclyl", "4-8 membered heterocycle" or "4-8 membered heterocycloalkyl" are understood to mean a saturated monocyclic, bicyclic or tricyclic ring having 4 to 8 atoms, wherein 1,2,3,4 or 5 ring atoms are selected from N, O and S, which may be attached through carbon or nitrogen, unless otherwise specified, wherein-CH is 2- The radical is optionally replaced by-C (O) -; and wherein, unless otherwise indicated to the contraryIt is stated that the ring nitrogen or sulfur atoms are optionally oxidized to form N-oxides or S-oxides or the ring nitrogen atoms are optionally quaternized; wherein-NH in the ring is optionally substituted with acetyl, formyl, methyl or methanesulfonyl; and the ring is optionally substituted with one or more halogens. It is understood that when the total number of S and O atoms in the heterocyclic group exceeds 1, these heteroatoms are not adjacent to each other. If the heterocyclyl is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclic group is monocyclic, it is not necessarily aromatic. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indolinyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one, and 2,5-dioxoimidazolidinyl.
The term "4-8 membered heterocycloalkenyl" is to be understood as a non-aromatic mono-or polycyclic group containing 4 to 8 ring atoms, preferably 5 to 6 ring atoms, wherein the 4-8 membered heterocycloalkenyl comprises 1 to 3 heteroatoms selected from N, O, S and P and contains at least one carbon-carbon double bond or carbon-nitrogen double bond. An aza, oxa or thia comprised in the group name means that at least one nitrogen, oxygen or sulfur atom respectively is a ring atom. The nitrogen or sulfur atom of the 4-8 membered heterocycloalkenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S-dioxide. Preferred 4-8 membered heterocycloalkenyl groups include, but are not limited to, 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, oxides thereof, and the like. "4-8 membered heterocycloalkenyl" can also include two available hydrogen atoms on the same carbon atom of the ring simultaneously substituted with a single group = O (i.e. forming a carbonyl group).
The term "6-to 10-membered aryl" is to be understood as meaning a monovalent radical having 6 to 10 carbon atoms, at least one ring having an aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring, in particular having 6 carbon atoms ("C) 6 Aryl "), such as phenyl; when the 6-to 10-membered aryl group is substituted, it may be mono-or poly-substituted. And, the substitution site thereof is not limited, and may be, for example, ortho-, para-or meta-substitution.
The term "6-11 membered heterospirocycloalkyl" refers to a bicyclic saturated heterocyclic ring having a total of 6, 7, 8, 9, 10 or 11 ring atoms, wherein both rings share a common ring carbon atom, said-heterospirocycloalkyl "containing one or two identical or different ring heteroatoms or heteroatom-containing groups selected from: n, NH, O, S, SO and SO 2 (ii) a The hetero-spirocycloalkyl group may be attached to the rest of the molecule through any one of the carbon atoms (other than the spiro carbon atom) or (if present) the nitrogen atom. Said heterospirocycloalkyl is for example azaspiro [2.3 ]]Hexyl, azaspiro [3.3]Heptyl, oxaazaspiro [3.3]Heptyl, thiaazaspiro [3.3]]Heptyl, oxaspiro [3.3]]Heptyl, oxaazaspiro [5.3]]Nonyl, oxaazaspiro [4.3 ]]Octyl, azaspiro [4,5]Decyl, oxaazaspiro [5.5 ]]Undecyl, diazaspiro [3.3]Heptyl, thiaazaspiro [3.3]]Heptyl, thiaazaspiro [4.3 ]]Octyl, or one of the skeletons of other homologues, e.g. spiro [3.4 ]]-, spiro [4.4]-, spiro [2.4 ]]-, spiro [2.5 ]]-, spiro [2.6 ]]-, spiro [3.5]-, spiro [3.6]-and spiro [4.5 ]]-。
The term "5-8 membered heteroaryl" is to be understood as a monovalent monocyclic, bicyclic or tricyclic aromatic ring group having 5-8 ring atoms, in particular 5 or 6 ring atoms, and comprising 1-5 heteroatoms independently selected from N, O and S. Preferably 1 to 3 heteroatoms independently selected from N, O and S, and, in addition, a case where a ring having an aromatic property is fused with a non-aromatic ring. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.
The term "halo" or "halogen" is fluorine, chlorine, bromine and iodine.
In addition, it should be noted that, unless otherwise explicitly indicated, the description of "… … independently" as used in the present invention is to be understood broadly to mean that the individual entities described are independent of each other and may be independently the same or different specific groups. In more detail, the description "… … independently" can mean that the specific options expressed between the same symbols do not affect each other in different groups, or that the specific options expressed between the same symbols do not affect each other in the same groups.
Advantageous effects
According to the embodiment of the invention, the invention has at least one of the following technical effects:
1) Provided is an HPK1 inhibitor which has a novel structure, excellent pharmacokinetic properties, and good drug efficacy or drug success, and which can be used for effectively treating or preventing HPK 1-related diseases and disorders.
2) According to the embodiment of the invention, in an in vitro enzyme test, the compound has a good inhibition effect on the HPK1 enzyme, and the inhibition activity is obviously better than that of a control compound, while in a cell test, the compound also has a good inhibition effect on the HPK1 enzyme, and the inhibition activity is obviously better than that of the control compound.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples do not specify particular techniques or conditions, and are performed according to techniques or conditions described in literature in the art or according to the product specification. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Unless otherwise specified, the compounds of the invention are structurally defined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). NMR shift in units of 10 -6 (ppm). Solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol and the like, and internal standard is Tetramethylsilane (TMS).
Abbreviations of the present invention are defined as follows:
m: molar concentration, e.g. 1M hydrochloric acid for 1mol/L hydrochloric acid solution
DCM: methylene dichloride
DMF: n, N-dimethylformamide
DMSO (dimethylsulfoxide): dimethyl sulfoxide
HEPES (high efficiency particulate air): (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid)
LC-MS: liquid chromatography-mass spectrometry
IC 50 : the median inhibitory concentration refers to the concentration at which half of the maximal inhibitory effect is achieved.
Test example 1: preparation of control Compound 1
5- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrole [2,3-b ] pyridin-3-yl) -2-isopropoxybenzonitrile (control compound 1)
Figure BDA0003677664240000241
Refer to patent WO 2019016071A.
1 H NMR(400MHz,CDCl 3 )δ9.25(br s,1H),8.19(d,J＝5.2Hz,1H),7.91-7.90(m,1H),7.85-7.83(m,1H),731(s,1H),7.09-7.07(m,2H),7.02-6.99(m,1H),6.34(d,J＝5.6Hz,1H),4.70-4.66(m,1H),4.19(s,2H),3.29(s,2H),1.45(s,3H),1.43(s,3H),1.20(s,6H).
LC-MS,M/Z(ESI):532.2[M+H] + 。
The "control Compound 1" described below refers to the compound described in test example 1.
Preparation example 1: intermediate A1
Synthesis of N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-amine (A1)
Figure BDA0003677664240000251
The synthetic route is as follows:
Figure BDA0003677664240000252
the first step is as follows: synthesis of 4- (2,6-difluoro-4-nitrophenoxy) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003677664240000253
To a solution of 4-hydroxy-7-azaindole (10g, 74.6mmol) in dimethyl sulfoxide (100 mL) at 25 ℃ was added K 2 CO 3 (20.61g, 149mmol). The reaction mixture was stirred at 25 ℃ for 10 minutes. 1,2,3-trifluoro-5-nitrobenzene (15.84g, 89mmol) was then added portionwise to the reaction solution. The reaction mixture was stirred at 25 ℃ for 2 hours. The reaction was poured slowly into 500mL of ice-water mixture. The mixture was extracted with ethyl acetate (100 mL. Times.3). Collecting the organic phase with anhydrous Na 2 SO 4 Drying, then filtering, and concentrating the filtrate to obtain a crude product. The crude product was isolated and purified by silica gel column (petroleum ether: ethyl acetate =10, 1-3:1) to give 4- (2,6-difluoro-4-nitrophenoxy) -1H-pyrrolo [2,3-b]Pyridine (12 g, 55.3% yield).
The second step is that: synthesis of 4- (2,6-difluoro-4-nitrophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003677664240000261
To a solution of 4- (2,6-difluoro-4-nitrophenoxy) -1H-pyrrolo [2,3-b ] pyridine (12g, 41.2mmol) in MeCN (20 mL) at 25 deg.C were added N, N-diisopropylethylamine (9.59g, 74.2mmol) and 2- (chloromethoxy) ethyltrimethoxysilane (9.62g, 57.7 mmol). The reaction mixture was stirred at 25 ℃ for 18 hours. The reaction mixture was concentrated to give crude. The crude product was purified by silica gel column separation (petroleum ether: ethyl acetate =100: 1-5:1) to give 4- (2,6-difluoro-4-nitrophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine as a yellow oil (15 g, 86% yield).
The third step: synthesis of 4- (2,6-difluoro-4-nitrophenoxy) -3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003677664240000262
To 4- (2,6-difluoro-4-nitrophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b at 25 deg.C]To a solution of pyridine (15g, 35.6 mmol) in DMF (150 mL) was added N-iodosuccinimide (8.81g, 39.1mmol). The reaction mixture was stirred at 25 ℃ for 18 hours. The reaction was poured slowly into 500mL of ice-water mixture. The mixture was extracted with ethyl acetate (100 mL. Times.3). The organic phases were combined and washed with saturated brine (100 mL). Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified by silica gel column (petroleum ether: ethyl acetate =100: 1-5:1) to give 4- (2,6-difluoro-4-nitrophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridine (15 g, 77% yield).
The fourth step: synthesis of 3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) aniline
Figure BDA0003677664240000263
At 80 deg.C, 4- (2,6-difluoro)-4-Nitrophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Ammonium chloride (2.93g, 54.8mmol) and iron powder (3.06g, 54.8mmol) were added in portions to a mixed solvent of pyridine (5g, 9.13mmol) in ethanol (50 mL) and water (5.00 mL). The reaction mixture was stirred at 80 ℃ for 3 hours. The reaction was cooled to room temperature, filtered through celite, and the filter cake rinsed with 50mL of ethanol. The filtrate was concentrated to give a crude product, to which ethyl acetate (100 mL) and water (50 mL) were added, the organic and aqueous phases were separated, and the aqueous phase was extracted with ethyl acetate (50 mL. Times.3). Collecting organic phase, and adding anhydrous Na 2 SO 4 Filtered and concentrated to give crude 3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b)]Pyridin-4-yl) oxy) aniline was used directly in the next reaction.
The fifth step: synthesis of o-phenyl (3,5-difluoro-4- ((3-iodo-1- (((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) thiocarbamate
Figure BDA0003677664240000271
Crude 3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b) from the previous step is reacted at 0 deg.C]Pyridin-4-yl) oxy) aniline was dissolved in tetrahydrofuran (50 mL), pyridine (7.39mL, 1mmol) was then added to the reaction solution, and phenyl thiocarbamate (2.367g, 13.71mmol) was then slowly added dropwise to the reaction solution. The reaction solution was stirred at 0 ℃ for 5 hours. After completion of the reaction, methylene chloride (100 mL) was added to the reaction mixture, and the organic phase was washed with water (100 mL. Times.3). Collecting the organic phase with anhydrous Na 2 SO 4 Filtering, and concentrating to obtain crude o-phenyl (3,5-difluoro-4- ((3-iodo-1- (((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b)]Pyridin-4-yl) oxy) phenyl) thiocarbamate was used directly in the next reaction.
And a sixth step: synthesis of 1- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -3- (3-hydroxy-2,2-dimethylpropyl) thiourea
Figure BDA0003677664240000272
Half of the crude product from the previous step was dissolved in DMF (30 mL) at 25 ℃ and 3-amino-2,2-dimethylpropan-1-ol (0.916g, 8.87mmol) was added to the reaction. The reaction solution was heated to 60 ℃ and stirred for 2 hours. After completion of the reaction, the reaction mixture was slowly poured into 150mL of an ice-water mixture, the mixture was extracted with ethyl acetate (80 mL. Times.3), the organic phase was collected, washed with saturated brine, and then with anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified by silica gel column (petroleum ether: ethyl acetate =100: 1-0:1) to give crude yellow solid 1- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-4-yl) oxy) phenyl) -3- (3-hydroxy-2,2-dimethylpropyl) thiourea (2.8 g).
The seventh step: synthesis of N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-amine (A1)
Figure BDA0003677664240000281
To a solution of crude 1- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -3- (3-hydroxy-2,2-dimethylpropyl) thiourea (2.8 g) in acetonitrile (30 mL) at 25 deg.C was added triethylamine (0.88mL, 6.34mmol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (1.620g, 8.45mmol). The reaction mixture was stirred at 50 ℃ for 18 hours. After the reaction is finished, concentrating and spin-drying the reaction solution to obtain a crude product. The crude product was purified by silica gel column separation (petroleum ether: ethyl acetate =100: 1-0:1) to give crude N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-amine (A1) (1.0g, 1.591mmol) as a yellow solid.
