WO2022258044A1 - 吡咯并吡啶酮类化合物及其制备方法和用途 - Google Patents
吡咯并吡啶酮类化合物及其制备方法和用途 Download PDFInfo
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- WO2022258044A1 WO2022258044A1 PCT/CN2022/098098 CN2022098098W WO2022258044A1 WO 2022258044 A1 WO2022258044 A1 WO 2022258044A1 CN 2022098098 W CN2022098098 W CN 2022098098W WO 2022258044 A1 WO2022258044 A1 WO 2022258044A1
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- Prior art keywords
- alkyl
- cycloalkyl
- heterocyclyl
- aryl
- heteroaryl
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
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- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
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- HQMYWQCBINPHBB-UHFFFAOYSA-N tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate Chemical compound CC1CC(=O)CCN1C(=O)OC(C)(C)C HQMYWQCBINPHBB-UHFFFAOYSA-N 0.000 description 1
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
Definitions
- the invention relates to the field of medical technology, in particular to pyrrolopyridone compounds and preparation methods, and the use of the compounds in the preparation of medicines for treating or preventing HPK1-mediated diseases and related diseases.
- Hematopoietic progenitor kinase 1 HPK1, Hematopoietic progenitor kinase 1
- HPK1 Hematopoietic progenitor kinase 1
- MAP4K1 mitogen-activated protein kinase kinase kinase kinase 1
- MAP4K5 mitogen-activated protein kinase kinase kinase kinase 1
- HPK1 The main process of HPK1 participating in the regulation of TCR is: (1) TCR binds to extracellular antigens through MHC, thereby activating the TCR pathway to transmit signals to downstream adapter protein molecules; (2) the adapter protein tyrosine kinase Lck and Zap70 activate SLP76, Then phosphorylate HPK1; (3) The activated HPK1 will then phosphorylate the receptor protein SLP-76; (4) The phosphorylation reaction of SLP-76 provides a variety of receptor proteins for 14-3-3 (TCR pathway inhibitor protein) (5) The SLP-76 phosphorylated complex participates in the downregulation of the Erk signaling pathway, and is connected to the ubiquitination degradation process of SLP76, resulting in a decrease in the TCR signaling pathway and T cell proliferation.
- HPK1 can negatively regulate the TCR signaling pathway. Therefore, HPK1 can serve as a new regulatory mechanism of T cell-mediated immune response and become a new immune anti-tumor target.
- T cell receptor (TCR)-mediated T cell activation plays a crucial role in the development of thymic T cells, the differentiation of T cell subsets, and the function of effector T cells.
- TCR can specifically recognize the antigenic peptide (peptide) presented by MHC on the surface of the antigen-presenting cell, and convert the extracellular antigenic peptide into a peptide that can be delivered to the inside of the cell through the recognition of MHC (major histocompatibility complex) Signal.
- the MHC molecules on the surface of antigen-presenting cells include MHC class II and MHC class I molecules, which can be specifically recognized by the corresponding co-receptor CD4 and CD8 molecules on the surface of CD4+ and CD8+ T cells, respectively, and then can cause downstream signaling pathways.
- Typical intracellular signals activated by TCR include MAPK (mitogen-activated protein kinases, mitogen-activated protein kinases), PKC (protein kinase C, protein kinase C) and calcium (calcium ions) and other signaling pathways. Activation of these signals ultimately activates specific gene expression of T cells, causes cell proliferation, and allows T cells to differentiate into effector T cells.
- HPK1 inhibitors are effective in malignant solid tumors or blood cancers (such as acute myeloid leukemia, bladder cancer, breast cancer, colon cancer, lung cancer, pancreatic cancer, melanoma), autoimmune diseases (such as systemic lupus erythematosus, psoriatic arthritis) and inflammatory response play an important role.
- blood cancers such as acute myeloid leukemia, bladder cancer, breast cancer, colon cancer, lung cancer, pancreatic cancer, melanoma
- autoimmune diseases such as systemic lupus erythematosus, psoriatic arthritis
- inflammatory response play an important role.
- WO2021050964, WO2016205942, CN109721620A, WO2019238067, WO2020103896, WO2021000925 disclose HPK1 inhibitors and uses thereof.
- HPK1 can interact with many adapter proteins, such as SLP-76 family, CARD11, HIS, HIP-55, GRB2 family, LAT, CRK family, etc., activate the JNK/SAPK signaling pathway of hematopoietic stem cells, thereby negatively regulating the TCR pathway adjust.
- the present invention aims to provide a compound with a novel structure of HPK1 inhibitory activity, which has good physical and chemical properties and pharmaceutical properties, and is selective in HPK1. It has good performance in aspect, and the compound of the present invention or its pharmaceutically acceptable salt has good safety, good drug effect and high bioavailability, therefore, the compound of the present invention has better application in the treatment of diseases mediated by HPK1 potential.
- One object of the present invention is to provide pyrrolopyridone compounds, which have good HPK1 inhibitory activity, show good HPK1 selectivity, and have good druggability, and can be used for the treatment or prevention of related diseases mediated by HPK1. disease.
- the present invention discloses pyrrolopyridones described in formula (I).
- the first embodiment includes the following aspects:
- R 1 is selected from hydrogen or -C 1-8 alkyl, said -C 1-8 alkyl is optionally substituted by at least one substituent R 1d ;
- R 1d is independently hydrogen, amino, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, Oxo, -CN, -NO 2 ;
- X is selected from NH or N C 1-8 alkyl
- R is selected from hydrogen , carboxyl, cyano, nitro, halogen atom, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl radical, heteroaryl, -OR 2a , -SO 2 R 2a , -SO 2 NR 2a R 2b , -COR 2a , -CO 2 R 2a , -CONR 2a R 2b , -POR 2a R 2b , -NR 2a R 2b , -NR 2a COR 2b , -NR 2a CONR 2b R 2c , -NR 2a CO 2 R 2b , -NR 2a SO 2 NR 2b R 2c , -NR 2a SO 2 R 2b , the -C 1-8 Alkyl, -C alkenyl, -C alkynyl , cycloalkyl, hetero
- R 2a , R 2b , and R 2c are each independently hydrogen, hydroxyl, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl base, or heteroaryl, each of the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted by at least one substituent R 2e ; or
- R 2d and R 2e are each independently hydrogen, amino, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl, oxo, -CN, -NO 2 , -OR 2f , -SO 2 R 2f , -SO 2 NR 2f R 2g , -COR 2f , -CO 2 R 2f , -CONR 2f R 2g , - NR 2f R 2g , -NR 2f COR 2g , -NR 2f CONR 2g R 2h , -NR 2f CO 2 R 2f , -NR 2f SO 2 NR 2g R 2h , or -NR 2f SO 2 R 2g , the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloal
- R 2f , R 2g , R 2h , R 2i , and R 2j are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl , cycloalkyl, heterocyclyl, aryl, or heteroaryl;
- R is selected from hydrogen, hydroxyl, carboxyl, cyano, nitro, halogen atom, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl , Aryl, Heteroaryl, -OR 3a , -SR 3a , -SO 2 R 3a , -SO 2 NR 3a R 3b , -COR 3a , -CO 2 R 3a , -CONR 3a R 3b , -POR 3a R 3b , -NR 3a R 3b , -NR 3a COR 3b , -NR 3a CONR 3b R 3c , -NR 3a CO 2 R 3b , -NR 3a SO 2 NR 3b R 3c , -NR 3a SO 2 R 3b , the Each of -C 1-8 alkyl, -C 2-8 alkenyl, -C
- R 3a , R 3b , and R 3c are each independently hydrogen, hydroxyl, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl base, or heteroaryl, each of the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted by at least one substituent R 3e ; or
- R 3d and R 3e are each independently hydrogen, amino, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl, oxo, -CN, -NO 2 , -OR 3f , -SO 2 R 3f , -SO 2 NR 3f R 3g , -COR 3f , -CO 2 R 3f , -CONR 3f R 3g , - NR 3f R 3g , -NR 3f COR 3g , -NR 3f CONR 3g R 3h , -NR 3f CO 2 R 3f , -NR 3f SO 2 NR 3g R 3h , or -NR 3f SO 2 R 3g , the -C 1-8 alkyl , -C alkenyl, -C alkynyl , cycloalkyl
- R 3f and R 3g together with one or more atoms to which they are attached form a 3- to 12-membered ring containing 0, 1, 2 or 3 nitrogen atoms independently selected from , heteroatoms in oxygen or sulfur as one or more ring members, the rings are optionally substituted by at least one substituent R 3k ;
- Each R 3k is independently selected from halogen, -C 1-8 alkyl, -OR 3i , -NR 3i R 3j , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and said -C 1 -8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally replaced by at least one member selected from hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituent substitution;
- R 3f , R 3g , R 3h , R 3i , and R 3j are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl , cycloalkyl, heterocyclyl, aryl, or heteroaryl;
- X 1 , X 2 , X 3 , and X 4 are each independently selected from N or C, provided that the valence theory is satisfied (ie, the resulting valence is chemically possible);
- R is selected from hydrogen, hydroxyl, amino, oxo, carboxyl, cyano, nitro, halogen atom, -C 1-8 alkyl , -C 2-8 alkenyl, -C 2-8 alkynyl, ring Alkyl, heterocyclyl, aryl, heteroaryl, -OR 4a , -SR 4a , -SO 2 R 4a , -SO 2 NR 4a R 4b , -COR 4a , -CO 2 R 4a , -CONR 4a R 4b , -POR 4a R 4b , -NR 4a R 4b , -NR 4a COR 4b , -NR 4a CONR 4b R 4c , -NR 4a CO 2 R 4b , -NR 4a SO 2 NR 4b R 4c , -NR 4a SO 2 R 4b , each of the -C 1-8 alkyl, -C 2-8 alkeny
- R 4a , R 4b , and R 4c are each independently hydrogen, hydroxyl, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl base, or heteroaryl, each of the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted by at least one substituent R 4e ; or
- R 4d and R 4e are each independently hydrogen, amino, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl, oxo, -CN, -NO 2 , -OR 4f , -SO 2 R 4f , -SO 2 NR 4f R 4g , -COR 4f , -CO 2 R 4f , -CONR 4f R 4g , - NR 4f R 4g , -NR 4f COR 4g , -NR 4f CONR 4g R 4h , -NR 4f CO 2 R 4f , -NR 4f SO 2 NR 4g R 4h , or -NR 4f SO 2 R 4g , the -C Each of 1-8 alkyl, -C alkenyl, -C alkynyl , cycloalky
- Each R 4k is independently selected from halogen, -C 1-8 alkyl, -OR 4i , -NR 4i R 4j , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and said -C 1 -8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally replaced by at least one member selected from hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituent substitution;
- R 4f , R 4g , R 4h , R 4i , and R 4j are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl , cycloalkyl, heterocyclyl, aryl, or heteroaryl;
- n 0, 1, 2, 3 or 4, provided the valence theory has been satisfied (ie, the resulting valences are chemically possible).
- Aspect 2 The compound according to Aspect 1, wherein X is NH, is one of the preferred embodiments.
- Aspect 3 The compound according to any one of Aspect 1-Aspect 2, wherein X 1 , X 2 , X 3 , and X 4 are all C, which is one of the preferred options.
- Aspect 4 The compound according to any one of Aspect 1-Aspect 2, wherein any one of X 1 , X 2 , X 3 , X 4 is N, and the rest are C.
- Aspect 5 The compound according to any one of Aspect 1-Aspect 2, wherein any two of X 1 , X 2 , X 3 , and X 4 are N, and the rest are C.
- Aspect 6 The compound according to any one of Aspect 1-Aspect 5, wherein R 1 is hydrogen, which is one of the preferred options.
- Aspect 7 The compound according to any one of aspects 1-5, wherein R 1 is selected from -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl.
- Aspect 8 A compound according to any one of aspects 1-5, wherein R is -C 1-8 alkyl optionally substituted by at least one substituent R 1d (preferably -C 1-6 alkyl , more preferably methyl or ethyl), R 1d is halogen, preferably fluorine, chlorine, bromine, more preferably fluorine.
- Aspect 10 A compound according to any one of aspects 1 to 9, wherein R 2 is selected from hydrogen, cyano, -SO 2 R 2a , -POR 2a R 2b , - optionally substituted by at least one substituent R 2d C 1-8 alkyl.
- Aspect 11 Compounds according to aspect 10, wherein R 2 is hydrogen or cyano.
- Aspect 12 Compound according to aspect 10, wherein R 2 is -SO 2 R 2a .
- Aspect 13 A compound according to aspect 12, wherein R 2a is selected from -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl.
- Aspect 14 A compound according to any one of aspect 12-aspect 13 , wherein R is
- Aspect 15 Compound according to aspect 10, wherein R 2 is -POR 2a R 2b .
- Aspect 16 the compound according to aspect 15, wherein R 2a and R 2b are selected from -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl.
- Aspect 17 A compound according to any one of aspects 15-16, wherein R is
- Aspect 18 A compound according to aspect 10, wherein R 2 is -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl, optionally substituted by at least one substituent R 2d .
- Aspect 19 Compounds according to aspect 18, wherein R 2d is selected from halogen, preferably fluorine, chlorine, bromine, more preferably fluorine.
- Aspect 20 Compounds according to any one of aspects 18-19, wherein R is
- Aspect 21 A compound according to any one of aspects 10-20, wherein R is H, cyano, Preferably cyano, More preferred is cyano.
- Aspect 22 A compound according to any one of aspects 1-21, wherein R is hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or hetero Each aryl group is optionally substituted by at least one substituent R 3d ;
- R 3d is hydrogen, amino, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxygen Substitute, -CN, -NO 2 , -OR 3f , -SO 2 R 3f , -SO 2 NR 3f R 3g , -COR 3f , -CO 2 R 3f , -CONR 3f R 3g , -NR 3f R 3g , -NR 3f COR 3g , -NR 3f CONR 3g R 3h , -NR 3f CO 2 R 3f , -NR 3f SO 2 NR 3g R 3h , or -NR 3f SO 2 R 3g , the -C 1-8 alkyl , -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl
- R 3f and R 3g together with one or more atoms to which they are attached form a 3- to 12-membered ring containing 0, 1, 2 or 3 nitrogen atoms independently selected from , heteroatoms in oxygen or sulfur as one or more ring members, the rings are optionally substituted by at least one substituent R 3k ;
- R 3f , R 3g , R 3h , R 3i , R 3j and R 3k are each independently hydrogen, -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 24 A compound according to aspect 23, wherein said aryl group is phenyl.
- Aspect 25 Compounds according to any one of aspects 23 to 24, wherein R is selected from
- Aspect 26 Compounds according to aspect 22, wherein R 3 is heteroaryl optionally substituted by at least one substituent R 3d .
- Aspect 28 A compound according to aspect 27, wherein said heteroaryl is pyridyl, pyrrolyl, pyrimidinyl, pyrazolyl, oxazolyl, or triazolyl.
- Aspect 29 A compound according to aspect 26, wherein said heteroaryl is an 8 to 12 membered fused heteroaryl comprising one or two or three heteroatoms independently selected from oxygen, nitrogen or sulfur.
- Aspect 30 Compounds according to aspect 29, wherein said heteroaryl is
- Aspect 31 Compounds according to any one of aspects 26-30, wherein R 3d is hydrogen, halogen, amino, oxo, -C 1-8 alkyl, -CONR 3f R 3g , -NR 3f COR 3g , Wherein R 3f and R 3g are each independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl; or
- R 3f and R 3g together with the atom(s) to which they are attached form a 3 to 12 membered ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur As one or more ring members.
- Aspect 32 Compounds according to aspect 31, wherein R 3d is -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 33 Compounds according to aspect 31, wherein R 3d is hydrogen, halogen, amino.
- Aspect 34 A compound according to aspect 31, wherein R 3d is -NR 3f COR 3g in which R 3f and R 3g are each independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl base or ethyl.
- Aspect 35 Compound according to aspect 34, wherein -NR 3f COR 3g is
- Aspect 36 A compound according to aspect 31, wherein R 3d is -CONR 3f R 3g , R 3f and R 3g are each independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl base or ethyl.
- Aspect 37 Compounds according to aspect 36, wherein R 3f and R 3g together with the atom(s) to which they are attached form a 3 to 12 membered ring, preferably a 4-6 membered ring, said ring comprising 0, 1, 2 or 3 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members.
- Aspect 38 Compound according to any one of aspects 36-aspect 37, wherein -CONR 3f R 3g is selected from
- Aspect 39 Compounds according to any one of aspects 26-38, wherein R is selected from
- Aspect 40 Compounds according to Aspect 22, wherein R3 is hydrogen.
- Aspect 41 Compounds according to aspect 22, wherein R 3 is -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl.
- Aspect 42 A compound according to aspect 22, wherein R 3 is cycloalkyl, preferably C 3-6 cycloalkyl, more preferably
- Aspect 43 Compounds according to Aspect 22, wherein R 3 is heterocyclyl optionally substituted by at least one substituent R 3d , wherein R 3d is hydrogen, halogen, amino, oxo, halogen, -C 1-8 alkane -OR 3f , -NR 3f R 3g , -CONR 3f R 3g , -NR 3f COR 3g , wherein R 3f and R 3g are each independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 Alkyl, more preferably methyl or ethyl.
- a compound according to aspect 40 wherein said heterocyclyl is a 4 to 7 membered ring comprising one or two heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably comprising a nitrogen or oxygen atom as 5, 6, or 7 membered saturated rings of ring members.
- Aspect 45 A compound according to Aspect 44, wherein said heterocyclyl is piperidinyl, tetrahydropyrrolidinyl, tetrahydropyran, or piperazinyl.
- Aspect 46 Compounds according to any one of aspects 40 to 45, wherein R 3d is hydrogen, halogen, amino, oxo, -C 1-8 alkyl, -CONR 3f R 3g , -NR 3f COR 3g , Wherein R 3f and R 3g are each independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 47 Compounds according to aspect 46, wherein R 3d is hydrogen, oxo or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 48 Compounds according to any one of aspects 40-47, wherein R is selected from
- Aspect 49 Compounds according to any one of aspects 22 to 48, wherein R is selected from H, methyl, ethyl, isopropyl, Preferably H, ethyl, isopropyl,
- Aspect 50 Compounds according to any one of aspects 1-48, wherein n is 1, 2 or 3, R 4 is as defined in formula (I).
- R is selected from hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl , heterocycly
- R 4a , R 4b are each independently hydrogen, hydroxyl, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or hetero Aryl, each of the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally replaced by at least A substituent R 4e is substituted;
- R 4d and R 4e are each independently hydrogen, amino, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl, oxo, -CN, -NO 2 , -OR 4f , -SO 2 R 4f , -SO 2 NR 4f R 4g , -COR 4f , -CO 2 R 4f , -CONR 4f R 4g , - NR 4f R 4g , -NR 4f COR 4g , -NR 4f CONR 4g R 4h , -NR 4f CO 2 R 4f , -NR 4f SO 2 NR 4g R 4h , or -NR 4f SO 2 R 4g , the -C Each of 1-8 alkyl, -C alkenyl, -C alkynyl , cycloalky
- Each R 4k is independently selected from halogen, -C 1-8 alkyl, -OR 4i , -NR 4i R 4j , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and said -C 1 -8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally replaced by at least one member selected from hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituent substitution;
- R 4f , R 4g , R 4h , R 4i , and R 4j are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl , cycloalkyl, heterocyclyl, aryl, or heteroaryl.
- a compound according to aspect 51 wherein R is a ring selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, said cycloalkyl, heterocyclyl, aryl or heteroaryl Aryl groups are each optionally substituted by at least one substituent R 4d ;
- R is independently hydrogen, amino, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, Oxo, -CN, -NO 2 , -OR 4f , -SO 2 R 4f , -SO 2 NR 4f R 4g , -COR 4f , -CO 2 R 4f , -CONR 4f R 4g , -NR 4f R 4g , -NR 4f COR 4g , -NR 4f CONR 4g R 4h , -NR 4f CO 2 R 4f , -NR 4f SO 2 NR 4g R 4h , or -NR 4f SO 2 R 4g , the -C 1-8 alkane
- Each R 4k is independently selected from halogen, -C 1-8 alkyl, -OR 4i , -NR 4i R 4j , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and said -C 1 -8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally replaced by at least one member selected from hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituent substitution;
- R 4f , R 4g , R 4h , R 4i , and R 4j are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl , cycloalkyl, heterocyclyl, aryl, or heteroaryl.
- Aspect 53 Compounds according to aspect 52, wherein R4 is cycloalkyl optionally substituted by at least one substituent R4d ;
- the R 4d is independently selected from halogen, oxo, -C 1-8 alkyl, -OR 4f , or -NR 4f R 4g , and the -C 1-8 alkyl is optionally replaced by -OR 4i , -NR 4i R 4j replace;
- R 4f , R 4g , R 4i and R 4j are each independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 54 A compound according to aspect 53, wherein R 4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl optionally substituted by R 4d .
- Aspect 55 Compounds according to aspect 54, wherein R 4d is -C 1-8 alkyl optionally substituted by -NR 4i R 4j , preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 56 Compounds according to aspect 55, wherein R 4i and R 4j are independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl.
- Aspect 57 Compounds according to any of aspects 53 - aspect 56, wherein R4 is
- Aspect 58 Compounds according to aspect 52, wherein R 4 is heterocyclyl optionally substituted by at least one substituent R 4d ;
- Aspect 60 A compound according to aspect 59, wherein the heterocyclyl is a monocyclic 4, 5, 6, or 7 membered saturated heterocyclyl comprising one or 2 nitrogen atoms as ring members.
- Aspect 61 A compound according to aspect 59 of aspect 60, wherein heterocyclyl is piperidinyl, or piperazinyl.
- Aspect 62 Compounds according to aspect 59, wherein heterocyclyl is a monocyclic 4, 5, 6, or 7 membered saturated heterocyclyl comprising one or 2 oxygen atoms as ring members.
- Aspect 63 Compounds according to Aspect 62, wherein heterocyclyl is
- Aspect 64 A compound according to aspect 59, wherein the heterocyclyl is a monocyclic 4, 5, 6, or 7 membered saturated heterocyclyl comprising one nitrogen atom and one oxygen atom as ring members.
- Aspect 65 Compounds according to Aspect 64, wherein heterocyclyl is
- Aspect 66 A compound according to aspect 58-, wherein heterocyclyl is a 7 to 12 membered fused heterocyclyl comprising one or two or three heteroatoms independently selected from oxygen, nitrogen or sulfur.
- a compound according to aspect 66, wherein the heterocyclyl is an 8-10 membered spirocyclic heterocyclyl comprising 1-2 nitrogen atoms, preferably
- Aspect 68 A compound according to aspect 66, wherein the heterocyclyl is an 8-10 membered bridged ring heterocyclyl comprising 1-2 nitrogen atoms, preferably
- Aspect 69 A compound according to any one of aspects 52-aspect 68, wherein R 4 is a ring optionally substituted by at least one substituent R 4d , said ring being selected from C 3-10 cycloalkyl, comprising 4, 5, 6, or 7-membered heterocyclic groups independently selected from nitrogen, oxygen, or optionally oxidized heteroatoms in sulfur, or containing one or two or three independently selected from oxygen, nitrogen or a 7- to 12-membered fused heterocyclyl of a heteroatom in sulfur;
- R 4 is a 4-7 membered monocyclic heterocyclic group or a 7-9 membered condensed heterocyclyl.
- Aspect 70 Compounds according to aspect 69, wherein R 4 is a ring optionally substituted by at least one substituent R 4d , said ring being cyclopropyl, piperidinyl, piperazinyl, Preferably piperidinyl, piperazinyl, more preferred further preferred
- Aspect 71 A compound according to any one of aspects 58-aspect 70, aspect 67, wherein R 4d is independently selected from hydrogen, halogen, oxo, -C 1-8 alkyl, cycloalkyl. hydrogen, halogen, oxo, -C 1-8 alkyl, cycloalkyl, heterocyclyl, -OR 4f , or -NR 4f R 4g , the -C 1-8 alkyl, cycloalkyl,
- the heterocyclic groups are each optionally substituted by at least one substituent R 4k as defined in formula (I), wherein R 4f and R 4g are as defined in formula (I), preferably hydrogen or -C 1-6 alkane group, more preferably methyl or ethyl.
- Aspect 72 Compounds according to aspect 71, wherein R 4k is selected from halogen, heterocyclyl, -C 1-8 alkyl, -OR 4i , -NR 4i R 4j ,
- R 4i and R 4j are each independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 73 Compounds according to Aspect 71, wherein R 4d is hydrogen.
- Aspect 74 Compounds according to Aspect 71, wherein R 4d is -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 75 Compounds according to aspect 71, wherein R 4d is -C 1-8 alkyl, preferably -C 1-6 alkyl , more preferably methyl or ethyl, optionally substituted by at least one -OR 4i .
- Aspect 76 Compounds according to aspect 75, wherein R 4i is hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 77 Compounds according to any one of aspects 75 to 76, wherein R 4d is
- Aspect 78 Compounds according to aspect 71, wherein R 4d is -C 1-8 alkyl optionally substituted by at least one -NR 4i R 4j , preferably -C 1-6 alkyl, more preferably methyl or ethyl .
- Aspect 79 Compounds according to aspect 78, wherein R 4i and R 4j are independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl.
- Aspect 80 Compounds according to Aspect 71, wherein R 4d is -C 1-8 alkyl optionally substituted by at least one heterocyclyl, preferably -C 1-6 alkyl , more preferably methyl or ethyl.
- Aspect 81 Compounds according to Aspect 80, wherein heterocyclyl is a 4, 5, 6, or 7 membered heterocyclyl comprising one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur.
- Aspect 82 Compounds according to any one of aspect 80-aspect 81, wherein R 4d is
- Aspect 83 Compounds according to Aspect 71, wherein R 4d is cycloalkyl, preferably C 4-6 cycloalkyl, more preferably C 4 cycloalkyl.
- Aspect 84 Compounds according to Aspect 71, wherein R 4d is a 4, 5, 6, or 7 membered heterocyclyl comprising one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur.
- Aspect 86 Compounds according to any one of aspects 71 to 85, wherein R 4d is independently selected from hydrogen, halogen, oxo, -C 1- 8 alkyl, cycloalkyl, heterocyclyl, -OR 4f , or -NR 4f R 4g , each of the -C 1-8 alkyl, cycloalkyl, and heterocyclic groups is optionally substituted by at least one substituent R 4k ,
- R 4k are each selected from halogen, heterocyclyl, -C 1-8 alkyl, -OR 4i , -NR 4i R 4j ,
- R 4i and R 4j are each independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl;
- R 4d is H, -C 1-8 alkyl, said -C 1-8 alkyl is optionally substituted by at least one substituent R 4k ;
- R 4k is independently heterocyclyl, hydroxyl;
- Aspect 87 Compounds according to any one of aspects 71 to 85, wherein R 4d is
- Aspect 88 Compounds according to any of aspects 52-aspect 87, wherein R 4 is
- Aspect 89 Compounds according to Aspect 51, wherein R 4 is selected from hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -OR 4a , -SR 4a , - SO 2 R 4a , -SO 2 NR 4a R 4b , -COR 4a , -CO 2 R 4a , -CONR 4a R 4b , -POR 4a R 4b , -NR 4a R 4b , -NR 4a COR 4b , -NR 4a CO 2 R 4b -NR 4a SO 2 R 4b , each of the -C 1-8 alkyl, -C 2-8 alkenyl, and -C 2-8 alkynyl is optionally substituted by at least one substituent R 4d ;
- R 4a , R 4b are each independently hydrogen, hydroxyl, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or hetero Aryl, each of the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally replaced by at least A substituent R 4e is substituted;
- R 4d and R 4e are each independently hydrogen, amino, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl, oxo, -CN, -NO 2 , -OR 4f , -SO 2 R 4f , -SO 2 NR 4f R 4g , -COR 4f , -CO 2 R 4f , -CONR 4f R 4g , - NR 4f R 4g , -NR 4f COR 4g , -NR 4f CONR 4g R 4h , -NR 4f CO 2 R 4f , -NR 4f SO 2 NR 4g R 4h , or -NR 4f SO 2 R 4g , the -C Each of 1-8 alkyl, -C alkenyl, -C alkynyl , cycloalky
- Each R 4k is independently selected from halogen, -C 1-8 alkyl, -OR 4i , -NR 4i R 4j , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and said -C 1 -8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally replaced by at least one member selected from hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituent substitution;
- R 4f , R 4g , R 4h , R 4i , and R 4j are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl , cycloalkyl, heterocyclyl, aryl, or heteroaryl.
- Aspect 90 Compounds according to Aspect 89, wherein R4 is hydrogen .
- Aspect 91 Compounds according to aspect 89, wherein R 4 is -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 92 Compounds according to aspect 89, wherein R 4 is -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl or ethyl), optionally substituted by at least one substituent R 4d , R 4d is independently -NR 4f R 4g , and R 4f and R 4g are each independently hydrogen or -C 1-8 alkyl.
- Aspect 94 A compound according to Aspect 89, wherein R 4 is -NR 4a R 4b , R 4a , R 4b are each independently hydrogen or -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl or ethyl), or cycloalkyl (preferably monocyclic-C 3-8 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), the -C 1-8 alkane and cycloalkyl are each optionally substituted with at least one substituent R 4e as defined in formula (I).
- Aspect 95 Compounds according to Aspect 94, wherein R 4e is independently hydrogen, amino, halogen (preferably fluoro, chloro, bromo, more preferably fluoro).
- Aspect 96 Compounds according to any one of aspects 94-95, wherein R 4 is
- Aspect 97 Compounds according to Aspect 52, wherein R 4 is -SR 4a , wherein R 4a is -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl or ethyl) or cycloalkyl (preferably monocyclic-C 3-8 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), each of said-C 1-8 alkyl and cycloalkyl is optionally replaced by at least One substituent R 4e as defined in formula (I) is substituted.
- R 4 is -NR 4a SO 2 R 4b , wherein R 4a and R 4b are each independently hydrogen or -C 1-8 alkyl (preferably -C 1-6 alkyl , More preferably methyl or ethyl) or cycloalkyl (preferably monocyclic-C 3-8 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), the -C 1-8 Alkyl and cycloalkyl are each optionally substituted with at least one substituent R 4e as defined in formula (I).
- Aspect 100 Compounds according to aspect 99, wherein R 4 is
- a compound according to aspect 52 wherein R 4 is -OR 4a , R 4a is -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n- Propyl, ), said -C 1-8 alkyl is optionally substituted by at least one substituent R 4e ;
- R 4e is hydrogen, halogen (preferably fluorine, chlorine, more preferably fluorine), cycloalkyl (preferably C 3-6 ring Alkyl, more preferably C 3 cycloalkyl), heterocyclyl, aryl, -CONR 4f R 4g , -CO 2 R 4f , or -NR 4f R 4g , the cycloalkyl, heterocyclyl, aryl each optionally substituted by at least one R substituent ;
- R 4k is selected from halogen (preferably fluorine, chlorine, bromine, more preferably fluorine), -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl);
- R 4f , R 4g and R 4h are each independently hydrogen, or -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl).
- Aspect 102 Compounds according to aspect 101, wherein R 4e is cycloalkyl, preferably C 3-6 cycloalkyl, more preferably C 3 cycloalkyl.
- Aspect 103 A compound according to aspect 102, wherein cycloalkyl is optionally substituted by at least one R substituent , R being selected from halogen (preferably fluorine, chlorine, bromine, more preferably fluorine), -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl).
- R being selected from halogen (preferably fluorine, chlorine, bromine, more preferably fluorine), -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl).
- Aspect 104 A compound according to Aspect 101, wherein R 4e is heterocyclyl, said heterocyclyl is 4, 5, 4, 5, or 4 containing one or two or three heteroatoms independently selected from oxygen, nitrogen or sulfur
- a 6- or 7-membered heterocyclic group preferably a 4-, 5-, 6-, or 7-membered saturated ring containing one nitrogen or oxygen atom as a ring member, more preferably a tetrahydropyrrole ring.
- Aspect 105 Compounds according to Aspect 101-Aspect 104, wherein R 4 is methoxy, ethoxy, isopropoxy,
- Aspect 107 Compounds according to Aspect 106, wherein R 4 is
- Aspect 108 Compounds according to aspect 89-aspect 107, wherein R 4 is H, -C 1-8 alkyl, -OR 4a , -NR 4a R 4b , -SR 4a , -NR 4a SO 2 R 4b , said -C 1-8 alkyl is optionally substituted by at least one substituent R 4d ;
- R 4a and R 4b are each independently hydrogen or -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl, ), or cycloalkyl (preferably monocyclic-C 3-8 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heterocyclyl (preferably tetrahydrofuryl, azetidinyl Alkyl, pyrrolidinyl, piperidinyl), said -C 1-8 alkyl, cycloalkyl and heterocyclyl are each optionally substituted by at least one substituent R 4e ;
- R 4d and R 4e are each independently hydrogen, halogen (preferably fluorine, chlorine, more preferably fluorine), cycloalkyl (preferably C 3-6 cycloalkyl, more preferably C 3 cycloalkyl), heterocyclyl, Aryl, -CONR 4f R 4g , -CO 2 R 4f , or -NR 4f R 4g , each of the cycloalkyl, heterocyclyl, and aryl is optionally substituted by at least one R 4k substituent;
- R 4k is selected from halogen (preferably fluorine, chlorine, bromine, more preferably fluorine), -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl);
- R 4f and R 4g are each independently hydrogen, or -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl).
- Aspect 109 Compounds according to aspect 108, wherein R 4 is H, -C 1-8 alkyl, -OR 4a ;
- R 4a is -C 1-8 alkyl, cycloalkyl, and said -C 1-8 alkyl, cycloalkyl are each optionally substituted by at least one substituent R 4e ;
- R 4e is halogen, cycloalkyl optionally substituted by at least one R 4k substituent
- R 4k is independently selected from halogen, -C 1-8 alkyl.
- Aspect 110 Compounds according to Aspect 89-Aspect 109, wherein R 4 is H, methyl, Preferably H, methyl, More preferably methyl, More preferably methyl,
- Aspect 111 Compounds according to aspect 50, wherein n is 1, and R 4 is as defined in any of aspects 52-88.
- Aspect 112 Compounds according to aspect 111, wherein R 4 is at X 2 or X 3 position.
- Aspect 113 Compounds according to aspect 50, wherein n is 2 , the first R4 is as defined in any one of aspects 52 - aspect 88, the second R4 is as defined in any one of aspects 89-aspect 107 as defined.
- Aspect 114 A compound according to aspect 113, wherein the first R 4 is at the X 2 position and the second R 4 is at the X 1 or X 3 position.
- Aspect 115 Compounds according to aspect 113, wherein the first R 4 is at X 3 position and the second R 4 is at X 2 or X 4 position.
- Aspect 116 Compounds according to aspect 50, wherein n is 3, the first R 4 is as defined in any of aspects 52-aspect 88, the second and third R 4 are as in aspect 89-aspect 107 defined by any one.
- Aspect 117 Compounds according to aspect 116, wherein the first R4 is at X2, the second R4 is at X1 and the third R4 is at X3 .
- Aspect 118 A compound according to aspect 116, wherein the first R4 is at X3 , the second R4 is at X2 and the third R4 is at X4 .
- the present invention discloses pyrrolopyridones described in formula (II).
- the second embodiment includes the following aspects:
- R 1 is selected from hydrogen or -C 1-8 alkyl, said -C 1-8 alkyl is optionally substituted by at least one substituent R 1d ;
- R 1d is independently hydrogen, amino, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, Oxo, -CN, -NO 2 ;
- X is selected from NH or N C 1-8 alkyl
- R is selected from hydrogen , carboxyl, cyano, nitro, halogen atom, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl radical, heteroaryl, -OR 2a , -SO 2 R 2a , -SO 2 NR 2a R 2b , -COR 2a , -CO 2 R 2a , -CONR 2a R 2b , -POR 2a R 2b , -NR 2a R 2b , -NR 2a COR 2b , -NR 2a CONR 2b R 2c , -NR 2a CO 2 R 2b , -NR 2a SO 2 NR 2b R 2c , -NR 2a SO 2 R 2b , the -C 1-8 Alkyl, -C alkenyl, -C alkynyl , cycloalkyl, hetero
- R 2a , R 2b , and R 2c are each independently hydrogen, hydroxyl, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl base, or heteroaryl, each of the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted by at least one substituent R 2e ; or
- R 2d and R 2e are each independently hydrogen, amino, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl, oxo, -CN, -NO 2 , -OR 2f , -SO 2 R 2f , -SO 2 NR 2f R 2g , -COR 2f , -CO 2 R 2f , -CONR 2f R 2g , - NR 2f R 2g , -NR 2f COR 2g , -NR 2f CONR 2g R 2h , -NR 2f CO 2 R 2f , -NR 2f SO 2 NR 2g R 2h , or -NR 2f SO 2 R 2g , the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloal
- R 2f , R 2g , R 2h , R 2i , and R 2j are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl , cycloalkyl, heterocyclyl, aryl, or heteroaryl;
- R is selected from hydrogen, hydroxyl, carboxyl, cyano, nitro, halogen atom, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl , Aryl, Heteroaryl, -OR 3a , -SR 3a , -SO 2 R 3a , -SO 2 NR 3a R 3b , -COR 3a , -CO 2 R 3a , -CONR 3a R 3b , -POR 3a R 3b , -NR 3a R 3b , -NR 3a COR 3b , -NR 3a CONR 3b R 3c , -NR 3a CO 2 R 3b , -NR 3a SO 2 NR 3b R 3c , -NR 3a SO 2 R 3b , the Each of -C 1-8 alkyl, -C 2-8 alkenyl, -C
- R 3a , R 3b , and R 3c are each independently hydrogen, hydroxyl, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl base, or heteroaryl, each of the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted by at least one substituent R 3e ; or
- R 3d and R 3e are each independently hydrogen, amino, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl, oxo, -CN, -NO 2 , -OR 3f , -SO 2 R 3f , -SO 2 NR 3f R 3g , -COR 3f , -CO 2 R 3f , -CONR 3f R 3g , - NR 3f R 3g , -NR 3f COR 3g , -NR 3f CONR 3g R 3h , -NR 3f CO 2 R 3f , -NR 3f SO 2 NR 3g R 3h , or -NR 3f SO 2 R 3g , the -C 1-8 alkyl , -C alkenyl, -C alkynyl , cycloalkyl
- R 3f and R 3g together with one or more atoms to which they are attached form a 3- to 12-membered ring containing 0, 1, 2 or 3 nitrogen atoms independently selected from , heteroatoms in oxygen or sulfur as one or more ring members, the rings are optionally substituted by at least one substituent R 3k ;
- Each R 3k is independently selected from halogen, -C 1-8 alkyl, -OR 3i , -NR 3i R 3j , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and said -C 1 -8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally replaced by at least one member selected from hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituent substitution;
- R 3f , R 3g , R 3h , R 3i , and R 3j are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl , cycloalkyl, heterocyclyl, aryl, or heteroaryl;
- X 1 , X 2 , X 3 , and X 4 are each independently selected from N or C, provided that the valence theory is satisfied (ie, the resulting valence is chemically possible);
- R is selected from hydrogen, hydroxyl, amino, oxo, carboxyl, cyano, nitro, halogen atom, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, ring Alkyl, heterocyclyl, aryl, heteroaryl, -OR 5a , -SR 5a , -SO 2 R 5a , -SO 2 NR 5a R 5b , -COR 5a , -CO 2 R 5a , -CONR 5a R 5b , -POR 5a R 5b , -NR 5a R 5b , -NR 5a COR 5b , -NR 5a CONR 5b R 5c , -NR 5a CO 2 R 5b , -NR 5a SO 2 NR 5b R 5c , -NR 5a SO 2 R 5b , each of the -C 1-8 alkyl, -C 2-8 alkenyl
- R 5a , R 5b , and R 5c are each independently hydrogen, hydroxyl, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl base, or heteroaryl, each of the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted by at least one substituent R 5e ; or
- R 5d and R 5e are each independently hydrogen, amino, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl, oxo, -CN, -NO 2 , -OR 5f , -SO 2 R 5f , -SO 2 NR 5f R 5g , -COR 5f , -CO 2 R 5f , -CONR 5f R 5g , - NR 5f R 5g , -NR 5f COR 5g , -NR 5f CONR 5g R 5h , -NR 5f CO 2 R 5f , -NR 5f SO 2 NR 5g R 5h , or -NR 5f SO 2 R 5g , the -C Each of 1-8 alkyl, -C alkenyl, -C alkynyl , cycloalky
- Each R 5k is independently selected from halogen, -C 1-8 alkyl, -OR 5i , -NR 5i R 5j , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and said -C 1 -8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally replaced by at least one member selected from hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituent substitution;
- R 5f , R 5g , R 5h , R 5i , and R 5j are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl , cycloalkyl, heterocyclyl, aryl, or heteroaryl;
- s 0, 1, 2 or 3, provided the valence theory has been satisfied (i.e., the resulting valence is chemically possible);
- Cy1 is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted by t R 6 ;
- R is selected from hydrogen, hydroxyl, amino, oxo, carboxyl, cyano, nitro, halogen atom, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2- 8 alkynyl , ring Alkyl, heterocyclyl, aryl, heteroaryl, -OR 6a , -SR 6a , -SO 2 R 6a , -SO 2 NR 6a R 6b , -COR 6a , -CO 2 R 6a , -CONR 6a R 6b , -POR 6a R 6b , -NR 6a R 6b , -NR 6a COR 6b , -NR 6a CONR 6b R 6c , -NR 6a CO 2 R 6b , -NR 6a SO 2 NR 6b R 6c , -NR 6a SO 2 R 6b , each of the -C 1-8 alkyl, -C 2-8 alkeny
- R 6a , R 6b , and R 6c are each independently hydrogen, hydroxyl, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl base, or heteroaryl, each of the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted by at least one substituent R 6e ; or
- R 6d and R 6e are each independently hydrogen, amino, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl, oxo, -CN, -NO 2 , -OR 6f , -SO 2 R 6f , -SO 2 NR 6f R 6g , -COR 6f , -CO 2 R 6f , -CONR 6f R 6g , - NR 6f R 6g , -NR 6f COR 6g , -NR 6f CONR 6g R 6h , -NR 6f CO 2 R 6f , -NR 6f SO 2 NR 6g R 6h , or -NR 6f SO 2 R 6g , the -C 1-8 alkyl , -C alkenyl, -C alkynyl , cycloalkyl
- Each R 6k is independently selected from halogen, -C 1-8 alkyl, -OR 6i , -NR 6i R 6j , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and said -C 1 -8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally replaced by at least one member selected from hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituent substitution;
- R 6f , R 6g , R 6h , R 6i , and R 6j are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl , cycloalkyl, heterocyclyl, aryl, or heteroaryl;
- t 0, 1, 2, 3 or 4, provided the valence theory has been satisfied (ie, the resulting valences are chemically possible).
- Aspect 2 The compound according to Aspect 1, wherein X is NH, is one of the preferred embodiments.
- Aspect 3 The compound according to any one of aspects 1-2, wherein X 1 , X 2 , X 3 , and X 4 are all C, which is one of the preferred options
- Aspect 4 The compound according to any one of Aspect 1-Aspect 2, wherein any one of X 1 , X 2 , X 3 , X 4 is N, and the rest are C.
- Aspect 5 The compound according to any one of Aspect 1-Aspect 2, wherein any two of X 1 , X 2 , X 3 , and X 4 are N, and the rest are C.
- Aspect 6 The compound according to any one of Aspect 1-Aspect 5, wherein R 1 is hydrogen, which is one of the preferred options.
- Aspect 7 The compound according to any one of aspects 1-5, wherein R 1 is selected from -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl.
- Aspect 8 A compound according to any one of aspects 1-5, wherein R is -C 1-8 alkyl optionally substituted by at least one substituent R 1d (preferably -C 1-6 alkyl , more preferably methyl or ethyl), R 1d is halogen, preferably fluorine, chlorine, bromine, more preferably fluorine.
- Aspect 10 A compound according to any one of aspects 6-9, wherein R is selected from hydrogen, -C 1-8 alkyl, -C 1-8 alkyl optionally substituted by at least one substituent R 1d ( Preferably -C 1-6 alkyl, more preferably methyl or ethyl), R 1d is halogen, preferably fluorine, chlorine, bromine, more preferably fluorine, preferably hydrogen, methyl, More preferably hydrogen;
- Aspect 11 A compound according to any one of aspects 1 to 10, wherein R 2 is selected from hydrogen, cyano, -SO 2 R 2a , -POR 2a R 2b , - optionally substituted by at least one substituent R 2d C 1-8 alkyl.
- Aspect 12 Compounds according to aspect 10, wherein R 2 is hydrogen or cyano, preferably cyano.
- Aspect 13 Compound according to aspect 10, wherein R 2 is -SO 2 R 2a .
- Aspect 14 A compound according to aspect 12, wherein R 2a is selected from -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl.
- Aspect 15 A compound according to any one of aspect 12-aspect 13 , wherein R is
- Aspect 16 Compound according to aspect 10, wherein R 2 is -POR 2a R 2b .
- Aspect 17 the compound according to aspect 15, wherein R 2a and R 2b are selected from -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl.
- Aspect 18 A compound according to any one of aspects 15-16, wherein R is
- Aspect 19 A compound according to aspect 10, wherein R 2 is -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl, optionally substituted by at least one substituent R 2d .
- Aspect 20 Compounds according to aspect 19, wherein R 2d is selected from halogen, preferably fluorine, chlorine, bromine, more preferably fluorine.
- Aspect 21 A compound according to any one of aspect 19-aspect 19 , wherein R is
- Aspect 22 Compounds according to any one of aspects 10-20, wherein R is H, cyano, Preferably cyano, More preferred is cyano.
- Aspect 23 A compound according to any one of aspects 1-22, wherein R is hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or hetero Each aryl group is optionally substituted by at least one substituent R 3d ;
- R 3d is hydrogen, amino, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxygen Substitute, -CN, -NO 2 , -OR 3f , -SO 2 R 3f , -SO 2 NR 3f R 3g , -COR 3f , -CO 2 R 3f , -CONR 3f R 3g , -NR 3f R 3g , -NR 3f COR 3g , -NR 3f CONR 3g R 3h , -NR 3f CO 2 R 3f , -NR 3f SO 2 NR 3g R 3h , or -NR 3f SO 2 R 3g , the -C 1-8 alkyl , -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl
- R 3f and R 3g together with one or more atoms to which they are attached form a 3 to 12 membered ring containing 0, 1, 2 or 3 independently selected from nitrogen , heteroatoms in oxygen or sulfur as one or more ring members, the rings are optionally substituted by at least one substituent R 3k ;
- R 3f , R 3g , R 3h , R 3i , R 3j and R 3k are each independently hydrogen, -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 24 A compound according to aspect 22, wherein R 3 is aryl optionally substituted by halogen, -C 1-8 alkyl, -OR 3f , or -NR 3f R 3g , wherein R 3f and R 3g are each independently is hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 25 A compound according to aspect 23, wherein said aryl group is phenyl.
- Aspect 26 Compounds according to any one of aspects 23 to 24, wherein R is selected from
- Aspect 27 Compounds according to aspect 22, wherein R 3 is heteroaryl optionally substituted by at least one substituent R 3d .
- Aspect 28 A compound according to aspect 26, wherein said heteroaryl is a 5, 6 or 7 membered heteroaryl comprising one, two or three heteroatoms independently selected from oxygen, nitrogen or sulfur.
- Aspect 29 A compound according to aspect 27, wherein said heteroaryl is pyridyl, pyrrolyl, pyrimidinyl, pyrazolyl, oxazolyl, or triazolyl.
- Aspect 30 A compound according to aspect 26, wherein said heteroaryl is an 8 to 12 membered fused heteroaryl comprising one or two or three heteroatoms independently selected from oxygen, nitrogen or sulfur.
- Aspect 32 Compounds according to any one of aspects 26 to 30, wherein R 3d is hydrogen, halogen, amino, oxo, -C 1-8 alkyl, -CONR 3f R 3g , -NR 3f COR 3g , Wherein R 3f and R 3g are each independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl; or
- R 3f and R 3g together with the atom(s) to which they are attached form a 3 to 12 membered ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur As one or more ring members.
- Aspect 33 Compounds according to aspect 31, wherein R 3d is -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 34 Compounds according to Aspect 31, wherein R 3d is hydrogen, halogen, amino.
- Aspect 35 A compound according to aspect 31, wherein R 3d is -NR 3f COR 3g in which R 3f and R 3g are each independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl base or ethyl.
- Aspect 36 Compound according to aspect 35, wherein -NR 3f COR 3g is
- Aspect 37 A compound according to aspect 31, wherein R 3d is -CONR 3f In R 3g , R 3f and R 3g are each independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl base or ethyl.
- Aspect 38 Compounds according to aspect 36, wherein R 3f and R 3g together with the atom(s) to which they are attached form a 3 to 12 membered ring, preferably a 4-6 membered ring, said ring comprising 0, 1, 2 or 3 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members.
- Aspect 39 Compound according to any one of aspects 36-aspect 37, wherein -CONR 3f R 3g is selected from
- Aspect 40 Compounds according to any one of aspects 26-38, wherein R is selected from
- Aspect 41 Compounds according to Aspect 22, wherein R3 is hydrogen.
- Aspect 42 Compounds according to aspect 22, wherein R 3 is -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl.
- Aspect 43 A compound according to aspect 22, wherein R 3 is cycloalkyl, preferably C 3-6 cycloalkyl, more preferably
- R 3 is heterocyclyl optionally substituted by at least one substituent R 3d , wherein R 3d is hydrogen, halogen, amino, oxo, -C 1-8 alkyl, -OR 3f , -NR 3f R 3g , -CONR 3f R 3g , -NR 3f COR 3g , wherein R 3f and R 3g are each independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl , more preferably methyl or ethyl.
- a compound according to aspect 40 wherein said heterocyclyl is a 4 to 7 membered ring comprising one or two heteroatoms independently selected from nitrogen, oxygen or sulfur, preferably comprising a nitrogen or oxygen atom as 5, 6, or 7 membered saturated rings of ring members.
- Aspect 46 A compound according to aspect 44, wherein said heterocyclyl is piperidinyl, tetrahydropyrrolidinyl, tetrahydropyran, or piperazinyl.
- Aspect 47 Compounds according to any one of aspects 40 to 45, wherein R 3d is hydrogen, halogen, amino, oxo, -C 1-8 alkyl, -CONR 3f R 3g , -NR 3f COR 3g , Wherein R 3f and R 3g are each independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 48 Compounds according to aspect 46, wherein R 3d is hydrogen, oxo or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 49 Compounds according to any one of aspects 40-47, wherein R is selected from
- Aspect 50 Compounds according to any one of aspects 22-48, wherein R is selected from H, methyl, ethyl, isopropyl, Preferably H, ethyl, isopropyl,
- Aspect 51 Compounds according to any one of aspects 1-50, wherein s is 0, 1 or 2, R 5 is as defined in formula (II).