Preparation example 2: intermediate A2
Synthesis of N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -2,6-dioxa-8-azaspiro [3.5] non-7-en-7-amine (A2)
Figure BDA0003677664240000282
The synthetic route is as follows:
Figure BDA0003677664240000283
the first step is as follows: synthesis of 1- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -3- ((3- (hydroxymethyl) oxetan-3-yl) methyl) thiourea
Figure BDA0003677664240000291
Half of the crude product from the previous step was dissolved in DMF (30 mL) at 25 deg.C, and (3- (aminomethyl) oxetan-3-yl) methanolate hydrochloride (1.401g, 9.12mmol) and triethylamine (1.271mL, 9.12mmol) were added to the reaction mixture. The reaction solution was heated to 60 ℃ and stirred for 6 hours. After completion of the reaction, the reaction mixture was slowly poured into 150mL of an ice-water mixture, the mixture was extracted with ethyl acetate (80 mL. Times.3), the organic phase was collected, washed with saturated brine, and then with anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude was purified by silica gel column separation (petroleum ether: ethyl acetate =100: 1-0:1) to give crude yellow solid 1- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-4-yl) oxy) phenyl) -3- ((3- (hydroxymethyl) oxetan-3-yl) methyl) thiourea (2.7 g).
The second step is that: synthesis of methyl-N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -N' - ((3- (hydroxymethyl) oxoalk-3-yl) methyl) carbamoylthio ester
Figure BDA0003677664240000292
To a solution of 1- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -3- ((3- (hydroxymethyl) oxetan-3-yl) methyl) thiourea (2.7 g, 3.99mmol) in acetone (30 ml) at 25 ℃ were added N-ethyl-N-diisopropyl-2-amine (2.321g, 17.96mmol) and iodomethane (2.266g, 15.96mmol). The reaction mixture was stirred under sealed conditions at 55 ℃ for 3 hours. The reaction mixture was concentrated to give crude methyl-N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridin-4-yl) oxy) phenyl) -N' - ((3- (hydroxymethyl) oxoalk-3-yl) methyl) carbamoylthio ester as a yellow solid which was used directly in the next reaction.
The third step: synthesis of N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -2,6-dioxa-8-azaspiro [3.5] non-7-en-7-amine (A2)
Figure BDA0003677664240000293
NaOH (0.398g, 9.96mmol) was added to a solution of crude methyl-N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridin-4-yl) oxy) phenyl) -N' - ((3- (hydroxymethyl) oxoalk-3-yl) methyl) carbamoylthio ester obtained in the previous step in tetrahydrofuran (30 mL) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 5 hours. After completion of the reaction, the reaction mixture was diluted with 50mL of water, and the mixture was extracted with ethyl acetate (30 mL. Times.3). The collected organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column separation (petroleum ether: ethyl acetate =100: 1-0:1) to give crude N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -2,6-dioxa-8-azaspiro [3.5] non-7-en-7-amine (A2) (1.1 g) as a yellow solid.
Preparation example 3: intermediate A3
N- (4- ((3-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -3,5-difluorophenyl) -5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-amine
Figure BDA0003677664240000301
The synthesis method refers to the synthesis of A1, and the bromination reagent is N-bromosuccinimide.
Example 1: preparation of target Compound I-1
4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (object compound I-1)
Figure BDA0003677664240000302
The route of the target compound I-1 is shown as follows:
Figure BDA0003677664240000311
the first step is as follows: synthesis of 4-bromo-N- (3-methoxypropyl) -N-methylbenzamide
Figure BDA0003677664240000321
To a solution of 4-bromobenzoic acid (2g, 9.95mmol) in dichloromethane (30 mL) was added O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (5.67g, 14.92mmol) and N, N-diisopropylethylamine (4.34ml, 24.87mmol) at 0 deg.C under nitrogen. The reaction mixture was stirred at 0 ℃ under nitrogen for 0.5 h. Then, 3-methoxy-N-methyl-1-propylamine hydrochloride (1.528g, 10.94mmol) was added in portions to the reaction liquid. The reaction mixture was stirred at 25 ℃ for 18 hours under nitrogen. After completion of the reaction, the reaction mixture was poured into an ice-water mixture (50 mL). The mixture was extracted with ethyl acetate (50 mL. Times.3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was isolated and purified by silica gel column (petroleum ether: ethyl acetate =20: 1-5:1) to give 4-bromo-N- (3-methoxypropyl) -N-methylbenzamide as a yellow oil (2.4 g, 84% yield).
The second step is that: synthesis of N- (3-methoxypropyl) -N-methyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide
Figure BDA0003677664240000322
To a solution of 4-bromo-N- (3-methoxypropyl) -N-methylbenzamide (1g, 3.49mmol), bis-pinacol boronate (1.331g, 5.24mmol) in 1,4-dioxane (10 ml) was added anhydrous potassium acetate (0.686g, 6.99mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.256g, 0.349mmol) under nitrogen protection at 25 ℃. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to dryness to give crude product. The crude product was isolated and purified by silica gel column (petroleum ether: ethyl acetate =10: 1-1:1) to give N- (3-methoxypropyl) -N-methyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide as a brown oil (1.1 g, 94% yield).
The third step: synthesis of 4- (2,6-difluoro-4-nitrophenoxy) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003677664240000323
To a solution of 4-hydroxy-7-azaindole (10g, 74.6mmol) in dimethyl sulfoxide (100 mL) at 25 ℃ was added K 2 CO 3 (20.61g, 149mmol). The reaction mixture was stirred at 25 ℃ for 10 minutes. 1,2,3-trifluoro-5-nitrobenzene (15.84g, 89mmol) was then added portionwise to the reaction solution. The reaction mixture was stirred at 25 ℃ for 2 hours. Reacting the reaction solutionPoured slowly into 500mL of ice-water mixture. The mixture was extracted with ethyl acetate (100 mL. Times.3). Collecting the organic phase with anhydrous Na 2 SO 4 Drying, then filtering, and concentrating the filtrate to obtain a crude product. The crude product was purified by silica gel column separation (petroleum ether: ethyl acetate =10, 1-3:1) to give 4- (2,6-difluoro-4-nitrophenoxy) -1H-pyrrolo [2,3-b]Pyridine (12 g, 55.3% yield).
The fourth step: synthesis of 4- (2,6-difluoro-4-nitrophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003677664240000331
To a solution of 4- (2,6-difluoro-4-nitrophenoxy) -1H-pyrrolo [2,3-b ] pyridine (12g, 41.2mmol) in MeCN (20 mL) at 25 deg.C were added N, N-diisopropylethylamine (9.59g, 74.2mmol) and 2- (chloromethoxy) ethyltrimethoxysilane (9.62g, 57.7 mmol). The reaction mixture was stirred at 25 ℃ for 18 hours. The reaction mixture was concentrated to give crude product. The crude product was purified by silica gel column separation (petroleum ether: ethyl acetate =100: 1-5:1) to give 4- (2,6-difluoro-4-nitrophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine as a yellow oil (15 g, 86% yield).
The fifth step: synthesis of 4- (2,6-difluoro-4-nitrophenoxy) -3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003677664240000332
To 4- (2,6-difluoro-4-nitrophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b at 25 deg.C]To a solution of pyridine (15g, 35.6 mmol) in DMF (150 mL) was added N-iodosuccinimide (8.81g, 39.1mmol). The reaction mixture was stirred at 25 ℃ for 18 hours. The reaction was poured slowly into 500mL of ice-water mixture. The mixture was extracted with ethyl acetate (100 mL. Times.3). The organic phases were combined and washed with saturated brine (100 mL). Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified by silica gel column (petroleum ether: ethyl acetate =100: 1-5:1) to give 4- (2,6-difluoro-4-nitrophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b as a yellow solid]Pyridine (15 g, 77% yield).
And a sixth step: synthesis of 4- (4- (2,6-difluoro-4-nitrophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide
Figure BDA0003677664240000341
To a mixed solution of 4- (2,6-difluoro-4-nitrophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine (1.2 g, 2.192mmol) and N- (3-methoxypropyl) -N-methyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) benzamide (1.096 g, 3.29mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was added cesium carbonate (1.429g, 4.38mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.160g, 0.219mmol) under nitrogen protection at 25 ℃. The reaction solution was stirred at 80 ℃ under nitrogen for 18 hours. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column separation (petroleum ether: ethyl acetate =100: 1-0:1) to give 4- (4- (2,6-difluoro-4-nitrophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide as a yellow solid (1.17 g, 85% yield).
The seventh step: synthesis of 4- (4- (4-amino-2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide
Figure BDA0003677664240000342
4- (4- (2,6-difluoro-4-nitrophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (1.17g, 1.867mmol) was dissolved in MeOH (15 mL) at 25 deg.C, wet Pd/C (0.2g, 0.188mmol, 10%) was added to the reaction solution, which was then replaced with hydrogen balloon three times, and the reaction solution was stirred under hydrogen balloon at 25 deg.C for 18 hours. After the reaction was completed, the reaction solution was filtered through celite, and the filtrate was spin-dried to give crude 4- (4- (4-amino-2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (1.1 g) which was used directly in the next reaction.
Eighth step: synthesis of o-phenyl (3,5-difluoro-4- ((3- (4- ((3-methoxypropyl) (methyl) carbamoyl) phenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridin-4-yl) oxy) phenyl) carbamate
Figure BDA0003677664240000351
Crude 4- (4- (4-amino-2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b) was obtained in one upward step at 0 deg.C]Pyridine (1.491mL, 18.43mmol) was added to a solution of pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (1.1 g) in tetrahydrofuran (10 mL). The reaction mixture was stirred at 0 ℃ for 0.5 h under nitrogen. Phenyl thiocarbamate (0.477g, 2.77mmol) was then added dropwise to the reaction. The reaction solution was stirred for 3 hours while being maintained at 0 ℃. The reaction solution was diluted with dichloromethane (50 mL) and washed with water (50 mL. Times.3). Collecting organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering, and concentrating the filtrate to provide crude o-phenyl (3,5-difluoro-4- ((3- (4- ((3-methoxypropyl) (methyl) carbamoyl) phenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b]Pyridin-4-yl) oxy) phenyl) carbamate. The crude product was used directly in the next reaction.
The ninth step: synthesis of 4- (4- (2,6-difluoro-4- (3- (3-hydroxy-2,2-dimethylpropyl) thioureido) phenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide
Figure BDA0003677664240000352
Crude o-phenyl (3,5-difluoro-4- ((3- (4- ((3-methoxypropyl) (methyl) carbamoyl) phenyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b) obtained in the previous step]Pyridin-4-yl) oxy) phenyl) carbamate and 3-amino-2,2-dimethyl-1-propanol (0.380g, 3.69mmol) were dissolved in DMF (15 mL). The reaction solution was stirred at 60 ℃ for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and then, the reaction solution was slowly poured into 60mL of an ice-water mixture. The mixture was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined and washed with saturated brine (50 mL). Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel column separation (ethyl acetate: methanol =1:0-15]Pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (720 mg).
The tenth step: synthesis of 4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide
Figure BDA0003677664240000361
To 4- (4- (2,6-difluoro-4- (3- (3-hydroxy-2,2-dimethylpropyl) thioureido) phenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole [2,3-b ] at 25 deg.C]Pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (720mg, 0.970mmol) and triethylamine (0.203ml, 1.456 mmol) in acetonitrile (15 mL) was added 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (372mg, 1.941mmol). The reaction mixture was stirred at 45 ℃ for 18 hours. The reaction is finishedAfter that, the reaction was cooled to room temperature, and the reaction mixture was slowly introduced into 60mL of an ice-water mixture. The mixture was extracted with ethyl acetate (60 mL. Times.3), and the organic phases were combined and washed with saturated brine (50 mL). Anhydrous Na for organic phase 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by silica gel column separation (ethyl acetate: methanol =1:0-15]Pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (500 mg, 72.8% yield).