- Aspect 52 A compound according to any one of aspects 1 to 50 , wherein R is selected from hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl , heterocyclyl, aryl, heteroaryl, -OR 5a , -SR 5a , -SO 2 R 5a , -SO 2 NR 5a R 5b , -COR 5a , -CO 2 R 5a , -CONR 5a R 5b , -POR 5a R 5b , -NR 5a R 5b , -NR 5a COR 5b , -NR 5a CO 2 R 5b , -NR 5a SO 2 R 5 , the -C 1-8 alkyl, -C 2-
- Each of alkenyl, -C alkynyl , cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by at least
- R 5a , R 5b are each independently hydrogen, hydroxyl, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or hetero Aryl, each of the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally replaced by at least One substituent R 5e is substituted;
- R 5d and R 5e are each independently hydrogen, amino, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl, oxo, -CN, -NO 2 , -OR 5f , -SO 2 R 5f , -SO 2 NR 5f R 5g , -COR 5f , -CO 2 R 5f , -CONR 5f R 5g , - NR 5f R 5g , -NR 5f COR 5g , -NR 5f CONR 5g R 5h , -NR 5f CO 2 R 5f , -NR 5f SO 2 NR 5g R 5h , or -NR 5f SO 2 R 5g , the -C Each of 1-8 alkyl, -C alkenyl, -C alkynyl , cycloalky
- Each R 5k is independently selected from halogen, -C 1-8 alkyl, -OR 5i , -NR 5i R 5j , cycloalkyl, heterocyclyl, aryl, or heteroaryl, and said -C 1 -8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally replaced by at least one member selected from hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituent substitution;
- R 5f , R 5g , R 5h , R 5i , and R 5j are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl , cycloalkyl, heterocyclyl, aryl, or heteroaryl.
- Aspect 53 Compounds according to aspect 52, wherein R 5 is hydrogen.
- Aspect 54 Compounds according to aspect 52, wherein R 5 is -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 55 A compound according to aspect 52, wherein R is -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl or ethyl), optionally substituted by at least one substituent R 5d , R 5d is independently -NR 5f R 5g , and R 5f and R 5g are each independently hydrogen or -C 1-8 alkyl.
- Aspect 56 Compounds according to aspect 55 , wherein R is
- R 5 is -NR 5a R 5b , R 5a , R 5b are each independently hydrogen or -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl group or ethyl), or cycloalkyl (preferably monocyclic -C 3-8 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), the -C 1-8 alkyl and cycloalkyl are each optionally substituted with at least one substituent R 5e as defined in formula (II).
- Aspect 58 A compound according to aspect 57, wherein R 5e is independently hydrogen, amino, halogen (preferably fluoro, chloro, bromo, more preferably fluoro).
- Aspect 59 Compounds according to any one of aspects 57-58, wherein R is
- a compound according to aspect 52 wherein R 5 is -NR 5a SO 2 R 5b , wherein R 5a and R 5b are each independently hydrogen or -C 1-8 alkyl (preferably -C 1-6 alkyl , More preferably methyl or ethyl) or cycloalkyl (preferably monocyclic-C 3-8 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), the -C 1-8 Alkyl and cycloalkyl are each optionally substituted with at least one substituent R 5e as defined in formula (II).
- a compound according to aspect 52 wherein R 5 is -OR 5a , R 5a is -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n- Propyl, ), said -C 1-8 alkyl is optionally substituted by at least one substituent R 5e ;
- R 5e is hydrogen, halogen (preferably fluorine, chlorine, more preferably fluorine), cycloalkyl (preferably C 3-6 ring Alkyl, more preferably C 3 cycloalkyl), heterocyclyl, aryl, -CONR 5f R 5g , -CO 2 R 5f , or -NR 5f R 5g , the cycloalkyl, heterocyclyl, aryl
- Each of the R groups is optionally substituted by at least one R substituent ;
- R 5k is selected from halogen (preferably fluorine, chlorine, bromine, more preferably fluorine), -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl);
- R 5f and R 5g are each independently hydrogen, or -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl).
- Aspect 65 Compounds according to aspect 101, wherein R 5e is cycloalkyl, preferably C 3-6 cycloalkyl, more preferably C 3 cycloalkyl.
- Aspect 66 A compound according to aspect 65, wherein cycloalkyl is optionally substituted by at least one R substituent , R being selected from halogen (preferably fluorine, chlorine, bromine, more preferably fluorine), -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl).
- R being selected from halogen (preferably fluorine, chlorine, bromine, more preferably fluorine), -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl).
- Aspect 68 Compounds according to Aspect 101 - Aspect 104, wherein R is methoxy, ethoxy, isopropoxy,
- Aspect 70 Compounds according to aspect 106, wherein R is
- Aspect 71 Compounds according to aspect 52, wherein R 5 is H, -C 1-8 alkyl, -OR 5a , -NR 5a R 5b , -SR 5a , -NR 5a SO 2 R 5b , said -C 1-8 alkyl groups are optionally substituted by at least one substituent R 5d ;
- R 5a and R 5b are each independently hydrogen or -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl, ), or cycloalkyl (preferably monocyclic-C 3-8 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heterocyclyl (preferably tetrahydrofuryl, azetidinyl Alkyl, pyrrolidinyl, piperidinyl), said -C 1-8 alkyl, cycloalkyl and heterocyclyl are each optionally substituted by at least one substituent R 5e ;
- R 5d and R 5e are each independently hydrogen, halogen (preferably fluorine, chlorine, more preferably fluorine), cycloalkyl (preferably C 3-6 cycloalkyl, more preferably C 3 cycloalkyl), heterocyclyl, Aryl, -CONR 5f R 5g , -CO 2 R 5f , or -NR 5f R 5g , each of the cycloalkyl, heterocyclyl, and aryl is optionally substituted by at least one R 5k substituent;
- R 5k is selected from halogen (preferably fluorine, chlorine, bromine, more preferably fluorine), -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl);
- R 5f and R 5g are each independently hydrogen, or -C 1-8 alkyl (preferably -C 1-6 alkyl, more preferably methyl).
- Aspect 72 Compounds according to aspect 71, wherein R 5 is H, -C 1-8 alkyl, -OR 5a ;
- R 5a is -C 1-8 alkyl, cycloalkyl, and said -C 1-8 alkyl, cycloalkyl are each optionally substituted by at least one substituent R 5e ;
- R 5e is halogen, cycloalkyl optionally substituted by at least one R 5k substituent
- R 5k is independently selected from halogen, -C 1-8 alkyl.
- Aspect 73 Compounds according to any one of aspects 52 to 72, wherein R is H, methyl, Preferably H, methyl, More preferably methyl, More preferably methyl,
- Aspect 74 A compound according to any one of aspects 1-aspect 107, wherein Cy1 is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted by t R 6 , t is 0 , 1 or 2, and R 6 is as defined in formula (II).
- Aspect 76 A compound according to aspect 74, wherein Cy1 is a 4, 5, 6, or 7 membered heterocyclyl comprising one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur.
- Aspect 77 Compounds according to aspect 76, wherein Cy1 is a monocyclic 4, 5, 6, or 7 membered saturated heterocyclyl comprising one or two nitrogen atoms as ring members.
- Aspect 78 Compounds according to any one of aspects 76-77, wherein Cy1 is piperidinyl, piperazinyl.
- Aspect 79 A compound according to aspect 76, wherein Cy1 is a monocyclic 4, 5, 6, or 7 membered saturated heterocyclyl comprising one or two oxygen atoms as ring members.
- Aspect 80 Compound according to aspect 79, wherein Cy1 is
- Aspect 81 Compounds according to Aspect 76, wherein Cy1 is a monocyclic 4, 5, 6, or 7 membered saturated heterocyclyl comprising one nitrogen atom and one oxygen atom as ring members.
- Aspect 82 Compound according to aspect 81, wherein Cy1 is
- Aspect 83 A compound according to aspect 74, wherein Cy1 is a 7 to 12 membered fused heterocyclyl comprising one or two or three heteroatoms independently selected from oxygen, nitrogen or sulfur.
- Aspect 84 A compound according to aspect 83, wherein the heterocyclyl is an 8-10 membered spirocyclic heterocyclyl comprising 1-2 nitrogen atoms, preferably
- Aspect 86 Compounds according to any one of aspects 74 to 85, wherein Cy1 is selected from C3-10 cycloalkyl, comprising one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur A 4, 5, 6, or 7-membered heterocyclic group, or a 7- to 12-membered fused heterocyclic group containing one or two or three heteroatoms independently selected from oxygen, nitrogen or sulfur;
- Cy1 is a 4-7 membered monocyclic heterocyclic group or a 7-9 membered fused heterocyclic group containing one or two heteroatoms independently selected from nitrogen and oxygen.
- Aspect 87 Compounds according to any one of aspects 74 to 84, wherein Cy1 is cyclopropyl, piperidinyl, piperazinyl, Preferably piperidinyl, piperazinyl, more preferred further preferred
- Aspect 88 Compounds according to any one of aspects 74 to 87, wherein R is independently selected from hydrogen, halogen, oxo, -C 1-8 alkyl, cycloalkyl, heterocyclyl, -OR 6a , or -NR 6a R 6b , each of the -C 1-8 alkyl, cycloalkyl, and heterocyclic groups is optionally substituted by at least one substituent R 6d as defined in formula (II), wherein R 6a and R 6b are as defined in formula (II), preferably hydrogen or -C 1-6 alkyl, more preferably methyl or ethyl.
- each of said R 6d is selected from halogen, heterocyclyl, -C 1-8 alkyl, -OR 6f , -NR 6f R 6g ,
- R 6f and R 6g are each independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 90 Compounds according to Aspect 88, wherein R 6 is hydrogen.
- Aspect 91 Compounds according to aspect 88, wherein R 6 is -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 92 Compounds according to aspect 88, wherein R 6 is -C 1-8 alkyl optionally substituted by at least one -OR 6f , preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 93 Compounds according to aspect 92, wherein R 6f is hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 94 Compounds according to any one of aspects 92-93 , wherein R is
- Aspect 95 Compounds according to aspect 88, wherein R 6 is -C 1-8 alkyl optionally substituted by at least one -NR 6f R 6g , preferably -C 1-6 alkyl, more preferably methyl or ethyl .
- Aspect 96 Compounds according to aspect 95, wherein R 6f and R 6g are independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl.
- Aspect 97 Compounds according to aspect 88, wherein R 6 is -C 1-8 alkyl optionally substituted by at least one heterocyclyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl.
- Aspect 98 A compound according to aspect 97, wherein heterocyclyl is a 4, 5, 6, or 7 membered heterocyclyl comprising one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur.
- Aspect 99 Compounds according to any one of aspects 97-98 , wherein R is
- Aspect 100 Compounds according to Aspect 88, wherein R 6 is cycloalkyl, preferably C 4-6 cycloalkyl, more preferably C 4 cycloalkyl.
- Aspect 101 Compounds according to Aspect 88, wherein R 6 is a 4, 5, 6, or 7 membered heterocyclyl comprising one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur.
- Aspect 103 The compound of any of Aspect 74-Aspect 102, wherein
- R 6 is independently selected from hydrogen, halogen, oxo, -C 1-8 alkyl, cycloalkyl, heterocyclyl, -OR 6a , or -NR 6a R 6b , the -C 1-8 alkane
- R 6d is independently selected from hydrogen, halogen, oxo, -C 1-8 alkyl, cycloalkyl, heterocyclyl, -OR 6a , or -NR 6a R 6b , the -C 1-8 alkane
- R 6d are each selected from halogen, heterocyclyl, -C 1-8 alkyl, -OR 6f , -NR 6f R 6g ;
- R 6f and R 6g are each independently hydrogen or -C 1-8 alkyl, preferably -C 1-6 alkyl, more preferably methyl or ethyl;
- R 6 is H, -C 1-8 alkyl, said -C 1-8 alkyl is optionally substituted by at least one substituent R 6d ; R 6d is independently a heterocyclic group, hydroxyl.
- Aspect 104 Compounds according to any one of Aspect 88 - Aspect 102, wherein R is hydrogen, methyl, ethyl, Preferably hydrogen, methyl, ethyl,
- Aspect 105 A compound according to any of aspects 74-104, wherein
- the structural part is
- Aspect 106 Compound according to any one of aspects 1-107, Cy1 is as defined in any one of aspects 74-105.
- Aspect 107 Compound according to aspect 106, wherein Cy1 is in position X2.
- Aspect 108 Compound according to aspect 106, wherein Cy1 is in position X3 .
- a compound according to aspect 107, R 5 is as defined in any one of aspects 50-107, s is 0, 1 or 2.
- Aspect 110 Compounds according to aspect 109, wherein s is 1 and R 5 is at position X 1 or X 3 .
- Aspect 111 Compounds according to aspect 109, wherein s is 2 , the first R5 is at the X1 position and the second R5 is at the X3 position.
- Aspect 112 Compounds according to Aspect 108, R 5 is as defined in any one of Aspects 52-Aspect 107, s is 0, 1 or 2.
- Aspect 113 Compounds according to aspect 112, wherein s is 1 and R 5 is at X 2 or X 4 .
- Aspect 114 Compounds according to aspect 112, wherein s is 2 , the first R5 is at the X2 position and the second R5 is at the X4 position.
- Aspect 115 A compound according to any of aspects 1 - 114, wherein:
- R1 is H ;
- X is NH
- X 1 , X 2 , X 3 , X 4 are C;
- R 2 is cyano, Preferably cyano
- R 3 is H, -C 1-8 alkyl, cycloalkyl, aryl, and said aryl is optionally substituted by at least one substituent R 3d ;
- R 3d is -C 1-8 alkyl
- R 5 is H, -C 1-8 alkyl, -OR 5a ;
- R 5a is -C 1-8 alkyl, cycloalkyl, and each of said -C 1-8 alkyl, cycloalkyl is optionally substituted by at least one substituent R 5e ;
- R 5e is halogen, cycloalkyl optionally substituted by at least one R 5k substituent
- R 5k is independently selected from halogen, -C 1-8 alkyl
- s 0, 1, 2;
- Cy1 is a heterocyclic group, the heterocyclic group is optionally substituted by t R 6 ;
- R 6 is H, -C 1-8 alkyl, said -C 1-8 alkyl is optionally substituted by at least one substituent R 6d ;
- R 6d is independently a heterocyclic group, a hydroxyl group
- t 0, 1, 2.
- Aspect 116 the compound according to aspect 115, said R 3 is H, -C 1-6 alkyl, C 3-10 cycloalkyl, 6-membered aryl, and said 6-membered aryl is optionally replaced by at least one substituent R 3d is substituted; and R 3d is -C 1-3 alkyl.
- Aspect 117 the compound according to aspect 116, wherein R 3 is H, ethyl, isopropyl,
- Aspect 118 A compound according to aspect 115, wherein R 5 is H, -C 1-6 alkyl, -OR 5a ;
- R 5a is -C 1-6 alkyl, C 3-10 cycloalkyl, and said -C 1-6 alkyl, C 3-10 cycloalkyl are each optionally substituted by at least one substituent R 5e ;
- R 5e is halogen, C 3-10 cycloalkyl optionally substituted by at least one R 5k substituent;
- R 5k is independently selected from halogen, -C 1-6 alkyl.
- R 5 is H, -C 1-3 alkyl, preferably H, methyl, Preferably methyl, More preferably methyl,
- Aspect 120 the compound according to aspect 115, said Cy1 is a 4-7 membered monocyclic heterocyclic group or a 7-9 membered fused heterocyclic group containing one or two heteroatoms independently selected from nitrogen and oxygen.
- Aspect 122 the compound according to aspect 115, said R 6 is H, -C 1-6 alkyl, said -C 1-6 alkyl is optionally substituted by at least one substituent R 6d ;
- R 6d is independently a hydroxyl group, or a 4-6 membered heterocyclic group containing one or two heteroatoms independently selected from nitrogen and oxygen;
- Aspect 123 A compound according to aspect 122, wherein R 6 is H, methyl, ethyl,
- Aspect 124 Compound according to aspect 115, said structure is preferred more preferred
- Aspect 125 Compound according to any of Aspect 115-Aspect 119, Cy1 is as defined in any of Aspect 120-Aspect 124.
- Aspect 126 Compound according to aspect 125, wherein Cy1 is in position X2.
- Aspect 127 Compound according to aspect 125, wherein Cy1 is in position X3 .
- Aspect 128 Compounds according to Aspect 126, R 5 is as defined in any one of Aspects 118-119, s is 0, 1 or 2.
- Aspect 129 Compounds according to aspect 128, wherein s is 1 and R 5 is at position X 1 or X 3 .
- Aspect 130 Compounds according to aspect 128, wherein s is 2 , the first R5 is at the X1 position and the second R5 is at the X3 position.
- Aspect 131 Compounds according to Aspect 127, R 5 is as defined in any one of Aspects 118-119, s is 0, 1 or 2.
- Aspect 132 Compounds according to aspect 131, wherein s is 1 and R5 is at X2 or X4 .
- Aspect 133 Compounds according to aspect 131, wherein s is 2 , the first R5 is at the X2 position and the second R5 is at the X4 position.
- the present invention provides the compound described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimera thereof, the compound being selected from the exemplary compounds disclosed herein, as shown in Table 1 below:
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising any compound of the present invention or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimera thereof, which may optionally contain one or more pharmaceutically acceptable carrier, and made into any pharmaceutically acceptable pharmaceutical preparation.
- the aforementioned pharmaceutical composition may further comprise one or more second therapeutically active agents.
- the second therapeutically active agent is anti-metabolite, growth factor inhibitor, mitosis inhibitor, anti-tumor hormone, alkylating agent, metal, topoisomerase inhibitor, hormone drug, immunomodulator, tumor Antibodies or small molecule drugs related to suppressing genes, cancer vaccines, immune checkpoints or tumor immunotherapy.
- the present invention also relates to a pharmaceutical preparation comprising any compound of the present invention or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimera thereof, and one or more pharmaceutically acceptable carriers.
- the pharmaceutical carrier described herein can be one or more solid or liquid filler or gel substances suitable for human use.
- the pharmaceutical carrier can be any conventional carrier and/or diluent in the field of pharmaceutical preparations, and preferably has sufficient purity and low enough toxicity, and is compatible with the active ingredient of the present invention and does not significantly reduce the active ingredient. effect.
- pharmaceutical carriers can be fillers, binders, disintegrants, lubricants, aqueous or non-aqueous solvents and the like.
- the pharmaceutical preparations described herein can be made into any pharmaceutically acceptable dosage form, and administered to patients or patients in need of such treatment by any suitable administration methods, such as oral, parenteral, rectal or pulmonary administration, etc. tester.
- oral administration it can be made into solid dosage forms, such as capsules, tablets, pills, lozenges, sugar-coated agents, granules, powders, ointments, creams, drops, etc.; it can also be made into liquid dosage forms, Such as elixirs, syrups, emulsions, dispersions, suspensions, solutions, sprays, etc.
- parenteral administration it can be made into injection solution, sterile powder for injection, etc.
- the compounds represented by formula I and their pharmaceutically acceptable salt stereoisomers and protac chimeras provided by the present invention have excellent HPK1 highly selective inhibitory activity, and can treat and/or prevent HPK1-mediated diseases and related diseases.
- the present invention provides a method for inhibiting HPK1 activity, the method comprising administering to a subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimera thereof, comprising the formula A compound of (I), a compound of formula (II), or a specific compound exemplified herein.
- the compound provided by the present invention has good HPK1 inhibitory activity, good physical and chemical properties and drug-making characteristics, and has good selectivity, specifically, compared with MAP4K2, MAP4K4, MAP4K4, MAP4K5, and MAP4K6, it has high selectivity for HPK1, For example, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold or 100-fold and more selectivity, or, high selectivity for HPK1 over MAP4K3
- the selectivity is 5-fold, 8-fold, 10-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold or 100-fold and more.
- the compound of the present invention or the pharmaceutically acceptable salt thereof has good safety, good drug effect and high bioavailability, so it has good application potential in treating diseases mediated by HPK1.
- WO2016205942A1 discloses a reference compound A compound. It has surprisingly been found that compounds of the invention having pyrrolopyridones show increased selectivity for HPK1.
- the present invention also relates to a method of treating a patient suffering from a disease that can be modulated by HPK1, comprising administering to the subject an effective amount of a compound of the present invention (such as a compound of formula (I), a compound of formula (II) or a specific compound exemplified herein ) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimera thereof.
- a compound of the present invention such as a compound of formula (I), a compound of formula (II) or a specific compound exemplified herein
- a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a protac chimera thereof.
- the present invention also relates to a method for inhibiting HPK1 activity in a patient in need of HPK1 activity inhibition, which comprises administering to the patient an effective amount of a compound of the present invention (such as a compound of formula (I), a compound of formula (II) or a compound exemplified herein specific compound) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimera thereof.
- a compound of the present invention such as a compound of formula (I), a compound of formula (II) or a compound exemplified herein specific compound
- a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a protac chimera thereof.
- the present invention also relates to the use of any compound of the present invention or its pharmaceutically acceptable salt, or its stereoisomer, or its protac chimera in the preparation of medicines for treating or preventing related diseases mediated by HPK1 application.
- HPK1 has a negative feedback regulatory effect in T cell-mediated signaling pathways, so HPK1 inhibitors can be used as immune anti-tumor drugs in the treatment of cancer or non-cancerous proliferative diseases, wherein the diseases include but are not limited to , lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast ductal carcinoma, head and neck cancer, endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, Esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin
- the present invention also relates to a method of treating cancer in a patient, comprising administering to the patient an effective amount of an HPK1 inhibitor (eg, a compound of formula (I)) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or A protac chimera thereof, and an effective amount of a second anticancer therapy (eg, chemotherapeutics, targeted therapy, radiation or surgery).
- an HPK1 inhibitor eg, a compound of formula (I)
- a pharmaceutically acceptable salt thereof eg, a stereoisomer thereof, or A protac chimera thereof
- a second anticancer therapy eg, chemotherapeutics, targeted therapy, radiation or surgery.
- the present invention also relates to a method of treating cancer in a patient, comprising administering to a subject an effective amount of an HPK1 inhibitor (for example, a compound of formula (I)) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or Its protac chimera, and an effective amount of an immunomodulator such as a checkpoint (checkpoint) inhibitor (for example, anti-PD-1 antibody, anti-CTLA4 antibody or anti-PD-L1 antibody) or a tryptophan oxidation inhibitor (for example, IDO1, IDO2 or TDO2 inhibitors).
- an HPK1 inhibitor for example, a compound of formula (I)
- an immunomodulator such as a checkpoint (checkpoint) inhibitor (for example, anti-PD-1 antibody, anti-CTLA4 antibody or anti-PD-L1 antibody) or a tryptophan oxidation inhibitor (for example, IDO1, IDO2 or TDO2 inhibitors).
- the present invention further relates to an HPK1 inhibitor (for example, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a protac chimera thereof) and a PD-1 inhibitor (such as Nivol Monoclonal antibody (nivolumab), pembrolizumab (pembrolizumab), pidilizumab (pidilizumab), BMS 936559, MPDL3280A, MSB0010718C or MEDI4736) in the preparation of drugs for the treatment or prevention of related diseases mediated by HPK1 wherein the diseases include lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, mammary ductal carcinoma, head and neck cancer, endometrial cancer, uterine body cancer, rectal cancer, Liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma,
- the compounds described in the present invention are named according to the chemical structural formula. If the name of the compound is inconsistent with the chemical structural formula when representing the same compound, the chemical structural formula shall prevail.
- protac chimera refers to a bifunctional compound formed by linking a compound of the present invention with an E3 ligase ligand, and its function is to recruit proteins targeting E3 ubiquitin ligase to degrade the target of the compound of the present invention target.
- alkyl refers to the group consisting of 1 to 18 (such as 1 to 12, further such as 1 to 10, further such as 1 to 8, or 1 to 6, or 1 to 4) carbon atoms
- the hydrocarbon groups in the straight chain and branched saturated hydrocarbon groups.
- alkyl groups containing 1 to 6 carbon atoms include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propane 1-butyl or isopropyl (“i-Pr”), 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or sec-butyl (“s-Bu”), 1,1-dimethylethyl or tert-butyl (“t-Bu”), 1-pentyl, 2-pentyl, 3 -Pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2- Hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pent
- halogen refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
- haloalkyl refers to an alkyl group in which one or more hydrogens are replaced by one or more halogen atoms such as fluorine, chlorine, bromine and iodine.
- haloalkyl include halogenated C 1-8 alkyl, halogenated C 1-6 alkyl or halogenated C 1-4 alkyl, but not limited to -CF 3 , -CH 2 Cl, -CH 2 CF 3 , -CHCl 2 , CF 3 , etc.
- alkenyl e.g., C alkenyl
- examples of alkenyl include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl , But-1-enyl, But-2-enyl, But-3-enyl, But-1,3-dienyl, 2-methylbut-1,3-dienyl, Hex-1- Alkenyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1,3-dienyl.
- alkynyl refers to a hydrocarbon group selected from straight and branched chain hydrocarbon groups comprising at least one C ⁇ C triple bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms.
- alkynyl e.g., C alkynyl
- examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl.
- alkyloxy or "alkoxy” means an alkyl group, as defined above, appended to the parent molecular moiety through an oxygen atom.
- alkyloxy e.g., C 1-6 alkyloxy or C 1-4 alkyloxy
- examples of alkyloxy include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butyl Oxygen, tert-butoxy, pentyloxy and hexyloxy, etc.
- alkoxy-alkyl- refers to an alkyl group as defined above further substituted with an alkoxy group as defined above.
- alkoxy-alkyl- e.g., C 1-8 alkoxy-C 1-8 alkyl-
- examples of alkoxy-alkyl- include, but are not limited to, methoxymethyl, ethoxymethyl, isopropoxymethyl , or propoxymethyl, etc.
- cycloalkyl refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (for example, bicyclic and tricyclic) groups, including fused cycloalkyl, bridged ring Alkyl or spirocycloalkyl.
- a cycloalkyl group may contain 3 to 12 (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5 or 3 to 4) carbon atoms.
- cycloalkyl groups may be selected from monocyclic groups comprising 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms.
- Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl , and cyclododecyl.
- examples of saturated monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- cycloalkyl is a monocyclic ring containing 3 to 6 carbon atoms (abbreviated as C 3-6 cycloalkyl), which includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- bicyclic cycloalkyls include those having 7 to 12 ring atoms arranged in the group selected from [4,4], [4,5], [5,5], [5,6] or [ 6,6] A fused bicyclic ring in a ring system, or arranged as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane.
- Other examples of bicyclic cycloalkyls include those arranged as bicyclic rings selected from the [5,6] and [6,6] ring systems, such as , where the wavy line indicates the point of attachment. Rings may be saturated or have at least one double bond (ie, partially unsaturated), but are not fully conjugated, and are not aromatic, as aromatic is defined herein.
- spirocycloalkyl refers to a ring structure containing carbon atoms and formed by at least two rings sharing one atom.
- 7 to 12 membered spirocycloalkyl refers to a ring structure containing 7 to 12 carbon atoms and formed by at least two rings sharing one atom.
- fused cycloalkyl refers to a fused ring containing carbon atoms and formed from two or more rings that share two adjacent atoms.
- fused cycloalkyl refers to a fused ring containing 4 to 10 ring carbon atoms and formed by two or more rings sharing two adjacent atoms.
- Examples include, but are not limited to, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[3.3.0]octyl, [4.2.0] Octyl, decahydronaphthalene, and benzo 3 to 8 membered cycloalkyl, benzo C 4-6 cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrazolyl, 1,4-dihydronaphthyl, etc.
- a preferred embodiment is an 8 to 9 membered fused ring, which refers to a ring structure containing 8 to 9 ring atoms in the above examples.
- bridged cycloalkyl refers to a ring structure that contains carbon atoms and is formed by two rings that share two atoms that are not adjacent to each other.
- 7 to 10 membered bridged cycloalkyl refers to a cyclic structure containing 7 to 12 carbon atoms and formed by two rings sharing two atoms that are not adjacent to each other.
- cycloalkenyl refers to a non-aromatic cyclic alkyl group of 3 to 10 carbon atoms, which has a monocyclic or polycyclic ring and has at least one double bond and preferably 1 to 2 double bonds.
- cycloalkenyl is cyclopentenyl (1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl) or cyclohexenyl (1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl), preferably cyclohexenyl.
- cycloalkynyl refers to a non-aromatic cycloalkyl group of 5 to 10 carbon atoms, having a monocyclic or polycyclic ring and having at least one triple bond.
- aryl used alone or in combination with other terms refers to a group selected from:
- bicyclic ring systems such as 7 to 12 membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, such as naphthyl and indanyl;
- Tricyclic ring systems such as 10 to 15 membered tricyclic ring systems, wherein at least one ring is carbocyclic and aromatic, eg fluorenyl.
- the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (ie, C 5-10 aryl).
- monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalen-1-yl, naphthalen-2-yl, anthracenyl, phenanthrenyl, and the like.
- the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a phenyl ring.
- the aromatic hydrocarbon ring is a phenyl ring.
- heteroaryl refers to a group selected from:
- a 7- to 12-membered bicyclic ring comprising at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms , the heteroatoms are selected from N, O and S, the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and
- an 11 to 14 membered tricyclic ring comprising at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms , the heteroatoms are selected from N, O and S, the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.
- the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other.
- the total number of S and O atoms in a heteroaryl is no greater than 2.
- the total number of S and O atoms in the aromatic heterocycle is no greater than one.
- the heteroatoms may be the same or different.
- a nitrogen atom in one or more rings of a heteroaryl can be oxidized to form an N-oxide.
- C-linked heteroaryl as used herein means that the heteroaryl is attached to the core molecule through a bond from a C-atom of the heteroaryl ring.
- the monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 ring members, wherein 1, 2, 3, or 4 heteroatom ring members are independently selected from nitrogen ( N), sulfur (S) and oxygen (O), and the remaining ring members are carbon.
- the monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O).
- the monocyclic or bicyclic aromatic heterocycle is a 5 to 6 membered heteroaryl ring that is monocyclic and has 1 or 2 atoms independently selected from nitrogen (N), sulfur (S) and oxygen ( O) heteroatom ring members.
- the monocyclic or bicyclic aromatic heterocyclic ring is an 8 to 10 membered heteroaryl ring that is bicyclic and has 1 or 2 heteroatom rings independently selected from nitrogen, sulfur and oxygen member.
- heteroaryl or monocyclic or bicyclic aromatic heterocyclic rings include, but are not limited to (as numbered from the attachment position assigned priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl or 4-pyridyl ), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazole thiadiazolyl (such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl or 1,3,4-thiadiazolyl), tetrazolyl, thienyl (such as thiophen-2-yl, thiophen-3-yl), triazinyl, benzothienyl, furyl (furyl or furanyl), benzofuryl, benzimidazolyl, in
- Heterocyclyl “heterocycle” or “heterocyclic” are interchangeable and refer to ring members containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur and the remaining Non-aromatic heterocyclic groups whose ring members are carbon, including monocyclic rings, fused rings, bridged rings, and spirocyclic rings, that is, monocyclic heterocyclic groups, bridged heterocyclic groups, spiroheterocyclic groups, and fused heterocyclic group.
- the term “optionally oxidized sulfur” as used herein refers to S, SO or SO2.
- monocyclic heterocyclyl refers to a monocyclic group in which at least one ring member is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. Heterocycles can be saturated or partially saturated.
- Exemplary monocyclic 4 to 9 membered heterocyclyl groups include, but are not limited to (as numbered from the attachment position assigned priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidine -2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidine Pyridin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridine -1-yl, aziridine-2-yl, azacyclooctane-1-yl, azacyclooctane-2-yl, azacyclooctane-3-yl, azacyclooct
- spiroheterocyclyl refers to a 5 to 20 membered polycyclic heterocyclyl group having rings joined by a shared carbon atom, called the spiro atom, containing one or more The heteroatoms in the sulfur serve as ring members and the remaining ring members are carbon.
- One or more rings of a spiroheterocyclyl may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system.
- the spiroheterocyclyl is 6 to 14 membered, and more preferably 7 to 12 membered.
- a spiroheterocyclyl is classified into a single spiroheterocyclyl, a dispiroheterocyclyl, or a polyspiroheterocyclyl, and preferably refers to a single spiroheterocyclyl or a dispiroheterocyclyl, and More preferably 4-membered/4-membered, 3-membered/5-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiroheterocyclic group.
- spiroheterocyclyl groups include, but are not limited to, the following groups: 2,3-dihydrospiro[indene-1,2'-pyrrolidine] (e.g., 2,3-dihydrospiro[indene-1,2 '-pyrrolidine]-1'-yl), 1,3-dihydrospiro[indene-2,2'-pyrrolidine] (for example, 1,3-dihydrospiro[indene-2,2'-pyrrolidine ]-1'-yl), azaspiro[2.4]heptane (for example, 5-azaspiro[2.4]heptane-5-yl), azaspiro[3.4]octane (for example, 6-azaspiro[2.4]heptane-5-yl), azaspiro[3.4]octane spiro[3.4]octane-6-yl), 2-oxa-6-azaspiro[3.4]octtan
- fused heterocyclic group means a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms (carbon and carbon atoms or carbon and nitrogen atoms) with another ring A group comprising as ring members one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur, the remaining ring members being carbon.
- One or more rings of a fused heterocyclic group may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system.
- the fused heterocyclic group is 6 to 14 membered, preferably 7 to 12 membered and more preferably 7 to 10 membered.
- fused heterocyclic groups are classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic fused heterocyclic groups, and more preferably 5-membered/ 5-membered, or 5-membered/6-membered bicyclic fused heterocyclic group.
- fused heterocycles include, but are not limited to, the following groups: octahydrocyclopenta[c]pyrrole (e.g., octahydrocyclopenta[c]pyrrol-2-yl), octahydrocyclopenta[c]pyrrol-2-yl), octahydrocyclopenta[c]pyrrol-2-yl, A[3,4-c]pyrrolyl, octahydroisoindolyl, isoindolinyl (for example, isoindolin-2-yl or isoindolin-5-yl), octahydro-benzo [b][1,4]dioxin, dihydropyridoxazinyl (for example, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl) or Dihydrobenzoxazepinyl (for example, 5-oxo-3,4-
- bridged heterocyclyl refers to a 5 to 14 membered polycyclic heterocycloalkyl group in which every two rings in the system share two unconnected atoms, containing one or more atoms selected from nitrogen, oxygen or optionally oxidized The heteroatoms in the sulfur serve as ring members and the remaining ring members are carbon.
- One or more rings of the bridged heterocyclyl may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system.
- the bridged heterocyclyl is 6 to 14 membered, and more preferably 7 to 10 membered.
- bridged heterocyclic groups are classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, and preferably refer to bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, and more preferably bicyclic or tricyclic Ring bridged heterocyclyl.
- Representative examples of bridged heterocyclyl groups include, but are not limited to, the following groups: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl base and 2-azabicyclo[3.3.2]decyl.
- alkylene refers to a divalent alkyl group as defined above, and refers to a saturated linear or branched divalent hydrocarbon group with a length of 1 to 18 carbon atoms (C 1-18 ), wherein The alkylene groups may be optionally independently substituted with one or more substituents described below. In another embodiment, the alkylene has one to eight carbon atoms (C 1-8 ) or one to six carbon atoms (C 1-6 ). Examples of alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), and the like.
- alkynylene refers to a divalent alkynyl group as defined above, and refers to a straight chain of three to eight carbon atoms (C 3-8 ) in length having at least one site of unsaturation, namely a carbon-carbon sp triple bond Or a branched divalent hydrocarbon group, wherein the alkynylene groups are optionally independently substituted with one or more substituents described herein. Examples include, but are not limited to, propynylene (propargylene, -CH2C ⁇ C- ), and the like.
- cycloalkylene refers to a divalent cycloalkyl group as defined above.
- heterocyclylene refers to a divalent heterocyclyl group as defined above.
- arylene refers to a divalent aryl group as defined above.
- heteroarylene refers to a divalent heteroarylene group as defined above.
- the compounds disclosed herein may contain asymmetric centers and, therefore, may exist as enantiomers.
- Enantiomers refer to two stereoisomers of a compound that are nonsuperimposable mirror images of each other. Where compounds disclosed herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to the broader class of stereoisomers. It is intended to include all such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are intended to be included. Reference to one isomer applies to any possible isomer unless specifically mentioned otherwise. Whenever no isomeric composition is specified, all possible isomers are included.
- the term “substantially pure” as used herein means that the target stereoisomer contains no more than 35% by weight (such as no more than 30%, further such as no more than 25%, even further such as no more than 20%) of any other one or more stereoisomers. In some embodiments, the term “substantially pure” means that the stereoisomer of interest contains no more than 10%, such as no more than 5%, such as no more than 1%, by weight of any other stereoisomer(s) isomer.
- the substituents found on the cyclohexyl or cyclobutyl ring can be formed in both cis and trans forms.
- the cis formation means that both substituents are found on the upper side of the 2 substituent positions on the carbon, while the trans means they are on the opposite side.
- “Pharmaceutically acceptable salts” means those which, within the scope of sound medical judgment, are suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc. and commensurate with a reasonable benefit/risk ratio Salt.
- Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base function with a suitable organic acid or by reacting an acidic group with a suitable base.
- the free base can be obtained by basifying a solution of the acid salt.
- the addition salt can be produced by dissolving the free base in a suitable organic solvent and/or water and treating the solution with an acid, following conventional procedures for the preparation of acid addition salts from base compounds, Such as pharmaceutically acceptable addition salts.
- pharmaceutically acceptable salts thereof include at least one salt of a compound of formula (I) and salts of stereoisomers of a compound of formula (I), such as salts of enantiomers and /or diastereomeric salts.
- administering when applied to animals, humans, experimental subjects, cells, tissues, organs or biological fluids mean exogenous agents, therapeutic agents, Contacting of a diagnostic agent or composition with said animal, human, subject, cell, tissue, organ or biological fluid. Treatment of cells encompasses contacting a reagent with a cell, as well as contacting a reagent with a fluid, wherein the fluid is in contact with the cell.
- administering and “treating” also mean in vitro and ex vivo treatment of, for example, a cell by an agent, diagnostic agent, binding compound or by another cell pair.
- subject herein includes any organism, preferably an animal, more preferably a mammal (eg rats, mice, dogs, cats, and rabbits) and most preferably a human.
- an effective amount refers to an amount of an active ingredient, such as a compound, which is sufficient when the compound is administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder. Affects such treatment of the disease, disorder or condition in question.
- a “therapeutically effective amount” can vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, the severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and /or the body weight of the subject to be treated. In any given instance, appropriate amounts will be apparent to those skilled in the art, or can be determined by routine experimentation.
- a “therapeutically effective amount” is at least one compound disclosed herein and/or at least one stereoisomer thereof and/or at least one pharmaceutically acceptable salt thereof effective for “treating” ( as defined above) the amount of the subject's disease or disorder.
- “therapeutically effective amount” refers to the total amount of the combination used to effectively treat the disease, disorder or condition.
- compositions comprising a compound disclosed herein can be administered to a subject in need thereof via oral, inhalational, rectal, parenteral or topical administration.
- the pharmaceutical composition can be conventional solid formulations such as tablets, powders, granules, capsules, etc., liquid formulations such as aqueous or oily suspensions, or other liquid formulations such as syrups, solutions, suspensions, etc.;
- the pharmaceutical composition may be a solution, an aqueous solution, an oily suspension concentrate, a lyophilized powder, and the like.
- the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays or injections, more preferably tablets or capsules.
- Pharmaceutical compositions may be administered in precise dosage form as a single unit.
- the pharmaceutical compositions may also contain additional active ingredients.
- compositions disclosed herein can be produced by conventional methods in the field of pharmacy.
- the active ingredient can be mixed with one or more excipients before preparing the desired formulation.
- “Pharmaceutically acceptable excipient” refers to conventional pharmaceutical carriers suitable for desired pharmaceutical preparations, for example: diluents, vehicles such as water, various organic solvents, etc., fillers such as starch, sucrose, etc., binders agents such as cellulose derivatives, alginate, gelatin and polyvinylpyrrolidone (PVP); wetting agents such as glycerin; disintegrants such as agar-agar, calcium carbonate and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; active agents, such as cetyl alcohol; absorbent carriers, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, polyethylene glycol, and the like.
- the pharmaceutical composition also contains other pharmaceutically acceptable
- disease refers to any disease, disorder, illness, symptom or indication, and is interchangeable with the terms “condition” or “disorder”.
- Cnm indicates an inclusive range where n and m are integers and indicate the number of carbons. Examples include C 1-8 , C 1-6 and the like.
- the mass spectrum is measured by LC/MS instrument, and the ionization method can be ESI or APCI.
- Thin-layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates for thin-layer chromatography (TLC).
- the size of the silica gel plate used is 0.15 mm to 0.2 mm, and the size of the thin layer chromatography separation and purification product is 0.4 mm to 0.5 mm.
- Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
- CD 3 OD deuterated methanol.
- T 3 P tripropylphosphoric anhydride.
- DPPA diphenylphosphoryl azide
- DIEA N,N-Diisopropylethylamine.
- the solution in the reaction refers to an aqueous solution.
- Reference compound A is the compound of WO2016205942A1, prepared according to the disclosed method,
- Embodiment 1 Preparation of compound C001
- Embodiment 2 preparation compound C002
- Step 4 Preparation of 6-methoxy-7-(5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-pyrrole[3,2- c] pyridine-3-carbonitrile
- Embodiment 3 preparation compound C003
- the reaction solution was poured into water (100 mL), then extracted with ethyl acetate, and the organic phases were combined.
- the organic phase was washed with saturated ammonium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered with suction, and concentrated to obtain a crude product.
- Step 7 Preparation of 7-formyl-6-methoxy-2-(o-tolyl)-1H-pyrrolo[3,2-c]pyridine-3-carbonitrile
- Step 8 Preparation of 6-methoxy-7-(5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-2-(o-tolyl)- 1H-Pyrrolo[3,2-c]pyridine-3-carbonitrile
- Embodiment 4 preparation compound C004
- Step 5 Preparation of 7-(4-ethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H -pyrrolo[3,2-c]pyridine-3-carbonitrile
- Embodiment 5 preparation compound C005
- Step 5 Preparation of 7-(4-(cyclopropylmethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)-6-methanol Oxy-1H-pyrrolo[3,2-c]pyridine-3-carbonitrile
- Embodiment 6 preparation compound C006
- Extract with ethyl acetate combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, filter with suction, and concentrate to obtain a crude product.
- Step 4 Preparation of 7-(4-(2,2-difluoroethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)- 6-Methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbonitrile
- Embodiment 7 preparation compound C010
- Embodiment 8 Preparation of compound C011
- reaction solution was poured into water (40 mL), then extracted with ethyl acetate, and the organic phases were combined.
- the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated by suction filtration to obtain a crude product.
- Step 4 Preparation of 7-(4-(difluoromethoxy)-5-(1-methylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy -1H-pyrrole[3,2-c]pyridine-3-carbonitrile
- Embodiment 9 Preparation of compound C013
- Extract with ethyl acetate combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, filter with suction, and concentrate to obtain a crude product.
- Step 2 Preparation of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitro-2-(2,2,2-trifluoroethoxy)aniline
- Step 4 Preparation of 6-methoxy-7-(5-(1-methylpiperidin-4-yl)-4-(2,2,2-trifluoroethoxy)-1H-benzo[d ]imidazol-2-yl)-1H-pyrrole[3,2-c]pyridine-3-carbonitrile
- Embodiment 10 Preparation of compound C016
- reaction solution was poured into water (40 mL), extracted with ethyl acetate, and the organic phases were combined.
- Extract with ethyl acetate combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, filter with suction, and concentrate to obtain a crude product.
- Step 4 Preparation of 7-(4-(2,2-difluoroethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)- 6-Methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbonitrile
- Step 5 Preparation of 7-(4-(2,2-difluoroethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl)- 6-oxo-5,6-dihydro-1H-pyrrolo[3,2-c]pyridine-3-carbonitrile
- Embodiment 12 Preparation of compound C020
- Step 1 Preparation of tert-butyl 2-(2-amino-6-bromo-3-nitrophenoxy)methyl)pyrrolidine-1-carboxylate
- Step 2 Preparation of tert-butyl 2-((2-amino-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-nitrophenoxy)methyl ) pyrrolidine-1-carboxylate
- Step 3 Preparation of tert-butyl 2-(2,3-diamino-6-(1-methylpiperidin-4-yl)phenoxy)methyl)pyrrolidine-1-carboxylate
- tert-butyl 2-((2-amino-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-nitrophenoxy (1)methyl)pyrrolidine-1-carboxylate (63mg, 0.146mmol) was dissolved in solvent ethanol (30mL), and PtO 2 (50mg, 0.22mmol) was added under nitrogen atmosphere.
- the reaction solution was suction-filtered through a celite layer and washed with methanol. The filtrate was concentrated to give tert-butyl 2-(2,3-diamino-6-(1-methylpiperidin-4-yl)phenoxy)methyl)pyrrolidine-1-carboxylate (50mg, yield 84.8 %).
- Step 4 Preparation of tert-butyl 2-((2-(3-cyano-6-methoxy-1H-pyrrole[3,2-c]pyridin-7-yl)-5-(1-methylpiper Pyridin-4-yl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)pyrrolidine-1-carboxylate converting 2-(2,3-diamino-6-(1- Methylpiperidin-4-yl)phenoxy)methyl)pyrrolidine-1-carboxylate tert-butyl ester (50mg, 0.12mmol) and 7-formyl-6-methoxy-1H-pyrrolo[3 ,2-c]pyridine-3-carbonitrile (65mg, 0.24mmol) was dissolved in N,N-dimethylformamide (5ml) solution, sodium metabisulfite (91.2mg, 0.48mmol) was added, and the temperature was raised to 90°C for reaction 16h.
- Step 2 Preparation of 7-(4-ethoxy-5-(1-methylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-2-( o-tolyl)-1H pyrrolo[3,2-c]pyridine-3-carbonitrile
- Step 1 Preparation of tert-butyl 2-methyl-4-((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate
- Step 2 Preparation of 4-(3-amino-2-(2,2-difluoroethoxy)-4-nitrophenyl)-2-methyl-3,6-dihydropyridine-1(2H) - tert-butyl carboxylate
- Step 3 Preparation of tert-butyl 4-(3,4-diamino-2-(2,2-difluoroethoxy)phenyl)-2-methylpiperidine-1-carboxylate
- Step 5 Preparation of 7-(4-(2,2-difluoroethoxy)-5-(1,2-dimethylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl )-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carbonitrile
- reaction solution was extracted three times with ethyl acetate and water, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 7-(4-(2,2-difluoroethoxy)-5-(1,2-di Methylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carbonitrile (20 mg, yield 69.4%).
- N-(3,5-dimethyl-4-morpholine-2-nitrophenyl)-2,2,2-trifluoroacetamide 200 mg, 0.81 mmol
- lithium hydroxide 58mg, 2.43mmol
- the reaction solution was concentrated to remove ethanol, then extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 3,5-dimethyl-4-morpholine-2-nitroaniline (170mg, yield 83.6 %).
- reaction solution was dripped into 50 mL of water to precipitate a solid, filtered to obtain a filter cake, dissolved in methanol, concentrated, and concentrated with acetonitrile 1 to 2 times to obtain the crude product 2-cyclopropyl-7-(4 , 6-Dimethyl-5-morpholinyl-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carbonitrile ( 200 mg, yield 90.5%).
- Step 1 Preparation of 2-(cyclopropylmethoxy)-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-6-nitroaniline
- 1-ethyl-1,2,3,6-tetrahydropyridine-4-trifluoromethanesulfonate (534 mg, 2.095 mmol), 2-(cyclopropylmethoxy)-6- Nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)aniline (700mg, 2.095mmol), Pd(dppf)Cl 2 (171mg, 0.209 mmol) and K2CO3 (868 mg , 6.28 mmol) were dissolved in 1,4-dioxane (13.5 mL) and water (1.5 mL). The mixture was stirred at 90 °C for 2 h.
- Step 3 Preparation of 7-(4-(cyclopropylmethoxy)-5-(1-ethylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy Base-1H-pyrrole[3,2-c]pyridine-3-carbonitrile
- 1-ethyl-1,2,3,6-tetrahydropyridine-4-trifluoromethanesulfonate (771 mg, 2.97 mmol), 2-3 (1 g, 2.97 mmol), Pd (dppf )Cl2 (218 mg , 0.297 mmol) and K2CO3 ( 1.2 g, 8.92 mmol) were dissolved in 1,4-dioxane (18 mL) and water (2 mL). The mixture was stirred at 90 °C for 2 h. LC-MS monitored the completion of the reaction, the mixture was filtered and the filtrate was concentrated.
- Step 3 Preparation of 7-(5-(1-ethylpiperidin-4-yl)-4-isobutoxy-1H-benzo[d]imidazol-2-yl)-6-methoxy-1H -pyrrolo[3,2-c]pyridine-3-carbonitrile
- Step 4 Preparation of 7-(4-(2,2-difluoroethoxy)-5-(1-ethylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6 -Methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbonitrile
- Step 1 Preparation of 7-(4-(2,2-difluoroethoxy)-5-(piperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-oxo- 5,6-Dihydro-1H-pyrrolo[3,2-c]pyridine-3-carbonitrile
- Step 1 Preparation of tert-butyl 4-(3-amino-2-(2,2-difluoroethoxy)-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate ester
- reaction solution was poured into water (40 mL), extracted with ethyl acetate, and the organic phases were combined.
- Step 2 Preparation of tert-butyl 4-(3,4-diamino-2-(2,2-difluoroethoxy)phenyl)piperidine-1-carboxylate
- tert-butyl 4-(3-amino-2-(2,2-difluoroethoxy)-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1g , 2.5 mmol) was dissolved in solvent ethanol (30 mL), and PtO 2 (300 mg) was added under nitrogen atmosphere. The reaction system was replaced with hydrogen three times, and stirred at room temperature for 16 h under the pressure of hydrogen (15 psi). The reaction solution was suction-filtered through a celite layer, and the filter residue was washed with methanol. The filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(3,4-diamino-2-(2,2-difluoroethoxy)phenyl)piperidine-1-carboxylate (900 mg, 97%).
- Step 3 Preparation of 4-(2-(3-cyano-6-methoxy-1H-pyrrolo[3,2-c]pyridin-7-yl)-4-(2,2-difluoroethoxy )-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate tert-butyl ester
- Step 4 Preparation of 7-(4-(2,2-difluoroethoxy)-5-(piperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-6-methoxy -1H-pyrrole[3,2-c]pyridine-3-carbonitrile
- Step 5 Preparation of 7-(4-(2,2-difluoroethoxy)-5-(1-(2-hydroxyethyl)piperidin-4-yl)-1Hbenzo[d]imidazole-2 -yl)-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carbonitrile
- reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined.
- Step 3 Preparation of 3-(2,2-difluoroethoxy)-4-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)benzene-1,2-di amine
- Step 4 Preparation of 7-(4-(2,2-difluoroethoxy)-5-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)-1Hbenzo [d]imidazol-2-yl)-6-methoxy-1H-pyrrole[3,2-c]pyridine-3-carbatriene
- NIS (2.23g, 9.90mmol) was added to the compound 7-bromo-6-methoxy-2-(4-methylpyridin-3-yl)-1H-pyrrole[3,2-c]pyridine at 0°C (3.0 g, 9.34 mmol) in dimethyl sulfoxide (100 mL), and the mixture was stirred at room temperature for 2 hours. After completion, the solvent was removed under reduced pressure, and the residual crude product was washed with water and petroleum ether, and dried to obtain 7-bromo-3-iodo-6-methoxy-2-(4-methylpyridin-3-yl)-1H - Pyrrolo[3,2-c]pyridine (3.6 g, 86% yield).
- Step 7 Preparation of 6-methoxy-2-(4-methylpyridin-3-yl)-7-vinyl-1H-pyrrolo[3,2-c]pyridine-3-carbonitrile
- the reaction mixture was concentrated, diluted with ethyl acetate (500 mL), washed with water (500 mL), the aqueous phase was added to sodium chloride to form a saturated solution, and extracted with tetrahydrofuran (500 mL x 2). The combined organic layers were dried and concentrated.