The eleventh step: synthesis of 4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrole [2,3-b ] pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (I-1)
Figure BDA0003677664240000362
To 4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b at 25 deg.C]Pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (500mg, 0.706mmol) was added dropwise to trifluoroacetic acid (5.00 mL) in DCM (5 mL). The reaction mixture was stirred at 25 ℃ for 18 hours. The reaction solution was concentrated to dryness, and then the concentrated mixture was dissolved in acetonitrile (5 mL), followed by addition of 5mL of aqueous ammonia (25%) to the reaction solution, which was stirred at 25 ℃ for 0.5 hour. After completion of the reaction, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (10 mL. Times.3), and the organic phase was collected and extracted with anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude was isolated and purified using preparative plates (ethyl acetate: methanol = 10) to give 4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrole [2,3-b]Pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (I-1) (178.7 mg, 43.8% yield)
1 H NMR(400MHz,CDCl 3 )δ10.86(br s,1H),8.14(d,J＝5.2Hz,1H),7.75(d,J＝8.4Hz,2H),7.40(d,J＝8.0Hz,2H),7.35(s,1H),6.96(d,J＝9.6Hz,2H),6.36(d,J＝5.6Hz,1H),3.98(s,2H),3.61(br s,1H),3.49-3.43(m,2H),3.35-3.24(m,3H),3.18(s,3H),3.04(br s,3H),1.94-1.82(m,2H),1.11(s,6H)。
LC-MS,M/Z(ESI):578.3[M+H] + 。
Example 2: preparation of the object Compound I-2
4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (object Compound I-2)
Figure BDA0003677664240000371
The synthetic route of the target compound I-2 is shown as follows:
Figure BDA0003677664240000372
the first step is as follows: synthesis of (4-bromophenyl) (morpholino) methanone
Figure BDA0003677664240000373
To a solution of 4-bromobenzoic acid (5 g, 24.87mmol) in dichloromethane (50 mL) was added 1-hydroxybenzotriazole (5.71g, 37.3mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (7.15g, 37.3mmol) and triethylamine (6.93ml, 49.7 mmol) at 0 deg.C under nitrogen. The reaction mixture was stirred at 0 ℃ for 0.5 h. Then, morpholine (2.82g, 32.3 mmol) was added to the reaction mixture at 0 ℃. The reaction mixture was stirred at 25 ℃ under nitrogen for 18 hours. After completion of the reaction, 50mL of methylene chloride was added to the reaction mixture, the organic phase was washed with saturated sodium bicarbonate (50 mL. Times.3), the organic phase was collected, further washed with 1M aqueous hydrochloric acid (50 mL. Times.3), and the organic phase was collected and washed with anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain (4-bromophenyl)) (morpholino) methanone (6.0 g, yield 89%).
The second step is that: synthesis of morpholino (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) methanone
Figure BDA0003677664240000381
To a solution of (4-bromophenyl) (morpholino) methanone (1g, 3.70mmol) and bispinanol borate (1.410g, 5.55mmol) in 1,4-dioxane (10 mL) was added anhydrous potassium acetate (0.727g, 7.40mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.27g, 0.37mmol) under nitrogen at 25 ℃. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, the filter cake was washed with methanol (20 mL), and the filtrate was concentrated to give a crude product. The crude was isolated and purified on a silica gel column (petroleum ether: ethyl acetate =100: 1-5:1) to give crude morpholino (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) methanone (1.0 g, 85% yield) as a yellow solid.
The third step: synthesis of (4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (morpholino) methanone
Figure BDA0003677664240000382
To N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b) under nitrogen blanket at 25 deg.C]Pyridin-4-yl) oxy) phenyl) -5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-amine (A1) (0.3g, 0.477mmol) and a mixed solution of morpholino (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) methanone (0.227g, 0.716mmol) 1,4-dioxane (6 mL) and water (1 mL) were added to a solution of K 2 CO 3 (0.132g, 0.955mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.035g, 0.048mmol). The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite,the filtrate was concentrated to give a crude product. The crude was purified by silica gel column separation (petroleum ether: ethyl acetate =100, 1-0:1, then ethyl acetate: methanol =100, 1-10) to give a crude yellow solid (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (morpholino) methanone (150 mg, 45.4% yield).
The fourth step: synthesis of (4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (morpholino) methanone (I-2)
Figure BDA0003677664240000391
To (4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b at 25 deg.C]Pyridin-3-yl) phenyl) (morpholino) methanone (150mg, 0.217mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3.00 mL). The reaction solution was stirred at 25 ℃ for 18 hours. The reaction solution was concentrated to give a crude product, which was then dissolved in acetonitrile (5 mL), and 5mL of aqueous ammonia (25%) was added to the reaction solution. The reaction solution was stirred at 25 ℃ for 1 hour. The reaction mixture was diluted with 20mL of dichloromethane and the organic phase was washed with water (10 mL. Times.3). Collecting organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified by preparative silica gel plate (ethyl acetate: methanol =10: 1) to give (4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (morpholino) methanone (I-2) (45.2 mg, 37.1% yield).
1 H NMR(400MHz,CDCl 3 )δ10.01(br s,1H),8.16(d,J＝5.6Hz,1H),7.79-7.70(m,2H),7.44-7.42(m,2H),7.35(s,1H),6.98-6.96(m,2H),6.38(d,J＝5.6Hz,1H),3.94(s,2H),3.72(br s,9H),3.16(s,2H),1.10(s,6H)。
LC-MS,M/Z(ESI):562.2[M+H] + 。
Example 3: preparation of target Compound I-3
(4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) ((2R, 6S) -2,6-dimethylmorpholino) methanone (target compound I-3)
Figure BDA0003677664240000392
The synthetic route of the target compound I-3 is shown as follows:
Figure BDA0003677664240000401
the first step is as follows: synthesis of (4-bromophenyl) (cis-2,6-dimethylmorpholino) methanone
Figure BDA0003677664240000402
To a solution of 4-bromobenzoic acid (5 g, 24.87mmol) in dichloromethane (50 mL) was added 1-hydroxybenzotriazole (5.71g, 37.3mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (7.15g, 37.3mmol) and triethylamine (6.93ml, 49.7 mmol) at 0 deg.C under nitrogen. The reaction mixture was stirred at 0 ℃ for 0.5 h. Cis-2,6-dimethylmorpholine (3.72g, 32.3 mmol) was then added to the reaction mixture at 0 ℃. The reaction mixture was stirred at 25 ℃ for 18 hours under nitrogen. After completion of the reaction, 50mL of methylene chloride was added to the reaction mixture, the organic phase was washed with saturated sodium bicarbonate (50 mL. Times.3), the organic phase was collected, further washed with 1M aqueous hydrochloric acid (50 mL. Times.3), and the organic phase was collected and washed with anhydrous Na 2 SO 4 Drying, filtration and concentration gave (4-bromophenyl) (cis-2,6-dimethylmorpholino) methanone (6.0 g, 81% yield).
The second step is that: synthesis of (cis-2,6-dimethylmorpholino) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanone
Figure BDA0003677664240000403
To a solution of (4-bromophenyl) (cis-2,6-dimethylmorpholino) methanone (1g, 3.35mmol) and bis-pinacol boronate (1.410g, 5.55mmol) in 1,4-dioxane (10 mL) was added anhydrous potassium acetate (0.658g, 6.71mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.24lg, 0.335mmol) under nitrogen at 25 ℃. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, the filter cake was washed with methanol (20 mL), and the filtrate was concentrated to give a crude product. The crude product was isolated and purified by silica gel column (petroleum ether: ethyl acetate =100: 1-1:1) to give crude yellow solid (cis-2,6-dimethylmorpholino) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanone (1.1 g, 95% yield).
The third step: synthesis of (4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (cis-2,6-dimethylmorpholino) methanone
Figure BDA0003677664240000411
To N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b) under nitrogen blanket at 25 deg.C]Pyridin-4-yl) oxy) phenyl) -5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-amine (A1) (0.3g, 0.477mmol) and a mixed solution of (cis-2,6-dimethylmorpholino) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanone (0.247g, 0.716mmol) 1,4-dioxane (6 mL) and water (1 mL) were added Cs 2 CO 3 (0.311g, 0.955mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.035g, 0.048mmol). The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude product was isolated and purified by silica gel column (petroleum ether: ethyl acetate =100, 1-0:1, then ethyl acetate: methanol =100, 1-10) to give (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (cis-2,6-dimethylmorpholino) methanone (150 mg, 43.7% yield).
The fourth step: synthesis of (4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (cis-2,6-dimethylmorpholino) methanone (I-3)
Figure BDA0003677664240000412
To (4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b at 25 deg.C]Pyridin-3-yl) phenyl) (cis-2,6-dimethylmorpholino) methanone (150mg, 0.208mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3.00 mL). The reaction mixture was stirred at 25 ℃ for 18 hours. The reaction solution was concentrated to give a crude product, which was then dissolved in acetonitrile (5 mL), and 5mL of ammonia water (25%) was added to the reaction solution. The reaction solution was stirred at 25 ℃ for 1 hour. The reaction mixture was diluted with 20mL of dichloromethane and the organic phase was washed with water (10 mL. Times.3). Collecting organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified by preparative silica gel plate (ethyl acetate: methanol =10: 1) to give (4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (cis-2,6-dimethylmorpholino) methanone (I-3) (18.0 mg, 14.65% yield).
1 H NMR(400MHz,CDCl 3 )δ10.31(br s,1H),8.16(d,J＝5.6Hz,1H),7.78(d,J＝8.0Hz,2H),7.41(d,J＝8.4Hz,2H),7.37(s,1H),6.96(d,J＝8.4Hz,2H),6.38(d,J＝5.6Hz,1H),4.58(br s,1H),3.95(s,2H),3.62(br s,2H),3.16(s,2H),2.83-2.54(m,4H),1.26-1.01(m,12H)。
LC-MS,M/Z(ESI):590.2[M+H] + 。
Example 4: preparation of target Compound I-4
(4- (4- (4- ((2,6-dioxo-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (cis-2,6-dimethylmorpholino) methanone (object compound I-4)
Figure BDA0003677664240000421
The synthetic route of the target compound I-4 is shown as follows:
Figure BDA0003677664240000422
the first step is as follows: synthesis of (4-bromophenyl) (cis-2,6-dimethylmorpholino) methanone
Figure BDA0003677664240000431
To a solution of 4-bromobenzoic acid (5 g, 24.87mmol) in dichloromethane (50 mL) was added 1-hydroxybenzotriazole (5.71g, 37.3mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (7.15g, 37.3mmol) and triethylamine (6.93ml, 49.7 mmol) at 0 deg.C under nitrogen. The reaction mixture was stirred at 0 ℃ for 0.5 h. Cis-2,6-dimethylmorpholine (3.72g, 32.3 mmol) was then added to the reaction mixture at 0 ℃. The reaction mixture was stirred at 25 ℃ for 18 hours under nitrogen. After completion of the reaction, 50mL of methylene chloride was added to the reaction mixture, the organic phase was washed with saturated sodium bicarbonate (50 mL. Times.3), the organic phase was collected, further washed with 1M aqueous hydrochloric acid (50 mL. Times.3), and the organic phase was collected and washed with anhydrous Na 2 SO 4 Drying, filtration and concentration gave (4-bromophenyl) (cis-2,6-dimethylmorpholino) methanone (6.0 g, 81% yield).
The second step is that: synthesis of (cis-2,6-dimethylmorpholino) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanone
Figure BDA0003677664240000432
To a solution of (4-bromophenyl) (cis-2,6-dimethylmorpholino) methanone (1g, 3.35mmol) and bisphenonanol borate (1.410g, 5.55mmol) in 1,4-dioxane (10 mL) was added anhydrous potassium acetate (0.658g, 6.71mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (0.24lg, 0.335mmol) under nitrogen at 25 ℃. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, the filter cake was washed with methanol (20 mL), and the filtrate was concentrated to give a crude product. The crude product was isolated and purified by silica gel column (petroleum ether: ethyl acetate =100: 1-1:1) to give (cis-2,6-dimethylmorpholino) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaboroborane-2-yl) phenyl) methanone (1.1 g, 95% yield).
The third step: synthesis of (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (cis-2,6-dimethylmorpholino) methanone
Figure BDA0003677664240000433
To N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b) under nitrogen blanket at 25 deg.C]Pyridin-4-yl) oxy) phenyl) -2,6-dioxa-8-azaspiro [3.5]To a mixed solution of non-7-en-7-amine (A2) (0.2g, 0.311mmol) and (cis-2,6-dimethylmorpholino) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanone (0.161g, 0.467mmol) in 1,4-dioxane (6 mL) and water (1 mL) was added K 2 CO 3 (0.086g, 0.623mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.023g, 0.031mmol). The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude was isolated and purified by silica gel column (petroleum ether: ethyl acetate =100, 1-0:1, then ethyl acetate: methanol =100, 1-10) to give a yellow solid (4- (4- ((2,6-dioxa-8-azaspiro [3.5]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methylYl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (cis-2,6-dimethylmorpholino) methanone (130 mg, 56.9% yield).
The fourth step: synthesis of (4- (4- (4- ((2,6-dioxo-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (cis-2,6-dimethylmorpholino) methanone (I-4)
Figure BDA0003677664240000441
At 25 deg.C, to (4- (4- ((2,6-dioxa-8-azaspiro [3.5]]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (cis-2,6-dimethylmorpholino) methanone (130mg, 0.177 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3.00 mL). The reaction solution was stirred at 25 ℃ for 18 hours. The reaction solution was concentrated to give a crude product, which was then dissolved in acetonitrile (5 mL), and 5mL of ammonia water (25%) was added to the reaction solution. The reaction solution was stirred at 25 ℃ for 1 hour. The reaction mixture was diluted with 20mL of dichloromethane, and the organic phase was washed with water (10 mL. Times.3). Collecting organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified using preparative silica gel plates (ethyl acetate: methanol = 10) to give (4- (4- (4- ((2,6-dioxo-8-azaspiro [3.5]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (cis-2,6-dimethylmorpholino) methanone (I-4) (17.2 mg, 16.09% yield).