- Step 8 Preparation of 7-formyl-6-methoxy-2-(4-methylpyridin-3-yl)-1H-pyrrolo[3,2-c]pyridine-3-carbonitrile
- Step 9 Preparation of 7-(4-(2,2-dimethylethoxy)-5-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-2-yl) -6-Methoxy-1H-pyrrolo[3,2-c]pyridine-3-carbonitrile
- Step 1 Preparation of 7-(5-(1-methylpiperidin-4-yl)-1Hbenzo[d]imidazol-2-yl)-2-(4-methylpyridin-3-yl)-6 -Oxo-5,6-dihydro-1H-pyrrolo[3,2-c]pyridine-3-carbonitrile
- Ethynyltrimethylsilane (16 g, 163.08 mmol) was added to a solution of 1-fluoro-2-iodo-3-methoxybenzene (13.7 g, 54.36 mmol) in TEA (150 mL) followed by Pd(PPh 3 ) 2 Cl 2 (954 mg, 1.36 mmol) and CuI (1.04 g, 5.44 mmol), and the reaction mixture was stirred under N 2 environment at 105° C. for 16 hours. After LC-MS showed the reaction was complete, the reaction mixture was filtered through celite.
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Abstract
提供式(I)所示的吡咯并吡啶酮类化合物或其药学上可接受的盐,所述化合物的药物制剂、药物组合物及其应用,所述化合物可用于制备治疗或者预防由MAP4K1介导的相关疾病。
Description
本发明涉及医药技术领域,具体涉及吡咯并吡啶酮类化合物及制备方法,以及所述化合物在制备用于治疗或预防HPK1介导的疾病及相关疾病的药物中的用途。
造血祖细胞激酶1(HPK1,Hematopoietic progenitor kinase 1),又称MAP4K1(mitogen-activated protein kinase kinase kinase kinase 1),是一种丝氨酸/苏氨酸激酶,作为MAP4K家族的成员之一。除此之外,其家族中还有5个成员,包括MAP4K2,MAP4K3,MAP4K4,MAP4K5,MAP4K6。
HPK1参与调控TCR的主要过程为:(1)TCR与胞外的抗原通过MHC结合,从而激活TCR通路向下游接头蛋白分子传递信号;(2)接头蛋白酪氨酸激酶Lck和Zap70活化的SLP76,继而磷酸化HPK1;(3)活化的HPK1会继而磷酸化受体蛋白SLP-76;(4)SLP-76的磷酸化反应为14-3-3(TCR通路抑制蛋白)受体蛋白提供多种蛋白结合位点,形成复合体;(5)SLP-76磷酸化的复合体参与Erk信号途径的下调,并接到SLP76的泛素化降解过程,从而导致TCR信号通路和T细胞增殖下降。综上,HPK1可负向调节TCR信号途径,因此,HPK1可作为T细胞介导的免疫反应的新调节机制,成为新的免疫抗肿瘤的靶点。
T细胞受体(TCR)介导的T细胞活化在胸腺T细胞发育、T细胞亚群分化以及效应T细胞功能发挥过程中均起着至关重要的作用。TCR能特异性识别抗原提呈细胞表面MHC提呈的抗原肽(peptide),并将胞外抗原肽通过MHC(主要组织相容性复合物,major histocompatibility complex)识别转化成可向细胞内部传递的信号。其中,抗原递呈细胞表面的MHC分子包括MHC II类和MHC I类分子,可分别被CD4+和CD8+T细胞表面相应的辅助受体CD4和CD8分子特异性识别,随后可以引起下游信号通路的活化。TCR活化的典型胞内信号包括MAPK(丝裂原活化蛋白激酶,mitogen-activated protein kinases)、PKC(蛋白激酶C,protein kinase C)以及calcium(钙离子)等信号通路。这些信号的活化最终激活T细胞的特异性基因表达,引起细胞的增殖,并使得T细胞分化成效应T细胞。
由于在免疫方面的重要作用,HPK1抑制剂在恶性实体肿瘤或者血液癌(如急性髓性白血病、膀胱上皮癌、乳腺癌、结肠癌、肺癌、胰腺癌、黑色素瘤)、自身免疫性疾病(如系统性红斑狼疮、银屑病关节炎)和炎症反应中均扮演重要的角色。
WO2021050964、WO2016205942、CN109721620A、WO2019238067、WO2020103896、WO2021000925公开了HPK1抑制剂及其用途。
HPK1可与许多接头蛋白结合,如SLP-76家族,CARD11,HIS,HIP-55,GRB2家族,LAT,CRK家族等相互作用,活化造血干细胞的JNK/SAPK信号途径,从而对TCR通路进行负向调节。目前针对HPK1靶点尚未有药物上市,为了更好的满足巨大的临床需求,本发明旨在提供一种新型结构的HPK1抑制活性的化合物,其具有良好的理化性质和成药特性,在HPK1选择性方面具有较好的表现,本发明化合物或其药学上可接受的盐安全性好,药效好,生物利用度高,因此,本发明化合物在治疗由HPK1介导的疾病方面有较好的应用潜力。
发明内容
本发明的一个目的是提供吡咯并吡啶酮类化合物,所述化合物具有良好的HPK1抑制活性,显示较好的HPK1选择性,并具有良好的成药性,可用于治疗或者预防由HPK1介导的相关疾病。
在第一个实施方案中,本发明公开了式(I)所述的吡咯并吡啶酮类化合物。第一实施方案包括以下方面:
方面1:一种通式(I)所述的化合物
或其药学上可接受的盐、或其立体异构体、或其protac嵌合物,其中
R
1选自氢或-C
1-8烷基,所述的-C
1-8烷基任选被至少一个取代基R
1d取代;
R
1d独立地是氢、氨基、卤素、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO
2;
X选自NH或N-C
1-8烷基;
R
2选自氢、羧基、氰基、硝基、卤素原子、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、-OR
2a、-SO
2R
2a、-SO
2NR
2aR
2b、-COR
2a、-CO
2R
2a、-CONR
2aR
2b、-POR
2aR
2b、-NR
2aR
2b、-NR
2aCOR
2b、-NR
2aCONR
2bR
2c、-NR
2aCO
2R
2b、-NR
2aSO
2NR
2bR
2c、-NR
2aSO
2R
2b,所述的-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R
2d取代;
R
2a、R
2b、和R
2c各自独立地是氢、羟基、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基,所述-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个取代基R
2e取代;或者
(R
2a和R
2b)、(R
2b和R
2c)、或(R
2c和R
2a)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R
2e取代;
R
2d和R
2e各自独立地是氢、氨基、卤素、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO
2、-OR
2f、-SO
2R
2f、-SO
2NR
2fR
2g、-COR
2f、-CO
2R
2f、-CONR
2fR
2g、-NR
2fR
2g、-NR
2fCOR
2g、-NR
2fCONR
2gR
2h、-NR
2fCO
2R
2f、-NR
2fSO
2NR
2gR
2h、或-NR
2fSO
2R
2g,所述-C
1-
8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个选自卤素、-C
1-8烷基、-OR
2i、-NR
2iR
2j、环烷基、杂环基、芳基、或杂芳基的取代基取代;
R
2f、R
2g、R
2h、R
2i、和R
2j各自独立地是氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-
8炔基、环烷基、杂环基、芳基、或杂芳基;
R
3选自氢、羟基、羧基、氰基、硝基、卤素原子、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、-OR
3a、-SR
3a、-SO
2R
3a、-SO
2NR
3aR
3b、-COR
3a、-CO
2R
3a、-CONR
3aR
3b、-POR
3aR
3b、-NR
3aR
3b、-NR
3aCOR
3b、-NR
3aCONR
3bR
3c、-NR
3aCO
2R
3b、-NR
3aSO
2NR
3bR
3c、-NR
3aSO
2R
3b,所述的-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R
3d取代;
R
3a、R
3b、和R
3c各自独立地是氢、羟基、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基,所述-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个取代基R
3e取代;或者
(R
3a和R
3b)、(R
3b和R
3c)、或(R
3c和R
3a)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R
3e取代;
R
3d和R
3e各自独立地是氢、氨基、卤素、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO
2、-OR
3f、-SO
2R
3f、-SO
2NR
3fR
3g、-COR
3f、-CO
2R
3f、-CONR
3fR
3g、-NR
3fR
3g、-NR
3fCOR
3g、-NR
3fCONR
3gR
3h、-NR
3fCO
2R
3f、-NR
3fSO
2NR
3gR
3h、或-NR
3fSO
2R
3g,所述-C
1-
8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个R
3k取代基取代;或者
(R
3f和R
3g)、(R
3g和R
3h)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R
3k取代;
每个R
3k独立地选自卤素、-C
1-8烷基、-OR
3i、-NR
3iR
3j、环烷基、杂环基、芳基、或杂芳基,所述的-C
1-8烷基、环烷基、杂环基、芳基、或杂芳基任选地被至少一个选自氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基的取代基取代;
R
3f、R
3g、R
3h、R
3i、和R
3j各自独立地是氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-
8炔基、环烷基、杂环基、芳基、或杂芳基;
X
1、X
2、X
3、X
4各自独立的选自N或C,前提是已满足化合价理论(即,所得化合价在化学上是可能的);
R
4选自氢、羟基、氨基、氧代基、羧基、氰基、硝基、卤素原子、-C
1-8烷基、-C
2-8烯基、-C
2-
8炔基、环烷基、杂环基、芳基、杂芳基、-OR
4a、-SR
4a、-SO
2R
4a、-SO
2NR
4aR
4b、-COR
4a、-CO
2R
4a、-CONR
4aR
4b、-POR
4aR
4b、-NR
4aR
4b、-NR
4aCOR
4b、-NR
4aCONR
4bR
4c、-NR
4aCO
2R
4b、-NR
4aSO
2NR
4bR
4c、-NR
4aSO
2R
4b,所述的-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R
4d取代;
R
4a、R
4b、和R
4c各自独立地是氢、羟基、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基,所述-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个取代基R
4e取代;或者
(R
4a和R
4b)、(R
4b和R
4c)、或(R
4c和R
4a)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R
4e取代;
R
4d和R
4e各自独立地是氢、氨基、卤素、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO
2、-OR
4f、-SO
2R
4f、-SO
2NR
4fR
4g、-COR
4f、-CO
2R
4f、-CONR
4fR
4g、-NR
4fR
4g、-NR
4fCOR
4g、-NR
4fCONR
4gR
4h、-NR
4fCO
2R
4f、-NR
4fSO
2NR
4gR
4h、或-NR
4fSO
2R
4g,所述-C
1-
8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个R
4k取代基取代;
每个R
4k独立地选自卤素、-C
1-8烷基、-OR
4i、-NR
4iR
4j、环烷基、杂环基、芳基、或杂芳基,所述的-C
1-8烷基、环烷基、杂环基、芳基、或杂芳基任选地被至少一个选自氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基的取代基取代;
R
4f、R
4g、R
4h、R
4i、和R
4j各自独立地是氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-
8炔基、环烷基、杂环基、芳基、或杂芳基;
n是0、1、2、3或4,前提是已满足化合价理论(即,所得化合价在化学上是可能的)。
方面2:根据方面1的化合物,其中X是NH,是优选方案之一。
方面3:根据方面1-方面2的任一项的化合物,其中X
1、X
2、X
3、X
4都是C,是优选方案之一。
方面4:根据方面1-方面2的任一项的化合物,其中X
1、X
2、X
3、X
4中任一个是N,其余是C。
方面5:根据方面1-方面2的任一项的化合物,其中X
1、X
2、X
3、X
4中任两个是N,其余是C。
方面6:根据方面1-方面5中任一项的化合物,其中R
1是氢,是优选方案之一。
方面7:根据方面1-方面5中任一项的化合物,其中R
1选自-C
1-8烷基,优选-C
1-6烷基,更优选甲基。
方面8:根据方面1-方面5中任一项的化合物,其中R
1是任选被至少一个取代基R
1d取代的-C
1-
8烷基(优选-C
1-6烷基,更优选甲基或乙基),R
1d是卤素,优选氟、氯、溴,更优选是氟。
方面9:根据方面8的化合物,其中R
1是
方面10:根据方面1-方面9中任一项的化合物,其中R
2选自氢、氰基、-SO
2R
2a、-POR
2aR
2b、 任选被至少一个取代基R
2d取代的-C
1-8烷基。
方面11:根据方面10的化合物,其中R
2是氢或氰基。
方面12:根据方面10的化合物,其中R
2是-SO
2R
2a。
方面13:根据方面12的化合物,其中R
2a选自-C
1-8烷基,优选-C
1-6烷基,更优选甲基。
方面14:根据方面12-方面13中任一项的化合物,其中R
2是
方面15:根据方面10的化合物,其中R
2是-POR
2aR
2b。
方面16:根据方面15的化合物,其中R
2a、R
2b选自-C
1-8烷基,优选-C
1-6烷基,更优选甲基。
方面17:根据方面15-方面16中任一项的化合物,其中R
2是
方面18:根据方面10的化合物,其中R
2是任选被至少一个取代基R
2d取代的-C
1-8烷基,优选-C
1-6烷基,更优选甲基。
方面19:根据方面18的化合物,其中R
2d选自卤素,优选是氟、氯、溴,更优选是氟。
方面22:根据方面1-方面21中任一项的化合物,其中R
3是氢、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基,所述的-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R
3d取代;
其中R
3d是氢、氨基、卤素、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO
2、-OR
3f、-SO
2R
3f、-SO
2NR
3fR
3g、-COR
3f、-CO
2R
3f、-CONR
3fR
3g、-NR
3fR
3g、-NR
3fCOR
3g、-NR
3fCONR
3gR
3h、-NR
3fCO
2R
3f、-NR
3fSO
2NR
3gR
3h、或-NR
3fSO
2R
3g,所述-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个选自卤素、-C
1-8烷基、-OR
3i、或-NR
3iR
3j的取代基取代;或者
(R
3f和R
3g)、(R
3g和R
3h)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R
3k取代;
R
3f、R
3g、R
3h、R
3i、R
3j和R
3k各自独立地是氢、-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面23:根据方面22的化合物,其中R
3是任选地被卤素、-C
1-8烷基、-OR
3f、或-NR
3fR
3g取代的芳基,其中R
3f和R
3g各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面24:根据方面23的化合物,其中所述的芳基是苯基。
方面26:根据方面22的化合物,其中R
3是任选地被至少一个取代基R
3d取代的杂芳基。
方面27:根据方面26的化合物,其中所述的杂芳基是包含一或二或三个独立地选自氧、氮或硫 中的杂原子的5、6或7元杂芳基。
方面28:根据方面27的化合物,其中所述的杂芳基是吡啶基、吡咯基、嘧啶基、吡唑基、噁唑基、或三唑基。
方面29:根据方面26的化合物,其中所述的杂芳基是包含一或二或三个独立地选自氧、氮或硫中的杂原子的8到12元稠合杂芳基。
方面31:根据方面26-方面30中任一项的化合物,其中R
3d是氢、卤素、氨基、氧代基、-C
1-8烷基、-CONR
3fR
3g、-NR
3fCOR
3g,其中R
3f和R
3g各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基;或者
(R
3f和R
3g)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员。
方面32:根据方面31的化合物,其中R
3d是-C
1-8烷基优选-C
1-6烷基,更优选甲基或乙基。
方面33:根据方面31的化合物,其中R
3d是氢、卤素、氨基。
方面34:根据方面31的化合物,其中R
3d是-NR
3fCOR
3g中R
3f和R
3g各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面36:根据方面31的化合物,其中R
3d是-CONR
3fR
3g,R
3f和R
3g各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面37:根据方面36的化合物,其中R
3f和R
3g与它们所附接的一个或多个原子一起形成3至12元环,优选4-6元环,所述环包含0、1、2或3个独立地选自氮、氧或任选氧化的硫中的另外的杂原子作为一个或多个环成员。
方面38:根据方面36-方面37中任一项的化合物,其中-CONR
3fR
3g选自
方面39:根据方面26-方面38中任一项的化合物,其中R
3选自
方面40:根据方面22的化合物,其中R
3是氢。
方面41:根据方面22的化合物,其中R
3是-C
1-8烷基,优选是-C
1-6烷基,更优选是甲基、乙基、异丙基。
方面43:根据方面22的化合物,其中R
3是任选地至少一个取代基R
3d取代的杂环基,其中R
3d是氢、卤素、氨基、氧代基、卤素、-C
1-8烷基、-OR
3f、-NR
3fR
3g、-CONR
3fR
3g、-NR
3fCOR
3g,其中R
3f和R
3g各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面44:根据方面40的化合物,其中所述的杂环基是包含一个或两个独立地选自氮、氧或硫中的杂原子的4至7元环,优选包含一个氮或氧原子作为环成员的5、6、或7元饱和环。
方面45:根据方面44的化合物,其中所述杂环基是哌啶基、四氢吡咯烷基、四氢吡喃、或哌嗪基。
方面46:根据方面40-方面45中任一项的化合物,其中R
3d是氢、卤素、氨基、氧代基、-C
1-8烷基、-CONR
3fR
3g、-NR
3fCOR
3g,其中R
3f和R
3g各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面47:根据方面46的化合物,其中R
3d是氢、氧代基或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面48:根据方面40-方面47中任一项的化合物,其中R
3选自
方面50:根据方面1-方面48中任一项的化合物,其中n是1、2或3,R
4是如式(I)所定义的。
方面51:根据方面1-方面50中任一项的化合物,其中R
4选自氢、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、-OR
4a、-SR
4a、-SO
2R
4a、-SO
2NR
4aR
4b、-COR
4a、-CO
2R
4a、-CONR
4aR
4b、-POR
4aR
4b、-NR
4aR
4b、-NR
4aCOR
4b、-NR
4aCO
2R
4b、-NR
4aSO
2R
4b,所述的-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R
4d取代;
R
4a、R
4b各自独立地是氢、羟基、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基,所述-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个取代基R
4e取代;
R
4d和R
4e各自独立地是氢、氨基、卤素、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO
2、-OR
4f、-SO
2R
4f、-SO
2NR
4fR
4g、-COR
4f、-CO
2R
4f、-CONR
4fR
4g、-NR
4fR
4g、-NR
4fCOR
4g、-NR
4fCONR
4gR
4h、-NR
4fCO
2R
4f、-NR
4fSO
2NR
4gR
4h、或-NR
4fSO
2R
4g,所述-C
1-
8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个R
4k取代基取代;或者
每个R
4k独立地选自卤素、-C
1-8烷基、-OR
4i、-NR
4iR
4j、环烷基、杂环基、芳基、或杂芳基,所述的-C
1-8烷基、环烷基、杂环基、芳基、或杂芳基任选地被至少一个选自氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基的取代基取代;
R
4f、R
4g、R
4h、R
4i、和R
4j各自独立地是氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-
8炔基、环烷基、杂环基、芳基、或杂芳基。
方面52:根据方面51的化合物,其中R
4是一个环,该环选自环烷基、杂环基、芳基、杂芳基,所述的环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R
4d取代;
R
4d独立地是氢、氨基、卤素、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO
2、-OR
4f、-SO
2R
4f、-SO
2NR
4fR
4g、-COR
4f、-CO
2R
4f、-CONR
4fR
4g、-NR
4fR
4g、-NR
4fCOR
4g、-NR
4fCONR
4gR
4h、-NR
4fCO
2R
4f、-NR
4fSO
2NR
4gR
4h、或-NR
4fSO
2R
4g,所述-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个R
4k取代基取代;或者
每个R
4k独立地选自卤素、-C
1-8烷基、-OR
4i、-NR
4iR
4j、环烷基、杂环基、芳基、或杂芳基,所述的-C
1-8烷基、环烷基、杂环基、芳基、或杂芳基任选地被至少一个选自氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基的取代基取代;
R
4f、R
4g、R
4h、R
4i、和R
4j各自独立地是氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-
8炔基、环烷基、杂环基、芳基、或杂芳基。
方面53:根据方面52的化合物,其中R
4是任选地被至少一个取代基R
4d取代的环烷基;
所述的R
4d独立地选自卤素、氧代基、-C
1-8烷基、-OR
4f、或-NR
4fR
4g,所述的-C
1-8烷基任选地被-OR
4i、-NR
4iR
4j取代;
其中R
4f、R
4g、R
4i和R
4j各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面54:根据方面53的化合物,其中R
4是任选地被R
4d取代的环丙基、环丁基、环戊基、环己基、环庚基或环辛基。
方面55:根据方面54的化合物,其中R
4d是任选地被-NR
4iR
4j取代的-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面56:根据方面55的化合物,其中R
4i和R
4j独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基。
方面58:根据方面52的化合物,其中R
4是任选地被至少一个取代基R
4d取代的杂环基;
方面59:根据方面58-的化合物,其中杂环基是包含一或二或三个独立地选自氧、氮或硫中的杂原子的4、5、6或7元杂环基。
方面60:根据方面59的化合物,其中杂环基是包含一个或2个氮原子作为环成员的单环4、5、6、或7元饱和杂环基。
方面61:根据方面60方面59的化合物,其中杂环基是哌啶基、或哌嗪基。
方面62:根据方面59的化合物,其中杂环基是包含一个或2个氧原子作为环成员的单环4、5、6、或7元饱和杂环基。
方面64:根据方面59的化合物,其中杂环基是包含一个氮原子和一个氧原子作为环成员的单环4、5、6、或7元饱和杂环基。
方面66:根据方面58-的化合物,其中杂环基是是包含一或二或三个独立地选自氧、氮或硫中的杂原子的7至12元稠合的杂环基。
方面69:根据方面52-方面68中任一项的化合物,其中R
4是被任选被至少一个取代基R
4d取代的环,所述的环是选自C
3-10环烷基、包含一个或两个独立地选自氮、氧或任选氧化的硫中的杂原子的4、5、6、或7元杂环基、或包含一或二或三个独立地选自氧、氮或硫中的杂原子的7至12元稠合的杂环基;
进一步的,R
4是被任选被至少一个取代基R
4d取代的包含一个或两个独立地选自氮、氧的杂原子的4-7元单环杂环基或7-9元稠合杂环基。
方面71:根据方面58-方面70方面67中任一项的化合物,其中R
4d独立的选自氢、卤素、氧代基、-C
1-8烷基、环烷基。氢、卤素、氧代基、-C
1-8烷基、环烷基、杂环基、-OR
4f、或-NR
4fR
4g,所述的-C
1-8烷基、环烷基、杂环基各自任选地被至少一个如式(I)中所定义的取代基R
4k取代,其中R
4f、R
4g如式(I)中所定义,优选为氢或-C
1-6烷基,更优选甲基或乙基。
方面72:根据方面71的化合物,其中R
4k选自卤素、杂环基、-C
1-8烷基、-OR
4i、-NR
4iR
4j,
其中R
4i和R
4j各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面73:根据方面71的化合物,其中R
4d是氢。
方面74:根据方面71的化合物,其中R
4d是-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面75:根据方面71的化合物,其中R
4d是任选地被至少一个-OR
4i取代的-C
1-8烷基,优选-C
1-
6烷基,更优选甲基或乙基。
方面76:根据方面75的化合物,其中R
4i是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面78:根据方面71的化合物,其中R
4d是任选地被至少一个-NR
4iR
4j取代的-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面79:根据方面78的化合物,其中R
4i和R
4j独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基。
方面80:根据方面71的化合物,其中R
4d是任选地被至少一个杂环基取代的-C
1-8烷基,优选-C
1-
6烷基,更优选甲基或乙基。
方面81:根据方面80的化合物,其中杂环基是包含一个或两个独立地选自氮、氧或任选氧化的硫中的杂原子的4、5、6、或7元杂环基。
方面82:根据方面80-方面81中任一项的化合物,其中R
4d是
方面83:根据方面71的化合物,其中R
4d是环烷基,优选C
4-6环烷基,更优选C
4环烷基。
方面84:根据方面71的化合物,其中R
4d是包含一个或两个独立地选自氮、氧或任选氧化的硫中的杂原子的4、5、6、或7元杂环基。
方面86:根据方面71-方面85中任一项的化合物,其中R
4d独立地选自氢、卤素、氧代基、-C
1-
8烷基、环烷基、杂环基、-OR
4f、或-NR
4fR
4g,所述的-C
1-8烷基、环烷基、杂环基各自任选地被至少一个取代基R
4k取代,
R
4k各自选自卤素、杂环基、-C
1-8烷基、-OR
4i、-NR
4iR
4j,
R
4i和R
4j各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基;
进一步的,
R
4d是H、-C
1-8烷基,所述的-C
1-8烷基任选被至少一个取代基R
4k取代;R
4k独立地是杂环基、羟基;
方面87:根据方面71-方面85中任一项的化合物,其中R
4d是
方面88:根据方面52-方面87中任一项的化合物,其中R
4是
方面89:根据方面51的化合物,其中R
4是选自氢、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、-OR
4a、-SR
4a、-SO
2R
4a、-SO
2NR
4aR
4b、-COR
4a、-CO
2R
4a、-CONR
4aR
4b、-POR
4aR
4b、-NR
4aR
4b、-NR
4aCOR
4b、-NR
4aCO
2R
4b-NR
4aSO
2R
4b,所述的-C
1-8烷基、-C
2-8烯基、-C
2-8炔基各自任选被至少一个取代基R
4d取代;
R
4a、R
4b各自独立地是氢、羟基、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基,所述-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个取代基R
4e取代;
R
4d和R
4e各自独立地是氢、氨基、卤素、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO
2、-OR
4f、-SO
2R
4f、-SO
2NR
4fR
4g、-COR
4f、-CO
2R
4f、-CONR
4fR
4g、-NR
4fR
4g、-NR
4fCOR
4g、-NR
4fCONR
4gR
4h、-NR
4fCO
2R
4f、-NR
4fSO
2NR
4gR
4h、或-NR
4fSO
2R
4g,所述-C
1-
8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个R
4k取代基取代;或者
每个R
4k独立地选自卤素、-C
1-8烷基、-OR
4i、-NR
4iR
4j、环烷基、杂环基、芳基、或杂芳基,所述的-C
1-8烷基、环烷基、杂环基、芳基、或杂芳基任选地被至少一个选自氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基的取代基取代;
R
4f、R
4g、R
4h、R
4i、和R
4j各自独立地是氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-
8炔基、环烷基、杂环基、芳基、或杂芳基。
方面90:根据方面89的化合物,其中R
4是氢。
方面91:根据方面89的化合物,其中R
4是-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面92:根据方面89的化合物,其中R
4是任选被至少一个取代基R
4d取代的-C
1-8烷基(优选-C
1-6烷基,更优选甲基或乙基),R
4d独立地是-NR
4fR
4g,R
4f、R
4g各自独立地是氢、-C
1-8烷基。
方面94:根据方面89的化合物,其中R
4是是-NR
4aR
4b,R
4a、R
4b各自独立地是氢或者-C
1-8烷基(优选-C
1-6烷基,更优选甲基或乙基),或环烷基(优选单环-C
3-8环烷基,更优选环丙基、环丁基、环戊基或环己基),所述-C
1-8烷基和环烷基各自任选地被至少一个如式(I)中所定义的取代基R
4e取代。
方面95:根据方面94的化合物,其中R
4e独立地是氢、氨基、卤素(优选氟、氯、溴,更优选是氟)。
方面97:根据方面52的化合物,其中R
4是-SR
4a,其中R
4a是-C
1-8烷基(优选-C
1-6烷基,更优选甲基或乙基)或环烷基(优选单环-C
3-8环烷基,更优选环丙基、环丁基、环戊基或环己基),所述-C
1-8烷基和环烷基各自任选地被至少一个如式(I)中所定义的取代基R
4e取代。
方面98:根据方面97的化合物,其中R
4是
方面99:根据方面52的化合物,其中R
4是-NR
4aSO
2R
4b,其中R
4a和R
4b各自独立地是氢或-C
1-
8烷基(优选-C
1-6烷基,更优选甲基或乙基)或环烷基(优选单环-C
3-8环烷基,更优选环丙基、环丁基、环戊基或环己基),所述-C
1-8烷基和环烷基各自任选地被至少一个如式(I)中所定义的取代基R
4e取代。
方面100:根据方面99的化合物,其中R
4是
方面101:根据方面52的化合物,其中R
4是-OR
4a,R
4a是-C
1-8烷基(优选-C
1-6烷基,更优选甲基、乙基、异丙基或正丙基、
),所述-C
1-8烷基任选地被至少一个取代基R
4e取代;R
4e是氢、卤素(优选氟、氯,更优选氟)、环烷基(优选C
3-6环烷基,更优选C
3环烷基)、杂环基、芳基、-CONR
4fR
4g、-CO
2R
4f、或-NR
4fR
4g,所述环烷基、杂环基、芳基各自任选地被至少一个R
4k取代基取代;
R
4k选自卤素(优选氟、氯、溴,更优选氟)、-C
1-8烷基(优选-C
1-6烷基,更优选甲基);
R
4f、R
4g和R
4h各自独立地是氢、或-C
1-8烷基(优选-C
1-6烷基,更优选甲基)。
方面102:根据方面101的化合物,其中R
4e是环烷基,优选C
3-6环烷基,更优选C
3环烷基。
方面103:根据方面102的化合物,其中环烷基任选地被至少一个R
4k取代基取代,R
4k选自卤素(优选氟、氯、溴,更优选氟)、-C
1-8烷基(优选-C
1-6烷基,更优选甲基)。
方面104:根据方面101的化合物,其中R
4e是杂环基,所述的杂环基是是包含一或二或三个独立地选自氧、氮或硫中的杂原子的4、5、6或7元杂环基,优选包含一个氮或氧原子作为环成员的4、5、6、或7元饱和环,更优选四氢吡咯环。
方面105:根据方面101-方面104的化合物,其中R
4是甲氧基、乙氧基、异丙氧基、
方面106:根据方面52的化合物,其中R
4是-OR
4a,R
4a是环烷基(优选C
3-6环烷基,更优选C
3环烷基),或杂环基(优选四氢呋喃基、氮杂环丁烷基、吡咯烷基、哌啶基),所述环烷基或杂环基任选地被至少一个取代基R
4e取代;R
4e是氢、卤素(优选氟、氯,更优选氟)、环烷基、芳基、-CONR
4fR
4g、-CO
2R
4f、或-NR
4fR
4g;R
4f、R
4g和R
4h各自独立地是氢、或-C
1-8烷基(优选-C
1-6烷基,更优选甲基)。
方面107:根据方面106的化合物,其中R
4是
方面108:根据方面89-方面107的化合物,其中R
4是H、-C
1-8烷基、-OR
4a、-NR
4aR
4b、-SR
4a、-NR
4aSO
2R
4b,所述的-C
1-8烷基任选被至少一个取代基R
4d取代;
R
4a、R
4b各自独立地是氢或者-C
1-8烷基(优选-C
1-6烷基,更优选甲基、乙基、异丙基或正丙基、
),或环烷基(优选单环-C
3-8环烷基,更优选环丙基、环丁基、环戊基或环己基),或杂环基(优选四氢呋喃基、氮杂环丁烷基、吡咯烷基、哌啶基),所述-C
1-8烷基、环烷基和杂环基各自任选地被至少一个取代基R
4e取代;
R
4d、R
4e各自独立地是是氢、卤素(优选氟、氯,更优选氟)、环烷基(优选C
3-6环烷基,更优选C
3环烷基)、杂环基、芳基、-CONR
4fR
4g、-CO
2R
4f、或-NR
4fR
4g,所述的环烷基、杂环基、芳基各自任选地被至少一个R
4k取代基取代;
R
4k选自卤素(优选氟、氯、溴,更优选氟)、-C
1-8烷基(优选-C
1-6烷基,更优选甲基);
R
4f、R
4g各自独立地是氢、或-C
1-8烷基(优选-C
1-6烷基,更优选甲基)。
方面109:根据方面108的化合物,其中R
4是H、-C
1-8烷基、-OR
4a;
R
4a是-C
1-8烷基、环烷基,且所述-C
1-8烷基、环烷基各自任选地被至少一个取代基R
4e取代;
R
4e是卤素、环烷基,所述环烷基任选地被至少一个R
4k取代基取代;
R
4k独立地选自卤素、-C
1-8烷基。
方面111:根据方面50的化合物,其中n是1,并且R
4是如方面52-方面88中任一项所定义的。
方面112:根据方面111的化合物,其中R
4在X
2或者X
3位上。
方面113:根据方面50的化合物,其中n是2,第一个R
4是如方面52-方面88中任一项所定义的,第二个R
4是如方面89-方面107中任一项所定义的。
方面114:根据方面113的化合物,其中第一个R
4在X
2位上,第二个R
4在X
1或者X
3位上。
方面115:根据方面113的化合物,其中第一个R
4在X
3位上,第二个R
4在X
2或者X
4位上。
方面116:根据方面50的化合物,其中n是3,第一个R
4是如方面52-方面88中任一项所定义的,第二和第三个R
4是如方面89-方面107中任一项所定义的。
方面117:根据方面116的化合物,其中第一个R
4在X
2位上,第二个R
4在X
1位上,第三个R
4在X
3位上。
方面118:根据方面116的化合物,其中第一个R
4在X
3位上,第二个R
4在X
2位上,第三个R
4在X
4位上。
在第二个实施方案中,本发明公开了式(II)所述的吡咯并吡啶酮类化合物。第二实施方案包括以下方面:
方面1:一种通式(II)所述的化合物
或其药学上可接受的盐、或其立体异构体、或其protac嵌合物,其中
R
1选自氢或-C
1-8烷基,所述的-C
1-8烷基任选被至少一个取代基R
1d取代;
R
1d独立地是氢、氨基、卤素、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO
2;
X选自NH或N-C
1-8烷基;
R
2选自氢、羧基、氰基、硝基、卤素原子、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、-OR
2a、-SO
2R
2a、-SO
2NR
2aR
2b、-COR
2a、-CO
2R
2a、-CONR
2aR
2b、-POR
2aR
2b、-NR
2aR
2b、-NR
2aCOR
2b、-NR
2aCONR
2bR
2c、-NR
2aCO
2R
2b、-NR
2aSO
2NR
2bR
2c、-NR
2aSO
2R
2b,所述的-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R
2d取代;
R
2a、R
2b、和R
2c各自独立地是氢、羟基、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、 芳基、或杂芳基,所述-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个取代基R
2e取代;或者
(R
2a和R
2b)、(R
2b和R
2c)、或(R
2c和R
2a)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R
2e取代;
R
2d和R
2e各自独立地是氢、氨基、卤素、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO
2、-OR
2f、-SO
2R
2f、-SO
2NR
2fR
2g、-COR
2f、-CO
2R
2f、-CONR
2fR
2g、-NR
2fR
2g、-NR
2fCOR
2g、-NR
2fCONR
2gR
2h、-NR
2fCO
2R
2f、-NR
2fSO
2NR
2gR
2h、或-NR
2fSO
2R
2g,所述-C
1-
8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个选自卤素、-C
1-8烷基、-OR
2i、-NR
2iR
2j、环烷基、杂环基、芳基、或杂芳基的取代基取代;
R
2f、R
2g、R
2h、R
2i、和R
2j各自独立地是氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-
8炔基、环烷基、杂环基、芳基、或杂芳基;
R
3选自氢、羟基、羧基、氰基、硝基、卤素原子、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、-OR
3a、-SR
3a、-SO
2R
3a、-SO
2NR
3aR
3b、-COR
3a、-CO
2R
3a、-CONR
3aR
3b、-POR
3aR
3b、-NR
3aR
3b、-NR
3aCOR
3b、-NR
3aCONR
3bR
3c、-NR
3aCO
2R
3b、-NR
3aSO
2NR
3bR
3c、-NR
3aSO
2R
3b,所述的-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R
3d取代;
R
3a、R
3b、和R
3c各自独立地是氢、羟基、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基,所述-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个取代基R
3e取代;或者
(R
3a和R
3b)、(R
3b和R
3c)、或(R
3c和R
3a)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R
3e取代;
R
3d和R
3e各自独立地是氢、氨基、卤素、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO
2、-OR
3f、-SO
2R
3f、-SO
2NR
3fR
3g、-COR
3f、-CO
2R
3f、-CONR
3fR
3g、-NR
3fR
3g、-NR
3fCOR
3g、-NR
3fCONR
3gR
3h、-NR
3fCO
2R
3f、-NR
3fSO
2NR
3gR
3h、或-NR
3fSO
2R
3g,所述-C
1-
8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个R
3k取代基取代;或者
(R
3f和R
3g)、(R
3g和R
3h)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R
3k取代;
每个R
3k独立地选自卤素、-C
1-8烷基、-OR
3i、-NR
3iR
3j、环烷基、杂环基、芳基、或杂芳基,所述的-C
1-8烷基、环烷基、杂环基、芳基、或杂芳基任选地被至少一个选自氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基的取代基取代;
R
3f、R
3g、R
3h、R
3i、和R
3j各自独立地是氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-
8炔基、环烷基、杂环基、芳基、或杂芳基;
X
1、X
2、X
3、X
4各自独立的选自N或C,前提是已满足化合价理论(即,所得化合价在化学上是可能的);
R
5选自氢、羟基、氨基、氧代基、羧基、氰基、硝基、卤素原子、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、-OR
5a、-SR
5a、-SO
2R
5a、-SO
2NR
5aR
5b、-COR
5a、-CO
2R
5a、-CONR
5aR
5b、-POR
5aR
5b、-NR
5aR
5b、-NR
5aCOR
5b、-NR
5aCONR
5bR
5c、-NR
5aCO
2R
5b、-NR
5aSO
2NR
5bR
5c、-NR
5aSO
2R
5b,所述的-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R
5d取代;
R
5a、R
5b、和R
5c各自独立地是氢、羟基、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基,所述-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任 选地被至少一个取代基R
5e取代;或者
(R
5a和R
5b)、(R
5b和R
5c)、或(R
5c和R
5a)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R
5e取代;
R
5d和R
5e各自独立地是氢、氨基、卤素、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO
2、-OR
5f、-SO
2R
5f、-SO
2NR
5fR
5g、-COR
5f、-CO
2R
5f、-CONR
5fR
5g、-NR
5fR
5g、-NR
5fCOR
5g、-NR
5fCONR
5gR
5h、-NR
5fCO
2R
5f、-NR
5fSO
2NR
5gR
5h、或-NR
5fSO
2R
5g,所述-C
1-
8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个R
5k取代基取代;
每个R
5k独立地选自卤素、-C
1-8烷基、-OR
5i、-NR
5iR
5j、环烷基、杂环基、芳基、或杂芳基,所述的-C
1-8烷基、环烷基、杂环基、芳基、或杂芳基任选地被至少一个选自氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基的取代基取代;
R
5f、R
5g、R
5h、R
5i、和R
5j各自独立地是氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-
8炔基、环烷基、杂环基、芳基、或杂芳基;
s是0、1、2或3,前提是已满足化合价理论(即,所得化合价在化学上是可能的);
Cy1选自环烷基、杂环基、芳基或杂芳基,它们各自任选地被t个R
6取代;
R
6选自氢、羟基、氨基、氧代基、羧基、氰基、硝基、卤素原子、-C
1-8烷基、-C
2-8烯基、-C
2-
8炔基、环烷基、杂环基、芳基、杂芳基、-OR
6a、-SR
6a、-SO
2R
6a、-SO
2NR
6aR
6b、-COR
6a、-CO
2R
6a、-CONR
6aR
6b、-POR
6aR
6b、-NR
6aR
6b、-NR
6aCOR
6b、-NR
6aCONR
6bR
6c、-NR
6aCO
2R
6b、-NR
6aSO
2NR
6bR
6c、-NR
6aSO
2R
6b,所述的-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R
6d取代;
R
6a、R
6b、和R
6c各自独立地是氢、羟基、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基,所述-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个取代基R
6e取代;或者
(R
6a和R
6b)、(R
6b和R
6c)、或(R
6c和R
6a)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R
6e取代;
R
6d和R
6e各自独立地是氢、氨基、卤素、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO
2、-OR
6f、-SO
2R
6f、-SO
2NR
6fR
6g、-COR
6f、-CO
2R
6f、-CONR
6fR
6g、-NR
6fR
6g、-NR
6fCOR
6g、-NR
6fCONR
6gR
6h、-NR
6fCO
2R
6f、-NR
6fSO
2NR
6gR
6h、或-NR
6fSO
2R
6g,所述-C
1-
8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个R
6k取代基取代;
每个R
6k独立地选自卤素、-C
1-8烷基、-OR
6i、-NR
6iR
6j、环烷基、杂环基、芳基、或杂芳基,所述的-C
1-8烷基、环烷基、杂环基、芳基、或杂芳基任选地被至少一个选自氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基的取代基取代;
R
6f、R
6g、R
6h、R
6i、和R
6j各自独立地是氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-
8炔基、环烷基、杂环基、芳基、或杂芳基;
t是0、1、2、3或4,前提是已满足化合价理论(即,所得化合价在化学上是可能的)。
方面2:根据方面1的化合物,其中X是NH,是优选方案之一。
方面3:根据方面1-方面2的任一项的化合物,其中X
1、X
2、X
3、X
4都是C,是优选方案之一
方面4:根据方面1-方面2的任一项的化合物,其中X
1、X
2、X
3、X
4中任一个是N,其余是C。
方面5:根据方面1-方面2的任一项的化合物,其中X
1、X
2、X
3、X
4中任两个是N,其余是C。
方面6:根据方面1-方面5中任一项的化合物,其中R
1是氢,是优选方案之一。
方面7:根据方面1-方面5中任一项的化合物,其中R
1选自-C
1-8烷基,优选-C
1-6烷基,更优选甲基。
方面8:根据方面1-方面5中任一项的化合物,其中R
1是任选被至少一个取代基R
1d取代的-C
1-
8烷基(优选-C
1-6烷基,更优选甲基或乙基),R
1d是卤素,优选氟、氯、溴,更优选是氟。
方面9:根据方面8的化合物,其中R
1是
方面10:根据方面6-方面9中任一项的化合物,其中R
1选自氢、-C
1-8烷基、任选被至少一个取代基R
1d取代的-C
1-8烷基(优选-C
1-6烷基,更优选甲基或乙基),R
1d是卤素,优选氟、氯、溴,更优选是氟,优选氢、甲基、
更优选氢;
方面11:根据方面1-方面10中任一项的化合物,其中R
2选自氢、氰基、-SO
2R
2a、-POR
2aR
2b、任选被至少一个取代基R
2d取代的-C
1-8烷基。
方面12:根据方面10的化合物,其中R
2是氢或氰基,优选是氰基。
方面13:根据方面10的化合物,其中R
2是-SO
2R
2a。
方面14:根据方面12的化合物,其中R
2a选自-C
1-8烷基,优选-C
1-6烷基,更优选甲基。
方面15:根据方面12-方面13中任一项的化合物,其中R
2是
方面16:根据方面10的化合物,其中R
2是-POR
2aR
2b。
方面17:根据方面15的化合物,其中R
2a、R
2b选自-C
1-8烷基,优选-C
1-6烷基,更优选甲基。
方面18:根据方面15-方面16中任一项的化合物,其中R
2是
方面19:根据方面10的化合物,其中R
2是任选被至少一个取代基R
2d取代的-C
1-8烷基,优选-C
1-6烷基,更优选甲基。
方面20:根据方面19的化合物,其中R
2d选自卤素,优选是氟、氯、溴,更优选是氟。
方面23:根据方面1-方面22中任一项的化合物,其中R
3是氢、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基,所述的-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R
3d取代;
其中R
3d是氢、氨基、卤素、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO
2、-OR
3f、-SO
2R
3f、-SO
2NR
3fR
3g、-COR
3f、-CO
2R
3f、-CONR
3fR
3g、-NR
3fR
3g、-NR
3fCOR
3g、-NR
3fCONR
3gR
3h、-NR
3fCO
2R
3f、-NR
3fSO
2NR
3gR
3h、或-NR
3fSO
2R
3g,所述-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个选自卤素、-C
1-8烷基、-OR
3i、或-NR
3iR
3j的取代基取代;或者
(R
3f和R
3g)、(R
3g和R
3h)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、 1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R
3k取代;
R
3f、R
3g、R
3h、R
3i、R
3j和R
3k各自独立地是氢、-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面24:根据方面22的化合物,其中R
3是任选地被卤素、-C
1-8烷基、-OR
3f、或-NR
3fR
3g取代的芳基,其中R
3f和R
3g各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面25:根据方面23的化合物,其中所述的芳基是苯基。
方面27:根据方面22的化合物,其中R
3是任选地被至少一个取代基R
3d取代的杂芳基。
方面28:根据方面26的化合物,其中所述的杂芳基是包含一或二或三个独立地选自氧、氮或硫中的杂原子的5、6或7元杂芳基。
方面29:根据方面27的化合物,其中所述的杂芳基是吡啶基、吡咯基、嘧啶基、吡唑基、噁唑基、或三唑基。
方面30:根据方面26的化合物,其中所述的杂芳基是包含一或二或三个独立地选自氧、氮或硫中的杂原子的8到12元稠合杂芳基。
方面32:根据方面26-方面30中任一项的化合物,其中R
3d是氢、卤素、氨基、氧代基、-C
1-8烷基、-CONR
3fR
3g、-NR
3fCOR
3g,其中R
3f和R
3g各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基;或者
(R
3f和R
3g)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员。
方面33:根据方面31的化合物,其中R
3d是-C
1-8烷基优选-C
1-6烷基,更优选甲基或乙基。
方面34:根据方面31的化合物,其中R
3d是氢、卤素、氨基。
方面35:根据方面31的化合物,其中R
3d是-NR
3fCOR
3g中R
3f和R
3g各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面37:根据方面31的化合物,其中R
3d是-CONR
3fR
3g中R
3f和R
3g各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面38:根据方面36的化合物,其中R
3f和R
3g与它们所附接的一个或多个原子一起形成3至12元环,优选4-6元环,所述环包含0、1、2或3个独立地选自氮、氧或任选氧化的硫中的另外的杂原子作为一个或多个环成员。
方面39:根据方面36-方面37中任一项的化合物,其中-CONR
3fR
3g选自
方面40:根据方面26-方面38中任一项的化合物,其中R
3选自
方面41:根据方面22的化合物,其中R
3是氢。
方面42:根据方面22的化合物,其中R
3是-C
1-8烷基,优选是-C
1-6烷基,更优选是甲基、乙基、异丙基。
方面44:根据方面22的化合物,其中R
3是任选被至少一个取代基R
3d取代的杂环基,其中R
3d是氢、卤素、氨基、氧代基、-C
1-8烷基、-OR
3f、-NR
3fR
3g、-CONR
3fR
3g、-NR
3fCOR
3g,其中R
3f和R
3g各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面45:根据方面40的化合物,其中所述的杂环基是包含一个或两个独立地选自氮、氧或硫中的杂原子的4至7元环,优选包含一个氮或氧原子作为环成员的5、6、或7元饱和环。
方面46:根据方面44的化合物,其中所述杂环基是哌啶基、四氢吡咯烷基、四氢吡喃、或哌嗪基。
方面47:根据方面40-方面45中任一项的化合物,其中R
3d是氢、卤素、氨基、氧代基、-C
1-8烷基、-CONR
3fR
3g、-NR
3fCOR
3g,其中R
3f和R
3g各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面48:根据方面46的化合物,其中R
3d是氢、氧代基或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面49:根据方面40-方面47中任一项的化合物,其中R
3选自
方面51:根据方面1-方面50中任一项的化合物,其中s是0、1或2,R
5是如式(II)所定义 的。
方面52:根据方面1-方面50中任一项的化合物,其中R
5选自氢、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、-OR
5a、-SR
5a、-SO
2R
5a、-SO
2NR
5aR
5b、-COR
5a、-CO
2R
5a、-CONR
5aR
5b、-POR
5aR
5b、-NR
5aR
5b、-NR
5aCOR
5b、--NR
5aCO
2R
5b、-NR
5aSO
2R
5,所述的-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R
5d取代;
R
5a、R
5b各自独立地是氢、羟基、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基,所述-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个取代基R
5e取代;
R
5d和R
5e各自独立地是氢、氨基、卤素、-C
1-8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO
2、-OR
5f、-SO
2R
5f、-SO
2NR
5fR
5g、-COR
5f、-CO
2R
5f、-CONR
5fR
5g、-NR
5fR
5g、-NR
5fCOR
5g、-NR
5fCONR
5gR
5h、-NR
5fCO
2R
5f、-NR
5fSO
2NR
5gR
5h、或-NR
5fSO
2R
5g,所述-C
1-
8烷基、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个R
5k取代基取代;或者
每个R
5k独立地选自卤素、-C
1-8烷基、-OR
5i、-NR
5iR
5j、环烷基、杂环基、芳基、或杂芳基,所述的-C
1-8烷基、环烷基、杂环基、芳基、或杂芳基任选地被至少一个选自氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-8炔基、环烷基、杂环基、芳基、或杂芳基的取代基取代;
R
5f、R
5g、R
5h、R
5i、和R
5j各自独立地是氢、-C
1-8烷基、C
1-8烷氧基-C
1-8烷基-、-C
2-8烯基、-C
2-
8炔基、环烷基、杂环基、芳基、或杂芳基。
方面53:根据方面52的化合物,其中R
5是氢。
方面54:根据方面52的化合物,其中R
5是-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面55:根据方面52的化合物,其中R
5是任选被至少一个取代基R
5d取代的-C
1-8烷基(优选-C
1-6烷基,更优选甲基或乙基),R
5d独立地是-NR
5fR
5g,R
5f、R
5g各自独立地是氢、-C
1-8烷基。
方面57:根据方面52的化合物,其中R
5是-NR
5aR
5b,R
5a、R
5b各自独立地是氢或者-C
1-8烷基(优选-C
1-6烷基,更优选甲基或乙基),或环烷基(优选单环-C
3-8环烷基,更优选环丙基、环丁基、环戊基或环己基),所述-C
1-8烷基和环烷基各自任选地被至少一个如式(II)中所定义的取代基R
5e取代。
方面58:根据方面57的化合物,其中R
5e独立地是氢、氨基、卤素(优选氟、氯、溴,更优选是氟)。
方面60:根据方面52的化合物,其中R
5是-SR
5a,其中R
5a是-C
1-8烷基(优选-C
1-6烷基,更优选甲基或乙基)或环烷基(优选单环-C
3-8环烷基,更优选环丙基、环丁基、环戊基或环己基),所述-C
1-8烷基和环烷基各自任选地被至少一个如式(II)中所定义的取代基R
5e取代。
方面61:根据方面60的化合物,其中R
5是
方面62:根据方面52的化合物,其中R
5是-NR
5aSO
2R
5b,其中R
5a和R
5b各自独立地是氢或-C
1-
8烷基(优选-C
1-6烷基,更优选甲基或乙基)或环烷基(优选单环-C
3-8环烷基,更优选环丙基、环丁基、环戊基或环己基),所述-C
1-8烷基和环烷基各自任选地被至少一个如式(II)中所定义的取代基R
5e取代。
方面63:根据方面99的化合物,其中R
5是
方面64:根据方面52的化合物,其中R
5是-OR
5a,R
5a是-C
1-8烷基(优选-C
1-6烷基,更优选甲基、乙基、异丙基或正丙基、
),所述-C
1-8烷基任选地被至少一个取代基R
5e取代;R
5e是氢、卤素(优选氟、氯,更优选氟)、环烷基(优选C
3-6环烷基,更优选C
3环烷基)、杂环基、芳基、-CONR
5fR
5g、-CO
2R
5f、或-NR
5fR
5g,所述的环烷基、杂环基、芳基各自任选地被至少一个R
5k取代基取代;
R
5k选自卤素(优选氟、氯、溴,更优选氟)、-C
1-8烷基(优选-C
1-6烷基,更优选甲基);
R
5f、R
5g各自独立地是氢、或-C
1-8烷基(优选-C
1-6烷基,更优选甲基)。
方面65:根据方面101的化合物,其中R
5e是环烷基,优选C
3-6环烷基,更优选C
3环烷基。
方面66:根据方面65的化合物,其中环烷基任选地被至少一个R
5k取代基取代,R
5k选自卤素(优选氟、氯、溴,更优选氟)、-C
1-8烷基(优选-C
1-6烷基,更优选甲基)。
方面67:根据方面101的化合物,其中R
5e是杂环基,所述的杂环基是是包含一或二或三个独立地选自氧、氮或硫中的杂原子的4、5、6或7元杂环基,优选包含一个氮或氧原子作为环成员的4、5、6、或7元饱和环,更优选四氢吡咯环。
方面68:根据方面101-方面104的化合物,其中R
5是甲氧基、乙氧基、异丙氧基、
方面69:根据方面52的化合物,其中R
5是-OR
5a,R
5a是环烷基(优选C
3-6环烷基,更优选C
3环烷基),或杂环基(优选四氢呋喃基、氮杂环丁烷基、吡咯烷基、哌啶基),所述环烷基或杂环基任选地被至少一个取代基R
5e取代;R
5e是氢、卤素(优选氟、氯,更优选氟)、环烷基、芳基、-CONR
5fR
5g、-CO
2R
5f、或-NR
5fR
5g;R
5f、R
5g和R
5h各自独立地是氢、或-C
1-8烷基(优选-C
1-6烷基,更优选甲基)。
方面70:根据方面106的化合物,其中R
5是
方面71:根据方面52的化合物,其中R
5是H、-C
1-8烷基、-OR
5a、-NR
5aR
5b、-SR
5a、-NR
5aSO
2R
5b,所述的-C
1-8烷基任选被至少一个取代基R
5d取代;
R
5a、R
5b各自独立地是氢或者-C
1-8烷基(优选-C
1-6烷基,更优选甲基、乙基、异丙基或正丙基、
),或环烷基(优选单环-C
3-8环烷基,更优选环丙基、环丁基、环戊基或环己基),或杂环基(优选四氢呋喃基、氮杂环丁烷基、吡咯烷基、哌啶基),所述-C
1-8烷基、环烷基和杂环基各自任选地被至少一个取代基R
5e取代;
R
5d、R
5e各自独立地是是氢、卤素(优选氟、氯,更优选氟)、环烷基(优选C
3-6环烷基,更优选C
3环烷基)、杂环基、芳基、-CONR
5fR
5g、-CO
2R
5f、或-NR
5fR
5g,所述的环烷基、杂环基、芳基各自任选地被至少一个R
5k取代基取代;
R
5k选自卤素(优选氟、氯、溴,更优选氟)、-C
1-8烷基(优选-C
1-6烷基,更优选甲基);
R
5f、R
5g各自独立地是氢、或-C
1-8烷基(优选-C
1-6烷基,更优选甲基)。
方面72:根据方面71的化合物,其中R
5是H、-C
1-8烷基、-OR
5a;
R
5a是-C
1-8烷基、环烷基,且所述-C
1-8烷基、环烷基各自任选地被至少一个取代基R
5e取代;
R
5e是卤素、环烷基,所述环烷基任选地被至少一个R
5k取代基取代;
R
5k独立地选自卤素、-C
1-8烷基。
方面74:根据方面1-方面107中任一项的化合物,其中Cy1选自环烷基、杂环基、芳基或杂芳基,它们各自任选地被t个R
6取代,t是0、1或2,并且R
6是如式(II)所定义的。
方面75:根据方面74的化合物,其中Cy1是C
3-10环烷基,优选环丙基、环丁基、环戊基、环己基、环庚基或环辛基,更优选环丙基。
方面76:根据方面74的化合物,其中Cy1是包含一个或两个独立地选自氮、氧或任选氧化的硫中的杂原子的4、5、6、或7元杂环基。
方面77:根据方面76的化合物,其中Cy1是包含一个或2个氮原子作为环成员的单环4、5、6、或7元饱和杂环基。
方面78:根据方面76-方面77中任一项的化合物,其中Cy1是哌啶基、哌嗪基。
方面79:根据方面76的化合物,其中Cy1是包含一个或2个氧原子作为环成员的单环4、5、6、或7元饱和杂环基。
方面81:根据方面76的化合物,其中Cy1是包含一个氮原子和一个氧原子作为环成员的单环4、5、6、或7元饱和杂环基。
方面83:根据方面74的化合物,其中Cy1是包含一或二或三个独立地选自氧、氮或硫中的杂原子的7至12元稠合的杂环基。
方面86:根据方面74-方面85中任一项的化合物,其中Cy1选自C
3-10环烷基、包含一个或两个独立地选自氮、氧或任选氧化的硫中的杂原子的4、5、6、或7元杂环基、或包含一或二或三个独立地选自氧、氮或硫中的杂原子的7至12元稠合的杂环基;
进一步的,Cy1是包含一个或两个独立地选自氮、氧的杂原子的4-7元单环杂环基或7-9元稠合杂环基。
方面88:根据方面74-方面87中任一项的化合物,其中R
6独立地选自氢、卤素、氧代基、-C
1-8烷基、环烷基、杂环基、-OR
6a、或-NR
6aR
6b,所述的-C
1-8烷基、环烷基、杂环基各自任选地被至少一个如式(II)中所定义的取代基R
6d取代,其中R
6a、R
6b如式(II)中所定义,优选为氢或-C
1-6烷基,更优选甲基或乙基。
方面89:根据方面88的化合物,所述的R
6d各自选自卤素、杂环基、-C
1-8烷基、-OR
6f、-NR
6fR
6g,
其中R
6f和R
6g各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面90:根据方面88的化合物,其中R
6是氢。
方面91:根据方面88的化合物,其中R
6是-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面92:根据方面88的化合物,其中R
6是任选地被至少一个-OR
6f取代的-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面93:根据方面92的化合物,其中R
6f是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面95:根据方面88的化合物,其中R
6是任选地被至少一个-NR
6fR
6g取代的-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面96:根据方面95的化合物,其中R
6f和R
6g独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基。
方面97:根据根据方面88的化合物,其中R
6是任选地被至少一个杂环基取代的-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基。
方面98:根据方面97的化合物,其中杂环基是包含一个或两个独立地选自氮、氧或任选氧化的硫中的杂原子的4、5、6、或7元杂环基。
方面99:根据方面97-方面98中任一项的化合物,其中R
6是
方面100:根据方面88的化合物,其中R
6是环烷基,优选C
4-6环烷基,更优选C
4环烷基。
方面101:根据方面88的化合物,其中R
6是包含一个或两个独立地选自氮、氧或任选氧化的硫中的杂原子的4、5、6、或7元杂环基。
方面103:方面74-方面102中任一项的化合物,其中
R
6独立地选自氢、卤素、氧代基、-C
1-8烷基、环烷基、杂环基、-OR
6a、或-NR
6aR
6b,所述的-C
1-
8烷基、环烷基、杂环基各自任选地被至少一个取代基R
6d取代,
R
6d各自选自卤素、杂环基、-C
1-8烷基、-OR
6f、-NR
6fR
6g;
R
6f和R
6g各自独立地是氢或-C
1-8烷基,优选-C
1-6烷基,更优选甲基或乙基;
进一步的,
R
6是H、-C
1-8烷基,所述的-C
1-8烷基任选被至少一个取代基R
6d取代;R
6d独立地是杂环基、羟基。
方面105:根据方面74-方面104中任一项的化合物,其中
方面106:根据方面方面1-方面107中任一项的化合物,Cy1是如方面74-方面105中任一项所定义的。
方面107:根据方面106的化合物,其中Cy1在X
2位上。
方面108:根据方面106的化合物,其中Cy1在X
3位上。
方面109:根据方面107的化合物,R
5是如方面50-方面107中任一项所定义的,s是0、1或者2。
方面110:根据方面109的化合物,其中s是1,R
5在X
1或者X
3位上。
方面111:根据方面109的化合物,其中s是2,第一个R
5在X
1位上,第二个R
5在X
3位上。
方面112:根据方面108的化合物,R
5是如方面52-方面107中任一项所定义的,s是0、1或者2。
方面113:根据方面112的化合物,其中s是1,R
5在X
2或者X
4位上。
方面114:根据方面112的化合物,其中s是2,第一个R
5在X
2位上,第二个R
5在X
4位上。
方面115:根据方面1-方面114中任一项的化合物,其中:
R
1是H;
X是NH;
X
1、X
2、X
3、X
4是C;
R
3是H、-C
1-8烷基、环烷基、芳基,且所述的芳基任选被至少一个取代基R
3d取代;并且
R
3d是-C
1-8烷基;
R
5是H、-C
1-8烷基、-OR
5a;并且
R
5a是-C
1-8烷基、环烷基,且所述-C
1-8烷基、环烷基各自任选地被至少一个取代基R
5e取代;并且
R
5e是卤素、环烷基,所述环烷基任选地被至少一个R
5k取代基取代;并且
R
5k独立地选自卤素、-C
1-8烷基;
s是0、1、2;
Cy1是杂环基,所述的杂环基任选地被t个R
6取代;
R
6是H、-C
1-8烷基,所述的-C
1-8烷基任选被至少一个取代基R
6d取代;并且
R
6d独立地是杂环基、羟基;
t是0、1、2。
方面116:根据方面115的化合物,所述的R
3是H、-C
1-6烷基、C
3-10环烷基、6元芳基,且所述的6元芳基任选被至少一个取代基R
3d取代;并且R
3d是-C
1-3烷基。
方面118:根据方面115的化合物,所述的R
5是H、-C
1-6烷基、-OR
5a;并且
R
5a是-C
1-6烷基、C
3-10环烷基,且所述-C
1-6烷基、C
3-10环烷基各自任选地被至少一个取代基R
5e取代;并且
R
5e是卤素、C
3-10环烷基,所述C
3-10环烷基任选地被至少一个R
5k取代基取代;并且
R
5k独立地选自卤素、-C
1-6烷基。
方面120:根据方面115的化合物,所述的Cy1是包含一个或两个独立地选自氮、氧的杂原子的4-7元单环杂环基或7-9元稠合杂环基。
方面122:根据方面115的化合物,所述的R
6是H、-C
1-6烷基,所述的-C
1-6烷基任选被至少一个取代基R
6d取代;并且
R
6d独立地是羟基,或者包含一个或两个独立地选自氮、氧的杂原子的4-6元杂环基;
方面125:根据方面115-方面119中任一项的化合物,Cy1是如方面120-方面124中任一项所定义的。
方面126:根据方面125的化合物,其中Cy1在X
2位上。
方面127:根据方面125的化合物,其中Cy1在X
3位上。
方面128:根据方面126的化合物,R
5是如方面118-方面119中任一项所定义的,s是0、1或 者2。
方面129:根据方面128的化合物,其中s是1,R
5在X
1或者X
3位上。
方面130:根据方面128的化合物,其中s是2,第一个R
5在X
1位上,第二个R
5在X
3位上。
方面131:根据方面127的化合物,R
5是如方面118-方面119中任一项所定义的,s是0、1或者2。
方面132:根据方面131的化合物,其中s是1,R
5在X
2或者X
4位上。
方面133:根据方面131的化合物,其中s是2,第一个R
5在X
2位上,第二个R
5在X
4位上。
本发明提供上文所述的化合物、或其药学上可接受的盐、或其立体异构体,或其protac嵌合物,所述化合物选自本文公开的例示化合物,如下表1所示:
表1:
本发明还涉及包含本发明的任一化合物或其药学上可接受的盐、或其立体异构体、或其protac嵌合物的药物组合物,其可以任选含有一种或多种药用载体,并制成药学上可接受的任一药物制剂。
在本发明的一种具体实施方案中,前述的药物组合物可以进一步包含一种或多种第二治疗活性剂。所述的第二治疗活性剂为抗代谢物、生长因子抑制剂、有丝分裂抑制剂、抗肿瘤激素类、烷化剂类、金属类、拓扑异构酶抑制剂、激素药、免疫调节剂、肿瘤抑制基因、癌疫苗、免疫检查点或肿瘤免疫治疗相关的抗体或小分子药物。
本发明还涉及包含本发明的任一化合物或其药学上可接受的盐、或其立体异构体、或其protac嵌合物的药物制剂,以及一种或多种药用载体。
本文所述的药用载体可以是一种或多种适合于人使用的固体或液体填料或凝胶物质。所述药用载体可以是药物制剂领域中任何常规的载体和/或稀释剂,优选具有足够的纯度和足够低的毒性,并且与本发明活性成分具有相容性且不明显减低活性成分的药效。例如,药用载体可以填充剂、粘合剂、崩解剂、润滑剂、水性溶剂或非水性溶剂等。
本文所述的药物制剂可以制成药学上可接受的任意剂型,以任何合适的给药方式,例如通过口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时,可以制成固体剂型,如胶囊、片剂、丸剂、锭剂、糖衣剂、颗粒剂、粉末剂、软膏剂、乳膏剂、滴剂等;还可以制成液体剂型,如酏剂、糖浆剂、乳剂、分散剂、悬浮剂、溶液剂、喷雾剂等。用于肠胃外给药时,可以制成注射液、注射用无菌粉末等。
本发明提供的如式I所示的化合物及其药学上可接受的盐立体异构体、protac嵌合物具有优秀的HPK1高选择性抑制活性,能够治疗和/或预防HPK1介导的疾病及相关疾病。
本发明提供一种抑制HPK1活性的方法,所述方法包括向受试者给予本文公开的化合物、或其药学上可接受的盐、或其立体异构体、或其protac嵌合物,包括式(I)的化合物、式(II)的化合物或本文例示的特定化合物。
本发明提供的化合物具有良好的HPK1抑制活性、良好的理化性质和成药特性,以及具有较好的选择性,具体而言,相对MAP4K2、MAP4K4、MAP4K4、MAP4K5、MAP4K6,对HPK1具有高选择性,例如选择性高5倍、10倍、15倍、20倍、25倍、30倍、35倍、40倍、45倍、50倍或100倍及更多,或者,相对MAP4K3,对HPK1具有高选择性,例如选择性高5倍、8倍、10倍、20倍、25倍、30倍、35倍、40倍、45倍、50倍或100倍及更多。本发明的化合物或其药学上可接受的盐安全性好,药效好,生物利用度高,因此在治疗由HPK1介导的疾病方面有较好的应用潜力。
WO2016205942A1公开了参考化合物A化合物。令人惊讶地发现,本发明的具有吡咯并吡啶酮的化合物显示出提高的HPK1选择性。
本发明还涉及治疗患有可通过HPK1调节的疾病的患者的方法,其包括给予对象有效量的本发明的化合物(如式(I)的化合物、式(II)的化合物或本文例示的特定化合物)或其药学上可接受的盐、或其立体异构体、或其protac嵌合物。
本发明还涉及一种在需要HPK1活性抑制的患者中抑制HPK1活性的方法,其包括给予患者有效量的本发明的化合物(如式(I)的化合物、式(II)的化合物或本文例示的特定化合物)或其药学上可接受的盐、或其立体异构体、或其protac嵌合物。
本发明还涉及本发明的任一化合物或其药学上可接受的盐、或其立体异构体、或其protac嵌合物在制备用于治疗或者预防由HPK1介导的相关疾病的药物中的应用。HPK1在T细胞介导的信号通路中具有负反馈调节作用,因此可将HPK1的抑制剂作为免疫抗肿瘤药物应用到癌症或非癌性增殖性疾病的治疗中,其中所述疾病包括但不限于,肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、乳腺癌、乳腺导管癌、头颈癌、子宫内膜癌、宫体癌、直肠癌、肝癌、肾癌、肾盂癌、食管癌、食管腺癌、神经胶质瘤、前列腺癌、甲状腺癌、女性生殖系统癌症、原位癌、淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、口腔癌、咽癌、多发性骨髓瘤、白血病、非霍奇金淋巴瘤、大肠绒毛腺瘤、黑色素瘤、细胞瘤和肉瘤,骨髓增生异常综合症。
本发明还涉及一种治疗患者的癌症的方法,其包括给予患者有效量的HPK1抑制剂(例如,式(I) 的化合物)或其药学上可接受的盐、或其立体异构体、或其protac嵌合物,和有效量的第二抗癌治疗(例如,化疗剂、靶向治疗剂、放射或手术)。
本发明还涉及一种治疗患者的癌症的方法,其包括给予对象有效量的HPK1抑制剂(例如,式(I)的化合物)或其药学上可接受的盐、或其立体异构体、或其protac嵌合物,和有效量的免疫调节剂如检验点(checkpoint)抑制剂(例如,抗PD-1抗体、抗CTLA4抗体或抗PD-L1抗体)或色氨酸氧化抑制剂(例如,IDO1、IDO2或TDO2抑制剂)。
本发明进一步涉及HPK1抑制剂(例如,式(I)的化合物、或其药学上可接受的盐、或其立体异构体、或其protac嵌合物)与PD-1抑制剂(如纳武单抗(nivolumab)、帕母单抗(pembrolizumab)、皮地利珠单抗(pidilizumab)、BMS 936559、MPDL3280A、MSB0010718C或MEDI4736)的组合在制备用于治疗或者预防由HPK1介导的相关疾病的药物中的应用,其中所述疾病包括肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、乳腺癌、乳腺导管癌、头颈癌、子宫内膜癌、宫体癌、直肠癌、肝癌、肾癌、肾盂癌、食管癌、食管腺癌、神经胶质瘤、前列腺癌、甲状腺癌、女性生殖系统癌症、原位癌、淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、口腔癌、咽癌、多发性骨髓瘤、白血病、非霍奇金淋巴瘤、大肠绒毛腺瘤、黑色素瘤、细胞瘤和肉瘤,骨髓增生异常综合症。
定义
本发明所表述的化合物,是依据化学结构式命名的,如果表示同一化合物时化合物的命名与化学结构式不符,则以化学结构式为准。
本发明中,除有另外说明,则本文中使用的科学和技术名词具有本领域技术人员通常理解的含义,然而为了更好地理解本发明,下面提供了部分术语的定义。当本发明所提供的术语的定义和解释与本领域技术人员通常理解的含义不同时,以本发明所提供的术语的定义和解释为准。
如本文(包括所附方面)所用,除非上下文另外清楚地规定,否则单数形式的词语例如“一个”、“一种”和“所述”包括它们对应的复数指示物。
除非上下文另外清楚地规定,否则术语“或”用于意指术语“和/或”并且可与其互换使用。
术语“protac嵌合物”是指将本发明的化合物与E3连接酶配体连接组合形成的双功能化合物,其功能是募集靶向E3泛素连接酶的蛋白质以进行降解本发明化合物靶向的靶点。
术语“烷基”是指选自包含1至18个(诸如1至12个,进一步诸如1至10个,更进一步诸如1至8个、或1至6个、或1至4个)碳原子的直链和支链饱和烃基中的烃基。包含1至6碳原子的烷基的例子(即,C
1-6烷基)包括但不限于甲基、乙基、1-丙基或正丙基(“n-Pr”)、2-丙基或异丙基(“i-Pr”)、1-丁基或正丁基(“n-Bu”)、2-甲基-1-丙基或异丁基(“i-Bu”)、1-甲基丙基或仲丁基(“s-Bu”)、1,1-二甲基乙基或叔丁基(“t-Bu”)、1-戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基和3,3-二甲基-2-丁基。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。
术语“卤代烷基”是指其中一个或多个氢被一个或多个卤素原子(诸如氟、氯、溴和碘)替代的烷基。卤代烷基的例子包括卤代C
1-8烷基、卤代C
1-6烷基或卤代C
1-4烷基,但不限于-CF
3、-CH
2Cl、-CH
2CF
3、-CHCl
2、CF
3等。
术语“烯基”是指选自包含至少一个C=C双键和2至18个(诸如2至8个,进一步诸如2至6个)碳原子的直链和支链烃基中的烃基。烯基(例如,C
2-6烯基)的例子包括但不限于乙烯基(ethenyl或vinyl)、丙-1-烯基、丙-2-烯基、2-甲基丙-1-烯基、丁-1-烯基、丁-2-烯基、丁-3-烯基、丁-1,3-二烯基、2-甲基丁-1,3-二烯基、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基和己-1,3-二烯基。
术语“炔基”是指选自包含至少一个C≡C三键和2至18个(诸如2至8个,进一步诸如2至6个)碳原子的直链和支链烃基中的烃基。炔基(例如,C
2-6炔基)的例子包括但不限于乙炔基、1-丙炔基、2-丙炔基(炔丙基)、1-丁炔基、2-丁炔基和3-丁炔基。
术语“烷基氧基”或“烷氧基”是指通过氧原子与母体分子部分附接的如上所定义的烷基。烷基氧基(例如,C
1-6烷基氧基或C
1-4烷基氧基)的例子包括但不限于甲氧基、乙氧基、异丙氧基、丙氧基、正丁氧基、叔丁氧基、戊氧基和己氧基等。
术语“烷氧基-烷基-”是指进一步被如上所定义的烷氧基取代的如上所定义的烷基。烷氧基-烷基-(例如,C
1-8烷氧基-C
1-8烷基-)的例子包括但不限于甲氧基甲基、乙氧基甲基、异丙氧基甲基、或丙氧基甲基等。
术语“环烷基”是指选自饱和环状烃基中的烃基,所述饱和环状烃基包括单环和多环(例如,双环和三环)基团,包括稠合环烷基、桥接环烷基或螺环烷基。
例如,环烷基可以包含3至12个(诸如3至10个,进一步诸如3至8个,进一步诸如3至6个、3至5个或3至4个)碳原子。甚至进一步例如,环烷基可以选自包含3至12个(诸如3至10个,进一步诸如3至8个、3至6个)碳原子的单环基团。单环环烷基的例子包括环丙基、环丁基、环戊基、环己基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、和环十二烷基。具体地,饱和单环环烷基(例如,C
3-8环烷基)的例子包括但不限于环丙基、环丁基、环戊基、环己基、环庚基和环辛基。在优选的实施方案中,环烷基是包含3至6个碳原子的单环(缩写为C
3-6环烷基),其包括但不限于环丙基、环丁基、环戊基和环己基。双环环烷基的例子包括具有7至12个环原子的那些,所述环原子排列为选自[4,4]、[4,5]、[5,5]、[5,6]或[6,6]环系中的稠合双环,或排列为选自双环[2.2.1]庚烷、双环[2.2.2]辛烷和双环[3.2.2]壬烷中的桥接双环。双环环烷基的其他例子包括排列为选自[5,6]和[6,6]环系中的双环的环(诸如)的那些,其中波浪线指示附接点。环可以是饱和的或具有至少一个双键(即,部分不饱和的),但不是完全共轭的,并且不是芳香族的,因为本文中定义了芳香族。
术语“螺环烷基”是指含有碳原子并且由共用一个原子的至少两个环形成的环状结构。术语“7至12元螺环烷基”是指含有7至12个碳原子并且由共用一个原子的至少两个环形成的环状结构。
术语“稠合环烷基”是指含有碳原子并且由共用两个相邻原子的两个或更多个环形成的稠合环。术语“4至10元稠合环烷基”是指含有4至10个环碳原子并且由共用两个相邻原子的两个或更多个环形成的稠合环。
例子包括但不限于双环[1.1.0]丁基、双环[2.1.0]戊基、双环[3.1.0]己基、双环[4.1.0]庚基、双环[3.3.0]辛基、双环[4.2.0]辛基、十氢化萘,以及苯并3至8元环烷基、苯并C
4-6环烯基、2,3-二氢-1H-茚基、1H-茚基、1,2,3,4-四唑基、1,4-二氢萘基等。优选的实施方案是8至9元稠合环,所述稠合环是指在以上例子中含有8至9个环原子的环状结构。
术语“桥接环烷基”是指含有碳原子并且由共用彼此不相邻的两个原子的两个环形成的环状结构。术语“7至10元桥接环烷基”是指含有7至12个碳原子并且由共用彼此不相邻的两个原子的两个环形成的环状结构。
术语“环烯基”是指3至10个碳原子的非芳香族环状烷基,其具有单环或多环并且具有至少一个双键并且优选1至2个双键。在一个实施方案中,环烯基是环戊烯基(1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基)或环己烯基(1-环己-1-烯基、1-环己-2-烯基、1-环己-3-烯基),优选环己烯基。
术语“环炔基”是指5至10个碳原子的非芳香族环烷基,其具有单环或多环并且具有至少一个三键。
单独使用或与其他术语组合使用的术语“芳基”是指选自以下的基团:
-5和6元碳环芳香族环,例如苯基;
-双环环系,诸如7至12元双环环系,其中至少一个环是碳环并且芳香族的,例如萘基和茚满基;以及
-三环环系,诸如10至15元三环环系,其中至少一个环是碳环并且芳香族的,例如芴基。
术语“芳香族烃环”和“芳基”贯穿本文的公开文本可互换使用。在一些实施方案中,单环或双环芳香族烃环具有5至10个成环碳原子(即,C
5-10芳基)。单环或双环芳香烃环的例子包括但不限于苯基、萘-1-基、萘-2-基、蒽基、菲基等。在一些实施方案中,芳香族烃环是萘环(萘-1-基或萘-2-基)或苯基环。在一些实施方案中,芳香族烃环是苯基环。
术语“杂芳基”是指选自以下的基团:
-5、6或7元芳香族单环的环,其包含至少一个杂原子,例如1至4个杂原子,或在一些实施方案中1至3个杂原子,在一些实施方案中1至2个杂原子,所述杂原子选自氮(N)、硫(S)和氧(O),其余的环原子是碳;
-7元至12元双环的环,其包含至少一个杂原子,例如1至4个杂原子,或在一些实施方案中1至3个杂原子,或在其他实施方案中1或2个杂原子,所述杂原子选自N、O和S,其余的环原子是碳,并且其中至少一个环是芳香族的并且芳香族环中存在至少一个杂原子;以及
-11至14元三环的环,其包含至少一个杂原子,例如1至4个杂原子,或在一些实施方案中1至3个杂原子,或在其他实施方案中1或2个杂原子,所述杂原子选自N、O和S,其余的环原子是碳,并且其中至少一个环是芳香族的并且芳香族环中存在至少一个杂原子。
当杂芳基中的S和O原子的总数超过1时,那些杂原子彼此不相邻。在一些实施方案中,杂芳基中的S和O原子的总数不大于2。在一些实施方案中,芳香族杂环中的S和O原子的总数不大于1。当杂芳基含有多于一个杂原子环成员时,所述杂原子可以相同或不同。杂芳基的一个或多个环中的氮原子可以被氧化以形成N-氧化物。如本文所用的术语“C-连接的杂芳基”意指杂芳基通过来自杂芳基环的C-原子的键与核心分子连接。
术语“芳香族杂环的环”和“杂芳基”贯穿本文的公开文本可互换使用。在一些实施方案中,单环或双环芳香族杂环具有5、6、7、8、9或10个成环成员,其中1、2、3或4个杂原子环成员独立地选自氮(N)、硫(S)和氧(O),并且其余的环成员是碳。在一些实施方案中,单环或双环芳香族杂环是包含1或2个独立地选自氮(N)、硫(S)和氧(O)中的杂原子环成员的单环或双环。在一些实施方案中,单环或双环芳香族杂环是5至6元杂芳基环,其为单环并且具有1或2个独立地选自氮(N)、硫(S)和氧(O)中的杂原子环成员。在一些实施方案中,单环或双环芳香族杂环的环是8至10元杂芳基环,其是双环的并且具有1或2个独立地选自氮、硫和氧中的杂原子环成员。
杂芳基或者单环或双环芳香族杂环的环的例子包括但不限于(如从指定优先级1的连接位置编号)吡啶基(诸如2-吡啶基、3-吡啶基或4-吡啶基)、噌啉基、吡嗪基、2,4-嘧啶基、3,5-嘧啶基、2,4-咪唑基、咪唑并吡啶基、异噁唑基、噁唑基、噻唑基、异噻唑基、噻二唑基(诸如1,2,3-噻二唑基、1,2,4-噻二唑基或1,3,4-噻二唑基)、四唑基、噻吩基(诸如噻吩-2-基、噻吩-3-基)、三嗪基、苯并噻吩基、呋喃基(furyl或furanyl)、苯并呋喃基、苯并咪唑基、吲哚基、异吲哚基、吲哚啉基、噁二唑基(诸如1,2,3-噁二唑基、1,2,4-噁二唑基或1,3,4-噁二唑基)、酞嗪基、吡嗪基、哒嗪基、吡咯基、三唑基(诸如1,2,3-三唑基、1,2,4-三唑基或1,3,4-三唑基)、喹啉基、异喹啉基、吡唑基、吡咯并吡啶基(诸如1H-吡咯并[2,3-b]吡啶-5-基)、吡唑并吡啶基(诸如1H-吡唑并[3,4-b]吡啶-5-基)、苯并噁唑基(诸如苯并[d]噁唑-6-基)、蝶啶基、嘌呤基、1-氧杂-2,3-二唑基、1-氧杂-2,4-二唑基、1-氧杂-2,5-二唑基、1-氧杂-3,4-二唑基、1-硫杂-2,3-二唑基、1-硫杂-2,4-二唑基、1-硫杂-2,5-二唑基、1-硫杂-3,4-二唑基、呋咱基(诸如呋咱-2-基、呋咱-3-基)、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基、呋喃并吡啶基、苯并噻唑基(诸如苯并[d]噻唑-6-基)、吲唑基(诸如1H-吲唑-5-基)以及5,6,7,8-四氢异喹啉。
“杂环基”、“杂环”或“杂环的”是可互换的并且是指包含一个或多个选自氮、氧或任选氧化的硫中的杂原子作为环成员并且其余的环成员是碳的非芳香族杂环基,包括单环的环、稠合环、桥接环和螺环,即,含有单环杂环基、桥接杂环基、螺杂环基、和稠合杂环基团。本文所用术语“任选氧化的硫”是指S、SO或SO
2。
术语“单环杂环基”是指其中至少一个环成员是选自氮、氧或任选氧化的硫中的杂原子的单环基团。杂环可以是饱和的或部分饱和的。
示例性单环4至9元杂环基包括但不限于(如从指定优先级1的连接位置编号)吡咯烷-1-基、吡咯烷-2-基、吡咯烷-3-基、咪唑烷-2-基、咪唑烷-4-基、吡唑烷-2-基、吡唑烷-3-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基、2,5-哌嗪基、吡喃基、吗啉基、吗啉代、吗啉-2-基、吗啉-3-基、环氧乙烷基、氮杂环丙烷-1-基、氮杂环丙烷-2-基、氮杂环辛烷-1-基、氮杂环辛烷-2-基、氮杂环辛烷-3-基、 氮杂环辛烷-4-基、氮杂环辛烷-5-基、硫杂环丙烷基、氮杂环丁烷-1-基、氮杂环丁烷-2-基、氮杂环丁烷-3-基、氧杂环丁烷基、硫杂环丁烷基、1,2-二硫杂环丁烷基、1,3-二硫杂环丁烷基、二氢吡啶基、四氢吡啶基、硫代吗啉基、氧杂硫杂环己烷基、哌嗪基、高哌嗪基、高哌啶基、氮杂环庚烷-1-基、氮杂环庚烷-2-基、氮杂环庚烷-3-基、氮杂环庚烷-4-基、氧杂环庚烷基、硫杂环庚烷基、1,4-氧杂硫杂环己烷基、1,4-二氧杂环庚烷基、1,4-氧杂硫杂环庚烷基、1,4-氧杂氮杂环庚烷基、1,4-二硫杂环庚烷基、1,4-硫杂氮杂环庚烷基和1,4-二氮杂环庚烷基、1,4-二硫杂环己烷基、1,4-氮杂硫杂环己烷基、氧氮杂卓基、二氮杂卓基、硫杂氮杂卓基、二氢噻吩基、二氢吡喃基、二氢呋喃基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢硫代吡喃基、1-吡咯啉基、2-吡咯啉基、3-吡咯啉基、吲哚啉基、2H-吡喃基、4H-吡喃基、1,4-二氧杂环己烷基、1,3-二氧戊环基、吡唑啉基、吡唑烷基、二噻烷基、二硫杂环戊烷基、吡唑烷基、咪唑啉基、嘧啶酮基、或1,1-二氧代-硫代吗啉基。
术语“螺杂环基”是指具有通过一个共用碳原子(称为螺原子)连接的环的5至20元多环杂环基,包含一个或多个选自氮、氧或任选氧化的硫中的杂原子作为环成员,其余的环成员是碳。螺杂环基的一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子体系。优选地,螺杂环基是6至14元的,并且更优选7至12元的。根据共用螺原子的数量,螺杂环基分为单螺杂环基、二螺杂环基、或多螺杂环基,并且优选地是指单螺杂环基或二螺杂环基,并且更优选4元/4元、3元/5元、4元/5元、4元/6元、5元/5元、或5元/6元单螺杂环基。螺杂环基的代表性例子包括但不限于以下基团:2,3-二氢螺[茚-1,2’-吡咯烷](例如,2,3-二氢螺[茚-1,2’-吡咯烷]-1’-基)、1,3-二氢螺[茚-2,2’-吡咯烷](例如,1,3-二氢螺[茚-2,2’-吡咯烷]-1’-基)、氮杂螺[2.4]庚烷(例如,5-氮杂螺[2.4]庚烷-5-基)、氮杂螺[3.4]辛烷(例如,6-氮杂螺[3.4]辛烷-6-基)、2-氧杂-6-氮杂螺[3.4]辛烷(例如,2-氧杂-6-氮杂螺[3.4]辛烷-6-基)、氮杂螺[3.4]辛烷(例如,6-氮杂螺[3.4]辛-6-基)、氮杂螺[3.4]辛烷(例如,6-氮杂螺[3.4]辛-6-基)、1,7-二氧杂螺[4.5]癸烷、2-氧杂-7-氮杂-螺[4.4]壬烷(例如,2-氧杂-7-氮杂-螺[4.4]壬-7-基)、7-氧杂-螺[3.5]壬基和5-氧杂-螺[2.4]庚基。
术语“稠合杂环基团”是指其中体系中的每个环与另一个环共用相邻的一对原子(碳和碳原子或碳和氮原子)的5至20元多环杂环基团,包含一个或多个选自氮、氧或任选氧化的硫中的杂原子作为环成员,其余的环成员是碳。稠合杂环基团的一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子体系。优选地,稠合杂环基是6至14元的,优选7至12元的并且更优选7至10元的。根据成员环的数量,稠合杂环基分为双环、三环、四环、或多环稠合杂环基,优选地是指双环或三环稠合杂环基,并且更优选5元/5元、或5元/6元双环稠合杂环基。稠合杂环的代表性例子包括但不限于以下基团:八氢环戊二烯并[c]吡咯(例如,八氢环戊二烯并[c]吡咯-2-基)、八氢吡咯并[3,4-c]吡咯基、八氢异吲哚基、异吲哚啉基(例如,异吲哚啉-2-基或异吲哚啉-5-基)、八氢-苯并[b][1,4]二噁英、二氢吡啶并噁嗪基(例如,2,3-二氢-1H-吡啶并[2,3-b][1,4]噁嗪基)或二氢苯并氧氮杂卓基(例如,5-氧代-3,4-二氢苯并[f][1,4]氧氮杂卓基)、苯并氮杂卓基(例如,2,3,4,5-四氢-1-氧代-2-苯并氮杂卓-6-基)、苯并氧氮杂卓基(例如,5-氧代-2,3,4,5-四氢-1,4-苯并氧氮杂卓-8-基)、二氢异喹啉基(例如,1-氧代-2-甲基-3,4-二氢异喹啉-6-基)、四氢异喹啉基(例如,2-甲基-1-氧代-1,2,3,4-四氢异喹啉-6-基)、二氢苯并噁嗪(例如,3,4-二氢-2H-1,4-苯并噁嗪-6-基)。
术语“桥接杂环基”是指其中体系中每两个环共用两个不相连的原子的5至14元多环杂环烷基,包含一个或多个选自氮、氧或任选氧化的硫中的杂原子作为环成员,其余的环成员是碳。桥接杂环基的一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子体系。优选地,桥接杂环基是6至14元的,并且更优选7至10元的。根据成员环的数量,桥接杂环基分为双环、三环、四环或多环桥接杂环基,并且优选地是指双环、三环或四环桥接杂环基,并且更优选双环或三环桥接杂环基。桥接杂环基的代表性例子包括但不限于以下基团:2-氮杂双环[2.2.1]庚基、氮杂双环[3.1.0]己基、2-氮杂双环[2.2.2]辛基和2-氮杂双环[3.3.2]癸基。
术语“亚烷基”是指如上所定义的二价烷基,是指长度为1个至18个碳原子(C
1-18)的饱和的直链或支链的二价的烃基,其中所述亚烷基可任选独立取代有一个或多个下述取代基。在另一个实施方案中,亚烷基具有一个至八个碳原子(C
1-8)或一个至六个碳原子(C
1-6)。亚烷基的实例包括但不局限于 亚甲基(-CH
2-)、亚乙基(-CH
2CH
2-)、亚丙基(-CH
2CH
2CH
2-)等。
术语“亚烯基”是指如上所定义的二价烯基,是指长度为两个个至八个碳原子(C
2-8)的具有至少一个不饱和位置即碳-碳sp
2双键的直链或支链的二价的烃基,其中所述亚烯基可任选独立取代有一个或多个本申请所描述的取代基且包括具有“顺式”和“反式”取向或“E”和“Z”取向的基团。实例包括但不局限于亚乙烯基(-CH=CH-)、亚烯丙基(-CH
2CH=CH-)等。。
术语“亚炔基”是指如上所定义的二价炔基,指长度为三个至八个碳原子(C
3-8)的具有至少一个不饱和位置即碳-碳sp叁键的直链或支链的二价的烃基,其中所述亚炔基可任选独立取代有一个或多个本申请所描述的取代基。实例包括但不局限于亚丙炔基(亚炔丙基、-CH
2C≡C-)等。
术语“亚环烷基”是指如上所定义的二价环烷基。术语“亚杂环基”是指如上所定义的二价杂环基。术语“亚芳基”是指如上所定义的二价芳基。术语“亚杂芳基”是指如上所定义的二价亚杂芳基。
本文公开的化合物可以含有不对称中心,并且因此可以作为对映异构体存在。“对映异构体”是指化合物的两种立体异构体,它们彼此是不可重叠的镜像。在本文公开的化合物具有两个或更多个不对称中心的情况下,它们可以另外作为非对映异构体存在。对映异构体和非对映异构体属于更广泛的立体异构体类别。旨在包括作为基本上纯的拆分的对映异构体、其外消旋混合物、以及非对映异构体的混合物的所有这些可能的立体异构体。旨在包括本文公开的化合物和/或其药学上可接受的盐的所有立体异构体。除非另外特别提及,否则提及一种异构体适用于任何可能的异构体。每当未指定异构体组成时,包括所有可能的异构体。
如本文所用的术语“基本上纯的”意指目标立体异构体含有按重量计不超过35%(诸如不超过30%,进一步诸如不超过25%,甚至进一步诸如不超过20%)的任何其他一种或多种立体异构体。在一些实施方案中,术语“基本上纯的”意指目标立体异构体含有按重量计不超过10%(例如不超过5%,诸如不超过1%)的任何其他一种或多种立体异构体。
当本文公开的化合物含有烯属双键时,除非另有指明,否则此类双键意在包括E和Z几何异构体两者。
当本文公开的化合物含有二取代的环己基或环丁基时,在环己基或环丁基环上发现的取代基可以采用顺式和反式形成。顺式形成意指发现两个取代基均在碳上的2个取代基位置的上侧,而反式意指它们在相对侧。
“药学上可接受的盐”是指在合理的医学判断范围内适合于与人和低等动物的组织接触使用而没有过度毒性、刺激、过敏反应等并与合理的利益/风险比相称的那些盐。药学上可接受的盐可以在本文公开的化合物的最终分离和纯化期间原位制备,或者通过使游离碱官能团与合适的有机酸反应或通过使酸性基团与合适的碱反应而单独制备。
另外,如果本文公开的化合物作为酸加成盐获得,则可以通过将酸式盐的溶液碱化来获得游离碱。相反,如果产物是游离碱,则可以按照用于从碱化合物制备酸加成盐的常规程序,通过将游离碱溶解在合适的有机溶剂和/或水中并且用酸处理溶液来产生加成盐,诸如药学上可接受的加成盐。本领域的技术人员将认识到可使用的在无需过度实验的情况下制备无毒的药学上可接受的加成盐的各种合成方法。
如本文所定义,“其药学上可接受的盐”包括至少一种式(I)的化合物的盐和式(I)的化合物的立体异构体的盐,诸如对映异构体的盐和/或非对映异构体的盐。
当应用于动物、人、实验受试者、细胞、组织、器官或生物流体时,术语“给予”(administration,administering)、“治疗”(treating和treatment)意指外源性药剂、治疗剂、诊断剂或组合物与所述动物、人、受试者、细胞、组织、器官或生物流体的接触。对细胞的处理涵盖试剂与细胞的接触、以及试剂与流体的接触,其中所述流体与所述细胞接触。术语“给予”和“治疗”还意指通过试剂、诊断剂、结合化合物或者通过另一种细胞对例如细胞的体外和离体治疗。本文的术语“受试者”包括任何生物体,优选动物,更优选哺乳动物(例如大鼠、小鼠、狗、猫、和兔)并且最优选人。
术语“有效量”或“治疗有效量”是指活性成分(诸如化合物)的如下量,当所述化合物被给予受试者以治疗疾病或者疾病或障碍的至少一种临床症状时所述量足以影响对所述疾病、障碍或症状的这种 治疗。“治疗有效量”可随以下变化:化合物,疾病,障碍,和/或疾病或障碍的症状,疾病、障碍和/或疾病或障碍的症状的严重程度,待治疗的受试者的年龄,和/或待治疗的受试者的体重。在任何给定的例子中,适当的量对于本领域技术人员来说是清楚的,或者可以通过常规实验来确定。在一些实施方案中,“治疗有效量”是本文公开的至少一种化合物和/或其至少一种立体异构体和/或其至少一种其药学上可接受的盐有效于“治疗”(如上定义)受试者的疾病或障碍的量。在组合疗法的情况下,“治疗有效量”是指用于有效治疗疾病、障碍或病症的组合对象的总量。
包含本文公开的化合物的药物组合物可以经由口服、吸入、直肠、肠胃外或局部给药给予至对其有需要的受试者。对于口服给药,药物组合物可以是常规固体配制品诸如片剂、粉剂、颗粒剂、胶囊等,液体配制品诸如水或油悬浮液,或其他液体配制品诸如糖浆、溶液、悬浮液等;对于肠胃外给药,药物组合物可以是溶液、水溶液、油悬浮液浓缩物、冻干粉末等。优选地,药物组合物的配制品选自片剂、包衣片剂、胶囊、栓剂、鼻喷雾剂或注射剂,更优选片剂或胶囊。药物组合物可以是具有准确剂量的单个单位给药。此外,药物组合物还可包含另外的活性成分。
本文公开的药物组合物的所有配制品可以通过制药领域中的常规方法产生。例如,可以将活性成分与一种或多种赋形剂混合,然后制备所希望的配制品。“药学上可接受的赋形剂”是指适用于所希望的药物配制品的常规药物载体,例如:稀释剂,媒介物诸如水、各种有机溶剂等,填料诸如淀粉、蔗糖等,粘合剂诸如纤维素衍生物,藻酸盐,明胶和聚乙烯吡咯烷酮(PVP);润湿剂,诸如甘油;崩解剂诸如琼脂、碳酸钙和碳酸氢钠;吸收增强剂,诸如季铵化合物;表面活性剂,诸如十六烷醇;吸收载体,诸如高岭土和皂土;润滑剂,诸如滑石、硬脂酸钙、硬脂酸镁、聚乙二醇等。此外,药物组合物还包含其他药学上可接受的赋形剂,诸如分散剂、稳定剂、增稠剂、络合剂、缓冲剂、渗透增强剂、聚合物、芳香剂、甜味剂和染料。
术语“疾病”是指任何疾病、不适、病、症状或适应症,并且可以与术语“病症”或“障碍”互换。
在整个说明书和随后的方面中,除非上下文另有要求,否则术语“包含”和变型诸如“包含”(“comprises”和“comprising”)旨在指明其后的特征的存在,但不排除存在或添加一个或多个其他功能。当本文所用时,术语“包含”可以用术语“含有”、“包括”代替或有时用“具有”代替。
在整个说明书和随后的方面中,术语“C
n-m”指示包括端点的范围,其中n和m是整数并且指示碳数。例子包括C
1-8、C
1-6等。
除非在本文件的其他地方明确定义,否则本文使用的所有其他技术和科学术语具有本发明所属领域的普通技术人员通常理解的含义。
下面结合具体实施例对本发明作进一步的详细说明,但这些实施例并非限制着本发明的范围。以下实施例用于理解本发明的方法和核心思想,对于本领域的技术人员来说,在不脱离本发明构思的前提下,进行任何可能的变化或替换,均属于本发明的保护范围。本发明实施例中未注明具体条件的实验方法,通常为常规条件,或按照原料或商品制造厂商所建议的条件;未注明来源的试剂,通常为通过商业途径可购得的常规试剂。
化合物的鉴定与表征
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。
1HNMR图谱是用Bruker仪器(400MHz)测定而得,化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。
1H NMR的表示方法:s=单峰,d=双重峰,t=三重峰,m=多重峰,br=变宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。
质谱是用LC/MS仪测定得到,离子化方式可为ESI或APCI。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)。
使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
在下列实例中,除非另有指明,所有温度为摄氏温度,除非另有指明,各种起始原料和试剂来 自市售或者是根据已知的方法合成,市售原料和试剂均不经进一步纯化直接使用,除非另有指明,市售厂家包括但不限于Aldrich Chemical Company,ABCR GmbH&Co.KG,Acros Organics,上海毕得医药科技有限公司和上海韶远试剂有限公司等处购买。
CD
3OD:氘代甲醇。
CDCl
3:氘代氯仿。
DMSO-d
6:氘代二甲基亚砜。
T
3P:三丙基磷酸酐。
DPPA:叠氮磷酸二苯酯。
DIEA:N,N-二异丙基乙胺。
实施例中无特殊说明,反应中的溶液是指水溶液。
对化合物进行纯化,采用柱层析和薄层色谱法的洗脱剂体系,其中该体系选自:A:石油醚和乙酸乙酯体系;B:二氯甲烷和甲醇体系;C:二氯甲烷和乙酸乙酯体系,D:二氯甲烷和乙醇体系,其中溶剂的体积比根据化合物的极性不同而不同,也可以加入少量的酸性或碱性试剂进行条件,如醋酸或三乙胺等。
参考化合物A是WO2016205942A1的化合物,按其公开的方法制备,
制备实施例
实施例1:制备化合物C001
步骤1:制备6-甲氧基-5-氮杂吲哚-7-甲醛
将化合物7-溴-6-甲氧基-5-氮杂吲哚(600mg,2.64mmol)溶于四氢呋喃(10mL)溶液中,在-78℃下将正丁基锂(1.6M,5mL,8mmol)缓慢滴加到反应体系中,搅拌反应0.5h,然后将N,N-二甲基甲酰胺(0.8mL,10mmol)滴加到反应体系中,搅拌反应1h。TLC监测反应结束后,加水淬灭,乙酸乙酯(20mL×2)萃取,合并有机相,饱和食盐水洗涤(10mL×2),减压蒸馏,柱层析纯化(石油醚/乙酸乙酯=4:1),得6-甲氧基-5-氮杂吲哚-7-甲醛(420mg,产率90.3%)。
步骤2:制备2-(6-甲氧基-1H-吡咯并[3,2-c]吡啶-7-基)-5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑
将化合物6-甲氧基-5-氮杂吲哚-7-甲醛(360mg,2.05mmol)和4-(4-甲基哌嗪-1-基)苯-1,2-二胺(515mg,2.5mmol)溶于乙酸(5mL)溶液中,加入碘(50mg,0.2mmol),在室温下敞口搅拌 反应20h。TLC监测反应结束后,加氨水淬灭,减压蒸馏,柱层析纯化(MeOH:DCM=1:9),得2-(6-甲氧基-1H-吡咯并[3,2-c]吡啶-7-基)-5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑(540mg,产率72.7%)。
步骤3:制备化合物C001
将化合物2-(6-甲氧基-1H-吡咯并[3,2-c]吡啶-7-基)-5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑(100mg,0.28mmol)溶于4M的盐酸1,4-二氧六环溶液(4mL)中,升温至90℃,搅拌反应5h。TLC监测反应结束后,加氨水淬灭,减压蒸馏,柱层析纯化(MeOH:DCM=1:9),得化合物C001(40mg,产率41.0%)。
MS m/z(ESI):349.2[M+H]
+;
1H NMR(400MHz,DMSO-d
6)δ:12.40(s,1H),12.27(s,1H),11.21(s,1H),8.04(s,1H),7.56(d,J=8.7Hz,1H),7.31(d,J=3.5Hz,1H),7.26(s,1H),6.97(dd,J=8.8,2.3Hz,1H),6.44(d,J=3.4Hz,1H),3.85–3.06(m,8H),2.81(s,3H)。
实施例2:制备化合物C002
步骤1:制备7-溴-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲醛
将三氯氧磷(5.27g,34.4mmol)溶于N,N-二甲基甲酰胺(5mL)溶液中,在0℃下搅拌反应10min,然后将化合物7-溴-6-甲氧基-5-氮杂吲哚(1.3g,5.73mmol)溶于N,N-二甲基甲酰胺(5mL)溶液中并缓慢滴加到反应体系中,在0℃下搅拌反应3h。TLC监测反应结束后,加碳酸钠饱和溶液淬灭,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,减压蒸馏,柱层析纯化(石油醚/乙酸乙酯=3:1),得7-溴-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲醛(436mg,产率30.0%)。
步骤2:制备7-溴-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈
将化合物7-溴-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲醛(436mg,1.72mmol)溶于二甲基甲酰胺(5mL)溶液中,加入盐酸羟胺(257mg,3.7mmol),1-丙基磷酸酐的乙酸乙酯溶液(2.4g,3.7mmol)和三乙胺(0.51mL,3.7mmol),升温至100℃,反应2.5h。TLC监测反应结束后,加水淬灭,EA萃取,合并有机相,饱和食盐水洗涤,减压蒸馏,柱层析纯化(石油醚/乙酸乙酯=6:1),得7-溴-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(430mg,产率99.2%)。
步骤3:制备7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈
将化合物7-溴-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(430mg,1.71mmol)溶于四氢呋喃(10mL)溶液中,在-78℃下将正丁基锂(3.2mL,5.13mmol)缓慢滴加到反应体系中,搅拌反应0.5h,然后将N,N-二甲基甲酰胺(0.53mL,6.84mmol)滴加到反应体系中,搅拌反应1h。TLC监测反应结束后,加水淬灭,EA萃取,合并有机相,饱和食盐水洗涤,减压蒸馏,柱层析纯化(石油醚/乙酸乙酯=4:1),得7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈(180mg,产率52.4%)。
步骤4:制备6-甲氧基-7-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吡咯[3,2-c]吡啶-3-甲腈
将化合物7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈(170mg,0.84mmol)和4-(4-甲基哌嗪-1-基)苯-1,2-二胺(260mg,1.26mmol)溶于N,N-二甲基甲酰胺(3mL)溶液中,加入焦亚硫酸钠 (240mg,1.26mmol),升温至90℃反应16h。TLC监测反应结束后,减压蒸馏,柱层析纯化(MeOH:DCM=1:6),得6-甲氧基-7-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吡咯[3,2-c]吡啶-3-甲腈(140mg,产率43.0%)。
步骤5:制备化合物C002
将化合物6-甲氧基-7-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-1H-吡咯[3,2-c]吡啶-3-甲腈(140mg,0.36mmol)溶于4M的盐酸1,4-二氧六环溶液(8mL)中,升温至90℃,搅拌反应4h。TLC监测反应结束后,加氨水淬灭,减压蒸馏,柱层析纯化(MeOH:DCM=1:6),得化合物C002(70mg,产率56.6%)。
MS m/z(ESI):374.2[M+H]
+。
1H NMR(400MHz,DMSO-d
6)δ12.78(s,1H),12.39(s,1H),10.87(s,1H),8.20(s,1H),8.19(s,1H),7.57(d,J=8.4Hz,1H),7.28(s,1H),7.00(dd,J=8.8,2.3Hz,1H),3.70(s,2H),3.50(s,2H),3.27–3.07(m,8H),2.82(s,3H).