1 H NMR(400MHz,CDCl 3 )δ10.34(br s,1H),8.15(d,J＝5.6Hz,1H),7.78(d,J＝8.0Hz,2H),7.41(d,J＝8.4Hz,2H),7.37(s,1H),7.08-7.06(m,2H),6.36(d,J＝5.6Hz,1H),4.60-4.54(m,4H),4.44(s,2H),3.69(s,2H),3.61(br s,2H),2.98-2.57(m,4H),1.26-1.15(m,6H)。
LC-MS,M/Z(ESI):604.2[M+H] + 。
Example 5: preparation of target Compound I-5
4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino-2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide (target compound I-5)
Figure BDA0003677664240000451
The synthetic route of the target compound I-5 is shown below:
Figure BDA0003677664240000452
the first step is as follows: synthesis of 4-bromo-N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide
Figure BDA0003677664240000453
To a solution of 4-bromobenzoic acid (0.3g, 1.492mmol) in dichloromethane (6 mL) was added 1-hydroxybenzotriazole (0.302g, 2.239mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (0.429g, 2.239mmol) and triethylamine (0.416 mL, 2.98mmol) at 0 deg.C under nitrogen. The reaction mixture was stirred at 0 ℃ for 0.5 h. 2-methyl-1- (methylamino) propan-2-ol (0.185g, 1.791 mmol) was then added to the reaction mixture at 0 ℃. The reaction mixture was stirred at 25 ℃ under nitrogen for 18 hours. After completion of the reaction, 10mL of methylene chloride was added to the reaction mixture, the organic phase was washed with saturated sodium bicarbonate (10 mL. Times.3), the organic phase was collected, further washed with 1M aqueous hydrochloric acid (10 mL. Times.3), and the organic phase was collected and washed with anhydrous Na 2 SO 4 Drying, filtration and concentration gave 4-bromo-N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide (0.4 g, 94% yield).
The second step is that: synthesis of N- (2-hydroxy-2-methylpropyl) -N-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) benzamide
Figure BDA0003677664240000461
To a solution of 4-bromo-N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide (0.4g, 1.398mmol) and bispinanol borate (0.532g, 2.097mmol) in 1,4-dioxane (6 mL) was added anhydrous potassium acetate (0.274g, 2.80mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.102g, 0.140mmol) under nitrogen protection at 25 ℃. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, the filter cake was washed with methanol (10 mL), and the filtrate was concentrated to give a crude product. The crude was isolated and purified on a silica gel column (petroleum ether: ethyl acetate =100: 1-1:1) to give crude N- (2-hydroxy-2-methylpropyl) -N-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) benzamide (0.2 g, 42.9% yield) as a yellow oil.
The third step: synthesis of 4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino-2,6-difluorophenoxy) -1- ((2- (trimethylsilanyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide
Figure BDA0003677664240000462
To N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b) under nitrogen protection at 25 deg.C]Pyridin-4-yl) oxy) phenyl) -2,6-dioxa-8-azaspiro [3.5]To a mixed solution of 1,4-dioxane (6 mL) and water (1 mL) of non-7-en-7-amine (0.2g, 0.311mmol) (A2) and N- (2-hydroxy-2-methylpropyl) -N-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) benzamide (0.156g, 0.467mmol) was added K 2 CO 3 (0.086g, 0.623mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.023g, 0.031mmol). The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude product was isolated and purified by silica gel column (petroleum ether: ethyl acetate =100, 1-0:1, then ethyl acetate: methanol =100, 1-10) to give 4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5]Non-7-en-7-yl) amino-2,6-difluorophenoxy) -1- ((2- (trimethylsilanyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridine-3-yl) -N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide (200 mg, 89% yield).
The fourth step: synthesis of 4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino-2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide (objective Compound I-5)
Figure BDA0003677664240000471
To 4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5 ]) at 25 deg.C]Non-7-en-7-yl) amino-2,6-difluorophenoxy) -1- ((2- (trimethylsilanyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]To a solution of pyridin-3-yl) -N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide (200mg, 0.277mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3.00 mL). The reaction mixture was stirred at 25 ℃ for 18 hours. The reaction solution was concentrated to give a crude product, which was then dissolved in acetonitrile (3 mL), and 3mL of ammonia water (25%) was added to the reaction solution. The reaction solution was stirred at 25 ℃ for 1 hour. The reaction mixture was diluted with 10mL of dichloromethane and the organic phase was washed with water (5 mL. Times.3). Collecting the organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified using preparative silica gel plates (ethyl acetate: methanol = 10) to give 4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5]Non-7-en-7-yl) amino-2,6-difluorophenoxy) -1H-pyrrolo [2,3-b]Pyridin-3-yl) -N- (2-hydroxy-2-methylpropyl) -N-methylbenzamide (target Compound I-5) (15.1 mg, 9.21% yield).
1 H NMR(400MHz,CDCl 3 )δ9.80(br s,1H),8.14(d,J＝5.6Hz,1H),7.77(d,J＝8.4Hz,2H),7.46(d,J＝8.0Hz,2H),7.36(s,1H),7.09-7.07(m,2H),6.35(d,J＝5.6Hz,1H),4.60-4.54(m,4H),4.44(s,2H),3.69(s,2H),3.61(s,2H),3.17(s,3H),1.32(s,6H)。
LC-MS,M/Z(ESI):592.1[M+H] + 。
Example 6: preparation of target Compound I-6
(4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone (target compound I-6)
Figure BDA0003677664240000472
The synthetic route of the target compound I-6 is shown below:
Figure BDA0003677664240000481
the first step is as follows: synthesis of (4-bromophenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone
Figure BDA0003677664240000482
To a solution of 4-bromobenzoic acid (0.5g, 2.487mmol) in dichloromethane (10 mL) was added ethyl [3- (dimethylamino) propyl ] at 0 ℃ under nitrogen]Carbodiimide hydrochloride (0.715g, 3.73mmol), 1-hydroxybenzotriazole (0.504g, 3.73mmol) and triethylamine (0.693ml, 4.97mmol), the reaction mixture was stirred at 0 ℃ for 0.5 h. Then, 2-oxa-6-azaspiro [3.3] is reacted at 0 deg.C]Heptane (0.296g, 2.98mmol) was added portionwise to the reaction. The reaction mixture was stirred at 25 ℃ for 18 hours under nitrogen. The reaction mixture was diluted with dichloromethane (10 mL), and the organic phase was washed with a saturated aqueous solution of sodium bicarbonate (10 mL. Times.3), the organic phase was collected, washed with a 1M aqueous solution of hydrochloric acid (10 mL. Times.3), the organic phase was collected, and anhydrous Na was added 2 SO 4 Dried, filtered and concentrated to give (4-bromophenyl) (2-oxa-6-azaspiro [3.3] as a yellow oil]Hept-6-yl) methanone (0.6 g, 85% yield).
The second step is that: synthesis of (2-oxa-6-azaspiro [3.3] hept-6-yl) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanone
Figure BDA0003677664240000483
To a solution of (4-bromophenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone (0.6 g, 2.127mmol) and bisphenopinacol boronate (0.810g, 3.19mmol) in 1,4-dioxane (10 mL) was added anhydrous potassium acetate (0.417g, 4.25mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.156g, 0.213mmol) under nitrogen protection at 25 ℃. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude product was isolated and purified by silica gel column (petroleum ether: ethyl acetate =100: 1-5:1) to give (2-oxa-6-azaspiro [3.3] hept-6-yl) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) methanone as a yellow solid (500 mg, 71.4% yield).
The third step: synthesis of (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone
Figure BDA0003677664240000491
To a mixed solution of N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -2,6-dioxa-8-azaspiro [3.5] non-7-en-7-amine (A2) (0.3g, 0.467mmol), (2-oxa-6-azaspiro [3.3] hept-6-yl) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) methanone (0.231g, 0.700mmol) 1,4-dioxane (10 mL) and water (1 mL) was added potassium carbonate (0.129g, 0.4mmol) and [ 3534' -bis (3534 zzft) ferrocene (0.030.7mmol) under nitrogen protection at 25 deg.C. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column separation (petroleum ether: ethyl acetate =100, 1-0:1, then ethyl acetate: methanol =100, 1-20) to give a yellow solid (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone (170 mg, 50.7% yield).
The fourth step: synthesis of (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3] hept-6-yl) methanone (I-6)
Figure BDA0003677664240000492
At 25 deg.C, to (4- (4- ((2,6-dioxa-8-azaspiro [3.5]]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3]To a solution of hept-6-yl) methanone (170mg, 0.237 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3.00 mL). The reaction solution was stirred at 25 ℃ for 18 hours. The reaction solution was concentrated to give a crude product, which was then dissolved in acetonitrile (3 mL), and 3mL of ammonia water (25%) was added to the reaction solution. The reaction solution was stirred at 25 ℃ for 1 hour. The reaction mixture was diluted with 10mL of dichloromethane, and the organic phase was washed with water (5 mL. Times.3). Collecting organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified using preparative silica gel plates (ethyl acetate: methanol = 10) to give (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (2-oxa-6-azaspiro [3.3]Hept-6-yl) methanone (I-6) (21.4 mg, 43.0% yield).
1 H NMR(400MHz,DMSO)δ12.21(d,J＝2.0Hz,1H),9.11(br s,1H),8.11(d,J＝5.6Hz,1H),7.81-7.71(m,4H),7.61(d,J＝8.4Hz,2H),7.54(br s,1H),6.33(d,J＝5.2Hz,1H),4.67(s,4H),4.53(s,2H),4.44-4.40(m,6H),4.20(s,2H),3.60(s,2H).
LC-MS,M/Z(ESI):588.1[M+H] + 。
Example 7: preparation of target Compound I-7
4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2-methoxyethyl) -N-methylbenzamide (target compound I-7)
Figure BDA0003677664240000501
The synthetic route of the target compound I-7 is shown below:
Figure BDA0003677664240000502
the first step is as follows: synthesis of 4-bromo-N- (2-hydroxyethyl) -N-methylbenzamide
Figure BDA0003677664240000511
To a solution of 4-bromobenzoic acid (0.5g, 2.487mmol) in dichloromethane (10 mL) was added ethyl [3- (dimethylamino) propyl ] at 0 ℃ under nitrogen]Carbodiimide hydrochloride (0.715g, 3.73mmol), 1-hydroxybenzotriazole (0.504g, 3.73mmol) and triethylamine (0.693ml, 4.97mmol), the reaction mixture was stirred at 0 ℃ for 0.5 h. Then, 2-methoxy-N-methylethylamine (0.266g, 2.98mmol) was added in portions to the reaction solution at 0 ℃. The reaction mixture was stirred at 25 ℃ for 3 hours under nitrogen. The reaction mixture was diluted with dichloromethane (20 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (20 mL), the organic phase was collected, washed with 0.5M aqueous hydrochloric acid (20 mL), the organic phase was collected, and anhydrous Na was used 2 SO 4 Dried, filtered and concentrated to give 4-bromo-N- (2-hydroxyethyl) -N-methylbenzamide as a yellow oil (650 mg, 96% yield).
The second step is that: synthesis of N- (2-hydroxyethyl) -N-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide
Figure BDA0003677664240000512
To a solution of 4-bromo-N- (2-hydroxyethyl) -N-methylbenzamide (650mg, 2.388mmol) and bispinanol boronate (1213mg, 4.78mmol) in 1,4-dioxane (10 mL) was added anhydrous potassium acetate (469mg, 4.78mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (175mg, 0.239mmol) under nitrogen protection at 25 ℃. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude product was isolated and purified by silica gel column (petroleum ether: ethyl acetate =100: 1-5:1) to give N- (2-hydroxyethyl) -N-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (0.5 g, 65.6% yield) as a yellow solid.
The third step: synthesis of 4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2-methoxyethyl) -N-methylbenzamide
Figure BDA0003677664240000513
To a mixed solution of N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -2,6-dioxa-8-azaspiro [3.5] non-7-en-7-amine (A2) (0.3g, 0.467mmol), N- (2-hydroxyethyl) -N-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) benzamide (0.224g, 0.700mmol) in 1,4-dioxane (8 mL) and water (1.5 mL) was added potassium carbonate (0.1290.934mmol) and [1,1' -bis (diphenylphosphino) phosphine ] palladium dichloride (0.4mg, 0.03048 g, 7mmol) under nitrogen protection at 25 deg.C. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude was purified by silica gel column separation (petroleum ether: ethyl acetate =100, 1-0:1, then ethyl acetate: methanol =100, 1-20) to give 4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2-methoxyethyl) -N-methylbenzamide as a yellow solid (170 mg, 51.4% yield).
The fourth step: synthesis of 4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (2-methoxyethyl) -N-methylbenzamide (I-7)
Figure BDA0003677664240000521
To 4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5 ]) at 25 deg.C]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]To a solution of pyridin-3-yl) -N- (2-methoxyethyl) -N-methylbenzamide (6) (170mg, 0.240mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3.00 mL). The reaction solution was stirred at 25 ℃ for 18 hours. The reaction solution was concentrated to give a crude product, which was then dissolved in acetonitrile (3 mL), and 3mL of ammonia water (25%) was added to the reaction solution. The reaction solution was stirred at 25 ℃ for 1 hour. The reaction mixture was diluted with 10mL of dichloromethane, and the organic phase was washed with water (5 mL. Times.3). Collecting organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified using preparative silica gel plates (ethyl acetate: methanol = 10) to give 4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b]Pyridin-3-yl) -N- (2-methoxyethyl) -N-methylbenzamide (I-7) (40.6 mg, 29.3% yield).
1 H NMR(400MHz,CDCl 3 )δ10.15(br s,1H),8.15(d,J＝5.6Hz,1H),7.74(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,2H),7.35(s,1H),7.06(d,J＝9.6Hz,2H),6.34(d,J＝5.6Hz,1H),4.61-4.55(m,4H),4.51(s,2H),3.72(s,2H),3.67-3.50(m,3H),3.39-3.28(m,4H),3.12(s,3H).
LC-MS,M/Z(ESI):578.1[M+H] + 。
Example 8: preparation of target Compound I-8
(4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (morpholino) methanone (target compound I-8)
Figure BDA0003677664240000531
The synthetic route of the target compound I-8 is shown below:
Figure BDA0003677664240000532
the first step is as follows: synthesis of (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (morpholino) methanone
Figure BDA0003677664240000533
To a mixed solution of N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -2,6-dioxa-8-azaspiro [3.5] non-7-en-7-amine (A2) (0.3g, 0.467mmol), morpholino (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) methanone (0.222g, 0.700mmol) of 1,4-dioxane (8 mL) and water (1.5 mL) was added potassium carbonate (0.097g, 0.700mmol) and [1,1' -bis (diphenylphosphino) dichloropalladium (0.034g, 7 mmol) under nitrogen protection at 25 deg.C. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column isolation (petroleum ether: ethyl acetate =100, 1-0:1, then ethyl acetate: methanol =100, 1-20) to give a yellow solid (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (morpholino) methanone (200 mg, 60.7% yield).
The second step: synthesis of (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (morpholino) methanone (I-8)
Figure BDA0003677664240000541
At 25 deg.C, to (4- (4- ((2,6-dioxa-8-azaspiro [3.5]]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (morpholino) methanone (0.2g, 0.283mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3.00 mL). The reaction mixture was stirred at 25 ℃ for 18 hours. The reaction solution was concentrated to give a crude product, which was then dissolved in acetonitrile (3 mL), and 3mL of aqueous ammonia (25%) was added to the reaction solution. The reaction mixture was stirred at 25 ℃ for 1 hour. The reaction mixture was diluted with 10mL of dichloromethane, and the organic phase was washed with water (5 mL. Times.3). Collecting the organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified using preparative silica gel plates (ethyl acetate: methanol = 10) to give (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (morpholino) methanone (I-8) (76.4 mg, 46.8% yield).
1 H NMR(400MHz,CD 3 OD)δ8.08(d,J＝5.6Hz,1H),7.82(d,J＝8.4Hz,2H),7.53(s,1H),7.44(d,J＝8.4Hz,2H),7.14(br s,2H),6.38(d,J＝5.6Hz,1H),4.58-4.54(m,4H),4.46(s,2H),3.70-3.59(m,10H).
LC-MS,M/Z(ESI):576.2[M+H] + 。
Example 9: preparation of target Compound I-9
(4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxy-3-methylazetidin-1-yl) methanone (target compound I-9)
Figure BDA0003677664240000542
The synthetic route of the target compound I-9 is shown below:
Figure BDA0003677664240000551
the first step is as follows: synthesis of (4-bromophenyl) (3-hydroxy-3-methylazetidin-1-yl) methanone
Figure BDA0003677664240000552
To a solution of 4-bromobenzoic acid (0.5g, 2.487mmol) in dichloromethane (10 mL) was added 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (0.715g, 3.73mmol), 1-hydroxybenzotriazole (0.504g, 3.73mmol) and triethylamine (0.693ml, 4.97mmol) at 25 ℃ under nitrogen. The reaction mixture was stirred for 10 minutes at 25 ℃ under nitrogen. 3-methylazetidine-3-ol hydrochloride (0.369g, 2.98mmol) was then added to the reaction under nitrogen at 25 ℃. The reaction mixture was stirred at 25 ℃ under nitrogen for 3 hours. After the reaction was complete, the reaction was diluted with dichloromethane (20 mL) and the organic phase was saturated NaHCO 3 (20 mL) aqueous wash. The organic phase was collected and washed with 0.5N HCl (20 mL) in water. Anhydrous Na for organic phase 2 SO 4 Drying, filtration and concentration gave (4-bromophenyl) (3-hydroxy-3-methylazetidin-1-yl) methanone (650 mg, 97% yield) as a yellow oil.
The second step is that: synthesis of (3-hydroxy-3-methylazetidin-1-yl) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) methanone
Figure BDA0003677664240000561
To a solution of (4-bromophenyl) (3-hydroxy-3-methylazetidin-1-yl) methanone (650mg, 2.406mmol) and bispinanol borate (1222mg, 4.81mmol) in 1,4-dioxane (10 mL) was added anhydrous potassium acetate (472mg, 4.81mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (176mg, 0.241mmol) under nitrogen protection at 25 ℃. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude product was isolated and purified by silica gel column (petroleum ether: ethyl acetate =100: 1-5:1) to give (3-hydroxy-3-methylazetidin-1-yl) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) methanone (0.3 g, 39.3% yield) as a yellow solid.
The third step: synthesis of (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxy-3-methylazetidin-1-yl) methanone
Figure BDA0003677664240000562
To a mixed solution of N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -2,6-dioxa-8-azaspiro [3.5] non-7-en-7-amine (A2) (0.3g, 0.467mmol), (3-hydroxy-3-methylazetidin-1-yl) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) methanone (0.222g, 0.700mmol) of 1,4-dioxane (8 mL) and water (1.5 mL) was added potassium carbonate (0.129g, 0.934mmol) and [1,1' -bis (diphenylphosphino) ferrocene (0.034mmol) under nitrogen protection at 25 deg.C. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude was purified by silica gel column separation (petroleum ether: ethyl acetate =100, 1-0:1, then ethyl acetate: methanol =100, 1-20) to give a yellow solid (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxy-3-methylazetidin-1-yl) methanone (0.2 g, 60.7% yield).
The fourth step: (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxy-3-methylazetidin-1-yl) methanone (target compound I-9)
Figure BDA0003677664240000571
At 25 deg.C, to (4- (4)- (4- ((2,6-dioxa-8-azaspiro [ 3.5)]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (3-hydroxy-3-methylazetidin-1-yl) methanone (0.2g, 0.283mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3.00 mL). The reaction mixture was stirred at 25 ℃ for 18 hours. The reaction solution was concentrated to give a crude product, which was then dissolved in acetonitrile (3 mL), and 3mL of ammonia water (25%) was added to the reaction solution. The reaction solution was stirred at 25 ℃ for 1 hour. The reaction mixture was diluted with 10mL of dichloromethane, and the organic phase was washed with water (5 mL. Times.3). Collecting organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified on preparative silica gel plates (ethyl acetate: methanol = 10) to give (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (3-hydroxy-3-methylazetidin-1-yl) methanone (title compound I-9) (23.4 mg, 14.35% yield).
1 H NMR(400MHz,CD 3 Cl)δ9.59(br s,1H),8.12-8.08(m,1H),7.73(d,J＝8.0Hz,2H),7.64(d,J＝8.4Hz,2H),7.34(s,1H),7.04(d,J＝9.2Hz,2H),6.32(d,J＝4.8Hz,1H),4.64-4.58(m,6H),4.30-4.18(m,4H),3.75(s,2H),1.57(s,3H).
LC-MS,M/Z(ESI):576.1[M+H] + 。
Example 10: preparation of target Compound I-10
4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (target compound I-10)
Figure BDA0003677664240000572
The synthetic route of the target compound I-10 is shown below:
Figure BDA0003677664240000581
the first step is as follows: synthesis of 4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (3)
Figure BDA0003677664240000582
To N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b) under nitrogen blanket at 25 deg.C]Pyridin-4-yl) oxy) phenyl) -2,6-dioxa-8-azaspiro [3.5]To a mixed solution of non-7-en-7-amine (A2) (0.3 g, 0.467mmol) and N- (3-methoxypropyl) -N-methyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) benzamide (0.233g, 0.700mmol) 1,4-dioxane (6 mL) and water (1 mL) was added K 2 CO 3 (0.129g, 0.934mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.034g, 0.047mmol). The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude was isolated and purified by silica gel column (petroleum ether: ethyl acetate =100, 1-0:1, then ethyl acetate: methanol =100, 1-10) to give 4- (4- ((2,6-dioxa-8-azaspiro [3.5]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (200 mg, 59.3% yield).
The second step is that: synthesis of 4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (target Compound I-10)
Figure BDA0003677664240000591
To 4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5 ]) at 25 deg.C]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) Methyl) -1H-pyrrolo [2,3-b]To a solution of pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (200mg, 0.277mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3.00 mL). The reaction solution was stirred at 25 ℃ for 18 hours. The reaction solution was concentrated to give a crude product, which was then dissolved in acetonitrile (3 mL), and 3mL of ammonia water (25%) was added to the reaction solution. The reaction solution was stirred at 25 ℃ for 1 hour. The reaction mixture was diluted with 10mL of dichloromethane and the organic phase was washed with water (5 mL. Times.3). Collecting organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified using preparative silica gel plates (ethyl acetate: methanol = 10) to give 4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b]Pyridin-3-yl) -N- (3-methoxypropyl) -N-methylbenzamide (title compound I-10) (70.5 mg, 43.0% yield).
1 H NMR(400MHz,CDCl 3 )δ9.81(br s,1H),8.15(d,J＝5.6Hz,1H),7.74(d,J＝8.4Hz,2H),7.41(d,J＝8.0Hz,2H),7.34(s,1H),7.09-7.07(m,2H),6.34(d,J＝5.6Hz,1H),4.61-4.55(m,4H),4.48(s,2H),3.71(s,2H),3.62(br s,1H),3.49-3.18(m,6H),3.07-3.04(m,3H),1.98-1.80(m,2H)。
LC-MS,M/Z(ESI):592.2[M+H] + 。
Example 11: preparation of target Compound I-11
(4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxy-3-methylazetidin-1-yl) methanone (target compound I-11)
Figure BDA0003677664240000592
The synthetic route of the target compound I-11 is shown below:
Figure BDA0003677664240000601
the first step is as follows: synthesis of (4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) dimethylphosphine oxide
Figure BDA0003677664240000602
To N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b) under nitrogen blanket at 25 deg.C]Pyridin-4-yl) oxy) phenyl) -5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-amine (A1) (0.3g, 0.477mmol) and a mixed solution of dimethyl (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) phosphine oxide (0.267g, 0.955mmol) 1,4-dioxane (6 mL) and water (1 mL) was added [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.035g, 0.048mmol) and K 2 CO 3 (0.132g, 0.955mmol). The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude product was isolated and purified by preparative silica gel plate (ethyl acetate: methanol =10: 1) to give (4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) dimethylphosphine oxide (0.2 g).
The second step is that: (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-hydroxy-3-methylazetidin-1-yl) methanone (target compound I-11)
Figure BDA0003677664240000603
To (4- (4- (((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b at 25 deg.C]Pyridin-3-yl) phenyl) dimethylphosphine oxide (0.2 g, 0.305mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3.00 mL). The reaction solution was stirred at 25 ℃ for 5 hours. Reacting the reaction solutionConcentration gave a crude product, which was then dissolved in acetonitrile (3 mL), and 3mL of ammonia (25%) was added to the reaction solution. The reaction solution was stirred at 25 ℃ for 1 hour. The reaction mixture was diluted with 10mL of dichloromethane, and the organic phase was washed with water (5 mL. Times.3). Collecting organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified using preparative silica gel plates (ethyl acetate: methanol = 10) to give (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (3-hydroxy-3-methylazetidin-1-yl) methanone (title compound I-11) (79.9 mg, 49.9% yield).
1 H NMR(400MHz,CD 3 OD)δ8.10(d,J＝5.6Hz,1H),7.93-7.90(m,2H),7.80-7.75(m,2H),7.58(s,1H),7.01(d,J＝10.4Hz,2H),6.42(d,J＝5.6Hz,1H),3.97(s,2H),3.11(s,2H),1.82(s,3H),1.78(s,3H),1.08(s,6H).