实施例3:制备化合物C003
步骤1:制备3-溴-2-甲氧基吡啶-4-胺
在0℃下,将NBS(14.3g,80mmol)缓慢加入2-甲氧基吡啶-4-胺(10.0g,80mmol)的二氯甲烷(500mL)溶液中。撤去冰浴,反应液在室温下搅拌2h。TLC(石油醚/乙酸乙酯=3/1)显示反应结束。反应液直接浓缩至干燥得粗品,粗品通过快速柱层析(石油醚/乙酸乙酯=6:1)纯化得到3-溴-2-甲氧基吡啶-4-胺(16.2g,产率94.7%)。
步骤2:制备3-溴-5-碘-2-甲氧基吡啶-4-胺
室温下,将NIS(12.2g,54.1mmol)分批加入到3-溴-2-甲氧基吡啶-4-胺(10.0g,49.2mmol)的乙腈(400mL)和(10mL)溶液中。反应液在室温下搅拌16h。TLC(石油醚/乙酸乙酯=20/1)显示反应结束。将反应液浓缩后,剩余物再用乙酸乙酯(300mL)溶解。该溶液用水洗涤,无水硫酸钠干燥,浓缩得粗品。粗品通过快速柱层析(石油醚:乙酸乙酯=20:1)纯化得到3-溴-5-碘-2-甲氧基吡啶-4-胺(11.8g,产率71.4%)。
步骤3:制备3-溴-2-甲氧基-5-(邻甲苯基乙炔基)吡啶-4-胺
在室温下,将3-溴-5-碘-2-甲氧基吡啶-4-胺(5.66g,17.22mmol),三乙胺(9.55mL,68.87mmol),碘化亚铜(0.01mL,0.34mmol)和双三苯基磷二氯化钯(0.27g,0.34mmol)加入THF(10mL)溶液中,氮气置换三次,在氮气保护下加入2-甲基苯乙炔(2.00g,17.22mmol)。反应液在室温下搅拌10h。TLC(石油醚/乙酸乙酯=20/1)检测反应结束。将反应液倒入水(100mL)中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和氯化铵水溶液洗涤,无水硫酸钠干燥,抽滤,浓缩得粗品。粗品通过快速柱层析(石油醚:乙酸乙酯=7:1)纯化得到3-溴-2-甲氧基-5-(邻甲苯基乙炔基)吡啶 -4-胺(4.82g,产率88.28%)。
步骤4:制备7-溴-6-甲氧基-2-(邻甲苯基)-1H-吡咯并[3,2-c]吡啶
将3-溴-2-甲氧基-5-(邻甲苯基乙炔基)吡啶-4-胺(3.80g,11.98mmol)溶于甲苯(20mL)中,然后加入三溴化铟(2.12g,5.99mmol),氮气置换三次,在氮气环境下升温到125℃,反应液在此温度下搅拌1h。TLC(石油醚/二氯甲烷=1/1)检测反应结束。反应液浓缩得粗品,将粗品通过快速柱层析(石油醚:二氯甲烷=2:1)纯化得到7-溴-6-甲氧基-2-(邻甲苯基)-1H-吡咯并[3,2-c]吡啶(3.25g,产率85.5%)。
步骤5:制备7-溴-6-甲氧基-2-(邻甲苯基)-1H-吡咯并[3,2-c]吡啶-3-甲醛
将三氯氧磷(1.46g,9.5mmol)溶于N,N-二甲基甲酰胺(5mL)溶液中,在0℃下搅拌反应10min,然后将化合物7-溴-6-甲氧基-2-(邻甲苯基)-1H-吡咯并[3,2-c]吡啶(1g,3.15mmol)溶于N,N-二甲基甲酰胺(5mL)溶液中并缓慢滴加到反应体系中,之后在室温下搅拌12h。TLC监测反应结束后,加碳酸钠饱和溶液淬灭,EA萃取,合并有机相,饱和食盐水洗涤,减压蒸馏,柱层析纯化(EA:PE=1:3),得7-溴-6-甲氧基-2-(邻甲苯基)-1H-吡咯并[3,2-c]吡啶-3-甲醛(950mg,产率82.7%)。
步骤6:制备7-溴-6-甲氧基-2-(邻甲苯基)-1H-吡咯并[3,2-c]吡啶-3-甲腈
将化合物7-溴-6-甲氧基-2-(邻甲苯基)-1H-吡咯并[3,2-c]吡啶-3-甲醛(1.07g,3.1mmol)溶于N,N-二甲基甲酰胺(5ml)溶液中,加入盐酸羟胺(431mg,6.2mmol),1-丙基磷酸酐的乙酸乙酯溶液(3.95g,6.2mmol)和三乙胺(0.86mL,6.2mmol),升温至100℃,反应12h。TLC监测反应结束后,加水淬灭,EA萃取,合并有机相,饱和食盐水洗涤,减压蒸馏,柱层析纯化(EA:PE=1:4),得7-溴-6-甲氧基-2-(邻甲苯基)-1H-吡咯并[3,2-c]吡啶-3-甲腈(650mg,产率61.3%)。
步骤7:制备7-甲酰基-6-甲氧基-2-(邻甲苯基)-1H-吡咯并[3,2-c]吡啶-3-甲腈
将化合物7-溴-6-甲氧基-2-(邻甲苯基)-1H-吡咯并[3,2-c]吡啶-3-甲腈(350mg,1.03mmol)溶于四氢呋喃(10mL)溶液中,在-78℃下将正丁基锂(1.9mL,3.09mmol)缓慢滴加到反应体系中,搅拌反应0.5h,然后将N,N-二甲基甲酰胺(0.32mL,4.12mmol)滴加到反应体系中,之后缓慢升温至0℃,搅拌反应2h。TLC监测反应结束后,加水淬灭,EA萃取,合并有机相,饱和食盐水洗涤,减压蒸馏,柱层析纯化(EA:PE=1:3),得7-甲酰基-6-甲氧基-2-(邻甲苯基)-1H-吡咯并[3,2-c]吡啶-3-甲腈(200mg,产率66.7%)。
步骤8:制备6-甲氧基-7-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-2-(邻甲苯基)-1H-吡咯[3,2-c]吡啶-3-甲腈
将化合物7-甲酰基-6-甲氧基-2-(邻甲苯基)-1H-吡咯并[3,2-c]吡啶-3-甲腈(200mg,0.69mmol)和4-(4-甲基哌嗪-1-基)苯-1,2-二胺(284mg,1.38mmol)溶于N,N-二甲基甲酰胺(5ml)溶液中,加入焦亚硫酸钠(262mg,1.38mmol),升温至90℃反应12h。TLC监测反应结束后,减压蒸馏,柱层析纯化(MeOH:DCM=1:9),得6-甲氧基-7-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-2-(邻甲苯基)-1H-吡咯[3,2-c]吡啶-3-甲腈(230mg,产率69.8%)。
步骤9:制备化合物C003
将化合物6-甲氧基-7-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-2-(邻甲苯基)-1H-吡咯[3,2-c]吡啶-3-甲腈(230mg,0.48mmol)溶于乙醇溶液(4mL)中,加入4M的盐酸1,4-二氧六环溶液(6mL),升温至90℃,搅拌反应3h。TLC监测反应结束后,加氨水淬灭,减压蒸馏,柱层析纯化(MeOH:DCM=1:6),得化合物C003(80mg,产率17.2%)。
1H NMR(400MHz,DMSO-d
6)δ12.82(s,1H),12.39(s,1H),11.18(s,1H),8.24(s,1H),7.66–7.60(m,1H),7.60–7.51(m,2H),7.50(s,1H),7.43(dd,J=7.4,1.7Hz,1H),7.26(s,1H),6.99(dd,J=8.8,2.3Hz,1H),3.69(s,2H),3.47(s,1H),3.16(s,5H),2.80(s,3H),2.46(s,3H).
MS m/z(ESI):464.20[M+H]
+。
实施例4:制备化合物C004
步骤1:2-氨基-6-溴-3-硝基苯酚
在250mL圆底烧瓶中加入反应物2-溴-5-硝基苯酚(5.0g,22.9mmol),1,1,1-三甲基肼-1-碘化物(5.1g,25.2mmol)和溶剂二甲基亚砜(100mL),降至0℃搅拌状态下,加入叔丁醇钠(6.6g,68.7mmol),升至室温反应18小时。LCMS监测反应结束,将反应液倒入100mL冰水中,并用4M盐酸调节溶液pH至5。混合液用乙酸乙酯萃取,合并有机相用饱和食盐水(150mL)洗涤,经过无水硫酸钠干燥后过滤,滤液浓缩蒸干,得到2-氨基-6-溴-3-硝基苯酚(4.7g,产率:88.1%)。
MS m/z(ESI):233.0[M+H]
+。
步骤2:3-溴-2-乙氧基-6-硝基苯胺
在100mL圆底烧瓶中加入反应物2-氨基-6-溴-3-硝基苯酚(700mg,3.0mmol),碳酸钾粉末(1.24g,9.0mmol)和溶剂乙腈(40mL),向混合液中滴加入碘乙烷(468mg,3.3mmol),室温下反应18小时。LCMS监测反应结束,将反应液倒入100mL水中并用乙酸乙酯(50mL x3)萃取,合并有机相用饱和食盐水(150mL)洗涤,经过无水硫酸钠干燥后过滤,滤液浓缩蒸干,得到3-溴-2-乙氧基-6-硝基苯胺(600mg,产率:76.6%)。
步骤3:2-乙氧基-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺
在100mL圆底烧瓶中,将3-溴-2-乙氧基-6-硝基苯胺(600mg,2.3mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,2,3,6-四氢吡啶(564mg,2.53mmol)溶于36mL 1,4-二氧六环中,滴加入4mL碳酸钾(952mg,6.9mmol)溶液。氮气换气3次,加入Pd(dppf)Cl
2(146mg,0.2mmol)再次换气3次,升温到90℃反应2小时。LCMS监测反应结束。将反应液倒入水(100mL)中用乙酸乙酯(50mL x3)萃取,合并有机相用饱和食盐水(100mL)洗涤,经无水硫酸钠干燥后过滤,滤液浓缩得到粗品。粗品通过硅胶柱(DCM:MeOH=50:1)纯化得到2-乙氧基-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(500mg,产率:78.5%)。
MS m/z(ESI):278.0[M+H]
+
步骤4:制备3-乙氧基-4-(1-甲基哌啶-4-基)苯-1,2-二胺
在100mL圆底烧瓶中,将2-乙氧基-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(250mg,1.0mmol)溶于溶剂乙醇(30mL)中,在氮气环境下加入PtO2(25mg,0.11mmol)。反应体系用氢气置换三次,然后在氢气(15psi)压力下,室温反应16h。TLC(二氯甲烷/甲醇=10/1)显示反应结束。将反应液通过硅藻土层抽滤,甲醇洗涤。滤液浓缩得3-乙氧基-4-(1-甲基哌啶-4-基)苯-1,2-二胺(200mg,粗品)。
MS m/z(ESI):250.2[M+H]
+
步骤5:制备7-(4-乙氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-腈
将7-甲酰基-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈和3-(乙氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(371mg,1.49mmol)溶于N,N-二甲基甲酰胺(10mL)溶液中,加入焦亚硫酸钠(564.3mg,2.97mmol),升温至90℃反应16h。TLC监测反应结束后,减压蒸馏,柱层析纯化(甲醇:二氯甲 烷=1:6),得7-(4-乙氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-腈(120mg,产率26.6%)。
MS m/z(ESI):431.2[M+H]
+
步骤6:制备化合物C004
将7-(4-乙氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-腈(112mg,0.26mmol)溶于4M的盐酸1,4-二氧六环溶液(8mL)中,升温至90℃,搅拌反应4h。TLC监测反应结束后,加氨水淬灭,减压蒸馏,送制备纯化得化合物C004(25.24mg,产率23.3%)。制备纯化条件为流速20ml/min,C18xbridge制备柱,10mmol碳酸氢氨体系,27-35%梯度的乙腈,后续类似步骤的制备纯化方法可参考此条件。
MS m/z(ESI):417.3[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ12.49(s,1H),11.92-11.23(m,1H),8.26(d,J=11.7Hz,3H),7.37(d,J=8.4Hz,1H),7.04(d,J=8.3Hz,1H),4.63(s,2H),3.03(s,2H),2.93(d,J=11.5Hz,2H),2.27(d,J=23.0Hz,3H),2.05(d,J=11.8Hz,2H),1.71(dd,J=37.5,11.9Hz,3H),1.37(dt,J=10.8,7.0Hz,3H)。
实施例5:制备化合物C005
步骤1:2-氨基-6-溴-3-硝基苯酚
在250mL圆底烧瓶中加入反应物2-溴-5-硝基苯酚(5.0g,22.9mmol),1,1,1-三甲基肼-1-碘化物(5.1g,25.2mmol)和溶剂二甲基亚砜(100mL),降至0℃搅拌状态下,加入叔丁醇钠(6.6g,68.7mmol),升至室温反应18小时。LCMS监测反应结束,将反应液倒入100mL冰水中,并用4M盐酸调节溶液pH至5。混合液用乙酸乙酯萃取,合并有机相用饱和食盐水(150mL)洗涤,经过无水硫酸钠干燥后过滤,滤液浓缩蒸干,得到2-氨基-6-溴-3-硝基苯酚(4.7g,产率88.1%)。
MS m/z(ESI):233.0,235.0[M+H]
+。
步骤2:3-溴-2-(环丙基甲氧基)-6-硝基苯胺
在100mL圆底烧瓶中加入反应物2-氨基-6-溴-3-硝基苯酚(700mg,3.0mmol),碳酸钾粉末(1.24g,9.0mmol)和溶剂乙腈(40mL),向混合液中滴加入溴甲基环丙烷(446mg,3.3mmol)。加热升温至80℃反应18小时。LCMS监测反应结束,将反应液倒入100mL水中并用乙酸乙酯萃取,合并有机相用饱和食盐水(150mL)洗涤,经过无水硫酸钠干燥后过滤,滤液浓缩蒸干,得到3-溴-2-(环丙基甲氧基)-6-硝基苯胺(650mg,产率75.5%)。
步骤3:2-(环丙基甲氧基)-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺
在100mL圆底烧瓶中,将3-溴-2-(环丙基甲氧基)-6-硝基苯胺(650mg,2.3mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,2,3,6-四氢吡啶(564mg,2.53mmol)溶于36mL 1,4- 二氧六环中,滴加入4mL碳酸钾(952mg,6.9mmol)溶液。氮气换气3次,加入Pd(dppf)Cl
2(146mg,0.2mmol)再次换气3次,升温到90℃反应2小时。LCMS监测反应结束。将反应液倒入水(100mL)中用乙酸乙酯萃取,合并有机相用饱和食盐水(100mL)洗涤,经无水硫酸钠干燥后过滤,滤液浓缩得到粗品。粗品通过硅胶柱(DCM:MeOH=50:1)纯化得到2-(环丙基甲氧基)-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(500mg,产率72%)。
MS m/z(ESI):304.0[M+H]
+
步骤4:制备3-(环丙基甲氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺
在100mL圆底烧瓶中,将2-(环丙基甲氧基)-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(250mg,0.83mmol)溶于甲醇(30mL)中,在氮气环境下加入PtO
2(25mg,0.11mmol)。反应体系用氢气置换三次,然后在氢气(15psi)压力下,室温反应16h。TLC(二氯甲烷/甲醇=10/1)显示反应结束。将反应液通过硅藻土层抽滤,甲醇洗涤。滤液浓缩得3-(环丙基甲氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(200mg,产率87.6%)。
MS m/z(ESI):276.0[M+H]
+
步骤5:制备7-(4-(环丙基甲氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-腈
将7-甲酰基-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(200mg,0.99mmol)和3-(环丙基甲氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(403mg,1.49mmol)溶于N,N-二甲基甲酰胺(10ml)溶液中,加入焦亚硫酸钠(564.3mg,2.97mmol),升温至90℃反应16h。TLC监测反应结束后,减压蒸馏,柱层析纯化(MeOH:DCM=1:6),得7-(4-(环丙基甲氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-腈(120mg,产率26.6%)。
MS m/z(ESI):457.0[M+H]
+
步骤6:制备化合物C005
将7-(4-(环丙基甲氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-腈(120mg,0.26mmol)溶于4M的盐酸1,4-二氧六环溶液(8mL)中,升温至90℃,搅拌反应4h。TLC监测反应结束后,加氨水淬灭,减压蒸馏,送制备纯化得化合物C005(13.58mg,产率11.9%)。
1H NMR(400MHz,DMSO-d
6)δ12.47(s,1H),11.53(s,1H),8.32–8.18(m,3H),7.36(s,1H),7.04(s,1H),4.45(s,2H),3.00(d,J=10.3Hz,4H),2.31(s,3H),1.80–1.64(m,4H),1.25(s,1H),0.54(s,1H),0.32(s,2H).
MS m/z(ESI):443.2[M+H]
+
实施例6:制备化合物C006
步骤1:3-溴-2-(2,2-二氟乙氧基)-6-硝基苯胺
在100mL圆底烧瓶中室温下,将2-氨基-6-溴-3-硝基苯酚(50mg,0.21mmol)溶于无水乙腈(30mL)中,然后加入1,1-二氟-2-碘乙烷(82mg,0.42mmol),K
2CO
3(86.9mg,0.63mmol)。TLC监测反应结束(石油醚:乙酸乙酯=5:1)显示反应结束,将反应液倒入水(60mL)中淬灭反应。用乙酸乙酯萃取,合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤,浓缩得粗产品。粗品通过柱层析 (石油醚:乙酸乙酯=10:1)纯化得到3-溴-2-(2,2-二氟乙氧基)-6-硝基苯胺(55mg,产率88.1%)。
MS m/z(ESI):314.1[M+H]
+
步骤2:制备2-(2,2-二氟乙氧基)-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺
在250mL圆底烧瓶中,将3-溴-2-(2,2-二氟乙氧基)-6-硝基苯胺(50mg,0.17mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,2,3,6-四氢吡啶(56mg,0.255mmol)溶于1,4-二氧六环(9mL)和H
2O(1mL)中,在氮气保护下,分别加入Pd(dppf)Cl
2(12mg,0.17mmol)和K
2CO
3(70mg,0.51mmol)。然后再升温到90℃反应2小时,得到黑色悬浊液。TLC监测反应结束。然后将反应液倒入水(20mL)中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤浓缩得粗品。粗品通过柱层析(石油醚:乙酸乙酯=10:1)得到2-(2,2-二氟乙氧基)-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(40mg,产率76.4%)。
MS m/z(ESI):314.1[M+H]
+
步骤3:制备3-(2,2-二氟乙氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺
在100mL圆底烧瓶中,将2-(2,2-二氟乙氧基)-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(230mg,0.73mmol)溶于溶剂乙醇(30mL)中,在氮气环境下加入PtO
2(25mg,0.11mmol)。反应体系用氢气置换三次,然后在氢气(15psi)压力下,室温反应16h。TLC(二氯甲烷/甲醇=10/1)显示反应结束。将反应液通过硅藻土层抽滤,甲醇洗涤。滤液浓缩得3-(2,2-二氟乙氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(200mg,产率96.1%)。
MS m/z(ESI):286.2[M+H]
+
步骤4:制备7-(4-(2,2-二氟乙氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈
将3-(2,2-二氟乙氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(50mg,0.16mmol)和7-甲酰基-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(65mg,0.24mmol)溶于N,N-二甲基甲酰胺(5ml)溶液中,加入焦亚硫酸钠(91.2mg,0.48mmol),升温至90℃反应16h。TLC监测反应结束后,减压蒸馏,柱层析纯化(MeOH:DCM=1:6),得7-(4-(2,2-二氟乙氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(60mg,产率80.0%)。
LCMS m/z(ESI):467.1[M+H]
+
步骤5:制备化合物C006
将7-(4-(2,2-二氟乙氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(250mg,0.53mmol)溶于4M的盐酸1,4-二氧六环溶液(10mL)中,升温至90℃,搅拌反应2h。TLC监测反应结束后,加氨水淬灭,减压蒸馏,送制备纯化得化合物C006(26.38mg,产率11%)。
1H NMR(400MHz,DMSO-d
6)δ12.59(s,1H),11.96–11.20(m,1H),8.34–8.10(m,3H),7.42(d,J=8.3Hz,1H),7.06(d,J=8.4Hz,1H),6.63–6.13(m,1H),4.91(s,2H),3.11(t,J=11.2Hz,1H),2.92(d,J=10.9Hz,2H),2.24(s,3H),2.04(t,J=9.9Hz,2H),1.73(dd,J=22.3,10.1Hz,4H).
MS m/z(ESI):453.4[M+H]
+
实施例7:制备化合物C010
步骤1:制备3-溴-2-甲氧基-6-硝基苯胺
将K
2CO
3(1.78mg,12.87mol)和碘甲烷(710mg,5mmol)加入2-氨基-6-溴-3-硝基苯酚(1g,4.29mmol)的无水乙腈(30mL)溶液中。该混合物在80℃搅拌16h,TLC监测反应结束。将反应液倒入水(60mL)中,乙酸乙酯萃取,合并有机相。有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤,滤液减压浓缩所得残余物用硅胶柱层析(PE:E
A=10:1)纯化得3-溴-2-甲氧基-6-硝基苯胺(800mg,产率75%)。
MS m/z(ESI):247.0[M+H]
+
步骤2:制备2-甲氧基-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺
将3-溴-2-甲氧基-6-硝基苯胺(800mg,3.24mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,2,3,6-四氢吡啶(867mg,3.89mmol)溶于1,4-二氧六环(27mL)和H
2O(4mL)中,然后在氮气保护下,向该混合物中加入Pd(dppf)Cl
2(234mg,0.32mmol)和K
2CO
3(1.34g,9.72mmol)。加料完毕,反应混合物升温至90℃搅拌2h。TLC监测反应结束,将反应液倒入水(20mL)中,乙酸乙酯萃取,合并有机相。有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,滤液减压浓缩所得残余物用柱层析(PE:E
A=10:1)纯化得2-甲氧基-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(500mg,产率59%)。
MS m/z(ESI):264.0[M+H]
+
步骤3:制备3-甲氧基-4-(1-甲基哌啶-4-基)苯-1,2-二胺
将2-甲氧基-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(500mg,1.9mmol)溶于乙醇(30mL)中,在氮气保护下加入PtO
2(250mg,1.1mmol)。反应体系用氢气置换三次,然后在氢气(15psi)压力下,室温搅拌16h。TLC监测反应结束,将反应液通过硅藻土抽滤,甲醇洗涤滤渣,收集滤液。滤液减压浓缩得3-甲氧基-4-(1-甲基哌啶-4-基)苯-1,2-二胺(400mg,产率89.6%),棕色固体。
MS m/z(ESI):236.0[M+H]
+
步骤4:制备6-甲氧基-7-(4-甲氧基-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-1H吡咯[3,2-c]吡啶-3-碳腈
将3-甲氧基-4-(1-甲基哌啶-4-基)苯-1,2-二胺(400mg,1.70mmol)和7-甲酰基-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(510mg,2.55mmol)溶于N,N-二甲基甲酰胺(5ml)中,加入焦亚硫酸钠(1.29g,6.8mmol)。将该混合物升温至90℃搅拌16h。TLC监测反应结束后,反应液减压浓缩所得残余物用硅胶柱层析(MeOH:DCM=1:6)纯化得6-甲氧基-7-(4-甲氧基-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-1H吡咯[3,2-c]吡啶-3-碳腈(300mg,产率41.2%),黄色固体。
MS m/z(ESI):417.0[M+H]
+
步骤5:制备化合物C010
将6-甲氧基-7-(4-甲氧基-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-1H吡咯[3,2-c]吡啶-3-碳腈(100mg,0.239mmol)溶于4M的盐酸1,4-二氧六环溶液(10mL)中,升温至90℃,搅拌反应2h。TLC监测反应结束,加氨水淬灭,减压浓缩,所得残余物HPLC制备纯化得化合物C010(11.3mg,产率11.7%)。
MS m/z(ESI):403.1[M+H]
+
1H NMR(400MHz,DMSO-d6)δ12.48(s,1H),8.29-8.22(m,3H),7.38(d,J=8.2Hz,1H),7.04(d,J=8.3Hz,1H),4.28(s,3H),3.00-2.90(m,4H),2.24(s,3H),2.08(t,J=11.3Hz,2H),1.80-1.6(m,4H)。
实施例8:制备化合物C011
步骤1:制备3-溴-2-(二氟甲氧基)-6-硝基苯胺
室温下,将2-氨基-6-溴-3-硝基苯酚(500mg,2.15mmol)溶于无水DMF(10mL)中,然后加入二氟氯乙酸钠(650mg,4.3mmol),碳酸钠(275mg,2.58mmol),加热搅拌16小时。TLC监测反应结束(石油醚:乙酸乙酯=5:1)显示反应结束,将反应液倒入水(60mL)中淬灭反应。用乙酸乙酯萃取,合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤,浓缩得粗产品。粗品通过柱层析(石油醚:乙酸乙酯=10:1)纯化得到3-溴-2-(二氟甲氧基)-6-硝基苯胺(450mg,产率75.8%)。
MS m/z(ESI):283.0[M+H]
+
步骤2:制备2-(二氟甲氧基)-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺
将3-溴-2-(二氟甲氧基)-6-硝基苯胺(360mg,1.3mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,2,3,6-四氢吡啶(423.7mg,1.9mmol)溶于1,4-二氧六环(18mL)和H
2O(2mL)中,在氮气保护下,分别加入Pd(dppf)Cl
2(95mg,0.13mmol)和K
2CO
3(538mg,3.9mmol)。然后再升温到90℃反应2h,得到黑色悬浊液。TLC监测反应结束。然后将反应液倒入水(40mL)中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤浓缩得粗品。粗品通过柱层析(石油醚:乙酸乙酯=10:1)得到2-(二氟甲氧基)-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(320mg,产率84.5%)。
MS m/z(ESI):300.1[M+H]
+
步骤3:制备3-(二氟甲氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺
将2-(二氟甲氧基)-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(300mg,1.0mmol)溶于溶剂乙醇(30mL)中,在氮气环境下加入PtO
2(30mg,0.13mmol)。反应体系用氢气置换三次,然后在氢气(15psi)压力下,室温反应16h。TLC(二氯甲烷/甲醇=10/1)显示反应结束。将反应液通过硅藻土层抽滤,甲醇洗涤。滤液浓缩得3-(二氟甲氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(260mg),粗品直接用于下一步。
MS m/z(ESI):272.1[M+H]
+
步骤4:制备7-(4-(二氟甲氧基)-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈
将7-甲酰基-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(114mg,0.57mmol)和3-(二氟甲氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(150mg,0.57mmol)溶于N,N-二甲基甲酰胺(10ml)溶液中,加入焦亚硫酸钠(433mg,2.28mmol),升温至90℃反应16h。TLC监测反应结束后,减压蒸馏,柱层析纯化(MeOH:DCM=1:6),得7-(4-(二氟甲氧基)-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(130mg,产率51.3%收率)。
MS m/z(ESI):453.1[M+H]
+
步骤5:制备化合物C011
将7-(4-(二氟甲氧基)-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(150mg,0.33mmol)溶于4M的盐酸1,4-二氧六环溶液(8mL)中,升温至90℃, 搅拌反应4h。TLC监测反应结束后,加氨水淬灭,减压蒸馏,送制备纯化得化合物C011(21.13mg,产率14.8%)。
MS m/z(ESI):439.1[M+H]
+
1H NMR(400MHz,DMSO-d
6)δ12.71(s,1H),8.61–8.27(m,4H),7.92(d,J=71.5Hz,1H),7.58(d,J=8.3Hz,1H),7.16(d,J=8.4Hz,1H),3.03(d,J=11.8Hz,1H),2.94(d,J=10.6Hz,2H),2.25(s,3H),2.08(t,J=10.9Hz,2H),1.79(dd,J=21.8,12.1Hz,2H),1.69(d,J=10.8Hz,2H).
实施例9:制备化合物C013
步骤1:制备3-溴-6-硝基-2-(2,2,2-三氟乙氧基)苯胺
将2-氨基-6-溴-3-硝基苯酚(800mg,3.44mmol)溶于无水乙腈(30mL)中,然后加入2,2,2-三氟乙基三氟甲烷磺酸盐(968mg,4.16mmol),K
2CO
3(950.88mg,6.88mmol)。TLC监测反应结束(石油醚:乙酸乙酯=5:1)显示反应结束,将反应液倒入水(60mL)中淬灭反应。用乙酸乙酯萃取,合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤,浓缩得粗产品。粗品通过柱层析(PE:E
A=10:1)纯化得3-溴-6-硝基-2-(2,2,2-三氟乙氧基)苯胺(800mg,产率73.8%)。
MS m/z(ESI):315.1[M+H]
+
步骤2:制备3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基-2-(2,2,2-三氟乙氧基)苯胺
将3-溴-6-硝基-2-(2,2,2-三氟乙氧基)苯胺(100mg,0.32mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)-1,2,3,6-四氢吡啶(107.10mg,0.48mmol)溶于1,4-二氧六环(18mL)和H
2O(2mL)中,在氮气保护下,分别加入Pd(dppf)Cl
2(4.4mg,0.032mmol)和K
2CO
3(836.68mg,0.96mmol)。然后再升温到90℃反应2小时,得到黑色悬浊液。TLC监测反应结束。然后将反应液倒入水(40mL)中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤浓缩得粗品。粗品通过柱层析(PE:E
A=10:1)得3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基-2-(2,2,2-三氟乙氧基)苯胺(320mg,产率84.5%)。
MS m/z(ESI):332.1[M+H]
+
步骤3:制备4-(1-甲基哌啶-4-基)-3-(2,2,2-三氟乙氧基)苯-1,2-二胺
将3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基-2-(2,2,2-三氟乙氧基)苯胺(150mg,0.45mmol)溶于溶剂乙醇(30mL)中,在氮气环境下加入PtO
2(204mg,0.9mmol)。反应体系用氢气置换三次,然后在氢气(15psi)压力下,室温反应16h。TLC(二氯甲烷/甲醇=10/1)显示反应结束。将反应液通过硅藻土层抽滤,甲醇洗涤。滤液浓缩得4-(1-甲基哌啶-4-基)-3-(2,2,2-三氟乙氧基)苯-1,2-二胺(90mg,粗品),棕色固体。
MS m/z(ESI):305[M+H]
+
步骤4:制备6-甲氧基-7-(5-(1-甲基哌啶-4-基)-4-(2,2,2-三氟乙氧基)-1H-苯并[d]咪唑-2-基)-1H-吡咯[3,2-c]吡啶-3-碳腈
将4-(1-甲基哌啶-4-基)-3-(2,2,2-三氟乙氧基)苯-1,2-二胺(50mg,0.16mmol)和7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(38.63mg,0.192mmol)溶于N,N-二甲基甲酰胺(10mL)溶液中,加入焦亚硫酸钠(91.24mg,0.48mmol),升温至90℃反应16h。TLC监测反应结束后,减压蒸馏,柱层析纯化(MeOH:DCM=1:6),得6-甲氧基-7-(5-(1-甲基哌啶-4-基)-4-(2,2,2-三氟乙氧基)-1H-苯并[d]咪唑-2-基)-1H-吡咯[3,2-c]吡啶-3-碳腈(67mg,产率86.4%)。
MS m/z(ESI):485.1[M+H]
+
步骤5:制备化合物C013
将6-甲氧基-7-(5-(1-甲基哌啶-4-基)-4-(2,2,2-三氟乙氧基)-1H-苯并[d]咪唑-2-基)-1H-吡咯[3,2-c]吡啶-3-碳腈(150mg,0.31mmol)溶于4M的盐酸1,4-二氧六环溶液(8mL)中,升温至90℃,搅拌反应4h。TLC监测反应结束后,加氨水淬灭,减压蒸馏,送制备纯化得化合物C013(56.84mg,产率40.3%)。
MS m/z(ESI):4711[M+H]
+
1H NMR(400MHz,DMSO-d
6)δ12.47(s,1H),11.53(s,1H),8.23(d,J=20.0Hz,3H),7.35(s,1H),7.05(s,1H),4.60(s,2H),3.09(s,1H),2.97(d,J=11.4Hz,2H),2.28(s,3H),2.12(t,J=10.2Hz,2H),1.82–1.60(m,4H).
实施例10:制备化合物C016
步骤1:制备3-溴-6-硝基-2-丙氧基苯胺
将2-氨基-6-溴-3-硝基苯酚(50mg,0.21mmol)溶于无水乙腈(30mL)中,然后将1-碘丙烷(72mg,0.42mmol)和K
2CO
3(86.9mg,0.63mmol)加入反应体系,室温搅拌,TLC监测至原料消失,将反应液倒入水(60mL)中。用乙酸乙酯萃取,合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤。滤液减压浓缩所得残留物用硅胶柱层析(石油醚:乙酸乙酯=10:1)纯化得到3-溴-6-硝基-2-丙氧基苯胺(45mg,产率77.9%)。
MS m/z(ESI):274.9,276.9[M+H]
+
步骤2:制备3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基-2-丙氧基苯胺
将3-溴-6-硝基-2-丙氧基苯胺(360mg,1.3mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,2,3,6-四氢吡啶(423.7mg,1.9mmol)加入1,4-二氧六环(18mL)和H
2O(2mL)中,在氮气保护下,加入Pd(dppf)Cl
2(95mg,0.13mmol)和K
2CO
3(538mg,3.9mmol).90℃搅拌2h,TLC监测反应结束。然后将反应液倒入水(40mL)中,用乙酸乙酯萃取,合并有机相。有机相用饱和食盐水(50mL)洗涤,无水硫酸干燥,过滤,滤液减压浓缩所得残留物用硅胶柱层(石油醚:乙酸乙酯=10:1)纯化得到3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基-2-丙氧基苯胺(320mg,产率84.5%)。
MS m/z(ESI):292.1[M+H]
+。
步骤3:制备4-(1-甲基哌啶-4-基)-3-丙氧基苯-1,2-二胺
将3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基-2-丙氧基苯胺(300mg,1.0mmol)溶于乙醇(30mL)中,在氮气保护下,加入PtO
2(30mg,0.13mmol)。反应体系置换氢气三次,然后在氢气(15psi)压力下,室温搅拌16h。TLC显示反应结束。将反应液经硅藻土过滤,并用甲醇洗涤滤饼,收集滤液。滤液减压浓缩得4-(1-甲基哌啶-4-基)-3-丙氧基苯-1,2-二胺(260mg,产率96.2%)。
MS m/z(ESI):264.2[M+H]
+
步骤4:6-甲氧基-7-(5-(1-甲基哌啶-4-基)-4-丙氧基-1H-苯并[d]咪唑-2-基)-1H-吡咯[3,2-c]吡啶-3-腈
将7-甲酰基-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(114mg,0.57mmol)和4-(1-甲基哌啶-4-基)-3-丙氧基苯-1,2-二胺(150mg,0.57mmol)溶于N,N-二甲基甲酰胺(10ml)中,并加入焦亚硫酸钠(433mg,2.28mmol)。反应体系升温至90℃搅拌16h,TLC监测反应结束。将反应液减压浓缩所得残留物用硅胶柱层(MeOH:DCM=1:6)纯化得6-甲氧基-7-(5-(1-甲基哌啶-4-基)-4-丙氧基-1H-苯并[d]咪唑-2-基)-1H-吡咯[3,2-c]吡啶-3-腈(130mg,产率51.3%)黄色固体。
MS m/z(ESI):445.3[M+H]
+
步骤5:制备化合物C016
将6-甲氧基-7-(5-(1-甲基哌啶-4-基)-4-丙氧基-1H-苯并[d]咪唑-2-基)-1H-吡咯[3,2-c]吡啶-3-腈(150mg,0.33mmol)溶于4M的盐酸1,4-二氧六环溶液(8mL)中,升温至90℃,搅拌反应4h。TLC监测反应结束后,加氨水淬灭,减压蒸馏,HPLC制备纯化得化合物C016(21.13mg,产率14.8%)。
MS m/z(ESI):431.6[M+H]
+
1H NMR(400MHz,DMSO-d6)δ12.47(s,1H),11.53(br,1H),8.26-8.20(m,3H),7.35(s,1H),7.05(s,1H),4.60(s,2H),3.09(s,1H),2.97(d,J=11.4Hz,2H),2.28(s,3H),2.12(t,J=10.2Hz,2H),1.82-1.67(m,6H),1.08(s,3H)。
实施例11:制备化合物C017
步骤1:制备3-溴-2-(2,2-二氟乙氧基)-6-硝基苯胺
在室温下,将2-氨基-6-溴-3-硝基苯酚(50mg,0.21mmol)溶于无水乙腈(30mL)中,然后加入1-iodo-2-methylpropane(77.28mg,0.42mmol),K
2CO
3(86.9mg,0.63mmol)。TLC监测反应结束(石油醚:乙酸乙酯=5:1)显示反应结束,将反应液倒入水(60mL)中淬灭反应。用乙酸乙酯萃取,合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤,浓缩得粗产品。粗品通过柱层析(PE:E
A=10:1)纯化得到3-溴-2-(2,2-二氟乙氧基)-6-硝基苯胺(60mg,产率99.0%)。
MS m/z(ESI):289.1[M+H]
+
步骤2:制备2-(2,2-二氟乙氧基)-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺
将3-溴-2-(2,2-二氟乙氧基)-6-硝基苯胺(60mg,0.20mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,2,3,6-四氢吡啶(56mg,0.255mmol)溶于1,4-二氧六环(9mL)和H
2O(1mL)中,在氮气保护下,分别加入Pd(dppf)Cl
2(12mg,0.17mmol)和K
2CO
3(70mg,0.51mmol)。然后再升温到90℃反应2h,得到黑色悬浊液。TLC监测反应结束。然后将反应液倒入水(20mL)中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤浓缩得粗品。粗品通过柱层析(PE:E
A=10:1)得2-(2,2-二氟乙氧基)-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(50mg,产率82%)。
MS m/z(ESI):306.1[M+H]
+
步骤3:制备3-(2,2-二氟乙氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺
将2-(2,2-二氟乙氧基)-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(56mg,0.73mmol)溶于溶剂乙醇(30mL)中,在氮气环境下加入PtO
2(25mg,0.11mmol)。反应体系用氢气置换三次,然后在氢气(15psi)压力下,室温反应16h。TLC(二氯甲烷/甲醇=10/1)显示反应结束。将反应液通过硅藻土层抽滤,甲醇洗涤。滤液浓缩得3-(2,2-二氟乙氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(50mg,产率98.6%)。
MS m/z(ESI):278.2[M+H]
+
步骤4:制备7-(4-(2,2-二氟乙氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈
将3-(2,2-二氟乙氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(50mg,0.16mmol)和7-甲酰基-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(65mg,0.24mmol)溶于N,N-二甲基甲酰胺(5ml)溶液中,加入焦亚硫酸钠(91.2mg,0.48mmol),升温至90℃反应16h。TLC监测反应结束后,减压蒸馏,柱层析纯化(MeOH:DCM=1:6),得7-(4-(2,2-二氟乙氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(60mg,产率80%)。
MS m/z(ESI):459.3[M+H]
+
步骤5:制备7-(4-(2,2-二氟乙氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-氧代-5,6-二氢-1H-吡咯并[3,2-c]吡啶-3-甲腈
将7-(4-(2,2-二氟乙氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(250mg,0.53mmol)溶于4M的盐酸1,4-二氧六环溶液(10mL)中,升温至90℃,搅拌反应2h。TLC监测反应结束后,加氨水淬灭,减压蒸馏,送制备纯化得7-(4-(2,2-二氟乙氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-氧代-5,6-二氢-1H-吡咯并[3,2-c]吡啶-3-甲腈(26.38mg,产率11%)。
MS m/z(ESI):445.2[M+H]
+
1H NMR(400MHz,DMSO-d
6)δ12.39(s,1H),11.60(s,1H),8.26(s,3H),7.37(d,J=8.3Hz,1H),7.05(d,J=8.4Hz,1H),4.33(s,2H),3.12(s,1H),2.92(d,J=10.9Hz,2H),2.24(s,3H),2.16–2.10(m,3H),1.85–1.70(m,4H),1.09(d,J=8.3Hz,6H).
实施例12:制备化合物C020
步骤1:制备2-(2-氨基-6-溴-3-硝基苯氧基)甲基)吡咯烷-1-羧酸叔丁酯
在100mL圆底烧瓶中室温下,将2-氨基-6-溴-3-硝基苯酚(500mg,2.48mmol)溶于甲苯(20mL)中,然后加入2-(羟甲基)吡咯烷-1-羧酸叔丁酯(578mg,2.48mmol)和三叔丁基磷(1.2g,5.47mmol),反应液在室温氮气氛围下搅拌1小时。然后在-10℃氮气氛围下把偶氮二甲酸二异丙酯(1.2g,5.47mmol)加入进去,反应液在室温氮气氛围下搅拌16小时。把反应液浓缩。粗品通过柱层析(石油醚: 乙酸乙酯=10:1)纯化得到2-(2-氨基-6-溴-3-硝基苯氧基)甲基)吡咯烷-1-羧酸叔丁酯(300mg,产率33.5%)。
步骤2:制备叔丁基2-((2-氨基-6-(1-甲基-1,2,3,6-四氢吡啶-4-基)-3-硝基苯氧基)甲基)吡咯烷-1-羧酸酯
在250mL圆底烧瓶中,将2-(2-氨基-6-溴-3-硝基苯氧基)甲基)吡咯烷-1-羧酸叔丁酯(83mg,0.20mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,2,3,6-四氢吡啶(56mg,0.255mmol)溶于1,4-二氧六环(9mL)和H2O(1mL)中,在氮气保护下,分别加入Pd(dppf)Cl
2(12mg,0.17mmol)和K
2CO
3(70mg,0.51mmol)。然后再升温到90℃反应2小时,得到黑色悬浊液。TLC监测反应结束。然后将反应液倒入水(20mL)中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤浓缩得粗品。粗品通过柱层析(石油醚:乙酸乙酯=10:1)得到叔丁基2-((2-氨基-6-(1-甲基-1,2,3,6-四氢吡啶-4-基)-3-硝基苯氧基)甲基)吡咯烷-1-羧酸酯(63mg,0.146mmol,产率73%)。
MS m/z(ESI):433.2[M+H]
+。
步骤3:制备2-(2,3-二氨基-6-(1-甲基哌啶-4-基)苯氧基)甲基)吡咯烷-1-羧酸叔丁酯
在100mL圆底烧瓶中,将叔丁基2-((2-氨基-6-(1-甲基-1,2,3,6-四氢吡啶-4-基)-3-硝基苯氧基)甲基)吡咯烷-1-羧酸酯(63mg,0.146mmol)溶于溶剂乙醇(30mL)中,在氮气环境下加入PtO
2(50mg,0.22mmol)。反应体系用氢气置换三次,然后在氢气(15psi)压力下,室温反应16h。TLC(二氯甲烷/甲醇=10/1)显示反应结束。将反应液通过硅藻土层抽滤,甲醇洗涤。滤液浓缩得2-(2,3-二氨基-6-(1-甲基哌啶-4-基)苯氧基)甲基)吡咯烷-1-羧酸叔丁酯(50mg,产率84.8%)。
MS m/z(ESI):405.2[M+H]
+。
步骤4:制备叔丁基2-((2-(3-氰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-4-基)氧基)甲基)吡咯烷-1-羧酸酯将2-(2,3-二氨基-6-(1-甲基哌啶-4-基)苯氧基)甲基)吡咯烷-1-羧酸叔丁酯(50mg,0.12mmol)和7-甲酰基-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(65mg,0.24mmol)溶于N,N-二甲基甲酰胺(5ml)溶液中,加入焦亚硫酸钠(91.2mg,0.48mmol),升温至90℃反应16h。TLC监测反应结束后,减压蒸馏,柱层析纯化(甲醇:二氯甲烷=1:6),得叔丁基2-((2-(3-氰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-4-基)氧基)甲基)吡咯烷-1-羧酸酯(65mg,产率93%)。
步骤5:制备化合物C020
将叔丁基2-((2-(3-氰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-4-基)氧基)甲基)吡咯烷-1-羧酸酯(65mg,0.11mmol)溶于4M的盐酸1,4-二氧六环溶液(10mL)中,升温至90℃,搅拌反应2h。TLC监测反应结束后,加氨水淬灭,减压蒸馏,送制备纯化得化合物C020(46.3mg,产率89.3%)。
MS m/z(ESI):472.2[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ8.26(d,J=9.3Hz,4H),8.20(s,1H),7.39(d,J=8.3Hz,1H),7.04(d,J=8.3Hz,1H),4.59–4.55(m,2H),3.82–3.80(m,1H),3.23–3.18(m,2H),3.07–3.02(m,1H),2.97(d,J=8.9Hz,2H),2.29(s,3H),2.23–2.05(m,2H),1.79–1.71(m,8H)。
实施例13:制备化合物C044
步骤1:制备7-甲酰基-6-甲氧基-2-(邻甲苯基)-1H-吡咯[3,2-c]吡啶-3-甲腈
在室温氮气保护下,将1.6M的正丁基锂(4.00mL,6.40mmol)溶于THF(11.0mL),然后将反应体系降温到-78℃。再将乙腈(340uL,7.00mmol)缓慢滴加到反应体系,搅拌15min。然后将7-溴-6-甲氧基-2-(邻甲苯基)-1H-吡咯[3,2-c]吡啶-3-甲腈(300mg,0.88mmol)的THF(3.00mL)溶液滴加到反应体系。缓慢升温到室温(不低于2h),搅拌30min。LCMS和TLC监测反应结束,产物生成。将反应液倒入NH
4Cl(30mL)水溶液中。然后溶乙酸乙酯萃取,合并有机相。有机相用饱和食盐水(50mL)洗涤三次。然后用无水硫酸钠干燥,抽滤,浓缩得粗品。粗品通过快速柱层析(石油醚/乙酸乙酯=3/1)纯化得到7-甲酰基-6-甲氧基-2-(邻甲苯基)-1H-吡咯[3,2-c]吡啶-3-甲腈(82mg,产率32%)。
MS m/z(ESI):292.1[M+H]
+。
步骤2:制备7-(4-乙氧基-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-2-(邻甲苯基)-1H吡咯[3,2-c]吡啶-3-甲腈
将7-甲酰基-6-甲氧基-2-(邻甲苯基)-1H-吡咯[3,2-c]吡啶-3-甲腈(82mg,0.28mmol)和3-乙氧基-4-(1-甲基哌啶-4-基)苯-1,2-二胺(69.7mg,0.28mmol)溶于N,N-二甲基甲酰胺(5ml)溶液中,加入焦亚硫酸钠(91.2mg,0.48mmol),升温至90℃反应16h。TLC监测反应结束后,减压蒸馏,柱层析纯化(MeOH:DCM=1:6),得7-(4-乙氧基-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-2-(邻甲苯基)-1H吡咯[3,2-c]吡啶-3-甲腈(80mg,产率55%)。
MS m/z(ESI):521.1[M+H]
+
步骤3:制备化合物C044
将7-(4-乙氧基-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-2-(邻甲苯基)-1H吡咯[3,2-c]吡啶-3-甲腈(80mg,0.154mmol)溶于4M的盐酸1,4-二氧六环溶液(10mL)中,升温至90℃,搅拌反应2h。TLC监测反应结束后,加氨水淬灭,减压蒸馏,送制备纯化得化合物C044(33.46mg,产率43.3%)。
MS m/z(ESI):507.4[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ12.45(br,s,1H),11.5(br,s,1H),8.29(s,1H),8.21(s,1H),7.67(d,J=7.9Hz,1H),7.59-7.50(m,2H),7.46(t,J=7.1Hz,1H),7.37(d,J=8.3Hz,1H),7.04(d,J=8.4Hz,1H),4.50-4.45(m,2H),3.05-3.01(m,1H),2.94(d,J=11.0Hz,2H),2.49(s,3H),2.26(s,3H),2.11(t,J=10.4Hz,2H),1.86-1.58(m,4H),1.28(s,3H)。
实施例14:化合物CP46
步骤1:制备2-甲基-4-((三氟甲基)磺酰)氧基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯
在氮气保护下,将2-甲基-4-氧哌啶-1-羧酸叔丁酯(1.0g,4.69mmol)的无水四氢呋喃(30mL)溶液中,冷却至-50℃,滴加双(三甲基硅基)氨基锂(5.16mL,5.16mmol),并在-50℃下搅拌1h。然后加入1,1,1-三氟-N-苯基-N-((三氟甲基)磺酰)甲烷磺酰胺(1.9g,5.16mmol)。反应液恢复至室温并搅拌1h。反应用饱和氯化铵溶液淬灭,乙酸乙酯萃取,合并有机相。有机相用无水硫酸钠干燥并浓缩。所得残余物用硅胶柱层析纯化得2-甲基-4-((三氟甲基)磺酰)氧基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1.5g,产率92.7%)。
步骤2:制备4-(3-氨基-2-(2,2-二氟乙氧基)-4-硝基苯基)-2-甲基-3,6-二氢吡啶-1(2H)-羧酸叔丁酯
将碳酸钾(160mg,1.15mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(43mg,0.05mmol)加入2-甲基-4-((三氟甲基)磺酰)氧基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(200mg,0.57mmol)和2-(2,2-二氟乙氧基)-6-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)苯胺(220mg,0.63mmol)的1,4-二氧六环(20mL)和水(4mL)溶液中。90℃搅拌2h。反应液冷却至室温,过滤,滤液用乙酸乙酯萃取,合并有机相。有机相用无水硫酸钠干燥并浓缩,所得残余物用硅胶柱层析纯化得到4-(3-氨基-2-(2,2-二氟乙氧基)-4-硝基苯基)-2-甲基-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(110mg,产率46.7%)。
步骤3:制备4-(3,4-二氨基-2-(2,2-二氟乙氧基)苯基)-2-甲基哌啶-1-羧酸叔丁酯
在室温下,将4-(3-氨基-2-(2,2-二氟乙氧基)-4-硝基苯基)-2-甲基-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(110mg,0.26mmol)溶解到乙醇(20mL)中,然后加入二氧化铂(110mg)。反应液在50℃,氢气氛围下搅拌16h。反应液过滤,滤液浓缩后得到4-(3,4-二氨基-2-(2,2-二氟乙氧基)苯基)-2-甲基哌啶-1-羧酸叔丁酯(100mg,99%)。
步骤4:制备3-(2,2-二氟乙氧基)-4-(1,2-二甲基哌啶-4-基)苯-1,2-二胺
将4-(3,4-二氨基-2-(2,2-二氟乙氧基)苯基)-2-甲基哌啶-1-羧酸叔丁酯(100mg,0.26mmol)溶于无水四氢呋喃(20mL)中,然后0℃下加入四氢铝锂(2.85mL,2.85mmol)。反应液在90℃下搅拌3h。反应液冷却至室温,缓缓加入十水硫酸钠,过滤,滤液浓缩后经过反相柱纯化得到3-(2,2-二氟乙氧基)-4-(1,2-二甲基哌啶-4-基)苯-1,2-二胺(20mg,产率25.7%)。
步骤5:制备7-(4-(2,2-二氟乙氧基)-5-(1,2-二甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈
室温下,将3-(2,2-二氟乙氧基)-4-(1,2-二甲基哌啶-4-基)苯-1,2-二胺(20mg,0.06mmol)和7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(14mg,0.06mmol)溶于N,N-二甲基甲酰胺(10mL)中,然后加入焦亚硫酸钠(26mg,0.13mmol)。反应液在90℃下搅16h。反应液用乙酸乙酯和水萃取3次,合并有机相,用无水硫酸钠干燥后浓缩得7-(4-(2,2-二氟乙氧基)-5-(1,2-二甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(20mg,产率69.4%)。
MS m/z(ESI):481.3[M+H]
+
步骤6:制备化合物CP46
室温下,将7-(4-(2,2-二氟乙氧基)-5-(1,2-二甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(20mg,0.04mmol)加入溶剂盐酸/二氧六环(5mL)中,反应液在90℃下搅拌3小时。LC-MS监测反应结束后,将反应液浓缩,粗品经过制备纯化得到化合物CP46(2.19mg,11.7%)。
MS m/z(ESI):447.1[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ12.59(br,1H),8.35(s,2H),8.25(d,J=3.3Hz,2H),7.41(d,J=8.3Hz,1H),7.06(t,J=8.7Hz,1H),6.40(tt,J=54.2,3.0Hz,1H),4.91(br,2H),2.92(d,J=10.7Hz,1H),2.59(d,J=11.5Hz,1H),2.36–2.07(m,5H),1.80–1.37(m,4H),1.06(d,J=6.1Hz,3H)。
实施例15:制备化合物CP47
步骤1:制备4-(4-溴-2,6-二甲基苯基)吗啉
室温下,将碳酸钾(5.2g,37.48mmol)和碘化钾(4.1g,24.99mmol)加入到4-溴-2,6-二甲基苯胺(5.0g,24.99mmol)和1-溴-2-(2-溴乙氧基)乙烷(8.7g,37.48mmol)的N,N-二甲基甲酰胺(60mL)溶液中。反应液在90℃下搅拌16小时。LC-MS监测反应结束,反应液过滤,滤液浓缩,粗品采用柱层析纯化得4-(4-溴-2,6-二甲基苯基)吗啉(3.2g,产率47.4%)。
步骤2:制备4-(4-溴-2,6-二甲基-3-硝基苯基)吗啉
室温下,将4-(4-溴-2,6-二甲基苯基)吗啉(1g,3.70mmol)溶于浓硫酸(15mL),并在冰水浴中搅拌3~5分钟,缓慢分批次加入硝酸钾(412mg,4.07mmol),混合物在0℃下搅拌40分钟。反应结束后,将反应液缓慢滴入冰水(100mL)中,用乙酸乙酯萃取,合并有机相,有机相用盐水洗涤,无水硫酸钠干燥,抽滤,浓缩得粗品。粗品通过柱层析纯化得到4-(4-溴-2,6-二甲基-3-硝基苯基)吗啉(800mg,产率68.6%)。
步骤3:制备N-(3,5-二甲基-4-吗啉-2-硝基苯基)-2,2,2-三氟乙酰胺
在室温下,将Pd
2(dba)
3(145mg,0.158mmol)、Xantphos(184mg,0.317mmol)和碳酸铯(1.6g,4.759mmol)加入到4-(4-溴-2,6-二甲基-3-硝基苯基)吗啉(500mg,1.59mmol)和三氟乙酰胺(215mg,1.904mmol)的1,4-二氧六环(15mL)溶液中,反应液在110℃下搅拌16小时。反应液过滤,滤液浓缩后用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥后浓缩得粗品。粗品经柱层析纯化得到N-(3,5-二甲基-4-吗啉-2-硝基苯基)-2,2,2-三氟乙酰胺(200mg,产率36.4%)。
MS m/z(ESI):348.0[M+H].
步骤4:制备3,5-二甲基-4-吗啉-2-硝基苯胺
在室温下,将N-(3,5-二甲基-4-吗啉-2-硝基苯基)-2,2,2-三氟乙酰胺(200mg,0.81mmol)和氢氧化锂(58mg,2.43mmol)溶于乙醇(5mL)和水(1mL)中,反应液在60℃下搅拌16h。反应液浓缩除去乙醇,再用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥后浓缩得3,5-二甲基-4-吗啉-2-硝基苯胺(170mg,产率83.6%)。
MS m/z(ESI):252.1[M+H]
+.
步骤5:制备3,5-二甲基-4-吗啉苯-1,2-二胺
室温下,将3,5-二甲基-4-吗啉-2-硝基苯胺(170mg,0.68mmol)、铁粉(151mg,2.71mmol)和氯化铵(289mg,5.41mmol)溶于乙醇(3mL)和水(3mL)中,反应液在70℃下搅拌3h。反应液过滤,滤液再用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥后浓缩得3,5-二甲基-4-吗啉苯-1,2-二胺(110mg,产率73.2%)。
MS m/z(ESI):222.1[M+H]
+.
步骤6:制备2-环丙基-7-(4,6-二甲基-5-吗啉基-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈
室温下,将3,5-二甲基-4-吗啉苯-1,2-二胺(110mg,0.50mmol)、2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(181mg,0.74mmol)和焦亚硫代硫酸钠(378mg,1.99mmol)溶于N,N-二甲基甲酰胺(5mL)中,反应液在90℃下搅拌2小时。LC-MS监测反应结束后,将反应液滴入50mL水中析出固体,过滤得到滤饼,滤饼用甲醇溶解后浓缩,并用乙腈浓缩1~2次得粗品2-环丙基-7-(4,6-二甲基-5-吗啉基-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(200mg, 产率90.5%)。
MS m/z(ESI):443.1[M+H]
+.
步骤7:制备化合物CP47
室温下,将三甲基氯硅烷(50mg,0.45mmol)加入到2-环丙基-7-(4,6-二甲基-5-吗啉基-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(100mg,0.23mmol)和碘化钠(68mg,0.45mmol)的乙腈(10mL)溶液中,反应液在30℃下搅拌4小时。将反应液浓缩,并用N,N-二甲基甲酰胺溶解过滤后,滤液经高效液相色谱纯化得化合物CP47(44.15mg,产率44.8%)。
MS m/z(ESI):429.1[M+H]
+.
1H NMR(400MHz,DMSO-d6)δ12.71(br,1H),11.81(br,1H),8.11(s,1H),7.39(s,1H),3.77-3.69(m,4H),3.21-3.13(m,2H),3.02(d,J=12.0Hz,2H),2.63(s,3H),2.45(s,3H),2.32(t,J=8.8Hz,1H),1.30-1.19(m,4H)。
实施例16:制备化合物C048
1.制备2-(环丙基甲氧基)-6-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)苯胺
步骤1:制备3-溴-2-(环丙基甲氧基)-6-硝基苯胺
室温下,将2-氨基-6-溴-3-硝基苯(4.5g,19.31mmol)和K
2CO
3(5.34g,38.62mmol)溶于乙腈(135mL),反应容器在25℃下搅拌0.5小时。然后加入(碘甲基)环丙烷(4.2g,23.17mmol),反应液升温至80℃搅拌16h。反应液用硅藻土过滤,滤液旋干。粗品通过快速柱层析(石油醚/乙酸乙酯)纯化得3-溴-2-(环丙基甲氧基)-6-硝基苯胺(4g,产率72.1%)。
步骤2:制备2-(环丙基甲氧基)-6-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)苯胺
室温下,将3-溴-2-(环丙基甲氧基)-6-硝基苯胺(4.1g,14.29mmol)、联硼酸频那醇酯(6.1g,23.96mmol)、KOAc(4.2g,42.82mmol)和Pd(dppf)Cl
2(1.3g,1.428mmol)加入二氧六环(80mL),混合物在90℃下搅拌12h。混合物用乙酸乙酯和H2O萃取,合并有机相,有机相用盐水(50mL*2)洗涤,无水硫酸钠干燥,抽滤,浓缩得粗品。粗品通过快速柱层析(石油醚/乙酸乙酯)和反相柱(乙腈/水)纯化得2-(环丙基甲氧基)-6-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)苯胺(1.4g,产率29.3%)。
2.制备化合物C048
步骤1:制备2-(环丙基甲氧基)-3-(1-乙基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺
在室温下,将1-乙基-1,2,3,6-四氢吡啶-4-三氟甲烷磺酸酯(534mg,2.095mmol)、2-(环丙基甲氧基)-6-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)苯胺(700mg,2.095mmol)、Pd(dppf)Cl
2(171mg,0.209mmol)和K
2CO
3(868mg,6.28mmol)溶于1,4-二氧六环(13.5mL)和水(1.5mL)中。混合物在90℃下搅拌2h。LC-MS监测反应结束,过滤混合物并浓缩滤液。粗品通过快速 柱层析(石油醚/乙酸乙酯=4/1)纯化得2-(环丙基甲氧基)-3-(1-乙基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(300mg,产率45.9%)。
步骤2:制备3-(环丙基甲氧基)-4-(1-乙基哌啶-4-基)苯-1,2-二胺
向2-(环丙基甲氧基)-3-(1-乙基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(200mg)在乙醇(60mL)中的溶液中添加PtO
2(400mg)。将混合物在50℃下在H2下搅拌16h。过滤混合物并浓缩滤液,得到的3-(环丙基甲氧基)-4-(1-乙基哌啶-4-基)苯-1,2-二胺(183mg,产率100%)。
MS m/z(ESI):290.2[M+H]
+。
步骤3:制备7-(4-(环丙基甲氧基)-5-(1-乙基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-腈
将7-甲酰基-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(104mg,0.5mmol)和3-(环丙基甲氧基)-4-(1-乙基哌啶-4-基)苯-1,2-二胺(150mg,0.5mmol)溶于N,N-二甲基甲酰胺(10mL)溶液中,加入焦亚硫酸钠(380mg,2.0mmol),升温至90℃反应16h。TLC监测反应结束后,减压蒸馏,柱层析纯化(甲醇:二氯甲烷=1:6),得7-(4-(环丙基甲氧基)-5-(1-乙基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-腈(120mg,产率52%)。
MS m/z(ESI):471[M+H]
+。
步骤4:制备化合物C048
将7-(4-(环丙基甲氧基)-5-(1-乙基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(150mg,0.32mmol)溶于4M的盐酸1,4-二氧六环溶液(8mL)中,升温至100℃,搅拌反应10mins。TLC监测反应结束后,加氨水淬灭,减压蒸馏,送制备纯化得化合物C048(1.83mg,产率1.25%)。
MS(ESI)m/z:457.3[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ8.38(s,3H),8.26(s,2H),7.37(d,J=8.1Hz,1H),7.06(d,J=8.5Hz,1H),4.36(s,2H),3.05-3.01(m,1H),2.67-2.23(m,1H),2.36(dd,J=16.2,9.0Hz,3H),2.05-2.01(m,2H),1.73-1.69(m,4H),1.26-1.21(m,1H),1.04(t,J=7.2Hz,3H),0.55-0.50(m,2H),0.34-0.30(m,2H)。
实施例17:制备化合物C049
1.制备2-异丁氧基-6-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)苯胺
步骤1:制备3-溴-2-异丁氧基-6-硝基苯胺
室温下,将2-氨基-6-溴-3-硝基苯(5g,21.46mmol)和K
2CO
3(5.9g,42.91mmol)溶于乙腈(50mL),反应容器在25℃下搅拌0.5小时。然后加入1-碘-2-甲基丙烷(4.7g,25.75mmol),反 应液升温至80℃搅拌16h。反应液用硅藻土过滤,滤液旋干。粗品通过快速柱层析(石油醚/乙酸乙酯=10/1)纯化得3-溴-2-异丁氧基-6-硝基苯胺(2.4g,产率38.7%)。
MS m/z(ESI):288.9,290.9[M+H]
+.
步骤2:制备2-异丁氧基-6-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)苯胺
室温下,将3-溴-2-异丁氧基-6-硝基苯胺(2.3g,7.98mmol)、联硼酸频那醇酯(6.1g,23.96mmol)、KOAc(2.3g,23.96mmol)和Pd(dppf)Cl
2(584mg,0.798mmol)加入二氧六环(30mL),混合物在90℃下搅拌12h。混合物用乙酸乙酯和水萃取,合并有机相,有机相用盐水(50mL*2)洗涤,无水硫酸钠干燥,抽滤,浓缩得粗品。粗品通过快速柱层析(石油醚/乙酸乙酯=8/1)和反相柱(乙腈/水)纯化得2-异丁氧基-6-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)苯胺(1.3g,产率48.6%)。
MS m/z(ESI):337.1[M+H]
+.
2.制备化合物C049
步骤1:制备3-(1-乙基-1,2,3,6-四氢吡啶-4-基)-2-异丁氧基-6-硝基苯胺
在室温下,将1-乙基-1,2,3,6-四氢吡啶-4-三氟甲烷磺酸酯(771mg,2.97mmol)、2-3(1g,2.97mmol)、Pd(dppf)Cl
2(218mg,0.297mmol)和K
2CO
3(1.2g,8.92mmol)溶于1,4-二氧六环(18mL)和水(2mL)中。混合物在90℃下搅拌2h。LC-MS监测反应结束,过滤混合物并浓缩滤液。粗品通过快速柱层析(石油醚/乙酸乙酯=10/1)纯化得到3-(1-乙基-1,2,3,6-四氢吡啶-4-基)-2-异丁氧基-6-硝基苯胺(600mg,产率63.2%)。
MS m/z(ESI):320.1[M+H]
+.
步骤2:制备4-(1-乙基哌啶-4-基)-3-异丁氧基苯-1,2-二胺
向3-(1-乙基-1,2,3,6-四氢吡啶-4-基)-2-异丁氧基-6-硝基苯胺(200mg)在乙醇(60mL)中的溶液中添加PtO
2(400mg)。将混合物在50℃下在氢气环境下搅拌2天。过滤混合物并浓缩滤液,得到4-(1-乙基哌啶-4-基)-3-异丁氧基苯-1,2-二胺(150mg,产率82.2%)。
MS m/z(ESI):292.2[M+H]
+。
步骤3:制备7-(5-(1-乙基哌啶-4-基)-4-异丁氧基-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-腈
将7-甲酰基-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(68.34mg,0.34mmol)和4-(1-乙基哌啶-4-基)-3-异丁氧基苯-1,2-二胺(100mg,0.34mmol)溶于N,N-二甲基甲酰胺(10mL)溶液中,加入焦亚硫酸钠(261mg,1.37mmol),升温至90℃反应16h。TLC监测反应结束后,减压蒸馏,柱层析纯化(甲醇:二氯甲烷=1:6),得7-(5-(1-乙基哌啶-4-基)-4-异丁氧基-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-腈(90mg,产率58.8%)。
MS m/z(ESI):473.1[M+H]
+。
步骤4:制备化合物C049
将7-(5-(1-乙基哌啶-4-基)-4-异丁氧基-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-腈(130mg,0.28mmol)溶于4M的盐酸1,4-二氧六环溶液(8mL)中,升温至100℃,搅拌反应10min。TLC监测反应结束后,加氨水淬灭,减压蒸馏,送制备纯化得化合物C049(15.95mg,产率12.5%),黄色固体。
MS m/z(ESI):459.2[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ12.46(s,1H),8.27(d,J=9.3Hz,3H),7.35(s,1H),7.07(s,1H),4.50(d,J=92.5Hz,2H),3.06–3.02(m,2H),2.38(dt,J=20.5,10.3Hz,3H),2.17-2.08(m,1H),2.02-1.98(m,2H),1.73-1.70(m,4H),1.09(d,J=6.6Hz,6H),1.04-1.01(m,3H).
实施例18:制备化合物C050
步骤1:制备化合物C050
将4-(2-(3-氰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-4-(2,2-二氟乙氧基)-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸叔丁酯(30mg,0.05mmol)加入4mol/L的盐酸1,4-二氧六环溶液(8mL)中,100℃搅拌1h。TLC监测反应结束后,加氨水淬灭,减压浓缩得化合物C050(5.82mg,产率26.5%)。
MS m/z(ESI):[M+H]
+=439.0.
1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.26(d,J=13.4Hz,2H),7.43(d,J=8.3Hz,1H),7.02(d,J=8.3Hz,1H),6.64-6.26(m,1H),4.93(s,2H),3.23(s,1H),2.84(s,4H),1.76(s,4H).
实施例19:制备化合物C051
步骤1:制备1-乙基-1,2,3,6-四氢吡啶-4-基三氟甲磺酸酯
将1-乙基哌啶-4-酮(1.0g,7.86mmol)溶于无水四氢呋喃(20mL)中,氮气换气并降温至零下50摄氏度,加入二(三甲基硅基)氨基锂(8.7mL,8.65mmol mmol,1.0M in THF),于该温度下反应1小时。随后加入N-苯基双(三氟甲烷磺酰)亚胺(3.1g,8.65mmol),移至室温再反应1小时。反应完全后,用饱和氯化铵淬灭,乙酸乙酯萃取3次,合并有机相,先后用水和饱和盐水洗涤,无水硫酸钠干燥,过滤并浓缩,所得的粗产品再通过硅胶柱层析(洗脱剂:乙酸乙酯/石油醚=1/1)得1-乙基-1,2,3,6-四氢吡啶-4-基三氟甲磺酸酯(1.4g,产率67%)。
1H NMR(400MHz,CDCl
3)δ5.75-5.73(m,1H),3.13(t,J=4.0Hz,2H),2.73(d,J=8.0Hz,2H),2.57-2.52(m,2H),2.55-2.46(m,2H),1.12(t,J=8.0Hz,2H)。
步骤2:制备2-(2,2-二氟乙氧基)-3-(1-乙基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺
将1-乙基-1,2,3,6-四氢吡啶-4-基三氟甲磺酸酯(233mg,0.89mmol)和3-(2,2-二氟乙氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧苯硼酸-2-基)苯-1,2-二胺(306mg,0.89mmol)溶于无水1,4-二氧六环(9.0mL)中,再加入Pd(dppf)Cl
2(66mg,0.09mmol)、碳酸钾(369mg,2.67mmol)、水(1.0mL),升温至90摄氏度反应2小时。反应完全后,用乙酸乙酯萃取3次,合并有机相,先后用水和饱和盐水洗涤,无水硫酸钠干燥,过滤并浓缩,所得的粗产品再通过硅胶板层析(二氯甲烷:甲醇=10:1)纯化得 2-(2,2-二氟乙氧基)-3-(1-乙基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(150mg,产率52%)。
MS(ESI)m/z:328.2[M+H]
+。
步骤3:制备3-(2,2-二氟乙氧基)-4-(1-乙基哌啶-4-基)苯-1,2-二胺
将2-(2,2-二氟乙氧基)-3-(1-乙基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(150mg,0.47mmol)溶解于乙醇(6.0mL)中,加入二氧化铂(150mg),氢气抽换气,加热至50摄氏度反应20小时。反应完全后,过滤并浓缩得3-(2,2-二氟乙氧基)-4-(1-乙基哌啶-4-基)苯-1,2-二胺(137mg,产率100%)。
MS(ESI)m/z:300.2[M+H]
+。
步骤4:制备7-(4-(2,2-二氟乙氧基)-5-(1-乙基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈
3-(2,2-二氟乙氧基)-4-(1-乙基哌啶-4-基)苯-1,2-二胺(137mg,0.53mmol)和反应物7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(235mg,1.17mmol)溶解于无水N,N-二甲基甲酰胺(10mL)中,加热至90摄氏度反应20分钟,再加入焦亚硫酸钠(300mg),氮气保护,90度搅拌反应3小时。反应结束,过滤浓缩,再用乙酸乙酯萃取3次,合并有机相,先后用水和饱和盐水洗涤,无水硫酸钠干燥,过滤浓缩得7-(4-(2,2-二氟乙氧基)-5-(1-乙基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈(150mg,产率68.2%)。
MS(ESI)m/z:481.3[M+H]
+。
步骤5:制备化合物C051
7-(4-(2,2-二氟乙氧基)-5-(1-乙基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈和盐酸的混合物加热至100摄氏度回流反应1小时,反应冷却后,用饱和碳酸氢钠调pH至中性,然后用乙酸乙酯萃取3次,合并有机相,先后用水和饱和盐水洗涤,无水硫酸钠干燥,过滤浓缩所得的粗产品通过HPLC制备得到化合物C051(5.74mg,产率2%)。
MS(ESI)m/z:476.3[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ12.86(s,1H),12.65(s,1H),9.14(s,1H),8.27(d,J=8.0Hz,2H),7.47(d,J=8.0Hz,1H),7.00(t,J=8.0Hz,1H),6.45-6.30(m,1H),5.05-4.97(m,2H),3.61(d,J=8.0Hz,2H),3.24-3.04(m,4H),1.99-1.88(m,4H),1.27-1.20(m,4H).
实施例20:制备化合物C052
步骤1:制备7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-氧代-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-碳腈
将4-(2-(3-氰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-4-(2,2-二氟乙氧基)-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸叔丁酯(150mg,0.27mmol)溶于4mol/L的盐酸1,4-二氧六环溶液(8mL)中,100℃搅拌1h。TLC监测反应结束后,加氨水淬灭。反应液减压浓缩得7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-氧代-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-碳腈(127mg,产率99%)。
MS m/z(ESI):438.2[M+H]
+
步骤2:制备化合物C052
将三乙酰基硼氢化钠(726mg,3.4mmol)加入7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-氧代-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-碳腈(127mg,0.27mmol)和氧杂环丁烷-3-酮(244.8mg,3.4mmol)得1,2-二氯乙烷(20mL)溶液中,室温搅拌16h。反应液减压蒸馏,所得 残余物用HPLC手性制备得化合物C052(3.44mg,产率2.5%)。
MS m/z(ESI):495.1[M+H]
+.
1H NMR(400MHz,DMSO-d6)δ8.26(s,1H),8.16(s,1H),7.40(d,J=7.6Hz,1H),7.05(d,J=8.5Hz,1H),6.40(s,1H),4.91(s,2H),4.55(t,J=6.5Hz,2H),4.46(t,J=6.1Hz,2H),2.83(d,J=11.1Hz,2H),1.86(s,4H),1.72(s,4H).
实施例21:制备化合物C053
步骤1:制备4-(3-氨基-2-(2,2-二氟乙氧基)-4-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯
氮气保护下,将Pd(dppf)Cl
2(246mg,0.337mmol)和K
2CO
3(1.4g,10.11mmol)加入3-溴-2-(2,2-二氟乙氧基)-6-硝基苯胺(1g,3.37mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1.04g,3.37mmol)得1,4-二氧六环(80mL)和H
2O(10mL)得溶液中,90℃搅拌2h。将反应液倒入水(40mL)中,乙酸乙酯萃取,合并有机相。有机相用饱和食盐水洗,无水硫酸钠干燥,抽滤,滤液减压浓缩所得残余物用硅胶柱层析(PE:EA=10:1)纯化得4-(3-氨基-2-(2,2-二氟乙氧基)-4-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1g,产率74.2%)。
MS m/z(ESI):400.1[M+H]
+.
步骤2:制备4-(3,4-二氨基-2-(2,2-二氟乙氧基)苯基)哌啶-1-羧酸叔丁酯
将4-(3-氨基-2-(2,2-二氟乙氧基)-4-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1g,2.5mmol)溶于溶剂乙醇(30mL)中,在氮气氛围下加入PtO
2(300mg)。反应体系用氢气置换三次,在氢气(15psi)压力下,室温搅拌16h。将反应液通过硅藻土层抽滤,滤渣用甲醇洗涤。滤液减压浓缩得4-(3,4-二氨基-2-(2,2-二氟乙氧基)苯基)哌啶-1-羧酸叔丁酯(900mg,97%)。
MS m/z(ESI):372.2[M+H]
+.
步骤3:制备4-(2-(3-氰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-4-(2,2-二氟乙氧基)-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸叔丁酯
将焦亚硫酸钠(950mg,4.8mmol)加入7-甲酰基-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(487.6mg,2.4mmol)和4-(3,4-二氨基-2-(2,2-二氟乙氧基)苯基)哌啶-1-羧酸叔丁酯(900mg,2.4mmol)得N,N-二甲基甲酰胺(20mL)溶液中,90℃搅拌16h。反应液减压浓缩,所得残余物用硅胶柱层析(MeOH:DCM=1:6)纯化,得4-(2-(3-氰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-4-(2,2-二氟乙氧基)-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸叔丁酯(900mg,产率67.9%)。
MS m/z(ESI):553.1[M+H]
+.
步骤4:制备7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈
将4-(2-(3-氰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-4-(2,2-二氟乙氧基)-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸叔丁酯(250mg,0.45mmol)溶于4mol/L HCl/1,4-二氧六环溶液(8mL)中,室温搅拌2h。TLC监测反应结束后,加氨水淬灭,减压浓缩得7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(160mg,产率78.6%)。
步骤5:制备7-(4-(2,2-二氟乙氧基)-5-(1-(2-羟乙基)哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈
将7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯(240mg,0.53mmol)溶于无水乙腈(30mL)中,然后加入2-碘仿-1-醇(91mg,0.53mmol),K
2CO
3(220mg,1.59mmol),80℃搅拌16h。将反应液倒入水(60mL)中,乙酸乙酯(50mL*2)萃取,合并有机相。有机相用饱和食盐水(30mL*2)洗涤,无水硫酸钠干燥,抽滤,滤液减压浓缩,所得残余物用硅胶柱层析(石油醚:乙酸乙酯=10:1)纯化得7-(4-(2,2-二氟乙氧基)-5-(1-(2-羟乙基)哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(180mg,产率68.6%)。
MS m/z(ESI):497.3[M+H]
+.
步骤6:制备化合物C053
将4-(2-(3-氰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-4-(2,2-二氟乙氧基)-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸叔丁酯(180mg,0.36mmol)溶于4mol/L HCl/1,4-二氧六环溶液(8mL)中,100℃搅拌2h。TLC监测反应结束后,加氨水,减压浓缩,所得残余物用HPLC制备纯化得化合物C053(11.82mg,产率7.4%)。
MS m/z(ESI):483.2[M+H]
+.
1H NMR(400MHz,DMSO-d6)δ12.83(br,1H),12.64(s,1H),11.53(s,1H),8.27(s,2H),7.46(d,J=8.3Hz,1H),7.03(s,1H),6.42(t,J=42.7Hz,1H),5.32(s,1H),5.00(td,J=15.6,3.0Hz,2H),3.77(s,2H),3.58(s,2H),3.39(s,1H),3.21(s,4H),1.96(d,J=29.6Hz,4H).
实施例22:化合物C054
步骤1:制备8-甲基-8-氮杂双环[3.2.1]oct-2-烯-3-基三氟甲烷磺酸盐
氮气保护下,将8-甲基-8-氮杂双环[3.2.1]辛烷-3-酮(1.1g,7.86mmol)的无水四氢呋喃(20mL)溶液冷却至-50℃,缓慢滴加1.0moL/L的二(三甲基硅基)氨基锂的四氢呋喃溶液(8.7mL,8.65mmol),搅拌1h。然后加入N-苯基双(三氟甲烷磺酰)亚胺(3.1g,8.65mmol),加料完毕,将反应液移至室温搅拌1h。想反应液中加入饱和氯化铵溶液,乙酸乙酯萃取,合并有机相。有机相先后用水和饱和食盐水洗,无水硫酸钠干燥,过滤并浓缩,所得残余物用硅胶柱层析(EA:PE=1:1)纯化得8-甲基-8-氮杂双环[3.2.1]oct-2-烯-3-基三氟甲烷磺酸酯(1.4g,产率63%)。
步骤2:制备2-(2,2-二氟乙氧基)-3-(8-甲基-8-氮杂双环[3.2.1]oct-2-烯-3-基)-6-硝基苯胺
将8-甲基-8-氮杂双环[3.2.1]oct-2-烯-3-基三氟甲烷磺酸酯(241mg,0.89mmol)和2-(2,2-二氟乙氧基)-6-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)苯胺(306mg,0.89mmol)溶于无水1,4-二氧六环(9.0mL)中,再加入Pd(dppf)Cl
2(66mg,0.09mmol)、碳酸钾(369mg,2.67mmol)和水(1.0mL),将该混合溶液升温至90℃搅拌2h。反应液用水稀释,乙酸乙酯萃取,合并有机相。 有机相先后用水和饱和食盐水洗,无水硫酸钠干燥,过滤并浓缩,所得残余物用硅胶板柱层析(MeOH:DCM=1:10)得2-(2,2-二氟乙氧基)-3-(8-甲基-8-氮杂双环[3.2.1]oct-2-烯-3-基)-6-硝基苯胺(170mg,产率58%)。
(ESI)m/z:340.2[M+H]
+.
步骤3:制备3-(2,2-二氟乙氧基)-4-(8-甲基-8-氮杂双环[3.2.1]辛烷-3-基)苯-1,2-二胺
2-(2,2-二氟乙氧基)-3-(8-甲基-8-氮杂双环[3.2.1]oct-2-烯-3-基)-6-硝基苯胺(150mg,0.44mmol)溶于乙醇(6.0mL)中,加入二氧化铂(150mg)。体系在氢气氛围下,50℃摄搅拌20h。将反应液过滤,收集滤液。滤液减压浓缩得3-(2,2-二氟乙氧基)-4-(8-甲基-8-氮杂双环[3.2.1]辛烷-3-基)苯-1,2-二胺(130mg,产率95%)。
(ESI)m/z:312.2[M+H]
+.
步骤4:制备7-(4-(2,2-二氟乙氧基)-5-(8-甲基-8-氮杂双环[3.2.1]辛烷-3-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳三烯
3-(2,2-二氟乙氧基)-4-(8-甲基-8-氮杂双环[3.2.1]辛烷-3-基)苯-1,2-二胺(130mg,0.51mmol)和反应物7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈(235mg,1.17mmol)溶解于无水DMF(10mL)中,加热至90℃搅拌20min。氮气保护下,加入焦亚硫酸钠(300mg),90℃搅拌3h。反应液过滤,滤液用水稀释,乙酸乙酯萃取,合并有机相。有机相先后用水和饱和食盐水洗,无水硫酸钠干燥,过滤,滤液减压浓缩得粗品7-(4-(2,2-二氟乙氧基)-5-(8-甲基-8-氮杂双环[3.2.1]辛烷-3-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳三烯(140mg),粗品直接用于下一步。
Ms(ESI)m/z:=493.3[M+H]
+.
步骤5:制备化合物C054
将上步所得粗品7-(4-(2,2-二氟乙氧基)-5-(8-甲基-8-氮杂双环[3.2.1]辛烷-3-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳三烯(140mg)溶于4mol/L的HCl/1,4-二氧六环溶液(10mL)中,100℃搅拌1h。将反应液冷却至室温,用饱和碳酸氢钠调pH至中性,乙酸乙酯萃取,合并有机相。有机相先后用水和饱和食盐水洗,无水硫酸钠干燥,过滤,滤液减压浓缩,所得残余物用HPLC制备纯化得化合物C054(16.82mg,产率12.4%)。
Ms(ESI)m/z:[M+H]
+=479.3.
1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),8.25(s,4H),7.39(d,J=8.3Hz,1H),7.09(d,J=8.5Hz,1H),6.61-6.21(m,1H),4.96-4.90(m,2H),3.59(d,J=6.4Hz,1H),3.47-3.41(m,2H),2.37-2.28(m,2H),2.25(s,3H),2.16-2.04(m,2H),1.61-1.58(m,2H),1.52-1.39(m,2H).
实施例23:制备化合物C056
步骤1:制备4-甲基-3-((三甲基硅基)乙炔基)吡啶
将乙炔基三甲基硅烷(16g,163.08mmol)加入3-碘-4甲基吡啶(13.7g,54.36mmol)的TEA(150mL)溶液中,然后加入Pd(PPh
3)
2Cl
2(954mg,1.36mmol)和CuI(1.04g,5.44mmol),并将反应混合物在N
2环境105℃下搅拌16小时。LC-MS显示反应结束后,反应混合物经硅藻土过滤。向滤液中加入水(200mL),所得溶液用乙酸乙酯(100mL×3)萃取,合并的有机萃取液用碳酸氢钠水溶液、盐水洗涤,无水硫酸钠干燥,在减压下过滤后浓缩溶剂得到粗品。残余物通过硅胶色谱法纯化,得到4-甲基-3-((三甲基硅基)乙炔基)吡啶(8g,产率66.7%)。
1H NMR(400MHz,DMSO-d6)δ7.21(td,J=8.4,7.0Hz,1H),6.83–6.61(m,2H),3.67(d,J=6.7Hz,3H),0.00(s,9H).
步骤2:制备4-甲基-3-炔基吡啶
将K
2CO
3(822mg,5.95mmol)加入到化合物4-甲基-3-((三甲基硅基)乙炔基)吡啶(441mg,1.98mmol)的甲醇(10mL)溶液中,并将混合物在室温搅拌2小时。混合物加水(100mL)并用甲基叔丁基醚(10mL*3)萃取。合并的有机层用盐水洗涤,经无水硫酸钠干燥并减压浓缩。所得粗品经快速硅胶色谱法(SiO
2,0-50%乙酸乙酯:石油醚)纯化得化合物4-甲基-3-炔基吡啶(200mg,产率67.3%)。
1H NMR(400MHz,DMSO-d6)δ7.40(dd,J=15.5,8.4Hz,1H),6.97-6.80(m,2H),4.51(s,1H),3.86(s,3H).
步骤3:制备3-溴-2-甲氧基-5-((4-甲基吡啶-3-基)乙炔基)吡啶-4-胺
将4-甲基-3-炔基吡啶(438mg,1.33mmol)和TEA(539mg,5.33mmol)加到化合物3-溴-5-碘-2-甲氧基吡啶-4-胺(200mg,1.33mmol)的THF(3mL)溶液中,然后加入Pd(PPh
3)
2Cl
2(19mg,0.03mmol)和CuI(5mg,0.03mmol),并将反应混合物在室温N
2下搅拌16小时。LC-MS显示反应结束后,反应混合物经硅藻土过滤。滤液中加入水(20mL),所得溶液用乙酸乙酯(10mL×3)萃取,合并的有机萃取物用饱和碳酸氢钠水溶液、盐水洗涤,无水硫酸钠干燥,过滤后在减压下浓缩溶剂得到粗品。粗品通过快速柱色谱法(SiO2,乙酸乙酯/石油醚=10%洗脱)纯化残余物,得3-溴-2-甲氧基-5-((4-甲基吡啶-3-基)乙炔基)吡啶-4-胺(300mg,产率64.5%)。
1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.47-7.39(m,1H),7.03-6.92(m,2H),6.30(s,2H),3.95(s,3H),3.89(s,3H).
步骤4:制备7-溴-6-甲氧基-2-(4-甲基吡啶-3-基)-1H-吡咯[3,2-c]吡啶
将t-BuOK(128mg,1.14mmol)加入3-溴-2-甲氧基-5-((4-甲基吡啶-3-基)乙炔基)吡啶-4-胺(200mg,0.57mmol)的NMP(3mL)溶液中,将混合物在100℃下搅拌2h。反应结束后,加入水(20ml),所得溶液用盐酸(1mol/L)调节PH=7,然后用乙酸乙酯(20mL x 3)萃取,合并的有机萃取液用盐水洗涤,经无水硫酸钠干燥,过滤后,减压浓缩溶剂。残余物通过快速柱色谱纯化,得7-溴-6-甲氧基-2-(4-甲基吡啶-3-基)-1H-吡咯[3,2-c]吡啶(150mg,产率75%)。
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),8.42(s,1H),7.46(dt,J=15.2,7.6Hz,1H),7.07–6.91(m,2H),6.72(s,1H),3.95(s,3H),3.83(s,3H).
步骤5:制备7-溴-3-碘-6-甲氧基-2-(4-甲基吡啶-3-基)-1H-吡咯[3,2-c]吡啶
0℃下将NIS(2.23g,9.90mmol)加入到化合物7-溴-6-甲氧基-2-(4-甲基吡啶-3-基)-1H-吡咯[3,2-c]吡啶(3.0g,9.34mmol)的二甲亚砜(100mL)溶液中,将混合物在室温搅拌2小时。完成后,减压除去溶剂,残余的粗产物用水、石油醚洗涤,干燥,得7-溴-3-碘-6-甲氧基-2-(4-甲基吡啶-3-基)-1H-吡咯[3,2-c]吡啶(3.6g,产率86%)。
1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),8.59-8.44(m,2H),8.20(s,1H),7.44(d,J=5.2Hz,1H),3.98(s,3H),2.23(s,3H)。
步骤6:制备7-溴-6-甲氧基-2-(4-甲基吡啶-3-基)-1H-吡咯[3,2-c]吡啶-3-甲腈
将Zn(CN)
2(529mg,4.50mmol)加入到7-溴-3-碘-6-甲氧基-2-(4-甲基吡啶-3-基)-1H-吡咯[3,2-c]吡啶(2g,4.50mmol)的N,N-二甲基甲酰胺(50mL)溶液中,然后加入Pd(PPh
3)
4(2.6g,2.25mmol)。将混合物在氮气和80℃下搅拌1小时。加入水(200mL),反应液中沉淀析出固体,过滤。滤渣用水洗涤并干燥,得到粗产物。粗品通过反相纯化得7-溴-6-甲氧基-2-(4-甲基吡啶-3-基)-1H-吡咯[3,2- c]吡啶-3-甲腈(500mg,产率32.3%)。
1H NMR(400MHz,DMSO-d6)δ12.91(s,1H),8.63(dd,J=14.3,9.2Hz,2H),7.68-7.44(m,2H),4.00(s,3H),2.36(s,3H)。
步骤7:制备6-甲氧基-2-(4-甲基吡啶-3-基)-7-乙烯基-1H-吡咯[3,2-c]吡啶-3-甲腈
将7-溴-6-甲氧基-2-(4-甲基吡啶-3-基)-1H-吡咯[3,2-c]吡啶-3-甲腈(4.5g,18.7mmoL)、三氟(乙烯基)-l4硼烷钾盐(5.0g,37.3mmoL)、N-环己基-N-甲基环己烷胺(7.3g,37.3mmoL)、[1,1'-二(二苯基膦基)二茂铁]二氯钯(II)(1.4g,1.9mmoL)与1,4-二氧六环(30mL)在90℃下搅拌16小时。浓缩反应混合物,用乙酸乙酯(500mL)稀释,用水(500mL)洗涤,将水相加入氯化钠形成饱和溶液,并用四氢呋喃(500mL x 2)萃取。将合并的有机层干燥并浓缩。粗产物用硅胶柱层析(石油醚/乙酸乙酯=10:1~5:1)纯化得6-甲氧基-2-(4-甲基吡啶-3-基)-7-乙烯基-1H-吡咯[3,2-c]吡啶-3-甲腈(2.5g,产率71%)。
MS(m/z):190.2[M+H]
+。
步骤8:制备7-甲酰基-6-甲氧基-2-(4-甲基吡啶-3-基)-1H-吡咯[3,2-c]吡啶-3-甲腈
在室温下向化合物6-甲氧基-2-(4-甲基吡啶-3-基)-7-乙烯基-1H-吡咯[3,2-c]吡啶-3-甲腈(600mg,2.3mmoL)、4-甲基吗啉N-氧化物(796mg,6.8mmoL)、高碘酸钠(963mg,4.5mmoL)的丙酮/水(15mL,3:2)溶液中加入二水合锇酸钾(VI)(40mg,0.1mmoL),并在室温下搅拌16h。LCMS显示主峰为产物。向反应液中加乙酸乙酯(500mL)并用水(500mL)洗涤。向水相加入氯化钠形成饱和溶液,并用THF(500mL x 2)萃取。将合并的有机层干燥并浓缩。粗产物用硅胶柱柱层析(石油醚/乙酸乙酯=5:1~3:1)纯化得7-甲酰基-6-甲氧基-2-(4-甲基吡啶-3-基)-1H-吡咯[3,2-c]吡啶-3-甲腈(300mg,产率50%)。
步骤9:制备7-(4-(2,2-二甲基乙氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈
将3-(2,2-二甲基乙氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(50mg,0.16mmol)和7-甲酰基-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(65mg,0.24mmol)溶于N,N-二甲基甲酰胺(5ml)溶液中,加入焦亚硫酸钠(91.2mg,0.48mmol),升温至90℃反应16h。TLC监测反应结束后,减压蒸馏,柱层析纯化(甲醇:二氯甲烷=1:6),得7-(4-(2,2-二甲基乙氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(60mg,产率80.0%)。
步骤10:制备化合物C056
将7-(4-(2,2-二甲基乙氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(250mg,0.53mmol)溶于4M的盐酸1,4-二氧六环溶液(10mL)中,升温至90℃,搅拌反应2h。TLC监测反应结束后,加氨水淬灭,减压蒸馏,送制备纯化得化合物C056(26.38mg,产率11%)。
MS(m/z):453.4[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ12.59(s,1H),11.96-11.20(m,1H),8.34-8.10(m,3H),7.42(d,J=8.3Hz,1H),7.06(d,J=8.4Hz,1H),6.63–6.13(m,1H),4.91(br,2H),3.99–3.73(m,4H),3.15–3.04(m,2H),2.92(d,J=10.9Hz,2H),2.31(s,3H),2.24(s,3H),2.22–2.15(m,1H),2.04(t,J=9.9Hz,2H),1.73(dd,J=22.3,10.1Hz,6H).
实施例24:制备化合物C057
步骤1:制备7-(5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-2-(4-甲基吡啶-3-基)-6-氧代- 5,6-二氢-1H-吡咯[3,2-c]吡啶-3-甲腈
将化合物7-甲酰基-6-甲氧基-2-(邻甲苯基)-1H-吡咯并[3,2-c]吡啶-3-甲腈(70mg,0.24mmol)和4-(4-甲基哌嗪-1-基)苯-1,2-二胺(49mg,0.24mmol)溶于N,N-二甲基甲酰胺(5ml)溶液中,加入焦亚硫酸钠(180mg,0.96mmol),升温至90℃反应12h。TLC监测反应结束后,减压蒸馏,柱层析纯化(甲醇:二氯甲烷=1:9),得6-甲氧基-7-(5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-2-(4-甲基吡啶-3-基)-1H吡咯[3,2-c]吡啶-3-甲腈(80mg,产率70%)。
步骤2:制备化合物C057
将化合物6-甲氧基-7-(5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-2-(4-甲基吡啶-3-基)-1H吡咯[3,2-c]吡啶-3-甲腈(230mg,0.48mmol)溶于乙醇溶液(4mL)中,加入4M的盐酸1,4-二氧六环溶液(6mL),升温至90℃,搅拌反应3h。TLC监测反应结束后,加氨水淬灭,减压蒸馏,柱层析纯化(MeOH:DCM=1:6),得化合物C057(8.52mg,产率3.82%)。
MS m/z(ESI):464.30[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ12.51(br,1H),8.75(s,1H),8.63(d,J=5.1Hz,1H),8.30(s,1H),7.60(d,J=8.4Hz,1H),7.55(s,1H),7.51(d,J=5.1Hz,1H),7.09(d,J=8.3Hz,1H),2.90(d,J=10.4Hz,2H),2.47(s,3H),2.35-2.31(m,1H),2.21(s,3H),2.08-2.03(m,2H),1.78-1.13(m,4H)。
实施例25:制备化合物C058
步骤1:制备((2-氟-6-甲氧基苯基)乙炔基)三甲基硅烷
将乙炔基三甲基硅烷(16g,163.08mmol)加入1-氟-2-碘-3-甲氧基苯(13.7g,54.36mmol)的TEA(150mL)溶液中,然后加入Pd(PPh
3)
2Cl
2(954mg,1.36mmol)和CuI(1.04g,5.44mmol),并将反应混合物在N
2环境105℃下搅拌16小时。LC-MS显示反应结束后,反应混合物经硅藻土过滤。向滤液中加入水(200mL),所得溶液用乙酸乙酯(100mL×3)萃取,合并的有机萃取液用NaHCO
3水溶液、盐水洗涤,无水硫酸钠干燥,在减压下过滤后浓缩溶剂得到粗品。残余物通过硅胶色谱法纯化,得((2-氟-6-甲氧基苯基)乙炔基)三甲基硅烷(8g,产率66.7%)。
1H NMR(400MHz,DMSO-d6)δ7.21(td,J=8.4,7.0Hz,1H),6.83–6.61(m,2H),3.67(d,J=6.7Hz,3H),0.00(s,9H).
步骤2:制备2-乙炔基-1-氟-3-甲氧基苯
将K
2CO
3(822mg,5.95mmol)加入到化合物((2-氟-6-甲氧基苯基)乙炔基)三甲基硅烷(441mg,1.98mmol)的MeOH(10mL)溶液中,并将混合物在室温搅拌2小时。混合物加水(100mL)并用甲基叔丁基醚(10mL*3)萃取。合并的有机层用盐水洗涤,经无水Na
2SO
4干燥并减压浓缩。所得粗品经快速硅胶色谱法(SiO
2,0-50%EtOAc:PE)纯化得2-乙炔基-1-氟-3-甲氧基苯(200mg,产率67.3%)。
1H NMR(400MHz,DMSO-d6)δ7.40(dd,J=15.5,8.4Hz,1H),6.97-6.80(m,2H),4.51(s,1H), 3.86(s,3H).
步骤3:制备3-溴-5-((2-氟-6-甲氧基苯基)乙炔基)-2-甲氧基吡啶-4-胺
将2-乙炔基-1-氟-3-甲氧基苯(438mg,1.33mmol)和TEA(539mg,5.33mmol)加到化合物3(200mg,1.33mmol)的THF(3mL)溶液中,然后加入Pd(PPh
3)
2Cl
2(19mg,0.03mmol)和CuI(5mg,0.03mmol),并将反应混合物在室温N
2下搅拌16小时。LC-MS显示反应结束后,反应混合物经硅藻土过滤。滤液中加入H
2O(20mL),所得溶液用乙酸乙酯(10mL×3)萃取,合并的有机萃取物用饱和NaHCO
3水溶液、盐水洗涤,无水硫酸钠干燥,过滤后在减压下浓缩溶剂得到粗品。粗品通过快速柱色谱法(SiO
2,乙酸乙酯/石油醚=10%洗脱)纯化残余物,得3-溴-5-((2-氟-6-甲氧基苯基)乙炔基)-2-甲氧基吡啶-4-胺(300mg,产率64.5%)。
1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.47-7.39(m,1H),7.03-6.92(m,2H),6.30(s,2H),3.95(s,3H),3.89(s,3H).
步骤4:制备7-溴-2-(2-氟-6-甲氧基苯基)-6-甲氧基-1H-吡咯[3,2-c]吡啶
将t-BuOK(128mg,1.14mmol)加入3-溴-5-((2-氟-6-甲氧基苯基)乙炔基)-2-甲氧基吡啶-4-胺(200mg,0.57mmol)的NMP(3mL)溶液中,将混合物在100℃下搅拌2h。反应结束后,加入水(20ml),所得溶液用盐酸(1mol/L)调节PH=7,然后用乙酸乙酯(20mL x 3)萃取,合并的有机萃取液用盐水洗涤,经无水硫酸钠干燥,过滤后,减压浓缩溶剂。残余物通过快速柱色谱纯化,得3-溴-5-((2-氟-6-甲氧基苯基)乙炔基)-2-甲氧基吡啶-4-胺(150mg,产率75%)。
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),8.42(s,1H),7.46(dt,J=15.2,7.6Hz,1H),7.07–6.91(m,2H),6.72(s,1H),3.95(s,3H),3.83(s,3H).
步骤5:制备7-溴-2-(2-氟-6-甲氧基苯基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲醛
在0℃下将POCl
3(1.53g,8.54mmol)加入到3-溴-5-((2-氟-6-甲氧基苯基)乙炔基)-2-甲氧基吡啶-4-胺(1g,2.85mmol)的DMF(12mL)溶液中,混合物在室温下搅拌16小时。加入饱和NaHCO
3(20mL)淬灭,反应液用水稀释析出固体,过滤,固体用水洗涤,然后真空冷冻干燥得3-溴-5-((2-氟-6-甲氧基苯基)乙炔基)-2-甲氧基吡啶-4-胺(700mg,产率42.4%)。
1H NMR(400MHz,DMSO-d6)δ12.66(s,1H),9.61(s,1H),8.84(s,1H),7.62(dd,J=15.2,7.7Hz,1H),7.17-6.97(m,2H),3.98(s,3H),3.81(s,3H)。
步骤6:制备7-溴-2-(2-氟-6-甲氧基苯基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈
将NH
2OH.HCl(367mg,5.27mmol)和TEA(1.06g,10.55mmol)加入到3-溴-5-((2-氟-6-甲氧基苯基)乙炔基)-2-甲氧基吡啶-4-胺(1g,2.64mmol)的DMF(15mL)溶液中,混合物在室温下搅拌1小时。然后加入T
3P(6.7g,21.10mmol),混合物在100℃下搅拌16小时。反应结束后加入水(20ml),所得溶液用乙酸乙酯(20mL x 3)萃取,合并的有机萃取液用盐水洗涤,经无水硫酸钠干燥,过滤后,减压浓缩溶剂得粗产品。残余物通过快速柱色谱纯化,得7-溴-2-(2-氟-6-甲氧基苯基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈(266mg,产率26.8%)。
步骤7:制备2-(2-氟-6-甲氧基苯基)-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈
将化合物7-溴-2-(2-氟-6-甲氧基苯基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈(641mg,1.71mmol)的四氢呋喃(50mL)的溶液冷却至-78℃,然后缓慢加入2mml/L n-BuLi的正己烷溶液(0.45mL,1.13mmol)。将反应溶液在-78℃下在N
2下搅拌0.5h。然后加入DMF(110mg,1.50mmol)。将反应溶液在-78℃和N 2下搅拌2h。反应混合物用NH4Cl饱和溶液(5mL)淬灭后。溶液用水(20mL)和乙酸乙酯萃取,合并的有机相用盐水(20mL)洗涤,干燥(Na
2SO
4),过滤并浓缩,得2-(2-氟-6-甲氧基苯基)-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈(455mg,产率82.1%)。
步骤8:制备2-(2-氟-6-甲氧基苯基)-6-甲氧基-7-(5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-1H吡咯[3,2-c]吡啶-3-甲腈
将化合物2-(2-氟-6-甲氧基苯基)-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈(60mg,0.22mmol)和化合物8(107mg,0.33mmol)溶于DMF(5ml)中,混合物在室温下搅拌20分钟,然后加入Na
2S
2O
5(165mg,0.87mmol)。将混合物在90℃搅拌4h。TLC显示原料反应完全,将反应液倒入冰水中,有固体析出,将混合物过滤,滤渣用水洗得2-(2-氟-6-甲氧基苯基)-6-甲氧基-7-(5-(1-甲 基哌啶-4-基)-1H苯并[d]咪唑-2-基)-1H吡咯[3,2-c]吡啶-3-甲腈(60mg,产率35.7%)。
LCMS(ESI)m/z:511.5[M+H]
+。
步骤9:制备化合物C058
将2-(2-氟-6-甲氧基苯基)-6-甲氧基-7-(5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-1H吡咯[3,2-c]吡啶-3-甲腈(60mg,0.13mmol)溶于盐酸的二氧六环溶液(15mL)中,将混合物在100℃搅拌2h。反应结束旋干二氧六环得到粗品。粗品通过反相制备纯化得化合物C058(6.49mg,产率10.0%)。
MS(m/z):497.1[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.30(s,1H),8.25(s,1H),7.71-7.63(m,1H),7.57(s,2H),7.18(d,J=8.6Hz,1H),7.10(dd,J=11.5,8.8Hz,2H),3.97(s,3H),2.89(d,J=10.7Hz,2H),2.57–2.52(m,1H),2.22(s,3H),2.02(t,J=10.5Hz,2H),1.84–1.62(m,4H).