LC-MS,M/Z(ESI):525.1[M+H] + 。
Example 12: preparation of target Compound I-12
(S) - (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-fluoropyrrolidin-1-yl) methanone (target compound I-12)
Figure BDA0003677664240000611
The synthetic route of the target compound I-12 is shown below:
Figure BDA0003677664240000621
the first step is as follows: synthesis of (S) - (4-bromophenyl) (3-fluoropyrrolidin-1-yl) methanone
Figure BDA0003677664240000622
To 4-bromobenzoic acid (0.5 g) at 0 ℃ under nitrogen blanket2.487 mmol) in dichloromethane (10 mL) was added ethyl [3- (dimethylamino) propyl ] group]Carbodiimide hydrochloride (0.715g, 3.73mmol), 1-hydroxybenzotriazole (0.504g, 3.73mmol) and triethylamine (0.693ml, 4.97mmol), the reaction mixture was stirred at 0 ℃ for 0.5 h. Then, (S) -3-fluoropyrrolidine (0.332g, 3.73mmol) was added to the reaction solution in portions at 0 ℃. The reaction mixture was stirred at 25 ℃ for 18 hours under nitrogen. The reaction mixture was diluted with dichloromethane (10 mL), and the organic phase was washed with a saturated aqueous solution of sodium bicarbonate (10 mL. Times.3), the organic phase was collected, washed with a 1M aqueous solution of hydrochloric acid (10 mL. Times.3), the organic phase was collected, and anhydrous Na was added 2 SO 4 Drying, filtration, and concentration gave (S) - (4-bromophenyl) (3-fluoropyrrolidin-1-yl) methanone (0.65 g, 96% yield) as a yellow oil.
The second step: synthesis of (S) - (3-fluoropyrrolidin-1-yl) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) methanone
Figure BDA0003677664240000623
To a solution of (S) - (4-bromophenyl) (3-fluoropyrrolidin-1-yl) methanone (650mg, 2.389mmol) and bisphenoenanol boronate (910mg, 3.58mmol) in 1,4-dioxane (8 mL) was added anhydrous potassium acetate (469mg, 4.78mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (175mg, 0.239mmol) under nitrogen protection at 25 ℃. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude product was isolated and purified on a silica gel column (petroleum ether: ethyl acetate =100: 1-5:1) to give (S) - (3-fluoropyrrolidin-1-yl) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) methanone as a yellow solid (600 mg, 79% yield).
The third step: synthesis of (S) - (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-fluoropyrrolidin-1-yl) methanone
Figure BDA0003677664240000631
To a mixed solution of N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -2,6-dioxa-8-azaspiro [3.5] non-7-en-7-amine (A2) (0.3g, 0.467mmol), (S) - (3-fluoropyrrolidin-1-yl) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) methanone (0.194g, 0.607mmol) of 3924-dioxane (10 mL) and water (1 mL) was added potassium carbonate (0.129g, 0.934mmol) and [ 3534 zxft' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.034mmol) under nitrogen protection at 25 deg.C. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude was isolated and purified on a silica gel column (petroleum ether: ethyl acetate =100, 1-0:1, then ethyl acetate: methanol =100, 1-20) to give (S) - (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-fluoropyrrolidin-1-yl) methanone (170 mg, 51.4% yield) as a yellow solid.
The fourth step: (S) - (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3-fluoropyrrolidin-1-yl) methanone (target compound I-12)
Figure BDA0003677664240000632
To (S) - (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5 ]) at 25 deg.C]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (3-fluoropyrrolidin-1-yl) methanone (170mg, 0.240mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3.00 mL). The reaction solution was stirred at 25 ℃ for 18 hours. The reaction solution was concentrated to give a crude product, which was then dissolved in acetonitrile (3 mL), and 3mL of ammonia water (25%) was added to the reaction solution. The reaction solution was stirred at 25 ℃ for 1 hour. The reaction mixture was diluted with 10mL of dichloromethane and the organic phase was usedWashed with water (5 mL. Times.3). Collecting organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified on preparative silica gel plates (ethyl acetate: methanol = 10) to give (S) - (4- (4- (4- ((2,6-dioxa-8-azaspiro [ 3.5)]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (3-fluoropyrrolidin-1-yl) methanone (target compound I-12) (50.8 mg, yield 36.6%).
1 H NMR(400MHz,CD 3 OD)δ8.09(d,J＝5.6Hz,1H),7.82(d,J＝8.4Hz,2H),7.58-7.53(m,3H),7.13(d,J＝10.8Hz,2H),6.38(d,J＝5.2Hz,1H),5.41-5.17(m,1H),4.58-4.54(m,4H),4.47(s,2H),3.87-3.70(m,4H),3.65(s,2H),2.32-2.04(m,2H).
LC-MS,M/Z(ESI):578.1[M+H] + 。
Example 13: preparation of target Compound I-13
(4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3,3-difluoroazetidin-1-yl) methanone (object Compound I-13)
Figure BDA0003677664240000641
The synthetic route of the target compound I-13 is shown below:
Figure BDA0003677664240000642
the first step is as follows: synthesis of (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3,3-difluoroazetidin-1-yl) methanone
Figure BDA0003677664240000651
To a mixed solution of N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -2,6-dioxa-8-azaspiro [3.5] non-7-en-7-amine (A2) (0.3g, 0.467mmol), (3,3-difluoroazetidin-1-yl) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) methanone (0.226g, 0.700mmol), 1,4-dioxane (5 mL) and water (1 mL) was added potassium carbonate (0.129g, 0.934mmol) and [1,1' -bis (diphenylphosphino) ferrocene (5 mL) ferrocene (0.034mmol) under nitrogen protection at 25 deg.C. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude was purified by silica gel column separation (petroleum ether: ethyl acetate =100, 1-0:1, then ethyl acetate: methanol =100, 1-20) to give a crude yellow solid (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3,3-difluoroazetidin-1-yl) methanone (310 mg, 93% yield).
The second step is that: (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3,3-difluoroazetidin-1-yl) methanone (object Compound I-13)
Figure BDA0003677664240000652
At 25 deg.C, to (4- (4- ((2,6-dioxa-8-azaspiro [3.5]]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (3,3-difluoroazetidin-1-yl) methanone (310mg, 0.436 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3.00 mL). The reaction solution was stirred at 25 ℃ for 18 hours. The reaction solution was concentrated to give a crude product, which was then dissolved in acetonitrile (3 mL), and 3mL of ammonia water (25%) was added to the reaction solution. The reaction solution was stirred at 25 ℃ for 1 hour. The reaction mixture was diluted with 10mL of dichloromethane, and the organic phase was washed with water (5 mL. Times.3). Collecting organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product is preparedPreparative silica gel plate separation and purification (ethyl acetate: methanol = 10) yielded (4- (4- ((2,6-dioxa-8-azaspiro [3.5]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (3,3-difluoroazetidin-1-yl) methanone (title compound I-13) (10.3 mg, 4.07% yield).
1 H NMR(400MHz,CD 3 OD)δ8.09(d,J＝5.6Hz,1H),7.86-7.84(m,2H),7.71-7.69(m,2H),7.56(s,1H),7.14(br s,2H),6.39(d,J＝5.6Hz,1H),4.74-4.54(m,8H),4.46(s,2H),3.65(s,2H).
LC-MS,M/Z(ESI):582.1[M+H] + 。
Example 14: preparation of target Compound I-14
(4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3,3-difluoropyrrolidin-1-yl) methanone (object compound I-14)
Figure BDA0003677664240000661
The synthetic route of the target compound I-14 is shown below:
Figure BDA0003677664240000662
the first step is as follows: synthesis of (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3,3-difluoropyrrolidin-1-yl) methanone
Figure BDA0003677664240000663
To a mixed solution of N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -2,6-dioxa-8-azaspiro [3.5] non-7-en-7-amine (A2) (0.3g, 0.467mmol), (3,3-difluoropyrrolidin-1-yl) (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) methanone (0.236g, 0.700mmol) 1,4-dioxane (5 mL) and water (1 mL) was added potassium carbonate (0.129g, 0.4mmol) and [1,1' -bis (diphenylphosphino) ferrocene (030.4mmol) under nitrogen protection at 25 deg.C, potassium carbonate (0.93030.4mmol) was added. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude was purified by silica gel column separation (petroleum ether: ethyl acetate =100, 1-0:1, then ethyl acetate: methanol =100, 1-20) to give a crude yellow solid (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3732 zxf3732-difluoropyrrolidin-1-yl) methanone (250 mg, 73.8% yield).
The second step is that: (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5] non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) (3,3-difluoropyrrolidin-1-yl) methanone (object compound I-14)
Figure BDA0003677664240000671
At 25 deg.C, to (4- (4- ((2,6-dioxa-8-azaspiro [3.5]]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (3,3-difluoropyrrolidin-1-yl) methanone (250mg, 0.344mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3.00 mL). The reaction solution was stirred at 25 ℃ for 18 hours. The reaction solution was concentrated to give a crude product, which was then dissolved in acetonitrile (3 mL), and 3mL of ammonia water (25%) was added to the reaction solution. The reaction solution was stirred at 25 ℃ for 1 hour. The reaction mixture was diluted with 10mL of dichloromethane, and the organic phase was washed with water (5 mL. Times.3). Collecting organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified using preparative silica gel plates (ethyl acetate: methanol = 10) to give (4- (4- (4- ((2,6-dioxa-8-azaspiro [3.5]Non-7-en-7-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) (3,3-difluoropyrroleAlk-1-yl) methanone (target compound I-14) (15.2 mg, 7.41% yield).
1 H NMR(400MHz,CD 3 OD)δ8.09(d,J＝5.6Hz,1H),7.83(d,J＝8.4Hz,2H),7.55(d,J＝8.4Hz,3H),7.14(d,J＝10.4Hz,2H),6.38(d,J＝5.6Hz,1H),4.58-4.54(m,4H),4.48(s,2H),3.95(t,J＝12.8Hz,2H),3.85-3.82(m,2H),3.65(s,2H),2.47-2.40(m,2).
LC-MS,M/Z(ESI):596.2[M+H] + 。
Example 15: preparation of target Compound I-15
Azetidin-1-yl (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (target compound I-15)
Figure BDA0003677664240000681
The synthetic route of the target compound I-15 is shown below:
Figure BDA0003677664240000682
the first step is as follows: synthesis of azetidin-1-yl (4-bromophenyl) methanone
Figure BDA0003677664240000683
To a solution of 4-bromobenzoic acid (0.6 g, 2.98mmol) in dichloromethane (10 mL) was added ethyl [3- (dimethylamino) propyl ] at 0 ℃ under nitrogen]Carbodiimide hydrochloride (0.858g, 4.48mmol), 1-hydroxybenzotriazole (0.605g, 4.48mmol) and triethylamine (0.832ml, 5.97mmol) and the reaction mixture was stirred at 0 ℃ for 0.5 h. Then, azetidine hydrochloride (0.419g, 4.48mmol) was added in portions to the reaction solution at 0 ℃. The reaction mixture was stirred at 25 ℃ for 18 hours under nitrogen. The reaction mixture was diluted with dichloromethane (10 mL), the organic phase was washed with saturated aqueous sodium bicarbonate (10 mL. Times.3), the organic phase was collected, and 1M aqueous hydrochloric acid was addedThe solution (10 mL. Times.3) was washed, the organic phase was collected and dried over anhydrous Na 2 SO 4 Drying, filtration and concentration gave azetidin-1-yl (4-bromophenyl) methanone (0.7 g, 98% yield) as a yellow oil.
The second step is that: synthesis of azetidin-1-yl (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanone
Figure BDA0003677664240000691
To a solution of azetidin-1-yl (4-bromophenyl) methanone (0.7 g, 2.92mmol) and bisphenoenanol borate (1.111g, 4.37mmol) in 1,4-dioxane (8 mL) was added anhydrous potassium acetate (0.572g, 5.83mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.213g, 0.292mmol) under nitrogen at 25 ℃. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude product was isolated and purified by silica gel column (petroleum ether: ethyl acetate =100: 1-5:1) to give azetidin-1-yl (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) methanone as a yellow solid (800 mg, 96% yield).
The third step: synthesis of azetidin-1-yl (4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone
Figure BDA0003677664240000692
To a mixed solution of N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -2,6-dioxa-8-azaspiro [3.5] non-7-en-7-amine (A1) (0.5g, 0.796 mmol), azetidin-1-yl (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) phenyl) methanone (0.343g, 1.193mmol) of 1,4-dioxane (10 mL) and water (1 mL) was added potassium carbonate (0.220g, 1.591mmol) and [1,1' -dichlorobis (diphenylphosphino) ferrocene ] palladium (0.050.8g, 0.0808 mmol) under nitrogen protection at 25 ℃. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude was purified by silica gel column separation (petroleum ether: ethyl acetate =100, 1-0:1, then ethyl acetate: methanol =100, 1-20) to give crude azetidin-1-yl (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (300 mg).
The fourth step: azetidin-1-yl (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) methanone (target compound I-15)
Figure BDA0003677664240000693
To azetidin-1-yl (4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] at 25 deg.C]Pyridin-3-yl) phenyl) methanone (0.3g, 0.453mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3.00 mL). The reaction solution was stirred at 25 ℃ for 18 hours. The reaction solution was concentrated to give a crude product, which was then dissolved in acetonitrile (3 mL), and 3mL of ammonia water (25%) was added to the reaction solution. The reaction mixture was stirred at 25 ℃ for 1 hour. The reaction mixture was diluted with 10mL of dichloromethane and the organic phase was washed with water (5 mL. Times.3). Collecting organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified by preparative silica gel plate (ethyl acetate: methanol =10: 1) to give azetidin-1-yl (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b]Pyridin-3-yl) phenyl) methanone (title compound I-15) (70.8 mg, 29.4% yield).
1 H NMR(400MHz,CD 3 OD)δ8.09(d,J＝5.6Hz,1H),7.82(d,J＝8.0Hz,2H),7.64(d,J＝8.4Hz,2H),7.54(s,1H),6.99(d,J＝10.8Hz,2H),6.41(d,J＝5.6Hz,1H),4.43(t,J＝7.6Hz,2H),4.20(t,J＝8.0Hz,2H),3.94(s,2H),3.10(s,2H),2.40-2.33(m,2H),1.07(s,6H).
LC-MS,M/Z(ESI):532.2[M+H] + 。
Example 16: preparation of target Compound I-16
Cyclopropyl (4- (4- (4- (((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3,6-dihydropyridin-1 (2H) -yl) methanone (target compound I-16)
Figure BDA0003677664240000701
The synthetic route of the target compound I-16 is shown below:
Figure BDA0003677664240000702
the first step is as follows: synthesis of cyclopropyl (4- (4- (4- (((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3,6-dihydropyridin-1 (2H) -yl) methanone
Figure BDA0003677664240000711
To a mixed solution of N- (3,5-difluoro-4- ((3-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) phenyl) -2,6-dioxa-8-azaspiro [3.5] non-7-en-7-amine (A1) (0.2g, 0.318mmol), cyclopropyl (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) -5,6-dihydropyridin-1 (2H) -yl) methanone (0.097g, 0.350mmol) 1,4-dioxane (5 mL) and water (1 mL) was added sodium carbonate (6.067g, 0.633262 mmol) and [1,1' -bis (diphenylphosphino) ferrocene (0320.0230 mmol) under nitrogen protection at 25 deg.C. The reaction mixture was stirred at 80 ℃ under nitrogen for 18 hours. After the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. The crude was purified by silica gel column separation (petroleum ether: ethyl acetate =100, 1-0:1, then ethyl acetate: methanol =100, 1-20.
The second step: cyclopropyl (4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -3,6-dihydropyridin-1 (2H) -yl) methanone (target compound I-16)
Figure BDA0003677664240000712
To cyclopropyl (4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b at 25 deg.C]Pyridin-3-yl) -3,6-dihydropyridin-1 (2H) -yl) methanone (80mg, 0.123mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3.00 mL). The reaction solution was stirred at 25 ℃ for 18 hours. The reaction solution was concentrated to give a crude product, which was then dissolved in acetonitrile (3 mL), and 3mL of ammonia water (25%) was added to the reaction solution. The reaction solution was stirred at 25 ℃ for 1 hour. The reaction mixture was diluted with 10mL of dichloromethane, and the organic phase was washed with water (5 mL. Times.3). Collecting organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified by preparative silica gel plate (ethyl acetate: methanol =10: 1) to give cyclopropyl (4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b]Pyridin-3-yl) -3,6-dihydropyridin-1 (2H) -yl) methanone (title compound I-16) (27.1 mg, 42.3% yield).
1 H NMR(400MHz,CD 3 OD)δ8.03(d,J＝5.6Hz,1H),7.32(d,J＝3.6Hz,1H),7.07(d,J＝9.6Hz,2H),6.35(d,J＝5.6Hz,1H),6.10(d,J＝21.6Hz,1H),4.41(d,J＝2.0Hz,1H),4.17(d,J＝2.4Hz,1H),4.05(s,2H),3.97(t,J＝5.6Hz,1H),3.79(t,J＝5.6Hz,1H),3.14(s,2H),2.78(s,1H),2.66(s,1H),2.07-2.00(m,1H),1.10(s,6H),0.92-0.87(m,2),084-0.79(m,2).
LC-MS,M/Z(ESI):522.2[M+H] + 。
Example 17: preparation of target Compound I-17
Azetidin-1-yl (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) cyclohexyl-3-en-1-yl) methanone (object compound I-17)
Figure BDA0003677664240000721
The target compound I-17 line is shown below:
Figure BDA0003677664240000722
the first step is as follows: synthesis of methyl 4- (4- (((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) cyclohex-3-ene-1-carboxylate
Figure BDA0003677664240000731
To N- (4- ((3-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b) under nitrogen protection at 25 deg.C]Pyridin-4-yl) oxy) -3,5-difluorophenyl) -5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-amine (A3) (1 g, 1.720mmol) to a mixed solution of 1,4-dioxane (10 ml) and water (1 ml) was added methyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl) cyclohexyl-3-enecarboxylate (0.54g, 2.064mmol), K 2 CO 3 (0.475g, 3.44mmol) and tetrakis (triphenylphosphine) palladium (0.199g, 0.172mmol). The reaction mixture was stirred at 100 ℃ for 18 hours under nitrogen. The reaction was filtered through celite, and the filtrate was concentrated to give crude which was purified by silica gel chromatography (PE: EA =10, 1-0:1, then with EA: meOH =100, 1-20) to give methyl4- (4- (((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-3-yl) cyclohex-3-ene-1-carboxylic acid ester (1.0 g, 91% yield)
The second step is that: synthesis of 4- (4- (4- (((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) cyclohex-3-ene-1-carboxylic acid
Figure BDA0003677664240000732
To a mixed solution of 4- (4- (((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) cyclohex-3-ene-1-carboxylic acid methyl ester (1.0 g,1.561 mmol) in methanol (10 ml) and water (2 ml) was added lithium hydroxide monohydrate (0.131g, 3.21mmol) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 18 hours. After the reaction, the reaction solution was concentrated to a crude product. The crude was dissolved in 20mL of water, then extracted with ethyl acetate (10 mL), the aqueous phase was collected, the pH was adjusted to 3-4, then the aqueous phase was extracted with ethyl acetate (10 mL. Times.3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 4- (4- (4- (((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) cyclohex-3-ene-1-carboxylic acid as a yellow solid (500 mg, 51.1% yield).
The third step: synthesis of azetidin-1-yl (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) cyclohex-3-en-1-yl) methanone
Figure BDA0003677664240000741
To a solution of 4- (4- (((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) cyclohex-3-ene-1-carboxylic acid (500mg, 0.798mmol) in dichloromethane (10 mL) under nitrogen protection was added 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (229mg, 1.197ft), 1-hydroxybenzotriazole (162mg, 1.197mmol) and triethylamine (0.8ml, 1.9944mmol), the reaction mixture was stirred under nitrogen protection for 10 minutes, then azetidine hydrochloride (mg, 1.197mmol) was added to the reaction mixture in portions and after the reaction mixture was diluted with aqueous solution of silica gel (4232-ethyl acetate) under nitrogen protection, crude dichloromethane (4232-ethyl acetate was filtered, crude dichloromethane (4232-ethyl acetate was purified by filtration Oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) cyclohex-3-en-1-yl) methanone (300 mg).
The fourth step: azetidin-1-yl (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b ] pyridin-3-yl) cyclohexyl-3-en-1-yl) methanone (object compound I-17)
Figure BDA0003677664240000742
To azetidin-1-yl (4- (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] at 25 deg.C]Pyridin-3-yl) cyclohex-3-en-1-yl) methanone (6) (0.3 g, 0.451mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3.00 mL). The reaction solution was stirred at 25 ℃ for 18 hours. The reaction solution was concentrated to give a crude product, which was then dissolved in acetonitrile (3 mL), and 3mL of aqueous ammonia (2)5%). The reaction solution was stirred at 25 ℃ for 1 hour. The reaction mixture was diluted with 10mL of dichloromethane, and the organic phase was washed with water (5 mL. Times.3). Collecting organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was isolated and purified by preparative silica gel plate (ethyl acetate: methanol =10: 1) to give azetidin-1-yl (4- (4- ((5,5-dimethyl-5,6-dihydro-4H-1,3-oxazin-2-yl) amino) -2,6-difluorophenoxy) -1H-pyrrolo [2,3-b]Pyridin-3-yl) cyclohexyl-3-en-1-yl) methanone (title compound I-17) (54.5 mg, 22.59% yield).
1 H NMR(400MHz,CDCl 3 )δ9.14(s,1H),8.07(d,J＝5.4Hz,1H),7.11(s,1H),7.00-6.95(m,2H),7.54(s,1H),6.31(d,J＝5.4Hz,1H),6.08-6.07(m,1H),4.21(t,J＝7.6Hz,2H),4.03(t,J＝8.0Hz,2H),3.92(s,2H),3.16(s,2H),2.71-2.67(m,1H),2.52-2.46(m,3H),2.31-2.20(m,3H),1.92-1.86(m,2H),1.10(s,6H).
LC-MS,M/Z(ESI):536.5[M+H] + 。
Test example 1: IC50 evaluation test for in vitro enzyme activity inhibition of recombinant HPK1 enzyme
The compounds prepared in examples 1 to 17 were tested for their inhibitory effect on HPK1 kinase using Lantha screen Assay.
The HPK1 kinase reaction system is 10 mu L, and the final concentration of each component is as follows: 0.5nM HPK1 recombinant enzyme (Carna, cat. NO. 07-410), small molecule inhibitors with different concentration gradients, 10mM MgCl 2 4mM DTT, 2.5. Mu.M ATP, 0.1. Mu.M FITC-PKC (Invitrogen, cat. NO. PV3506), 0.01% Tween-20, 0.01% BSA and 50mM HEPES at pH 7.5. Specifically, 2 × HPK1 recombinase and 2 × test compound are added to a buffer system in a 384-well plate and incubated at room temperature for 10 minutes, while a negative control well not containing the enzyme, a positive control well not containing the compound, and a control well to which the same concentration of control compound 1 is added, 2 × polypeptide substrate and ATP are added, the reaction is started, 10 μ L of a mixture of 2 × phosphorylated antibodies Tb-PSer (PKC) and EDTA is added after incubation at room temperature for 90 minutes to terminate the reaction, and the reaction is left at room temperature for 60 minutes. The values of excitation at 340nm, emission at 520nm and emission at 495nm were read on an Envision 2104Multilabel Reader to calculate RFU 520nm/RFU 495nm, calculating the inhibition rate by the following formula, drawing a curve by taking the Log value of the concentration of the inhibitor as an X axis and the inhibition rate as a Y axis, and calculating the IC by using Graphpad7.0 50 。
Inhibition％＝(max-Lantha signal ratio)/(max-min)*100
"min" is the reading from the negative control well for reactions without enzyme; "max" is the positive control well reading without compound added.
Table 1: test Compounds for in vitro inhibitory Activity against recombinant HPK1 enzymes
Figure BDA0003677664240000751
Figure BDA0003677664240000761
In vitro enzyme test results show that the compound has good inhibition effect on HPK1 enzyme, and the inhibition activity is obviously superior to that of a control compound.
Test example 2: jurkat Pho-SLP76 (Ser 376) ELISA assay
Jurkat cells were used to evaluate the inhibitory activity of the compounds synthesized in examples 1 to 17 on the intracellular HPK1 enzyme activity. Cells were cultured in RPMI1640 complete medium (RPMI-1640, 10% fetal bovine serum, 1% Pen/Strep). The cells were collected by centrifugation at 300 Xg for 10 minutes, resuspended in RPMI-1640 without FBS at 1X 10 5 Each cell was seeded in a 96-well cell culture plate, and the test compound was added to the 96-well plate in a diluted concentration gradient, while positive control wells containing no compound, blank control wells containing only medium, and control wells containing control compound 1 at the same concentration as the test compound were set, and then the concentration of CO was 5% at 37 ℃ 2 Then adding anti-human CD3 (OKT-3) with the final concentration of 1ug/mL for stimulating for 30 minutes, setting a negative control hole without the stimulator OKT-3, placing a 96-well plate in a horizontal centrifuge for centrifuging at 1200rpm for 1 minute, slowly sucking away the supernatant culture medium, and then adding the precooled lysate to fine particlesIn the wells, the cells were placed on ice for 30 minutes to sufficiently lyse the cells, and the cell lysates were transferred to pre-coated ELISA plates and used
Figure BDA0003677664240000763
Phospho-SLP76 (Ser 376) Sandwich ELISA Kit (CST, 78222C), intracellular Phospho-SLP76 levels were determined according to the supplier's protocol. Calculating the inhibition rate of absorbance signal value at 450nm detected by microplate reader by the following formula, drawing curve with the concentration Log value of compound as X axis and the inhibition rate as Y axis, and calculating with Graphpad7.0 to obtain IC 50 。
Inhibition% = (max-compound pore absorbance value)/(max-min) × 100
"min" is the absorbance value of negative control wells incubated without adding the stimulator OKT-3; "max" is the absorbance value of the positive control well incubated without compound.