实施例26:制备化合物C059
步骤1:制备3-溴-2-甲氧基-4-氨基吡啶
将化合物2-甲氧基-4-氨基吡啶(5g,0.40.32mmol)溶解于DCM(50ml)中,在0℃下,缓慢分批加入NBS(7.2g,40.32mmol)。加料完毕,该混合物恢复至室温搅拌2h。然后向反应体系中加水(50mL),DCM(25ML×3)萃取,合并有机相。有机相用盐水洗,无水Na
2SO
4干燥,过滤,滤液减压浓缩得3-溴-2-甲氧基-4-氨基吡啶(6.0g,73产率)。
MS m/z(ESI):205.1[M+H]
+
步骤2:制备3-溴-5碘-2-甲氧基-4-氨基吡啶
将3-溴-2-甲氧基-4-氨基吡啶(6g,29.5mmoL)溶于乙腈(240ml)和乙酸(6mL)的混合溶液中,并向该混合物中分批缓慢加入NIS(7.3g,32.5mmol),加料完毕,室温搅拌过夜。向反应体系中加水(300ml),EA(100MLX3)索取,合并有机相。有机相依次用亚硫酸钠溶液和饱和食盐水洗,无水Na
2SO
4干燥,过滤,滤液减压浓缩所得残留物用制备大板分离得3-溴-5碘-2-甲氧基-4-氨基吡啶(9g,产率92.7%)。
MS(ESI)m/z:330.8[M+H]
+
步骤3:制备3-溴-2-甲氧基-5-(丙-1-炔基-1-基)-4-胺基吡啶
将3-溴-5碘-2-甲氧基-4-氨基吡啶(3g,9.12mmol)溶解于TEA(75ml)中,在氮气氛围下加入Pd(PPh
3)
2Cl
2(160mg,0.23mmol)和CuI(174mg,0.91)和丙炔,该混合物在室温下搅拌16h。然后将反应液过滤,滤液中加入100ml水,并用DCM萃取,合并有机相。有机相依次用饱和氯化铵溶液和饱和食盐水洗涤,无水Na
2SO
4干燥,过滤,滤液减压浓缩所得残留物用SGC纯化得3-溴-2-甲氧基-5-(丙-1-炔基-1-基)-4-胺基吡啶(1.0g,产率46.1%)。
步骤4:制备7-溴-6-甲氧基-2-甲基-1H-吡咯[3,2-c]吡啶
将t-BuOK(591mg,5.27mmol)加入到3-溴-2-甲氧基-5-(丙-1-炔基-1-基)-4-胺基吡啶(635mg,2.63mmol)的NMP(8mL)溶液中,该混合物在100℃下搅拌1h。LCMS显示反应结束后, 向该混合物中加入水(20ml),并用1mol/L盐酸调至PH弱碱性,然后用乙酸乙酯(10mL×3)萃取,合并有机相。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩所得残余物通过硅胶柱层析(二氯甲烷:甲醇=30:1)纯化,得7-溴-6-甲氧基-2-甲基-1H-吡咯[3,2-c]吡啶(540mg,85.8%)。
步骤5:制备7-溴-3-碘-6-甲氧基-2-甲基-1H-吡咯[3,2-c]吡啶
将NIS(489mg,2.18mmol)加入到7-溴-6-甲氧基-2-甲基-1H-吡咯[3,2-c]吡啶的DMSO(8mL)溶液中,该混合物在室温下搅拌16h。反应结束后,向反应液中加水(20ml),用EA萃取,合并有机相。有机相依次用饱和亚硫酸钠溶液和盐水洗涤,无水Na2SO4干燥,过滤,滤液减压浓缩所得残留物用硅胶柱层析(10%EtOAc/PE)纯化得到7-溴-3-碘-6-甲氧基-2-甲基-1H-吡咯[3,2-c]吡啶(600mg,产率79.2%)。
1H NMR(400MHz,DMSO-d6)δ11.81(s,1H),7.99(s,1H),3.93(s,3H),2.37(s,3H).
步骤6:制备7-溴-6-甲氧基-2-甲基-3-氰基-1H-吡咯[3,2-c]吡啶
将Zn(CN)
2(417mg,3.55mmol)加入到7-溴-3-碘-6-甲氧基-2-甲基-1H-吡咯[3,2-c]吡啶(1.3g,3.55mmol)的DMF(40ml)溶液中,然后在氮气保护下,向该体系中加入Pd(PPh
3)
4,该混合物在80℃下搅拌0.5h。然后向该混合物中加入水(100ml),有固体析出。过滤,滤饼用水洗涤,真空干燥得粗产物。粗产物用硅胶柱层析(10-50%EtOAc/PE)纯化得7-溴-6-甲氧基-2-甲基3-氰基-1H-吡咯[3,2-c]吡啶(500mg,53%)。
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.38(s,1H),3.95(s,3H),2.54(s,3H).
步骤7:制备7-甲酰基-6-甲氧基-2-甲基-1H-吡咯[3,2-c]吡啶-3-碳腈
在氮气保护下,将7-溴-6-甲氧基-2-甲基3-氰基-1H-吡咯[3,2-c]吡啶(100mg,1.71mmol)的四氢呋喃(5ml)溶液冷却至-78℃,然后缓慢滴加2.5mol/L的正丁基锂的正己烷溶液(0.45ml,1.13mmol),保持-78℃下搅拌0.5h。然后加入DMF(110mg,1.50mmol),该混合物继续在-78℃下搅拌2h。然后向反应液中加入饱和NH
4Cl溶液(5mL)和水(20mL)淬灭反应,并用EA(20mL×3)萃取,合并有机相。有机相用盐水洗涤,无水Na
2SO
4干燥,过滤,滤液减压浓缩得7-甲酰基-6-甲氧基-2-甲基-1H-吡咯[3,2-c]吡啶-3-碳腈(255mg,产率69.4%)。
步骤8:制备7-(4-异丁氧基-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-2-甲基-1H-吡咯[3,2-c]吡啶-3-碳腈
将7-甲酰基-6-甲氧基-2-甲基-1H-吡咯[3,2-c]吡啶-3-碳腈(60mg,0.22mmol)和3-异丁氧基-4-(1-甲基哌啶-4-基)苯-1,2-二胺(70mg,0.33mmol)溶于DMF(5ml)中,该混合物在室温下搅拌20分钟,然后加入Na
2S
2O
5(165mg,0.87mmol)。将混合物升温至90℃并搅拌4h。TLC显示原料转化完全,将反应液倒入冰水中,有固体析出,过滤,滤饼用水洗,收集固体,真空干燥7-(4-异丁氧基-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-2-甲基-1H-吡咯[3,2-c]吡啶-3-碳腈(60mg,产率57.8%)。
MS(ESI)m/z:473.5[M+H]
+
步骤9:制备化合物C059
将7-(4-异丁氧基-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-2-甲基-1H-吡咯[3,2-c]吡啶-3-碳腈(60mg,0.13mmol)和NaI(38mg,0.25mmol)加入倒乙腈(15ml)中,然后加入TMCS(28mg,0.25mmol)。该混合物在室温下搅拌3h。然后将反应液减压浓缩所得残留物用反相制备纯化得化合物C059(14.6mg,产率24.6%)。
MS(ESI)m/z:459.3[M+H]
+
1H NMR(400MHz,DMSO-d6)δ8.27(s,1H),8.01(s,1H),7.35(d,J=8.1Hz,1H),7.04(d,J=8.3Hz,1H),4.29(br,2H),3.05(s,1H),2.93(d,J=11.1Hz,2H),2.58(s,3H),2.24(s,3H),2.19–2.12(m,1H),2.06(t,J=10.1Hz,2H),1.77–1.68(m,4H),1.12(d,J=6.7Hz,6H).
实施例27:制备化合物C060
步骤1:制备3-溴-2-甲氧基-5-(丁-1-炔基-1-基)-4-胺基吡啶
将化合物3-溴-5碘-2-甲氧基-4-氨基吡啶(1g,3.04mmol)溶解于MeOH:DMA:H2O=1:1:1(15ml)中。在氮气氛围下加入CsCO
3(1.49g,4.56mmol),CuI(58mg,0.30mmol)、Pd(PPh
3)
2Cl
2(43mg,0.06mmol)和丁-1-炔基三甲基硅烷。该混合物在80℃下搅拌16h。反应结束后,将反应液过滤,滤液中加入100ml水,并用DCM萃取,合并有机相。有机相用饱和盐水洗涤,无水Na
2SO
4干燥,过滤,滤液减压浓缩所得残留物经SGC纯化得3-溴-2-甲氧基-5-(丁-1-炔基-1-基)-4-胺基吡啶(400mg,产率51.6%)。
1H NMR(400MHz,DMSO-d6)δ7.79(s,1H),6.10(s,2H),3.84(s,3H),2.50–2.43(m,2H),1.18(t,J=7.5Hz,3H).
步骤2:制备7-溴-6-甲氧基-2-乙基-1H-吡咯[3,2-c]吡啶
将t-BuOK(440mg,3.92mmol)加入到溶有化合物3-溴-2-甲氧基-5-(丁-1-炔基-1-基)-4-胺基吡啶(500mg,1.96mmol)的NMP(8mL)溶液中,该混合物在100℃下搅拌1h。LCMS显示反应结束后,加入水(20ml),将所得溶液用盐酸溶液(1mol/L)调至PH>7,并用乙酸乙酯(10mL×3)萃取,合并有机相。有机相用盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩所的残留物用硅胶柱层析纯化得7-溴-6-甲氧基-2-乙基-1H-吡咯[3,2-c]吡啶(400mg,产率80.3%)。
MS(ESI)m/z:255.0[M+H]
+;
步骤3:制备7-溴-3-碘-6-甲氧基-2-乙基-1H-吡咯[3,2-c]吡啶
将NIS(417mg,1.85mmol)加入到7-溴-6-甲氧基-2-乙基-1H-吡咯[3,2-c]吡啶(450mg,1.76mmol)的DMSO(8mL)溶液中,然后将该混合物在室温下搅拌16h。反应结束后,加水(20ml),并用EA(25ml X3)萃取,合并有机相。有机相用饱和亚硫酸钠溶液和盐水洗涤,无水Na2SO4干燥,过滤,滤液减压浓缩所得残留物用硅胶柱层析(10%EtOAc/PE)纯化得7-溴-3-碘-6-甲氧基-2-乙基-1H-吡咯[3,2-c]吡啶(550mg,产率82.2%)。
步骤4:制备7-溴-6-甲氧基-2-乙基-3-氰基-1H-吡咯[3,2-c]吡啶
将Zn(CN)
2(616mg,5.25mmol)加入到7-溴-3-碘-6-甲氧基-2-乙基-1H-吡咯[3,2-c]吡啶(2g,5.25mmol)的DMF(40mL)溶液中,在氮气保护下加入Pd(PPh
3)
4。该混合物在80℃下搅拌0.5h,然后加入水(100ml),有固体析出。过滤,滤饼用水洗涤,干燥,得到粗产物。粗产物用硅胶柱层析(10-50%EtOAc/PE)得7-溴-6-甲氧基-2-乙基-3-氰基-1H-吡咯[3,2-c]吡啶(800mg,产率55%),黄色固体。
1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),8.40(s,1H),3.95(s,3H),2.90(q,J=7.6Hz,2H),1.33(t,J=7.6Hz,3H).
步骤5:制备7-甲酰基-6-甲氧基-2-乙基-1H-吡咯[3,2-c]吡啶-3-碳腈
氮气保护下,将7-溴-6-甲氧基-2-乙基-3-氰基-1H-吡咯[3,2-c]吡啶(400mg,1.43mmol)的四氢呋喃(5mL)溶液冷却至-78℃,然后缓慢滴加2.5mol/L n-BuLi的正己烷溶液(1.7ml,4.28mmol), 保持-78℃搅拌0.5h。然后向体系中加入DMF(417mg,5.71mmol),保持-78℃继续搅拌2h。让后向该混合物中加入饱和NH
4Cl溶液和水,并用EA萃取,合并有机相。有机相用饱和食盐水洗涤,无水Na
2SO
4干燥,过滤,滤液减压浓缩所得残留物用硅胶柱层析出花得7-甲酰基-6-甲氧基-2-乙基-1H-吡咯[3,2-c]吡啶-3-碳腈(320mg,产率46.0%)。
1H NMR(400MHz,DMSO-d6)δ12.48(s,1H),10.40(s,1H),8.70(s,1H),4.05(s,3H),2.95(dd,J=15.1,7.6Hz,2H),1.35(dd,J=9.4,1.0Hz,3H).
步骤6:制备7-(4-异丁氧基-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-2-乙基-1H-吡咯[3,2-c]吡啶-3-碳腈
将7-甲酰基-6-甲氧基-2-乙基-1H-吡咯[3,2-c]吡啶-3-碳腈(74mg,0.27mmol)和3-异丁氧基-4-(1-甲基哌啶-4-基)苯-1,2-二胺(92mg,0.40mmol)溶于DMF(5mL)中,该混合物室温搅拌20分钟。然后加入Na
2S
2O
5(203mg,1.07mmol),并将混合物在90℃搅拌4h。TLC显示原料转化完全,将反应液倒入冰水中,有固体析出,过滤,滤饼用水洗,收集固体真空干燥得7-(4-异丁氧基-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-2-乙基-1H-吡咯[3,2-c]吡啶-3-碳腈(70mg,产率53.3%)。
MS(m/z):487.5[M+H]
+
步骤7:制备化合物C060
将7-(4-异丁氧基-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-2-乙基-1H-吡咯[3,2-c]吡啶-3-碳腈(70mg,0.14mmol)和NaI(43mg,0.29mmol)溶于乙腈(6mL)中,然后加入TMCS(31mg,0.29mmol)。该混合物室温搅拌3h。反应结束后,减压浓缩所得残留物用制备大板纯化(二氯甲烷:甲醇=10:1)得化合物C060(20.6mg,产率31.2%)。
LCMS(ESI)m/z:473.3[M+H]
+
1H NMR(400MHz,DMSO-d6)δ14.15(s,1H),12.42(s,1H),8.27(s,1H),8.10(s,1H),7.35(d,J=7.2Hz,1H),7.04(d,J=7.9Hz,1H),6.84(d,J=8.4Hz,1H),6.47(d,J=8.4Hz,1H),4.43(s,1H),4.15–3.99(m,1H),3.05-2.91(m,4H),2.41(dd,J=7.4,3.3Hz,1H),2.13(dt,J=13.0,6.8Hz,4H),1.77-1.72(m,2H),1.65–1.51(m,2H),1.37(t,J=7.6Hz,2H),1.11(dd,J=9.4,6.8Hz,6H),0.73(t,J=7.6Hz,1H).
实施例28:制备化合物C061
步骤1:制备3-溴-2-甲氧基-5-(3-甲基-1-丁炔基)-4-氨基吡啶
将化合物3-溴-5碘-2-甲氧基-4-氨基吡啶(5g,15.20mmol)溶于四氢呋喃(50mL)和三乙胺(6.15g,60.80mmol)的溶液中,依次加入碘化亚铜(50mg,0.3040mmol)和二(三苯基膦)二氯化钯(213.4mg,0.30mmol),置换氮气,然后加入3-甲基-1-丁炔(1.24g,18.24mmol),室温搅拌过夜。反应结束后用加水(50mL),乙酸乙酯萃取,合并有机相。有机相用饱和食盐水洗涤,无水Na
2SO
4干燥,过滤,滤液减压蒸馏所得残留物用硅胶柱层析(石油醚:乙酸乙酯=10:1)纯化得3-溴-2-甲氧基-5-(3-甲基-1-丁炔基)-4-氨基吡啶(2.7g,产率66.3%)。
MS(ESI)m/z:268.9[M+H]
+
步骤2:制备7-溴-6-甲氧基-2-异丙基-1H-吡咯[3,2-c]吡啶
将化合物3-溴-2-甲氧基-5-(3-甲基-1-丁炔基)-4-氨基吡啶(2.5g,9.33mmol)溶解于NMP(40mL)中,加入t-BuOK(2.1g,18.66mmol),反应液在100℃下搅拌1h。反应结束后向混合物中加水,并用1mol/L盐酸调节PH=7,乙酸乙酯萃取,合并有机相。有机相用盐水洗涤,无水Na
2SO
4干燥,过滤,滤液减压浓缩所得残留物用硅胶柱层析(石油醚:乙酸乙酯=10:1)纯化得7-溴-6-甲氧基-2-异丙基-1H-吡咯[3,2-c]吡啶(1.95g,产率77.4%)。
MS(ESI)m/z:270.8[M+H]
+
步骤3:制备7-溴-3-碘-6-甲氧基-2-异丙基-1H-吡咯[3,2-c]吡啶
将化合物7-溴-6-甲氧基-2-异丙基-1H-吡咯[3,2-c]吡啶(1.8g,6.72mmol)溶解于DMSO(35ml)中,在搅拌下缓慢分批加入NIS(1.6g,7.05mmol),该混合物室温搅拌过夜。反应结束后相该混合物中加水(40mL),乙酸乙酯萃取,合并有机相。有机相用盐水洗涤,无水Na
2SO
4干燥,过滤,滤液减压浓缩所得残留物用硅胶柱层析(石油醚:乙酸乙酯=10:1)得7-溴-3-碘-6-甲氧基-2-异丙基-1H-吡咯[3,2-c]吡啶(2.0g,产率75.5%)。
MS(ESI)m/z:395.0[M+H]
+
步骤4:制备7-溴-6-甲氧基-2-异丙基-3-氰基-1H-吡咯[3,2-c]吡啶
在氮气保护下,将氰化锌(0.7g,5.84mmol)和加入四(三苯基膦)钯(1.35g,1.17mmol)加入到化合物7-溴-3-碘-6-甲氧基-2-异丙基-1H-吡咯[3,2-c]吡啶(2.32g,5.84mmol)的DMF(80mL)溶液中,并在80℃下搅拌0.5h。反应结束后向反应液中加水有固体析出,布氏漏斗抽滤,收集滤饼,滤饼用硅胶柱层析(石油醚:乙酸乙酯=5:1)纯化得7-溴-6-甲氧基-2-异丙基-3-氰基-1H-吡咯[3,2-c]吡啶(1.6g,产率92.9%)。
MS(m/z):295.8[M+H]
+
步骤5:制备7-甲酰基-6-甲氧基-2-异丙基-1H-吡咯[3,2-c]吡啶-3-碳腈
将7-溴-6-甲氧基-2-异丙基-3-氰基-1H-吡咯[3,2-c]吡啶(600mg,2.04mmol)溶解于四氢呋喃(30ml)中,在0℃下加入正丁基锂(2.5ml),搅拌0.5h。降温至-78℃,向反应液中加入DMF(600mg,8.16mmol),保持-78℃搅拌2h。反应结束后加入饱和氯化铵溶液淬灭反应,乙酸乙酯萃取,合并有机相。有机相用盐水洗涤,无水Na
2SO
4干燥,过滤,滤液减压浓缩所得残留物用硅胶柱层析(石油醚:乙酸乙酯=5:1)得7-甲酰基-6-甲氧基-2-异丙基-1H-吡咯[3,2-c]吡啶-3-碳腈(450mg,产率90.8%)。
MS(m/z):244.3[M+H]
+
步骤6:制备7-(4-丙氧基-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-2-异丙基-1H-吡咯[3,2-c]吡啶-3-碳腈
将7-甲酰基-6-甲氧基-2-异丙基-1H-吡咯[3,2-c]吡啶-3-碳腈(100mg,0.36mmol)和3-丙氧基-4-(1-甲基哌啶-4-基)苯-1,2-二胺(180mg,0.72mmol)溶解在DMF中,室温搅拌20分钟。然后向反应液中加入焦亚硫酸钠(275mg,1.44mmol),并在90℃搅拌4h。反应结束后真空浓缩得7-(4-异丁氧基-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-2-异丙基-1H-吡咯[3,2-c]吡啶-3-碳腈(170mg,产率94.4%)。
LC\\MS(ESI)m/z:487.4[M+H]
+
步骤7:制备化合物C061
将7-(4-丙氧基-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-2-异丙基-1H-吡咯[3,2-c]吡啶-3-碳腈(170mg,0.36mmol)溶解在乙腈(18ml)中,加入碘化钠(108mg,0.72mmol)和TMCS(78mg,0.72mmol),室温搅拌3h。反应结束后,将反应液减压浓缩所得残留物HPLC制备纯化得化合物C061(1mg,产率0.6%)。
LCMS(ESI)m/z:473.2[M+H]
+
1H NMR(400MHz,DMSO-d6)δ12.49(s,1H),8.12(s,1H),7.62–7.48(m,1H),7.39(d,J=8.3Hz,1H),7.00(d,J=7.8Hz,1H),6.55(s,1H),4.47(d,J=6.4Hz,2H),2.77(br,1H),2.49(s,3H),1.99-1.90(m,4H),1.46–1.30(m,6H),1.24–1.15(m,4H),1.10(d,J=6.7Hz,6H).
实施例29:制备化合物C062
步骤1:制备3-溴-2-甲氧基吡啶-4-胺
在0℃环境下,将NBS(28.7g,161.3mmol)缓慢加入2-甲氧基吡啶-4-胺(20g,161.3mmol)的二氯甲烷(200mL)溶液中。撤去冰浴,反应液在室温下搅拌2h。TLC(石油醚/乙酸乙酯=3/1)显示反应结束。反应液直接浓缩至干燥得粗品,粗品通过快速柱层析(石油醚/乙酸乙酯=6/1)纯化得到3-溴-2-甲氧基吡啶-4-胺(25g,产率76.7%)。
步骤2:制备3-溴-5-碘-2-甲氧基吡啶-4-胺
室温下,将NIS(24.4g,108.37mmol)分批加入到3-溴-2-甲氧基吡啶-4-胺(20g,98.52mmol)的乙腈(200mL)和乙酸(20mL)溶液中。反应液在室温下搅拌16h。TLC(石油醚/乙酸乙酯=20/1)显示反应结束。将反应液浓缩后,剩余物再用乙酸乙酯(300mL)溶解。该溶液用水洗涤,无水硫酸钠干燥,浓缩得粗品。粗品通过快速柱层析(石油醚/乙酸乙酯=20/1)纯化得到3-溴-5-碘-2-甲氧基吡啶-4-胺(30g,产率92.8%)。
步骤3:制备3-溴-5-(环丙炔基)-2-甲氧基吡啶-4-胺
在室温下,将3-溴-5-碘-2-甲氧基吡啶-4-胺(10g,30.40mmol),三乙胺(12.3g,121.60mmol),碘化亚铜(115mg,0.61mmol)和双三苯基磷二氯化钯(425mg,0.61mmol)加入THF(100mL)溶液中,氮气置换三次,在氮气保护下加入乙炔环丙烷(2.0g,30.40mmol)。反应液在室温下搅拌16h。TLC(石油醚/乙酸乙酯=20/1)检测反应结束。将反应液倒入水(100mL)中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和氯化铵水溶液洗涤,无水硫酸钠干燥,抽滤,浓缩得粗品。粗品通过快速柱层析(石油醚/乙酸乙酯=7/1)纯化得到3-溴-5-(环丙炔基)-2-甲氧基吡啶-4-胺(7.3g,产率90.1%)。
MS m/z:269.0[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ7.78(s,1H),6.06(s,2H),3.83(s,3H),1.58(ddd,J=13.2,6.6,4.1,1H),0.88(ddd,J=11.3,5.2,2.9,2H),0.84–0.78(m,2H).
步骤4:制备7-溴-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶
将3-溴-5-(环丙炔基)-2-甲氧基吡啶-4-胺(7.3g,27.34mmol)溶于甲苯(80ml)中,然后加入三溴化铟(4.8g,13.67mmol),氮气置换三次,在氮气环境下升温到125℃,反应液在此温度下搅拌2h。TLC(石油醚/二氯甲烷=1/1)检测反应结束。反应液浓缩得粗品,将粗品通过快速柱层析(石油醚/二氯甲烷=2/1)纯化得到7-溴-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶(830mg,产率11.5%)。
MS(m/z):266.9[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),8.18(s,1H),6.12(d,J=1.7,1H),3.89(s,3H),2.01(d,J=16.5,1H),1.02–0.92(m,2H,),0.81–0.72(m,2H).
步骤5:制备7-溴-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳醛
将三氯氧磷(4.13g,26.95mmol)溶于N,N-二甲基甲酰胺(30mL)溶液中,在0℃下搅拌反应10min,然后将化合物7-溴-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶(2.4g,8.98mmol)溶于N,N- 二甲基甲酰胺(10mL)溶液中并缓慢滴加到反应体系中,之后在室温下搅拌12h。TLC监测反应结束后,加碳酸钠饱和溶液淬灭,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,减压蒸馏,柱层析纯化(乙酸乙酯:石油醚=1:3),得黄色固体的7-溴-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳醛(2g,产率43.8%)。
MS(m/z):295.0[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),10.17(s,1H),8.73(s,1H),3.94(s,3H),2.68(tt,J=8.6,5.3,1H),1.36–1.28(m,2H),1.24–1.19(m,2H).
步骤6:制备7-溴-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈
将化合物7-溴-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳醛(2g,6.77mmol)溶于N,N-二甲基甲酰胺(30mL)溶液中,加入盐酸羟胺(942mg,13.55mmol),1-丙基磷酸酐的乙酸乙酯溶液(10.9g,33.88mmol)和三乙胺(1.4g,13.55mmol),升温至100℃,反应12h。TLC监测反应结束后,加水淬灭,乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,减压蒸馏,柱层析纯化(乙酸乙酯:石油醚=1:4),得7-溴-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(280mg,产率14.1%)。
MS(m/z):292.0[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ12.18(s,1H,),8.33(s,1H),3.94(s,3H),2.23(ddd,J=10.4,8.5,5.3,1H),1.27–1.23(m,2H),1.22–1.18(m,2H).
步骤7:制备2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈
将7-溴-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(210mg,0.72mmol)溶于四氢呋喃(8mL)溶液中,在-78℃下将正丁基锂(0.9mL,2.16mmol)缓慢滴加到反应体系中,搅拌反应0.5h,然后将N,N-二甲基甲酰胺(210mg,2.88mmol)滴加到反应体系中,之后缓慢升温至0℃,搅拌反应2h。TLC监测反应结束后,加水淬灭,二氯甲烷萃取,合并有机相,饱和食盐水洗涤,减压蒸馏,柱层析纯化(乙酸乙酯:石油醚=1:3),得2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(100mg,产率57.7%)。
MS(m/z):242.0[M+H]
+。
步骤8:制备2-环丙基-6-甲氧基-7-(5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-1H吡咯[3,2-c]吡啶-3-碳腈
将化合物2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(80mg,0.33mmol)和4-(1-甲基哌啶-4-基)苯-1,2-二胺(103mg,0.5mmol)溶于N,N-二甲基甲酰胺(2mL)溶液中,加入焦亚硫酸钠(125mg,0.66mmol),升温至90℃反应4h。TLC监测反应结束后,减压蒸馏,柱层析纯化(甲醇:二氯甲烷=1:9),得2-环丙基-6-甲氧基-7-(5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-1H吡咯[3,2-c]吡啶-3-碳腈(120mg,产率85.4%)。
MS(m/z):427.0[M+H]
+。
步骤9:制备化合物C062
将化合物2-环丙基-6-甲氧基-7-(5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-1H吡咯[3,2-c]吡啶-3-碳腈(100mg,0.23mmol)溶于乙腈溶液(2mL)中,加入三甲基氯硅烷(75mg,0.69mmol)和碘化钠(100mg,0.69mmol),室温搅拌反应2h。TLC监测反应结束后,制备纯化得化合物C062(69mg,产率71.3%)。
MS(m/z):413.2[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ12.43(s,2H),7.97(d,J=12.8Hz,1H),7.85–7.35(m,2H),7.10(dd,J=8.4,1.5Hz,1H),3.00(d,J=10.7Hz,2H),2.60(d,J=11.3Hz,2H),2.32(s,3H),2.21(s,2H),2.06–1.63(m,4H),1.27–1.18(m,4H).
实施例30:制备化合物C063
步骤1:制备3-溴-2-乙氧基-6-硝基苯胺
将2-氨基-6-溴-3-硝基苯酚(1g,4.29mmol)溶于无水乙腈(30mL)中,然后加入碘乙烷(803mg,5.15mmol),K
2CO
3(1.78mg,12.87mmol)。TLC监测显示反应结束,将反应液倒入水(60mL)中淬灭反应。用乙酸乙酯萃取,合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤,浓缩得粗产品。粗品通过柱层析(石油醚:乙酸乙酯=10:1)纯化得到3-溴-2-乙氧基-6-硝基苯胺(800mg,产率71.6%)。
MS m/z(ESI):[M+H]
+=261.0.
步骤2:制备2-乙氧基-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺
将3-溴-2-甲氧基-6-硝基苯胺(800mg,3.07mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,2,3,6-四氢吡啶(821mg,3.68mmol)溶于1,4-二氧六环(27mL)和H
2O(4mL)中,在氮气保护下,分别加入Pd(dppf)Cl
2(227mg,0.31mmol)和K
2CO
3(1.27g,9.21mmol)。然后再升温到90℃反应2h,得到黑色悬浊液。TLC监测反应结束。然后将反应液倒入水(20mL)中,然后用乙酸乙酯(30mL*3)萃取,合并有机相。有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤浓缩得粗品。粗品通过柱层析(PE:EA=10:1)得到2-乙氧基-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(500mg,产率59%)。
MS m/z(ESI):278.0[M+H]
+;
步骤3:制备3-乙氧基-4-(1-甲基哌啶-4-基)苯-1,2-二胺
将2-乙氧基-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(500mg,1.81mmol)溶于溶剂乙醇(30mL)中,在氮气环境下加入PtO
2(250mg,1.1mmol)。反应体系用氢气置换三次,然后在氢气(15psi)压力下,室温反应16h。TLC显示反应结束。将反应液通过硅藻土层抽滤,甲醇洗涤。滤液浓缩得3-乙氧基-4-(1-甲基哌啶-4-基)苯-1,2-二胺(400mg,产率88.8%)。
MS m/z(ESI):250.0[M+H]
+.
步骤4:制备2-环丙基-7-(4-乙氧基-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈
将3-乙氧基-4-(1-甲基哌啶-4-基)苯-1,2-二胺(400mg,1.61mmol)和2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(386mg,1.61mmol)溶于N,N-二甲基甲酰胺(5mL)溶液中,加入焦亚硫酸钠(1.22mg,6.44mmol),升温至90℃反应16h。TLC监测反应结束后,减压蒸馏,柱层析纯化(MeOH:DCM=1:6),得2-环丙基-7-(4-乙氧基-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(300mg,产率40%)。
MS m/z(ESI):471.0[M+H]
+.
步骤5:制备化合物C063
将2-环丙基-7-(4-乙氧基-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(160mg,0.34mmol)溶于6ml的乙腈,然后加入碘化钠(102mg,0.68mmol),三甲基氯硅烷(73mg,0.68mmol)室温反应3小时。TLC监测反应结束后,送制备纯化得化合物C063 (14.85mg,产率9.6%)。
MS m/z(ESI):[M+H]+=457.2.
1H NMR(400MHz,DMSO-d6)δ12.62(s,1H),12.44(s,1H),11.41(br,1H),9.36(s,1H),8.06(s,1H),7.38(d,J=8.6Hz,1H),6.98(d,J=8.4Hz,1H),4.74(d,J=7.1Hz,2H),3.52(d,J=11.7Hz,2H),3.18(br,2H),2.83(s,3H),2.46-2.26(m,1H),1.99-1.90(s,4H),1.48(t,J=7.0Hz,3H),1.33(d,J=6.3Hz,2H),1.15(s,2H).
实施例31:制备化合物C064
步骤1:制备3-溴-2-异丁氧基-6-硝基苯胺
将1-碘-2-甲基丙烷(622mg,4.38mmol)和K
2CO
3(1.51g,10.94mmol)加入2-氨基-6-溴-3-硝基苯酚(850mg,3.65mmol)的无水乙腈(30mL)溶液中。该混合物室温搅拌16h,TLC监测反应结束,将反应液倒入水(60mL)中,乙酸乙酯(50mL×2)萃取,合并有机相。有机相用饱和食盐水(30mL2)洗涤,无水硫酸钠干燥,抽滤,滤液减压浓缩所得残余物用硅胶柱层析(PE:E
A=10:1)纯化得3-溴-2-异丁氧基-6-硝基苯胺(1g,产率95%)。
MS m/z(ESI):289.1[M+H]
+
步骤2:制备2-异丁氧基-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺
将3-溴-2-异丁氧基-6-硝基苯胺(1g,3.47mmol)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,2,3,6-四氢吡啶(937mg,4.2mmol)溶于1,4-二氧六环(27mL)和H
2O(4mL)中,在氮气保护下,向该混合物中加入Pd(dppf)Cl
2(292mg,0.4mmol)和K
2CO
3(1.45g,10.5mmol)。加料完毕,升温至90℃搅拌2h,TLC监测反应结束。将反应液倒入水(20mL)中,乙酸乙酯(30mL×3)萃取,合并有机相。有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤,滤液减压浓缩所得残余物用硅胶柱层析(PE:E
A=10:1)纯化得2-异丁氧基-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(1g,产率94%)。
MS m/z(ESI):306.1[M+H]
+
步骤3:制备3-异丁氧基-4-(1-甲基哌啶-4-基)苯-1,2-二胺
将2-异丁氧基-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(1g,3.28mmol)溶于乙醇(30mL)中,在氮气环境下加入PtO
2(500mg,2.2mmol)。然后将反应体系用氢气置换三次,在氢气(15psi)氛围下,室温搅拌16h,TLC显示反应结束。将反应液通过硅藻土抽滤,甲醇洗涤滤渣,收集滤液。滤液减压浓缩得3-异丁氧基-4-(1-甲基哌啶-4-基)苯-1,2-二胺(750mg,产率83%)。
MS m/z(ESI):278.2[M+H]
+
步骤4:制备2-环丙基-7-(4-异丁氧基-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳三烯
将3-异丁氧基-4-(1-甲基哌啶-4-基)苯-1,2-二胺(250mg,0.90mmol)和2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(338mg,1.41mmol)溶于N,N-二甲基甲酰胺(5ml)溶液中,加入焦亚硫酸钠(1072mg,5.64mmol),升温至90℃搅拌16h。TLC监测反应结束后,将反应液减压浓缩,所得残余物用硅胶柱层析(MeOH:DCM=1:6)纯化得2-环丙基-7-(4-异丁氧基-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳三烯(100mg,产率22.2%)。
MS m/z(ESI):499.0[M+H]
+
步骤5:制备化合物C064
将碘化钠(60mg,0.40mmol)和三甲基氯硅烷(43mg,0.4mmol)加入2-环丙基-7-(4-异丁氧基-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳三烯(250mg,0.53mmol)的乙腈(6mL)溶液中,室温搅拌3小时。TLC监测反应结束后,将反应液减压浓缩,所得残余物用HPLC制备纯化得化合物C064(10.23mg,产率10%)。
MS m/z(ESI):485.3[M+H]
+
1H NMR(400MHz,DMSO-d6)δ12.62(s,1H),12.48(s,1H),11.24(s,1H),9.36(s,1H),8.07(s,1H),7.32(d,J=8.3Hz,1H),6.98(d,J=7.6Hz,1H),4.44(d,J=6.3Hz,2H),3.52(d,J=11.6Hz,2H),3.12(s,2H),2.84(s,3H),2.66(s,1H),2.32(s,1H),2.22–2.12(m,1H),1.94(s,4H),1.30(d,J=7.5Hz,2H),1.12(d,J=6.7Hz,7H).
实施例32:制备化合物C065
步骤1:制备1-(溴甲基)-1-甲基环丙烷
将1-(羟甲基)-1-甲基环丙烷(1.0g,7.18mmol)和CBr
4(5.4g,16.25mmol)溶于二氯甲烷(30mL)中,氮气保护下,在0℃加入PPh
3(4.3g,16.25mmol)。加料完毕恢复至室温并继续搅拌3h。TLC检测反应原料消失,所得的反应液不做任何处理直接应用于下一步反应。
步骤2:制备3-溴-2-((1-甲基环丙基)甲氧基)-6-硝基苯胺
将碳酸钾(4.8g,34.83mmol)加入2-氨基-6-溴-3-硝基苯酚(3.0g,12.77mmol)的乙腈(30mL)溶液中,室温搅拌20分钟,然年在氮气保护下,向反应液中缓慢滴加步骤1所得混合溶液。滴加完毕,升温至80℃搅拌16h。冷却至室温,硅藻土过滤,收集滤液,滤液减压浓缩,所得残留物用硅胶柱层析(EA/PE 0%~20%)分离得3-溴-2-((1-甲基环丙基)甲氧基)-6-硝基苯胺(1.3g,产率37%)。
MS:(ESI)m/z:303.2[M+H]
+
步骤3:制备2-((1-甲基环丙基)甲氧基)-6-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧苯硼-2-基)苯胺
将3-溴-2-((1-甲基环丙基)甲氧基)-6-硝基苯胺(344mg,1.27mmol)溶解于1,4-二氧六环(20mL)中,再加入(Bpin)
2(3.3g,12.96mmol)、Pd(dppf)Cl
2(316mg,0.43mmol)和KOAc(1.3g,12.96mmol),氮气保护下升温至90℃搅拌16h。反应完全后,用乙酸乙酯萃取,合并有机相。有机相依次水和饱和盐水洗涤,无水硫酸钠干燥,过滤并浓缩,所得的粗产品用硅胶柱层析(EA/PE0%~10%)纯化得2-((1-甲基环丙基)甲氧基)-6-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)苯胺(270mg,产率61.1%)。
MS:(ESI)m/z:349.4[M+H]
+
步骤4:制备3-(1-乙基-1,2,3,6-四氢吡啶-4-基)-2-((1-甲基环丙基)甲氧基)-6-硝基苯胺
氮气保护下,将1-乙基-1,2,3,6-四氢吡啶-4-三氟甲烷磺酸酯(894mg,3.45mmol)、Pd(dppf)Cl
2(252mg,0.35mmol)、碳酸钾(1.4g,10.35mmol)和水(2mL)加入到3-(1-乙基-1,2,3,6-四氢吡啶-4-基)-2-((1-甲基环丙基)甲氧基)-6-硝基苯胺(270mg,0.80mmol)的1,4-二氧六环(18mL)溶液中中,升温至90摄氏度搅拌2h。反应冷却至室温,过滤,收集滤液并浓缩,所得的粗产品用硅胶柱层析(EA/PE 0%~100%)得3-(1-乙基-1,2,3,6-四氢吡啶-4-基)-2-((1-甲基环丙基)甲氧基)-6-硝基苯胺(348mg,产率30%)。
MS:(ESI)m/z:332.4[M+H]
+
步骤5:制备4-(1-乙基哌啶-4-基)-3-((1-甲基环丙基)甲氧基)苯-1,2-二胺
3-(1-乙基-1,2,3,6-四氢吡啶-4-基)-2-((1-甲基环丙基)甲氧基)-6-硝基苯胺(249mg,0.80mmol)溶解于乙醇(15mL)中,加入二氧化铂(183mg),氢气氛围下,加热至50℃搅拌20h。反应冷却至室温,硅藻土过滤,收集滤液并减压浓缩得4-(1-乙基哌啶-4-基)-3-((1-甲基环丙基)甲氧基)苯-1,2-二胺(167mg,产率68.9%)。
MS:(ESI)m/z:304.2[M+H]
+
步骤6:制备2-环丙基-7-(6-(1-乙基哌啶-4-基)-7-((1-甲基环丙基)甲氧基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈
将4-(1-乙基哌啶-4-基)-3-((1-甲基环丙基)甲氧基)苯-1,2-二胺(167mg,0.55mmol)和2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(132mg,0.55mmol)加入无水DMF(10mL)中,该混合物90搅拌20分钟后,再加入焦亚硫酸钠(418mg,2.20mmol)。然后在氮气保护下,90℃继续搅拌2小时。反应冷却至室温,乙酸乙酯萃取,合并有机相。有机相依次用水和饱和盐水洗涤,无水硫酸钠干燥,过滤浓缩得2-环丙基-7-(6-(1-乙基哌啶-4-基)-7-((1-甲基环丙基)甲氧基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(278mg,产率96.5%)。
LC-MS:(ESI)m/z:525.5[M+H]
+;
步骤7:制备化合物C065
2-环丙基-7-(6-(1-乙基哌啶-4-基)-7-((1-甲基环丙基)甲氧基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(278mg,0.53mmol)、TMSCl(115mg,1.06mmol)、NaI(159mg,1.06mmol)和乙腈(4.0mL)的混合溶液,在氮气保护下,室温搅拌2h。反应结束后,乙酸乙酯萃取3次,合并有机相,并依次通过水和饱和盐水洗,无水硫酸钠干燥,过滤并浓缩,所得的粗产品用HPLC制备得化合物C065(20mg,产率7%)。
MS(ESI)m/z:511.5[M+H]
+
1H NMR(400MHz,DMSO-d6)δ12.64(s,1H),9.33(s,1H),8.06(s,1H),7.40(d,J=8.3Hz,1H),7.00(d,J=8.4Hz,1H),4.42(s,2H),3.62(d,J=11.3Hz,3H),3.24–3.14(m,3H),3.08(M,2H),2.40–2.26(m,1H),2.07–1.86(m,4H),1.36(s,3H),1.34–1.21(m,5H),1.21–1.12(m,2H),0.65(t,J=4.5Hz,2H),0.47(t,J=4.7Hz,2H).
实施例33:制备化合物C066
1.制备(1-氟环丙基)4-甲基苯磺酸甲酯
步骤1:制备(1-氟环丙基)甲醇
在0℃和氮气保护下,将四氢铝锂(110g,110mmol)缓慢加入1-氟环丙烷-1-羧酸(10.4g,100mmol)的THF(100mL)溶液中。撤去冰浴,反应液在室温下搅拌3h。TLC(二氯甲烷/甲醇=10/1)显示反应结束。在反应液中加入十水合硫酸钠(30g)进行淬灭并过滤,将滤液直接浓缩得到(1-氟环丙基)甲醇(9g,产率100%)。
1H NMR(400MHz,DMSO-d6)δ4.98(t,J=5.9Hz,1H),3.65(d,J=5.9Hz,1H),3.35–3.30(m,1H),0.92(dt,J=13.5,6.5Hz,2H),0.75–0.58(m,2H).
步骤2:制备(1-氟环丙基)4-甲基苯磺酸甲酯
在0℃下,将TsCl(21g,110mmol)缓慢加入(1-氟环丙基)甲醇(9g,100mmol)的超干的二氯甲烷(90mL)溶液中。撤去冰浴,反应液在室温下搅拌16h。TLC(石油醚/乙酸乙酯=5/1)显示反应结束。将反应液浓缩得粗品。粗品通过快速柱层析(石油醚/乙酸乙酯=5/1)纯化得到(1-氟环丙基)4-甲基苯磺酸甲酯(10g,产率41.7%)。
1H NMR(400MHz,DMSO-d6)δ7.81(d,J=8.3Hz,2H),7.49(d,J=8.0Hz,2H),4.39(d,J=22.7Hz,2H),2.43(s,3H),1.06(dt,J=18.3,7.1Hz,2H),0.78(dt,J=14.8,7.2Hz,2H)。
2.制备化合物C066
步骤1:制备3-氟-2-硝基苯胺
在室温下,将3-氟-2-硝基苯胺(40g,251.57mmol)溶于氨甲醇溶液(200mL)中,室温反应48小时。LC-MS显示反应结束后,向反应液中加入水(300mL),所得溶液用二氯甲烷萃取。合并的有机萃取液用盐水(100ml)洗涤,无水硫酸钠干燥,在减压下过滤后浓缩溶剂得到混合物。向混合物中加入石油醚(200mL)有红色固体析出,将混合物过滤得3-氟-2-硝基苯胺(28g,产率70%)。
MS m/z(ESI):157.0[M+H]
+。
步骤2:制备4-溴-3-氟-2-硝基苯胺
在500mL圆底烧瓶中,将3-氟-2-硝基苯胺(28g,179.48mmol)溶于无水N,N-二甲基甲酰胺(300mL)中,降至0℃加入NBS(31.8g,179.48mmol)搅拌30分钟,然后再升温到0℃反应2小时。LC-MS显示反应结束后,然后将反应液倒入水(200mL)中,然后用乙酸乙酯(100mL*2)萃取,合并有机相。有机相用饱和食盐水(50mL)洗涤,再用饱和氯化锂水溶液洗涤,无水硫酸钠干燥,抽滤浓缩得4-溴-3-氟-2-硝基苯胺(28g,产率99.8%)。
MS m/z(ESI):234.9[M+H]
+
步骤3:制备叔丁基(4-溴-3-氟-2-硝基苯基)(叔丁氧羰基)氨基甲酸酯
在500mL圆底烧瓶中,将4-溴-3-氟-2-硝基苯胺(24g,102.1mmol),溶于无水四氢呋喃溶液(250mL),再加入TEA(20.67g,204.2mmol),DMAP(1.25g,10.2mmol),(Boc)
2O(44.57g,204.2mmol)室温下搅拌5h。LC-MS显示反应结束后,将反应液倒入水(200mL)中,然后用乙酸乙酯(100mL*2)萃取,合并有机相。有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤浓缩得粗品,粗品通过柱层析(石油醚:乙酸乙酯=5:1)纯化得叔丁基(4-溴-3-氟-2-硝基苯基)(叔丁氧羰基)氨基甲酸酯(22g,产率91.6%)。
步骤4:制备3-氨基-6-溴-2-硝基苯酚
在500ml三颈烧瓶中,将叔丁基(4-溴-3-氟-2-硝基苯基)(叔丁氧羰基)氨基甲酸酯(15g,64.65mmol)溶于无水DMSO(300mL)中,再滴加氢氧化钾水溶液(37.5g/75mL),升温至100℃搅拌16h。LC-MS显示反应结束后,向反应液中滴加盐酸中和至pH=7,将溶液倒入水中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤浓缩得粗品,粗品通 过柱层析(石油醚:乙酸乙酯=5:1)纯化得3-氨基-6-溴-2-硝基苯酚(5g,产率33.3%)。
MS m/z(ESI):230.9[M+H]
+。
步骤5:制备4-溴-3-((1-氟环丙基)甲氧基)-2-硝基苯胺
在室温下,将3-氨基-6-溴-2-硝基苯酚(2g,8.62mmol)溶于N,N-二甲基甲酰胺(20mL)溶液中,加入(1-氟环丙基)4-甲基苯磺酸甲酯(3.1g,12.9mmol),碳酸钾(2.4g,17.2mmol)和碘化钾(143mg,0.86mmol)。反应液在80℃下搅拌16h。LCMS监测反应结束。将反应液倒入水(200mL)中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,抽滤,浓缩得粗品。粗品通过快速柱层析(石油醚/乙酸乙酯=5/1)纯化得到4-溴-3-((1-氟环丙基)甲氧基)-2-硝基苯胺(1.9g,产率72.5%)。
MS m/z(ESI):304.8[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ7.44(d,J=9.1Hz,1H),6.67(d,J=9.1Hz,1H),6.35(s,2H),4.28(d,J=22.9Hz,2H),1.10(dt,J=18.3,7.0Hz,2H),0.85(dt,J=14.7,7.2Hz,2H).
步骤6:制备3-((1-氟环丙基)甲氧基)-4-(1-甲基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯胺
在100mL圆底烧瓶中,将4-溴-3-((1-氟环丙基)甲氧基)-2-硝基苯胺(1g,3.28mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)-1,2,3,6-四氢吡啶(950mg,4.26mmol)溶于1,4-二氧六环(10mL)和H
2O(2mL)中,在氮气保护下,分别加入Pd(dppf)Cl
2(268mg,0.33mmol)和K
2CO
3(1.36g,9.84mmol)。然后再升温到90℃反应3小时,得到黑红色混悬液。将反应液倒入水(100ml)中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,抽滤,浓缩得粗品。粗品通过快速柱层析(甲醇/二氯甲烷=10/1)纯化得3-((1-氟环丙基)甲氧基)-4-(1-甲基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯胺(760mg,产率72.2%)。
MS m/z(ESI):322.0[M+H]
+。
步骤7:制备3-((1-氟环丙基)甲氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺
在室温下,将3-((1-氟环丙基)甲氧基)-4-(1-甲基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯胺(260mg,0.81mmol)溶于甲醇(5mL)溶液中,加入二氧化铂(52mg),氢气下室温搅拌反应16h。(950mg,黄色固体)。TLC(二氯甲烷/甲醇=10/1)显示反应结束后,将反应液通过硅藻土层抽滤,甲醇洗涤。滤液减压蒸馏得3-((1-氟环丙基)甲氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(200mg,产率84.3%)。
MS m/z(ESI):294.0[M+H]
+。
步骤8:制备2-环丙基-7-(4-((1-氟环丙基)甲氧基)-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-腈
将化合物3-((1-氟环丙基)甲氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(150mg,0.51mmol)溶于N,N-二甲基甲酰胺(2mL)溶液中,加入中间体2-环丙基-7-甲酰基-6-甲氧基-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-碳腈(148mg,0.61mmol)和焦亚硫酸钠(195mg,1.02mmol),升温至90℃,反应3h。TLC监测反应结束后,在反应液中加入少量水(1mL)并调调节pH为7~8,有白色固体析出,过滤并回收滤饼,得2-环丙基-7-(4-((1-氟环丙基)甲氧基)-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-腈(225mg,产率85.8%)。
MS m/z(ESI):515.0[M+H]
+。
步骤9:制备化合物C066
将2-环丙基-7-(4-((1-氟环丙基)甲氧基)-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-腈(300mg,0.58mmol)和NaI(184mg,1.75mmol)溶于乙腈(3mL)中,然后加入三甲基氯硅烷(191mg,1.75mmol)。混合物在室温下搅拌2小时。LCMS监测反应结束后,在反应液中加入少量甲醇并调节pH为7~8,将滤液送制备纯化得化合物C066(45.34mg,产率15.6%)。
MS m/z(ESI):501.20[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ12.44(s,2H),8.04(s,1H),7.38(d,J=8.5Hz,1H),7.06(d,J=8.6Hz,1H),4.86(d,J=23.5Hz,2H),3.14(s,1H),2.90(d,J=11.1Hz,2H),2.33(s,1H),2.21(s,3H),1.99(t, J=9.5Hz,2H),1.79–1.63(m,4H),1.28(d,J=5.8Hz,2H),1.15(dd,J=19.1,6.6Hz,4H),0.89(q,J=7.7Hz,2H).
实施例34:制备化合物C067
步骤1:制备3-溴-2-(2,2-二氟乙氧基)-6-硝基苯胺
将2-氨基-6-溴-3-硝基苯酚(850mg,3.65mmol)溶于无水乙腈(30mL)中,然后加入1,1-二氟-2-碘乙烷(841mg,4.38mmol),K
2CO
3(1.51g,10.94mmol)。TLC监测显示反应结束,将反应液倒入水(60mL)中淬灭反应。用乙酸乙酯萃取,合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤,浓缩得粗产品。粗品通过柱层析(PE:EA=10:1)纯化得到3-溴-2-(2,2-二氟乙氧基)-6-硝基苯胺(1g,3.37mmol,产率92.3%)。
MS m/z(ESI):297.1.[M+H]
+
步骤2:制备2-(2,2-二氟乙氧基)-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺
将3-溴-2-(2,2-二氟乙氧基)-6-硝基苯胺(1g,3.37mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,2,3,6-四氢吡啶(914mg,4.1mmol)溶于1,4-二氧六环(27mL)和H
2O(4mL)中,在氮气保护下,分别加入Pd(dppf)Cl
2(249mg,0.34mmol)和K
2CO
3(1.39g,10.1mmol)。然后再升温到90℃反应2h,得到黑色悬浊液。TLC监测反应结束。然后将反应液倒入水中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤浓缩得粗品。粗品通过柱层析(PE:EA=10:1)得到2-(2,2-二氟乙氧基)-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(1g,产率94.7%)。
MS m/z(ESI):314.0[M+H]
+.