Table 2: in vitro inhibitory Activity of test Compounds on Jurkat Pho-SLP76 (Ser 376)
Figure BDA0003677664240000762
Figure BDA0003677664240000771
Cell test results show that the compound has good inhibition effect on HPK1 enzyme, and the inhibition activity is obviously superior to that of a control compound.

Claims (14)

1. A compound of formula I, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs thereof:
Figure FDA0003677664230000011
wherein, the first and the second end of the pipe are connected with each other,
R 1 independently is H, cyano, halogen, substituted by 1-5 identically or differently halogen-substituted C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl radical, C 3 -C 6 Cycloalkyl or-O- (C) 1 -C 6 Alkyl groups);
ring A is independently 6-10 membered aryl, 5-8 membered heteroaryl, 4-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl or C 3 -C 10 A cycloalkenyl group;
R 2 independently is
Figure FDA0003677664230000012
R 21 And R 22 Each independently of the other being unsubstituted or substituted by R 211 Substituted C 1 -C 6 Alkyl, or, unsubstituted or substituted by R 211 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 211 Substituted C 1 -C 6 Alkyl or by R 211 Substituted C 3 -C 6 In the cycloalkyl group, the R is 211 The substitution may be one or more, and R is 211 Each independently is the following substituent: hydroxy, halogen, -O- (C) 1 -C 6 Alkyl group), C 1 -C 6 Alkylamino or C 3 -C 6 A cycloalkyl group; when the number of the substituents is plural, the substituents may be the same or different; the R is 21 And R 22 At least one is represented by R 211 Substituted C 1 -C 6 Alkyl or by R 211 Substituted C 3 -C 6 A cycloalkyl group;
ring B is independently unsubstituted or substituted with R 23 Substituted 4-8 membered heterocycloalkyl, or unsubstituted or substituted by R 23 A substituted 6-11 membered hetero spirocycloalkyl group; the quilt R 23 Substituted 4-8 membered heterocycloalkyl or by R 23 In the substituted 6-to 11-membered heterospirocycloalkyl group, said R 23 The substitution may be one or more, R 23 Each independently is the following substituent: hydroxy, cyano, halogen, C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group; when the substituent isWhen plural, the substituents are the same or different;
R 24 independently is unsubstituted or substituted by R 241 Substituted C 3 -C 6 A cycloalkyl group; the quilt R 241 Substituted C 3 -C 6 In the cycloalkyl group, said R 241 The substitution may be one or more, R 241 Each independently is the following substituent: cyano, halogen, C substituted by 1-5 halogen, the same or different 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl or C 3 -C 6 A cycloalkyl group; when the number of the substituents is plural, the substituents may be the same or different;
R 3 independently halogen, CN, C substituted by 1-5 same or different halogens 1 -C 6 Alkyl or C 1 -C 6 An alkyl group;
n is 0,1, 2 or 3;
R 4 and R 5 Each independently of the other is C substituted by 1 to 5 identical or different halogens 1 -C 6 Alkyl or C 1 -C 6 An alkyl group; or R 4 And R 5 The carbon atoms to which they are commonly attached may form a 4-8 membered cycloalkyl or 4-8 membered heterocycloalkyl group.
2. The compound of claim 1, which is
Figure FDA0003677664230000021
。
3. A compound according to any one of claims 1 to 2, which is of formula (III) or formula (IV)
Figure FDA0003677664230000022
Wherein the content of the first and second substances,
ring C is independently 5-8 membered heteroaryl, 4-8 membered heterocycloalkyl, or 4-8 membered heterocycloalkenyl.
4. A compound according to any one of claims 1 to 2, which is of formula (V) or formula (VI),
Figure FDA0003677664230000023
wherein the content of the first and second substances,
ring D is 6-10 membered aryl or C 3 -C 10 A cycloalkenyl group;
R 2 is composed of
Figure FDA0003677664230000024
5. The compound of claim 1,
when ring a is a 6-10 membered aryl, the 6-10 membered aryl is benzene or naphthalene, preferably benzene;
and/or, when ring a is a 5-8 membered heteroaryl, said 5-8 membered heteroaryl is pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl or triazinyl, preferably pyrrolyl, oxazolyl, thiazolyl or pyridyl;
and/or, when ring a is 4-8 membered heterocycloalkyl, said 4-8 membered heterocycloalkyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, morpholinyl or piperazinyl, preferably azetidinyl, morpholinyl or morpholinyl;
and/or, when ring a is 4-8 membered heterocycloalkenyl, said 4-8 membered heterocycloalkenyl is 4H-pyranyl, 2H-pyranyl, tetrahydropyridinyl, 2,5-dihydro-1H-pyrrolyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothienyl, 2,3-dihydrothienyl, or 4,5-dihydrooxazolyl, preferably tetrahydropyridinyl;
and/or, when ring A is C 3 -C 10 Cycloalkenyl groupWhen C is in contact with 3 -C 10 Cycloalkenyl is cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, preferably cyclohexenyl;
and/or, R 2 Is composed of
Figure FDA0003677664230000031
And/or, R 2 Is composed of
Figure FDA0003677664230000032
And/or when R 21 And R 22 Is unsubstituted or substituted by R 211 Substituted C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl, preferably methyl, ethyl, n-propyl or isobutyl;
and/or when R 21 And R 22 Is unsubstituted or substituted by R 211 Substituted C 3 -C 6 When a cycloalkyl group is said C 3 -C 6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl;
and/or, R 21 And R 22 Is represented by R 211 Substituted C 1 -C 6 Alkyl or by R 211 Substituted C 3 -C 6 When cycloalkyl is present, said R 211 The number of substitutions is 1,2,3,4 or 5, preferably 1 or 2;
and/or, R 211 Is a hydroxyl group;
and/or when R 211 When halogen is used, the halogen is F, cl, br or I, preferably F or Cl;
and/or when R 211 is-O- (C) 1 -C 6 Alkyl) of said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl, n-propyl or isopropyl;
and/or when R 211 Is C 1 -C 6 When there is an alkylamino group, the radical C 1 -C 6 Alkylamino is-NHCH 3 、-N(CH 3 ) 2 、-NHCH 2 CH 3 、-N(CH 3 )CH 2 CH 3 、-NHCH 2 CH 2 CH 3 or-NHCH 2 (CH 3 ) 2 preferably-NHCH 3 、-N(CH 3 ) 2 or-NHCH 2 CH 3 ；
And/or when R 211 Is C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl;
and/or, R 2 Is composed of
Figure FDA0003677664230000041
And/or, when ring B is unsubstituted or substituted by R 23 Substituted 4-8 membered heterocycloalkyl, said 4-8 membered heterocycloalkyl is aziridinyl, azetidinyl, azepinyl, azacyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl, preferably azetidinyl, azepinyl or morpholinyl;
and/or, when ring B is unsubstituted or substituted by R 23 When substituted 6-11 membered hetero spiro cycloalkyl, the 6-11 membered hetero spiro cycloalkyl is preferably azaspiro [3.3]]Heptyl, oxaazaspiro [3.3]]Heptyl, thiaazaspiro [3.3]]Heptyl or oxazaspiro [5.3]]Nonyl, more preferably oxaazaspiro [3.3]]A heptyl group;
and/or ring B is substituted by R 23 Substituted 4-8 membered heterocycloalkyl or by R 23 Substituted 6-11 membered heterospirocycloalkyl, said R 23 The number of substitutions is 1,2,3,4 or 5, preferably 1 or 2;
and/or, R 23 Is a hydroxyl group;
and/or, R 23 Is cyano;
and/or when R 23 When it is halogen, the halogen is F,Cl, br or I, preferably F or Cl;
and/or when R 23 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl;
and/or when R 23 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 When alkyl, the halogen is F, cl, br or I, preferably F or Cl;
and/or when R 23 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 In the case of alkyl, the number of said halogen is 1,2,3,4 or 5, preferably 1,2 or 3;
and/or when R 23 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl;
and/or when R 23 Is C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl;
and/or, R 2 Is composed of
Figure FDA0003677664230000042
And/or when R 24 Is unsubstituted or substituted by R 241 Substituted C 3 -C 6 When a cycloalkyl group is said C 3 -C 6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl;
and/or when R 24 Is unsubstituted or substituted by R 241 Substituted C 3 -C 6 When cycloalkyl is present, said R 241 The number of substitutions is 1,2,3,4 or 5, preferably 1 or 2;
and/or, R 241 Is cyano;
and/or when R 241 When it is halogen, theHalogen is F, cl, br or I, preferably F or Cl;
and/or when R 241 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl;
and/or when R 241 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 When alkyl, the halogen is F, cl, br or I, preferably F or Cl;
and/or when R 241 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 In the case of alkyl, the number of said halogen is 1,2,3,4 or 5, preferably 1,2 or 3;
and/or when R 241 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl;
and/or when R 241 Is C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl;
and/or n is 0,1 or 2;
and/or when R 3 When halogen is used, the halogen is F, cl, br or I, preferably F or Cl;
and/or when R 3 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl;
and/or when R 3 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 When alkyl, the halogen is F, cl, br or I, preferably F or Cl;
and/or when R 3 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 In the case of alkyl, the number of said halogens is 1,2,3,4 or 5,preferably 1,2 or 3;
and/or when R 3 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl.
6. The compound of claim 1,
when R is 4 And R 5 Is C 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl;
and/or when R 4 And R 5 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 When alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl or isopropyl, preferably methyl or ethyl;
and/or when R 4 And R 5 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 When alkyl, the halogen is F, cl, br or I, preferably F or Cl;
and/or when R 4 And R 5 Is C substituted by 1 to 5 identical or different halogens 1 -C 6 In the case of alkyl, the number of said halogen is 1,2,3,4 or 5, preferably 1,2 or 3;
and/or, R 4 And R 5 When the carbon atoms to which they are both attached form a 4-8 membered heterocycloalkyl group, the 4-8 membered heterocycloalkyl group is aziridinyl, oxetanyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl, preferably oxetanyl.
7. The compound of claim 1,
Figure FDA0003677664230000061
is composed of
Figure FDA0003677664230000062
Figure FDA0003677664230000063
Preferably is
Figure FDA0003677664230000064
And/or the presence of a gas in the gas,
Figure FDA0003677664230000065
is composed of
Figure FDA0003677664230000066
Figure FDA0003677664230000067
Preferably is
Figure FDA0003677664230000068
And/or the presence of a gas in the gas,
Figure FDA0003677664230000069
is composed of
Figure FDA00036776642300000610
Figure FDA00036776642300000611
Preferably is
Figure FDA00036776642300000612
Figure FDA00036776642300000613
8. The compound of claim 1,
R 1 is H;
and/or the presence of a gas in the gas,
Figure FDA0003677664230000071
is composed of
Figure FDA0003677664230000072
And/or, R 2 Is composed of
Figure FDA0003677664230000073
And/or when R 2 Is composed of
Figure FDA0003677664230000074
When is in use, the
Figure FDA0003677664230000075
Is composed of
Figure FDA0003677664230000076
Figure FDA0003677664230000077
And/or when R 2 Is composed of
Figure FDA0003677664230000078
When is in use, the
Figure FDA0003677664230000079
Is composed of
Figure FDA00036776642300000710
Figure FDA00036776642300000711
And/or when R 2 Is composed of
Figure FDA00036776642300000712
When is in use, the
Figure FDA00036776642300000713
Is composed of
Figure FDA00036776642300000714
And/or, R 4 And R 5 Is methyl;
and/or, R 4 And R 5 The heterocyclic ring formed by the carbon atoms to which they are both attached is
Figure FDA00036776642300000715
9. The compound of claim 1, selected from any one of the following:
Figure FDA0003677664230000081
Figure FDA0003677664230000082
or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof.
10. A pharmaceutical composition, comprising a compound of formula I, as defined in any one of claims 1 to 9, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof.
11. The pharmaceutical composition of claim 10, further comprising a pharmaceutically acceptable excipient.
12. Use of a compound, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof according to any one of claims 1 to 9 in combination with a PD-1/PD-L1/CTLA-4 antibody or a PD-1/PD-L1/CTLA-4 inhibitor for the manufacture of a medicament for the treatment or prevention of a disease associated with HPK 1.
13. Use of a compound according to any one of claims 1-9, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof, or a pharmaceutical composition according to claim 10 or 11, for the preparation of a medicament for the treatment or prophylaxis of a disease associated with HPK 1.
14. The use according to claim 12 or 13, wherein the HPK1 associated disease comprises at least one selected from the group consisting of: solid tumors, hematologic cancers, non-small cell lung cancer, cutaneous melanoma, merkel cell carcinoma, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the anal canal or skin, urothelial cancer, clear cell or non-clear cell renal cell carcinoma, triple negative breast cancer, endometrial cancer, cervical cancer, gastroesophageal cancer, and hepatocellular carcinoma.
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