步骤3:制备3-(2,2-二氟乙氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺
将2-(2,2-二氟乙氧基)3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-6-硝基苯胺(1g,3.19mmol)溶于溶剂乙醇(30mL)中,在氮气环境下加入PtO
2(500mg,2.2mmol)。反应体系用氢气置换三次,然后在氢气(15psi)压力下,室温反应16h。TLC显示反应结束。将反应液通过硅藻土层抽滤,甲醇洗涤。滤液浓缩得3-(2,2-二氟乙氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(750mg,产率82.4%)。
MS m/z(ESI):286.0[M+H]
+.
步骤4:制备2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-腈
将3-(2,2-二氟乙氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(250mg,0.88mmol)和2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(338mg,1.41mmol)溶于N,N-二甲基甲酰胺(5mL)溶液中,加入焦亚硫酸钠(1.07g,5.64mmol),升温至90℃反应16h。TLC监测反应结束后,减压蒸馏,柱层析纯化(MeOH:DCM=1:6),得2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-腈(100mg,产率22.7%)。
MS m/z(ESI):507.0[M+H]
+.
步骤5:制备化合物C067
2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H- 吡咯[3,2-c]吡啶-3-腈(120mg,0.24mmol)溶于乙腈(6mL),然后加入碘化钠(72mg,0.48mmol),三甲基氯硅烷(51.8mg,0.48mmol)室温反应3h。TLC监测反应结束后,送制备纯化得化合物C067(4.58mg,产率3.9%)。
MS m/z(ESI):493.3[M+H]
+.
1H NMR(400MHz,DMSO-d6)δ12.66(s,1H),12.58(s,1H),11.18(s,1H),9.39(s,1H),8.07(s,1H),7.45(d,J=8.2Hz,1H),7.01(d,J=8.5Hz,1H),6.50(t,J=54.6Hz,1H),4.98(dd,J=15.4,11.9Hz,2H),3.54(d,J=11.4Hz,2H),3.12(s,2H),2.84(s,3H),2.33(s,1H),1.99-1.89(m,4H),1.27(dd,J=8.3,3.7Hz,2H),1.23-1.17(m,2H).
实施例35:制备化合物C068
步骤1:制备8-甲基-8-氮杂双环[3.2.1]oct-2-烯-3-基三氟甲烷磺酸酯
3-甲基-3-氮杂双环[3.2.1]辛烷-8-酮(1.0g,7.18mmol)溶于无水四氢呋喃(20mL)中,氮气保护下降温至-50℃,加入1.0M二(三甲基硅基)氨基锂得四氢呋喃溶液(8.0mL,7.90mmol),并在该温度搅拌1h。然后向反应体系中加入N-苯基双(三氟甲烷磺酰)亚胺(2.8g,7.90mmol),恢复至室温继续搅拌1h。反应完全后,用饱和氯化铵淬灭,乙酸乙酯萃取,合并有机相,并依次用水和饱和盐水洗涤,无水硫酸钠干燥,过滤并浓缩,所得的残留物用硅胶柱层析(PE:EA=1/1)得到8-甲基-8-氮杂双环[3.2.1]oct-2-烯-3-基三氟甲烷磺酸酯(800mg,产率41%)。
MS:(ESI)m/z:272.0[M+H]
+
步骤2:制备2-(2,2-二氟乙氧基)-6-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)苯胺
将联硼酸频那醇酯(3.8g,14.80mmol)、Pd(dppf)Cl
2(293mg,0.40mmol)和乙酸钾(1.8g,18.50mmol)加入4-溴-3-(2,2-二氟乙氧基)-2-硝基苯胺(1.1g,3.70mmol)的无水1,4-二氧六环(20mL)溶液中,氮气保护下,90℃搅拌16h。反应完全后,减压浓缩所得残留物用水溶解,并用乙酸乙酯萃取,合并有机相。有机相依次用水和饱和盐水洗涤,无水硫酸钠干燥,过滤并浓缩,所得的残留物用硅胶柱层析(EA/PE 0%~50%)得3-(2,2-二氟乙氧基)-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧苯硼酸-2-基)苯胺(1.2g,产率94.5%)。
MS(ESI)m/z:345.2[M+H]
+
步骤3:制备3-(2,2-二氟乙氧基)-4-(8-甲基-8-氮杂双环[3.2.1]oct-2-烯-3-基)-2-硝基苯胺
将8-甲基-8-氮杂双环[3.2.1]oct-2-烯-3-基三氟甲烷磺酸酯(344mg,1.27mmol)和3-(2,2-二氟乙氧基)-2-硝基-4-(4,4,5,5-四甲基-1,3,2-二氧苯硼酸-2-基)苯胺(437mg,1.27mmol)溶于1,4-二氧六环(9.0mL)中,再加入Pd(dppf)Cl
2(95mg,0.13mmol)、碳酸钾(527mg,3.81mmol)和水(1.0mL),升温至90℃反应2h。反应完全后,乙酸乙酯萃取,合并有机相,并依次用水和饱和盐水洗涤,无水硫酸钠干燥,过滤并浓缩,所得的粗产品用硅胶制备大板(DCM:MeOH=10:1)得3-(2,2-二氟乙氧基)-4-(8-甲基-8-氮杂双环[3.2.1]oct-2-烯-3-基)-2-硝基苯胺(168mg,产率39%)。
MS(ESI)m/z:340.3[M+H]
+
步骤4:制备3-(2,2-二氟乙氧基)-4-(8-甲基-8-氮杂双环[3.2.1]辛烷-3-基)苯-1,2-二胺
将二氧化铂(270mg)加入3-(2,2-二氟乙氧基)-4-(8-甲基-8-氮杂双环[3.2.1]oct-2-烯-3-基)- 2-硝基苯胺(270mg,0.80mmol)的乙醇(15mL)中。反应体系置换氢气后,加热至50℃搅拌20h。反应完全后,过滤并浓缩,得3-(2,2-二氟乙氧基)-4-(8-甲基-8-氮杂双环[3.2.1]辛烷-3-基)苯-1,2-二胺(247mg,产率99.1%)。
MS(ESI)m/z:312.4[M+H]
+
步骤5:2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(8-甲基-8-氮杂双环[3.2.1]辛烷-3-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-腈
将3-(2,2-二氟乙氧基)-4-(8-甲基-8-氮杂双环[3.2.1]辛烷-3-基)苯-1,2-二胺(247mg,0.80mmol)和2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(192mg,0.80mmol)溶于无水DMF(10mL)中。该混合物90℃搅拌20分钟后,加入焦亚硫酸钠(608mg,3.20mmol),并在氮气保护,90℃搅拌3h。反应结束,向反应液中加入水稀释,并用乙酸乙酯萃取,合并有机相。有机相依次用水和饱和盐水洗涤,无水硫酸钠干燥,过滤浓缩得2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(8-甲基-8-氮杂双环[3.2.1]辛烷-3-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-腈(255mg,产率60.0%)。
MS(ESI)m/z:533.5[M+H]
+
步骤5:制备化合物C068
氮气保护先,向2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(8-甲基-8-氮杂双环[3.2.1]辛烷-3-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-腈(255mg,0.48mmol)的乙腈(5.0mL)溶液中,依次加入TMSCl(104mg,0.96mmol)和NaI(144mg,0.96mmol)。该混合物室温搅拌2h。反应结束后,向反应液体中加入水,并用乙酸乙酯萃取,合并有机相。有机相用饱和盐水洗,无水硫酸钠干燥,过滤,滤液减压浓缩,所得粗产品通过HPLC制备得化合物C068(14.42mg,产率6%)。
MS(ESI)m/z:519.3[M+H]
+
1H NMR(400MHz,DMSO-d6)δ12.62(br,1H),11.15(s,1H),9.50(s,1H),8.06(s,1H),7.43(d,J=8.4Hz,1H),7.18(dd,J=70.5,29.8Hz,1H),6.53(tt,J=54.9,3.4Hz,1H),4.99(t,J=14.2Hz,2H),3.91(s,2H),3.67–3.56(m,1H),2.70(d,J=4.7Hz,3H),2.60–2.52(m,1H),2.40–2.17(m,2H),2.14–1.87(m,4H),1.36–1.12(m,4H).
实施例36:制备化合物C069
步骤1:制备(4-溴-3-((2,2-二氟乙基)氨基)-2-硝基苯基)(叔丁氧基羰基)氨基甲酸叔丁酯
在室温下,将制备叔丁基(4-溴-3-氟-2-硝基苯基)(叔丁氧羰基)氨基甲酸酯2,2-二氟乙胺(454mg,5.6mmol),DIEA(1.8g,13.8mmol)缓慢加入1(2g,4.6mmol)的二甲亚砜(20mL)溶液中。反应液在100℃下搅拌3h。向反应液加入200mL水,用乙酸乙酯(3*50mL)萃取,萃取液直接浓缩至干燥得粗品,粗品通过快速柱层析(PE:EA=5:1)纯化得叔丁基(叔丁氧基羰基)(3-((2,2-二 氟乙基)氨基)-4-(1-甲基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯基)氨基甲酸酯(1.1g,产率48.2%)。
MS(ESI)m/z:341.8[M-Boc-Bu+MeCN]
+。
步骤2:制备叔丁基(叔丁氧基羰基)(3-((2,2-二氟乙基)氨基)-4-(1-甲基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯基)氨基甲酸酯
室温下,将1-甲基-1,2,3,6-四氢吡啶-4-硼酸频哪醇酯(589mg,2.64mmol),Pd(dppf)Cl
2(161mg,0.22mmol),K
2CO
3(911mg,6.6mmol)加入到叔丁基(叔丁氧基羰基)(3-((2,2-二氟乙基)氨基)-4-(1-甲基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯基)氨基甲酸酯(1.1g,2.2mmol)的二氧六环(10mL)和水(2mL)溶液中。反应液在100℃氮气保护下搅拌2h。将反应液浓缩后得到粗品。粗品通过快速柱层析(二氯甲烷:甲醇=5:1)纯化得N1-(2,2-二氟乙基)-6-(1-甲基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯-1,3-二胺(1g,产率88%)。
MS(ESI)m/z:513.3[M+H]
+。
步骤3:制备N1-(2,2-二氟乙基)-6-(1-甲基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯-1,3-二胺
在室温下,将N1-(2,2-二氟乙基)-6-(1-甲基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯-1,3-二胺(1g,产率88%)3(1g,1.95mmol)加入到4M的HCl/dioxane(10mL)溶液中。反应液在室温下搅拌2h。反应液减压蒸馏得到粗品。粗品通过快速柱层析(二氯甲烷:甲醇=10:1)纯化得N1-(2,2-二氟乙基)-6-(1-甲基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯-1,3-二胺(600mg,产率98.4%)。
MS(ESI)m/z:312.9[M+H]
+。
步骤4:制备N1-(2,2-二氟乙基)-6-(1-甲基哌啶-4-基)苯-1,2,3-三胺
将PtO
2(300mg)加入到N1-(2,2-二氟乙基)-6-(1-甲基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯-1,3-二胺(600mg,1.9mmol)的甲醇(30mL)溶液中。反应液在50℃氢气氛围下搅拌16h。反应液通过硅藻土过滤,浓缩滤液得N1-(2,2-二氟乙基)-6-(1-甲基哌啶-4-基)苯-1,2,3-三胺(500mg,产率91.5%)。
MS(ESI)m/z:285.1[M+H]
+。
步骤5:制备2-环丙基-7-(4-((2,2-二氟乙基)氨基)-5-(1-甲基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈
将2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(540mg,2.2mmol),Na
2S
2O
5(680mg,3.6mmol)加入到(500mg,1.8mmol)的DMF(10mL)溶液中,之后在90℃搅拌2h。向反应液加入200mL水,用乙酸乙酯(50mL*3)萃取,合并有机相减压蒸馏,柱层析纯化(二氯甲烷:甲醇=8:1),得N1-(2,2-二氟乙基)-6-(1-甲基哌啶-4-基)苯-1,2,3-三胺6(250mg,产率28.1%)。
MS(ESI)m/z:506.0[M+H]
+。
步骤6:制备化合物C069
将TMSCl(65mg,0.6mmol),NaI(90mg,0.6mmol)加入到N1-(2,2-二氟乙基)-6-(1-甲基哌啶-4-基)苯-1,2,3-三胺(100mg,0.2mmol)的乙腈(2mL)溶液中。反应液减压蒸馏,粗品送制备纯化得化合物C069(26.57mg,产率27.3%)。
MS(ESI)m/z:492.3[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ12.60(s,1H),12.38(s,1H),11.03(s,1H),9.29(s,1H),7.15(s,1H),6.91(d,J=8.6Hz,1H),6.22(t,J=56.4Hz,1H),5.43(s,1H),4.25(s,2H),3.56(d,J=12.0Hz,2H),3.11(d,J=12.1Hz,3H),2.85(d,J=4.6Hz,3H),2.30(s,1H),2.02–1.78(m,4H),1.29–1.21(m,4H).
实施例37:制备化合物C070
步骤1:制备4-溴-3-(2,2-二氟乙氧基)-2-硝基苯胺
室温下,将2-氨基-6-溴-3-硝基苯酚(850mg,3.65mmol)溶于无水乙腈(30mL)中,然后加入1,1-二氟-2-碘乙烷(841mg,4.38mmol),K
2CO
3(1.51g,10.94mmol)。TLC监测反应结束(PE:E
A=5:1)显示反应结束,将反应液倒入水(60mL)中淬灭反应。用乙酸乙酯萃取,合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤,浓缩得粗产品。粗品通过柱层析(PE:E
A=10:1)纯化得4-溴-3-(2,2-二氟乙氧基)-2-硝基苯胺(1g,产率92.3%)。
MS m/z(ESI):297.1[M+H]
+
步骤2:制备4-(4-氨基-2-(2,2-二氟乙氧基)-3-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯
将4-溴-3-(2,2-二氟乙氧基)-2-硝基苯胺(1g,3.37mmol),4-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1.27mg,4.1mmol)溶于1,4-二氧六环(27mL)和H
2O(4mL)中,在氮气保护下,分别加入Pd(dppf)Cl
2(249mg,0.34mmol)和K
2CO
3(1.39g,10.1mmol)。然后再升温到90℃反应2h,得到黑色悬浊液。TLC监测反应结束。然后将反应液倒入水(20mL)中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤浓缩得粗品。粗品通过柱层析(PE:E
A=10:1)得4-(4-氨基-2-(2,2-二氟乙氧基)-3-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1g,产率74%)。
MS m/z(ESI):400.1[M+H]
+
步骤3:制备4-(3,4-二氨基-2-(2,2-二氟乙氧基)苯基)哌啶-1-羧酸叔丁酯
将4-(4-氨基-2-(2,2-二氟乙氧基)-3-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1g,2.51mmol)溶于溶剂乙醇(30mL)中,在氮气环境下加入PtO
2(500mg,2.2mmol)。反应体系用氢气置换三次,然后在氢气(15psi)压力下,50℃反应16h。TLC(DCM/MeOH=10/1)显示反应结束。将反应液通过硅藻土层抽滤,甲醇洗涤。滤液浓缩得4-(3,4-二氨基-2-(2,2-二氟乙氧基)苯基)哌啶-1-羧酸叔丁酯(750mg,产率80%)。
MS m/z(ESI):316.2[M+H]
+
步骤4:制备叔丁基4-(2-(3-氰基-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-4-(2,2-二氟乙氧基)-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸酯
将3-(2,2-二氟乙氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(250mg,0.88mmol)和2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(338mg,1.41mmol)溶于N,N-二甲基甲酰胺(5mL)溶液中,加入焦亚硫酸钠(1.07g,5.64mmol),升温至90℃反应16h。TLC监测反应结束后,反相柱层析纯化(MeCN:H
2O=5:1),得叔丁基4-(2-(3-氰基-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-4-(2,2-二氟乙氧基)-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸酯(600mg,产率:50%)。
MS m/z(ESI):593.0[M+H]
+
步骤5:制备2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈
将叔丁基4-(2-(3-氰基-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-4-(2,2-二氟乙氧基)-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸酯(250mg,0.42mmol)溶于6mL的盐酸1,4-二氧六环,室温反 应10分钟。TLC监测反应结束后,加无水乙醚洗涤得2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(200mg,产率99%)。
MS m/z(ESI):493.1[M+H]
+
步骤6:制备2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(1-(2-羟乙基)哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈
将2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(250mg,0.5mmol)溶于6mL的乙腈,然后加入碘乙醇(123mg,0.82mmol),碳酸钾(89mg,0.82mmol)50℃反应16h。TLC监测反应结束后,乙酸乙酯萃取浓缩得2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(1-(2-羟乙基)哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(200mg,产率84%)。
MS m/z(ESI):537.3[M+H]
+
步骤7:制备化合物C070
将2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(1-(2-羟乙基)哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(200mg,0.42mmol)溶于6mL的乙腈,然后加入碘化钠(123mg,0.82mmol),三甲基氯硅烷(89mg,0.82mmol)45℃反应3h。TLC监测反应结束后,乙酸乙酯萃取浓缩所得残余物,用反相柱层析纯化(MeCN:H
2O=5:1)得化合物C070(49.63mg,产率23.8%)。
MS m/z(ESI):523.1[M+H]
+
1H NMR(400MHz,DMSO-d
6)δ12.66(s,1H),12.59(s,1H),11.19(s,1H),9.24(s,1H),8.07(s,1H),7.46(d,J=8.3Hz,1H),7.00(t,J=12.6Hz,1H),6.64–6.36(m,1H),5.38(s,1H),4.98(t,J=15.2Hz,2H),3.78(s,2H),3.64(d,J=11.2Hz,2H),3.16(d,J=12.2Hz,2H),2.51(s,1H),2.34(s,1H),2.07–1.91(m,5H),1.37–1.12(m,4H).
实施例38:制备化合物C071
步骤1:制备2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-氧基-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-碳腈
将2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(250mg,0.5mmol)溶于6mL的乙腈,然后加入碘化钠(123mg,0.82mmol),三甲基氯硅烷(89mg,0.82mmol)45℃反应3h。TLC监测反应结束后,乙酸乙酯萃取浓缩得2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-氧基-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-碳腈(200mg,产率84%)。
MS m/z(ESI):479.0[M+H]
+
步骤2:制备化合物C071
将2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-氧基-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-碳腈(200mg,0.42mmol)溶于5mL的乙腈和15mL的1,4-二氧六环,然后加入乙酸(26mg,0.42mmol),常温搅拌1h。再加入氰基硼氢化钠(92mg,1.46mmol),40℃反应16h。TLC监测反应结束后,加入氨水调节pH为碱性,乙酸乙酯萃取浓缩所得残余物,经反相纯化,得化合物C071(31.6mg,产率13.8%.)
MS m/z(ESI):549.2[M+H]
+
1H NMR(400MHz,DMSO-d
6)δ12.63(s,1H),12.51(s,1H),11.23(s,1H),8.04(s,1H),7.40(d,J=8.3Hz,1H),7.06(d,J=8.5Hz,1H),6.60–6.33(m,1H),4.88(dd,J=15.3,12.1Hz,2H),4.66(dd,J= 7.8,5.9Hz,2H),4.28(t,J=6.1Hz,2H),3.30–3.17(m,1H),3.06(s,1H),2.88(d,J=11.1Hz,2H),2.77–2.55(m,2H),2.34(s,1H),2.04(s,2H),1.68(s,4H),1.45–1.03(m,4H).
实施例39:制备化合物C072
步骤1:制备4-(3-氨基-4-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯
将5-溴-2-硝基苯胺(5g,23.03mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,2,3,6-四氢吡啶(8.54g,27.64mmol)溶于1,4-二氧六环(100mL)和H
2O(12mL)中,在氮气保护下,分别加入Pd(dppf)Cl
2(1.683g,2.30mmol)和K
2CO
3(9.53g,69.17mmol)。然后再升温到90℃反应2h,得到黑色悬浊液。TLC监测反应结束。将反应液倒入水(20mL)中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,抽滤浓缩得粗品。粗品通过柱层析(PE:E
A=5:1)得到4-(3-氨基-4-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(2.5g,产率50%)。
MS m/z(ESI):264.1[M+H]
+
步骤2:制备4-(3,4-二氨基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯
将4-(3-氨基-4-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(14g,53.23mmol)溶于溶剂乙醇(300mL)中,在氮气环境下加入PtO
2(5g,19.01mmol)。反应体系用氢气置换三次,然后在氢气(15psi)压力下,室温反应16h。TLC(DCM/MeOH=10/1)显示反应结束。将反应液通过硅藻土层抽滤,甲醇洗涤。滤液浓缩得4-(3,4-二氨基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(14g,粗品)。
MS m/z(ESI):290.2[M+H]
+
步骤3:制备4-(3,4-二氨基苯基)哌啶-1-羧酸叔丁酯
将4-(3,4-二氨基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(14g,48.44mmol)溶于溶剂甲醇(300mL)中,在氮气环境下加入Pd/C(5g,17.29mmol)。反应体系用氢气置换三次,然后在氢气(15psi)压力下,室温反应16h。TLC(二氯甲烷/甲醇=10/1)显示反应结束。将反应液通过硅藻土层抽滤,甲醇洗涤。滤液浓缩得4-(3,4-二氨基苯基)哌啶-1-羧酸叔丁酯(12g,粗品)。
MS m/z(ESI):236.2[M+H]
+
步骤4:制备4-(2-(3-氰基-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸叔丁酯
将4-(3,4-二氨基苯基)哌啶-1-羧酸叔丁酯(4g,13.75mmol)和2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(4.95g,20.63mmol)溶于N,N-二甲基甲酰胺(20ml)溶液中,加入焦亚硫酸钠(10.45g,55mmol),升温至90℃反应16h。TLC监测反应结束后,在冰浴下加水析出固体,抽滤得固体。将所得固体经过过反相柱(水:乙腈=5:1)纯化,得4-(2-(3-氰基-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸叔丁酯(3.5g,产率45.1%)。
MS m/z(ESI):457.2[M+H]
+
步骤5:制备2-环丙基-6-甲氧基-7-(5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-1H吡咯[3,2-c]吡啶-3-碳腈
将4-(2-(3-氰基-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸叔丁酯(500mg,0.98mmol)溶于16ml的盐酸1,4-二氧六环,室温反应10分钟。TLC监测反应结束后,加入无水乙醚洗涤抽滤得2-环丙基-6-甲氧基-7-(5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-1H吡咯[3,2-c]吡啶-3-碳腈(400mg,产率99%)。
MS m/z(ESI):413.0[M+H]
+
步骤6:制备2-环丙基-7-(5-(1-乙基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈
将2-环丙基-6-甲氧基-7-(5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-1H吡咯[3,2-c]吡啶-3-碳腈(100mg,0.24mmol)溶于6ml乙腈,再加入碘乙烷(123mg,0.82mmol),碳酸钾(89mg,0.82mmol)80度反应16小时。TLC监测反应结束后,加入无水乙醚洗涤抽滤得2-环丙基-7-(5-(1-乙基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(80mg,产率75%)。
MS m/z(ESI):441.2[M+H]
+
步骤7:制备化合物C072
将2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(1-(2-羟乙基)哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(80mg,0.18mmol)溶于6mL的乙腈,然后加入碘化钠(123mg,0.82mmol),三甲基氯硅烷(89mg,0.82mmol)45度反应3小时。TLC监测反应结束后,乙酸乙酯萃取浓缩得残余物经反相纯化,得化合物C072(22.1mg,产率29%)。
MS m/z(ESI):427.2[M+H]
+
1H NMR(400MHz,DMSO-d
6)δ12.40(br,2H),8.18(s,1H),7.99(s,1H),7.63–7.57(m,2H),7.10(d,J=8.0Hz,1H),3.09(s,2H),2.68(s,1H),2.33(s,1H),2.24–2.10(m,2H),1.84–1.72(m,5H),1.35–1.18(m,5H),1.08(t,J=7.2Hz,3H).
实施例40:制备化合物C073
步骤1:制备化合物C073
室温下,将2-环丙基-6-氧代-7-(5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-碳腈(70mg,0.161mmol)、氧代烷-3-碳醛(21mg,0.242mmol)和醋酸(10mg,0.161mmol)溶于乙腈(3.5mL)和1,4-二氧六环(1mL),混合物在室温下搅拌1小时。氰基硼氢化钠(35mg,0.563mmol)加入反应液中并搅拌4小时。LC-MS监测反应结束后,加入氨水(3mL)调反应液pH为碱性,用乙酸乙酯萃取,合并有机相,有机相干燥浓缩。粗品通过C18柱纯化(乙腈/水,乙腈5~95%,梯度:35%MeCN/65%H
2O)得化合物C073(28.3mg,产率37.5%)。
MS m/z(ESI):469.1[M+H]
+
1H NMR(400MHz,DMSO-d
6)δ12.44(s,2H),7.98(s,1H),7.60(d,J=8.3Hz,1H),7.55(s,1H),7.09(d,J=7.9Hz,1H),4.70–4.65(m,2H),4.28(t,J=6.1Hz,2H),2.87(d,J=10.7Hz,2H),2.66(d,J=7.3Hz,4H),2.33(s,1H),2.05(t,J=11.3Hz,2H),1.77(s,2H),1.67(d,J=9.9Hz,2H),1.29–1.20(m,6H).
实施例41:制备化合物C074
步骤1:制备化合物C074
室温下,将2-环丙基-6-氧代-7-(5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-碳腈(104mg,0.240mmol)、氧代烷-3-碳醛(36mg,0.359mmol)和醋酸(14mg,0.240mmol)溶于乙腈(5.25mL)和1,4-二氧六环(1.5mL),混合物在室温下搅拌1小时。氰基硼氢化钠(53mg,0.810mmol)加入反应液中并于40℃搅拌20小时。LC-MS监测反应结束后,加入氨水(4mL)调反应液pH为碱性,用乙酸乙酯萃取,合并有机相,有机相干燥浓缩。粗品通过高效液相(乙腈/0.1%FA水,乙腈5~95%,梯度:24%~34%MeCN/76%~66%水)得化合物C074(8.08mg,产率6.9%)。
MS m/z(ESI):483.3[M+H]
+
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.21(s,1H),7.99(s,1H),7.64–7.54(m,2H),7.10(d,J=8.1Hz,1H),3.91(d,J=8.7Hz,2H),3.05(d,J=10.5Hz,3H),2.67(s,2H),2.36–2.21(m,4H),1.83(s,2H),1.72(t,J=12.5Hz,4H),1.49(d,J=9.2Hz,3H),1.31–1.12(m,4H).
实施例42:制备化合物C075
步骤1:制备化合物C075
室温下,将2-环丙基-6-氧代-7-(5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-碳腈(80mg,0.184mmol)、tetrahydro-2H-pyran-4-carbaldehyde(32mg,0.276mmol)和醋酸(11mg,0.184mmol)溶于乙腈(10mL)和1,4-二氧六环(5mL),混合物在室温下搅拌1h。氰基硼氢化钠(41mg,0.645mmol)加入反应液中并于40℃搅拌16h。LC-MS监测反应结束后,加入氨水(4mL)调反应液pH为碱性,用乙酸乙酯萃取,合并有机相,有机相干燥浓缩。粗品通过高效液相(乙腈/0.1%FA水,乙腈5~95%,梯度:24%~34%MeCN/76%~66%水)得到得化合物C075(21.47mg,产率10.6%)。
MS m/z(ESI):497.2[M+H]
+;
1H NMR(400MHz,DMSO-d
6)δ12.41(br,2H),8.21(s,1H),7.99(s,1H),7.64–7.54(m,2H),7.10(d,J=8.1Hz,1H),3.91(d,J=8.7Hz,2H),3.05(d,J=10.5Hz,2H),2.72–2.52(s,2H),2.49–2.42(s,2H),2.36–2.21(m,2H),2.12–2.02(m,3H),1.92–1.60(s,6H),1.31–1.12(m,6H).
实施例43:制备化合物C076
步骤1:合成4-溴-3-(环丙基甲氧基)-2-硝基苯胺
将碳酸钾(2.7g,19.31mmol)加到3-氨基-6-溴-2-硝基苯酚(1.5g,6.44mmol)的MeCN(45mL)溶液中,该混合物在室温下搅拌30min。然后将(碘甲基)环丙烷(1.4g,7.72mmol)加到上 述反应液中,混合物在80℃下反应16个小时。反应结束后,向反应混合物中加H
2O(50mL)。用乙酸乙酯(3x30mL)萃取混合物。用盐水洗涤合并的有机提取物,然后干燥(无水Na
2SO
4)并减压浓缩。快速色谱法(SiO
2,10-50%乙酸乙酯-石油醚)得到化合物4-溴-3-(环丙基甲氧基)-2-硝基苯胺(1.8g,产率97.3%)。
MS m/z:289.2[M+H]
+;
步骤2:合成3-(环丙基甲氧基)-4-(1-乙基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯胺
将K
2CO
3(722mg,5.22mmol)的水溶液(3mL)加到4-溴-3-(环丙基甲氧基)-2-硝基苯胺(500mg,1.74mmol)和1-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧苯硼酸-2-基)-1,2,3,6-四氢吡啶(826mg,3.48mmol)的1,4二氧六环(27mL)溶液中,然后在N
2下添加Pd(dppf)Cl
2(127mg,0.17mmol),反应混合物在90℃下搅拌2小时。反应结束后,加H
2O(30mL)。用乙酸乙酯萃取混合物。用盐水洗涤合并的有机提取物,然后干燥(无水Na
2SO
4)并减压浓缩。通过快速色谱法(SiO
2,0-10%甲醇-二氯甲烷)纯化得到3-(环丙基甲氧基)-4-(1-乙基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯胺(490mg,产率88.8%)。
MS m/z:318.3[M+H]
+;
步骤3:合成3-(环丙基甲氧基)-4-(1-乙基哌啶-4-基)苯-1,2-二胺
将PtO
2(250mg)添加到3-(环丙基甲氧基)-4-(1-乙基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯胺(290mg,0.91mmol)的乙醇(25mL)溶液中,然后在将该混合物在50℃、H
2下搅拌16小时。反应结束后,在减压下过滤并浓缩滤液。通过快速硅胶色谱法(SiO
2,0-10%甲醇-二氯甲烷)纯化粗品得3-(环丙基甲氧基)-4-(1-乙基哌啶-4-基)苯-1,2-二胺(240mg,产率82.8%)。
MS m/z:290.1[M+H]
+;
步骤4:合成2-环丙基-7-(4-(环丙基甲氧基)-5-(1-乙基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈
将3-(环丙基甲氧基)-4-(1-乙基哌啶-4-基)苯-1,2-二胺(240mg,0.83mmol)和int(251mg,1.04mmol)溶于DMF(5mL)中,混合物在室温下搅拌20分钟,然后加入Na
2S
2O
5(631mg,3.32mmol)。将混合物在90v搅拌4小时。TLC显示原料反应完全,将反应液倒入冰水中,用饱和碳酸氢钠溶液调至PH=8,有固体析出,将混合物过滤,滤渣用水洗得到粗产物。通过快速色谱法(SiO2,0-10%甲醇-二氯甲烷)纯化得到2-环丙基-7-(4-(环丙基甲氧基)-5-(1-乙基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈(300mg,产率70.8%)。
MS m/z:511.4[M+H]
+;
步骤5:制备化合物C076
将2-环丙基-7-(4-(环丙基甲氧基)-5-(1-乙基哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈(300mg,0.59mmol)和NaI(176mg,1.17mmol)溶于MeCN(15mL)中,然后加入TMCS(128mg,1.17mmol)。混合物在室温下搅拌16小时。反应结束旋干乙腈得到粗品。粗品通过乙腈打浆纯化得到产物C076(101.80mg,产率34.4%)。
MS m/z:497.1[M+H]
+;
1H NMR(400MHz,DMSO-d
6)δ12.38(s,2H),11.34(s,1H),8.04(s,1H),7.35(d,J=7.2Hz,1H),7.05(d,J=8.6Hz,1H),4.43(s,2H),3.17–3.08(m,1H),3.01(d,J=10.0Hz,2H),2.37(dd,J=14.1,7.0Hz,2H),2.08(s,1H),1.99(s,2H),1.70(s,4H),1.31(d,J=7.3Hz,3H),1.16(s,2H),1.04(t,J=7.1Hz,3H),0.59(d,J=6.7Hz,2H),0.39(d,J=4.5Hz,2H).
实施例44:制备化合物C077
步骤1:制备化合物C077
将2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-氧基-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-碳腈(100mg,0.21mmol)溶于5mL的乙腈和15mL的1,4-二氧六环,然后加入乙酸(13mg,0.21mmol),常温搅拌1h。再加入氰基硼氢化钠(46mg,0.73mmol),40度反应16h。TLC监测反应结束后,加入氨水调节pH为碱性,乙酸乙酯萃取浓缩,所得残余物经反相柱层析纯化(MeCN:H
2O=4:1)纯化,得化合物C077(32.0mg,产率13.8%)。
MS m/z(ESI):507.0[M+H]
+
1H NMR(400MHz,DMSO-d
6)δ12.51(br,2H),11.2(s,1H),9.15(s,1H),8.07(s,1H),7.40(d,J=8.3Hz,1H),7.06(d,J=8.5Hz,1H),6.50–6.36(m,1H),4.88(dd,J=15.3,12.1Hz,2H),3.66(dd,J=7.8,5.9Hz,2H),3.28(t,J=6.1Hz,2H),3.20–3.05(m,4H),2.34(s,1H),2.04(s,4H),1.45–1.03(m,5H).
实施例45:制备化合物C078
步骤1:制备1-(4-溴-2,6-二甲基苯基)-4-甲基哌嗪
在室温下,将二(2-氯乙基)胺盐酸盐(5.8g,30.1mmol),TsOH(7.2g,37.7mmol)缓慢加入4-溴-2,6-二甲基苯胺(5g,25.1mmol)的Xylene(50mL)溶液中。反应液在145℃下搅拌48h。向反应液加入600mL H
2O,用EA(3 x 100mL)萃取,萃取液直接浓缩至干燥得粗品,粗品通过快速柱层析(DCM:MeOH=10:1)纯化得1-(4-溴-2,6-二甲基苯基)-4-甲基哌嗪(2g,产率28.2%)。
LCMS(ESI)m/z:283.0[M+H]
+
步骤2:制备1-(4-溴-2,6-二甲基-3-硝基苯基)-4-甲基哌嗪
室温下,将KNO
2(789mg,7.81mmol)缓慢加入到1-(4-溴-2,6-二甲基苯基)-4-甲基哌嗪(2g,7.1mmol)的H
2SO
4(30mL)溶液中。反应液在0℃下搅拌0.5h。将反应液加入H
2O(200mL)中,用氢氧化钠调节PH=10,用EA(60mL x 3)萃取,将萃取液浓缩后得到粗品。粗品通过快速柱层析(DCM:MeOH=10:1)纯化得1-(4-溴-2,6-二甲基-3-硝基苯基)-4-甲基哌嗪(1.1g,47.3%)。
LCMS(ESI)m/z:328.0[M+H]
+
步骤3:制备N-(3,5-二甲基-4-(4-甲基哌嗪-1-基)-2-硝基苯基)-2,2,2-三氟乙酰胺
在室温下,将1-(4-溴-2,6-二甲基-3-硝基苯基)-4-甲基哌嗪(500mg,1.53mmol)加入到三氟乙酰胺(208mg,1.84mmol),Pd
2(dba)
3(140mg,0.153mmol),Xantphos(180mg,0.31mmol),碳酸铯(1.5g,4.59mmol)的dioxane(10mL)溶液中。反应液在110℃搅拌16h。将反应液浓缩得到粗品。粗品通过快速柱层析(DCM:MeOH=10:1)纯化得N-(3,5-二甲基-4-(4-甲基哌嗪-1-基) -2-硝基苯基)-2,2,2-三氟乙酰胺(200mg,产率36.3%)。
LCMS(ESI)m/z:360.9[M+H]
+
步骤4:制备3,5-二甲基-4-(4-甲基哌嗪-1-基)-2-硝基苯胺
将LiOH(70mg,3.75mmol)加入到4(450mg,1.25mmol)的EtOH(5mL),H
2O(1mL)溶液中。反应液在60℃下搅拌16h。浓缩滤液用硅胶柱(DCM:MeOH=10:1)纯化得到产品3,5-二甲基-4-(4-甲基哌嗪-1-基)-2-硝基苯胺(250mg,产率75.5%)。
LCMS(ESI)m/z:265.2[M+H]
+
步骤5:制备3,5-二甲基-4-(4-甲基哌嗪-1-基)苯-1,2-二胺
将Pd/C(200mg)加入到3,5-二甲基-4-(4-甲基哌嗪-1-基)-2-硝基苯胺(250mg,0.94mmol)的MeOH(10mL)溶液中,之后氢气氛围下室温搅拌16h。反应液用硅藻土过滤,浓缩滤液得3,5-二甲基-4-(4-甲基哌嗪-1-基)苯-1,2-二胺(200mg,产率90.5%)。
LCMS(ESI)m/z:235.2[M+H]
+
步骤6:制备2-环丙基-7-(4,6-二甲基-5-(4-甲基哌嗪-1-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳三烯
将2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(186mg,0.77mmol),Na
2S
2O
5(243mg,1.28mmol)加入到3,5-二甲基-4-(4-甲基哌嗪-1-基)苯-1,2-二胺(150mg,0.64mmol)的DMF(2mL)溶液中,之后在90℃搅拌2h。向反应液加入200mL H
2O,用EA萃取,合并有机相减压蒸馏,柱层析纯化(DCM:MeOH=8:1),得2-环丙基-7-(4,6-二甲基-5-(4-甲基哌嗪-1-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳三烯(200mg,产率68.5%)。
LCMS(ESI)m/z:456.0[M+H]
+
步骤7:制备化合物C078
将TMSCl(108mg,0.99mmol),NaI(149mg,0.99mmol)加入到2-环丙基-7-(4,6-二甲基-5-(4-甲基哌嗪-1-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳三烯(150mg,0.33mmol)的ACN(5mL)溶液中。反应液减压蒸馏,粗品送制备纯化得化合物C078(43mg,产率28.5%)。
LCMS(ESI)m/z:442.3[M+H]
+
1H NMR(400MHz,DMSO-d
6)δ12.19(s,2H),8.15(s,1H),7.98(s,1H),7.31(s,1H),3.22(s,2H),3.07(s,2H),2.67(s,2H),2.60(s,3H),2.53(s,2H),2.38(d,J=4.4Hz,6H),1.42–1.11(m,5H).
实施例46:制备化合物C079
步骤1:制备1-(2-溴-5-硝基苯基)-N,N-二甲基甲胺
室温下,将2-溴-5-硝基苯甲醛(20g,87.35mmol)溶于1,2-二氯乙烷溶液(200mL)中,再加入二甲胺的四氢呋喃溶液(35.28mL,122.3mmol)室温反应16h。LC-MS显示反应结束后,向反应液中加入水(300mL),所得溶液用二氯甲烷萃取。合并的有机萃取液用盐水(100mL)洗涤,无水硫酸钠干燥,在减压下过滤后浓缩溶剂得到混合物。粗品通过柱层析(石油醚:乙酸乙酯=5:1)纯化得到1-(2-溴-5-硝基苯基)-N,N-二甲基甲胺(15g,产率75%)。
MS m/z(ESI):261.0[M+H]
+
步骤2:制备4-溴-3-((二甲氨基)甲基)苯胺
将1-(2-溴-5-硝基苯基)-N,N-二甲基甲胺(20g,77.51mmol)溶于乙醇(300mL),氯化铵(41.47g,775.1mmol)溶于H
2O(60mL)中,分三次间隔15min加入Fe粉(21.7g,387.5mmol)80℃搅拌2h。LC-MS显示反应结束后,反应液经砂芯漏斗过滤后倒入水(200mL)中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,在减压下过滤后浓缩溶剂得到混合物。粗品通过柱层析(二氯甲烷:无水甲醇=15:1)纯化得到4-溴-3-((二甲氨基)甲基)苯胺(15g,产率75%)。
MS m/z(ESI):230.9[M+H]
+
步骤3:制备N-(4-溴-3-((二甲氨基)甲基)苯基)乙酰胺
将4-溴-3-((二甲氨基)甲基)苯胺(15g,63.15mmol),溶于1,2—二氯乙烷溶液(100mL),再加入TEA(12.75g,126.31mmol),DMAP(769mg,6.31mmol),Ac
2O(7.729g,75.78mmol)室温下搅拌16h。LC-MS显示反应结束后,将反应液倒入水(200mL)中,然后用乙酸乙酯(100mL x 2)萃取,合并有机相。有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤浓缩得粗品,粗品通过柱层析(二氯甲烷:无水甲醇=10:1)纯化得到N-(4-溴-3-((二甲氨基)甲基)苯基)乙酰胺(12g,产率80%)。
MS m/z(ESI):271.0[M+H]
+
步骤4:制备N-(4-溴-5-((二甲氨基)甲基)-2-硝基苯基)乙酰胺
在0℃下,将N-(4-溴-3-((二甲氨基)甲基)苯基)乙酰胺(5g,18.45mmol)溶于浓硫酸(20mL)中,再加硝酸钾(5.1g,31.9mmol),搅拌3h。LC-MS显示反应结束后,向反应液中滴加碳酸钾水溶液中和至PH=7,将溶液倒入水(200mL)中,然后用乙酸乙酯(100mL x 2)萃取,合并有机相。有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤浓缩得粗品,粗品通过柱层析(二氯甲烷:乙酸乙酯=10:1)纯化得到N-(4-溴-5-((二甲氨基)甲基)-2-硝基苯基)乙酰胺(2g,产率40%)。
MS m/z(ESI):316.1[M+H]
+
步骤5:制备N-(4-(3,6-二氢-2H-吡喃-4-基)-5-(二甲氨基)甲基)-2-硝基苯基)乙酰胺
在室温下,将N-(4-溴-5-((二甲氨基)甲基)-2-硝基苯基)乙酰胺(1g,110mmol)和2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧苯甲醛(917.7mg,4.37mmol)溶于无水1,4—二氧六环(18mL)和H
2O(2mL),氮气换气三次后缓慢加入Pd(dppf)Cl
2(294.12mg,0.36mmol),氮气换气三次,升温至80℃搅拌2h。LC-MS显示反应结束。反应液经砂芯漏斗过滤后倒入水(200mL)中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,在减压下过滤后浓缩溶剂得到混合物。粗品通过柱层析(二氯甲烷:无水甲醇=15:1)纯化得到N-(4-(3,6-二氢-2H-吡喃-4-基)-5-(二甲氨基)甲基)-2-硝基苯基)乙酰胺(700mg,产率70.0%)。
MS m/z(ESI):320.2[M+H]
+
步骤6:制备4-(3,6-二氢-2H-吡喃-4-基)-5-(二甲氨基)甲基)-2-硝基苯胺
在室温下,将N-(4-(3,6-二氢-2H-吡喃-4-基)-5-(二甲氨基)甲基)-2-硝基苯基)乙酰胺(486mg,152mmol)溶于盐酸水溶液(6mL,15mL H
2O)。在氮气保护下,升温至100℃搅拌16h。LC MS显示反应结束。向反应液中加入碳酸钾水溶液调节PH至6。将反应液倒入水(200mL)中,然后用乙酸乙酯(80mL x 2)萃取,合并有机相。有机相用饱和氯化钠水溶液(100mL x 2)洗涤,无水硫酸钠干燥,抽滤,浓缩得粗品。粗品通过快速柱层析(二氯甲烷:无水甲醇=15:1)纯化得到4-(3,6-二氢-2H-吡喃-4-基)-5-(二甲氨基)甲基)-2-硝基苯胺(300mg,产率61.7%)。
MS m/z(ESI):278.2[M+H]
+
步骤7:制备4-((二甲氨基)甲基)-5-(四氢-2H-吡喃-4-基)苯-1,2-二胺
在室温下,将4-(3,6-二氢-2H-吡喃-4-基)-5-(二甲氨基)甲基)-2-硝基苯胺(300mg,1.08mmol)溶于无水MeOH(10mL)溶液中,加入Pd/C(300mg,2.81mmol)。反应液在50℃下搅拌5h。LCMS监测反应结束。反应液经砂芯漏斗过滤后抽滤,浓缩得粗品4-((二甲氨基)甲基) -5-(四氢-2H-吡喃-4-基)苯-1,2-二胺(210mg,产率70.0%),浅黄色固体。
MS m/z(ESI):[M+H]
+
步骤8:制备2-环丙基-7-(5-((二甲氨基)甲基)-6-(四氢-2H-吡喃-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-腈
在100mL圆底烧瓶中,将4-((二甲氨基)甲基)-5-(四氢-2H-吡喃-4-基)苯-1,2-二胺(100mg,0.404mmol),2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(97.16mg,0.404mmol)溶于无水DMF(5mL)中,在氮气保护下,加入Na
2S
2O
5(307mg,1.619mmol)。然后再升温到90℃反应1小时。将反应液倒入冰水(10mL)中,缓缓滴入碳酸钾水溶液,直至固体析出,用布氏漏斗将固体滤出,得到粗品2-环丙基-7-(5-((二甲氨基)甲基)-6-(四氢-2H-吡喃-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-腈(130mg,产率68.5%)。
MS m/z(ESI):471.0[M+H]
+
步骤9:合成化合物C079
在室温下,将2-环丙基-7-(5-((二甲氨基)甲基)-6-(四氢-2H-吡喃-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-腈(100mg,0.213mmol)溶于乙腈(8mL)中,加入NaI(64.1mg,0.427mmol)和TMSCl(4642mg,0.427mmol)在氮气保护下室温搅拌反应4h。LC MS显示反应结束后,送酸法制备纯化得到化合物C079(20.10mg,产率20.1%)。
MS m/z(ESI):457.0[M+H]
+
1H NMR(400MHz,DMSO-d
6)δ12.74–12.05(m,2H),8.27(s,1H),7.99(s,1H),7.63(s,1H),7.54(s,1H),3.99(d,J=11.5Hz,2H),3.49(s,4H),2.67(s,1H),2.33(s,1H),2.18(s,6H),1.71(s,4H),1.24(d,J=5.6Hz,4H).
实施例47:制备化合物C080
步骤1:制备叔丁基(叔丁氧羰基)(3-(2,2-二氟乙基)氨基)-4-(3,6-二氢吡喃-4-基)-2-硝基苯基氨基甲酸酯
向叔丁基(4-溴-3-((2,2-二氟乙基)氨基)-2-硝基苯基叔丁基羰基氨基甲酸酯(1.5g,3.03mmol)的1,4-二氧六环(15mL)和水(2mL)混合溶液中加入3,6-二氢-2H-吡喃-4-硼酸频哪醇酯(4.64g,19.99mmol),在氮气保护下,分别加入Pd(dppf)Cl
2(245mg,0.30mmol)和碳酸钾(1.26g,9.09mmol)。然后再升温到100℃反应2小时,得到黑色悬浊液。TLC(石油醚:乙酸乙酯=3:1)监测反应结束。然后将反应液直接拉干。粗品通过快速柱层析(石油醚:乙酸乙酯=10:1~5:1)纯化得到叔丁基(叔丁氧羰基)(3-(2,2-二氟乙基)氨基)-4-(3,6-二氢吡喃-4-基)-2-硝基苯基氨基甲酸酯(1.20g,产率79.5%)。
MS m/z(ESI):=399.9[M-100]
+
步骤2:制备N1-(2,2-二氟乙基)-6-(3,6-二氢吡喃-4-基)-2-硝基苯-1,3-二胺
将叔丁基(叔丁氧羰基)(3-(2,2-二氟乙基)氨基)-4-(3,6-二氢吡喃-4-基)-2-硝基苯基氨基甲酸酯溶于盐酸/1,4-二氧六环(20mL)中,反应液在25℃下搅拌反应2h。TLC(石油醚:乙酸乙酯=3:1)和LCMS监测反应结束。将反应液浓缩。粗品通过柱层析(石油醚:乙酸乙酯=3:1)得到N1-(2,2-二氟乙基)-6-(3,6-二氢吡喃-4-基)-2-硝基苯-1,3-二胺(480mg,产率72.8%)。
MS m/z(ESI):=299.9[M+H]
+
步骤3:制备N1-(2,2-二氟乙基)-6-四氢吡喃-4-基苯-1,2,3-三胺
向N1-(2,2-二氟乙基)-6-(3,6-二氢吡喃-4-基)-2-硝基苯-1,3-二胺(400mg,1.34mmol)的MeOH溶液(20mL)溶液中加入钯碳(300mg),反应液在50℃下搅拌反应16h。TLC(石油醚:乙酸乙酯=1:1)和LCMS监测反应结束。将反应液浓缩。粗产物通过快速柱层析(石油醚:乙酸乙酯=1:1)纯化得到产品N1-(2,2-二氟乙基)-6-四氢吡喃-4-基苯-1,2,3-三胺(300mg,产率82.87%)。
MS m/z(ESI):=472.0[M+H]
+
步骤4:制备2-环丙基-7-(4-(2,2-二氟乙基)氨基)-5-(四氢吡喃-4-基)-1H-苯并咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈
向N1-(2,2-二氟乙基)-6-四氢吡喃-4-基苯-1,2,3-三胺(200mg,0.74mmol)的N,N-二甲基甲酰胺(4mL)溶液中加入2-环丙基-7-甲酰基-6-甲氧基吡咯并[3,2-c]吡啶-3-甲腈(215mg,0.89mmol)和焦亚硫酸钠(281mg,1.48mmol),反应液在90℃下搅拌2h。LCMS监测反应结束。将反应液浓缩。粗产物通过快速柱层析(石油醚:乙酸乙酯=1:1)纯化得到产品2-环丙基-7-(4-(2,2-二氟乙基)氨基)-5-(四氢吡喃-4-基)-1H-苯并咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(300mg,产率82.6%)。
MS m/z(ESI):=493.3[M+H]
+
步骤5:制备化合物C080
向2-环丙基-7-(4-(2,2-二氟乙基)氨基)-5-(四氢吡喃-4-基)-1H-苯并咪唑-2-基)-6-甲氧基-1H-吡咯并[3,2-c]吡啶-3-甲腈(250mg,0.51mmol)的乙腈溶液(5mL)中加入三甲基氯硅烷(167mg,1.53mmol)和碘化钠(230mg,1.53mmol),反应液在25℃下搅拌反应2h。TLC(二氯甲烷:甲醇=20:1)和LCMS监测反应结束。将反应液浓缩。粗产物通过快速柱层析(二氯甲烷:甲醇=20:1)纯化得化合物C080(30.08mg,产率12.42%)。
MS m/z(ESI):=479.2[M+H]
+
1H NMR(400MHz,DMSO-d
6)δ12.60(s,1H),12.32(s,1H),11.07(s,1H),8.00(s,1H),7.11(d,J=8.2Hz,1H),6.99(d,J=8.2Hz,1H),6.21(t,J=57.0Hz,1H),5.41(s,1H),4.25(s,2H),3.96(d,J=10.4Hz,2H),3.54(s,2H),2.29(s,1H),1.67(s,4H),1.22(d,J=9.9Hz,5H).
实施例48:制备化合物C081
步骤1:制备化合物C081
将2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-氧基-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-碳腈(100mg,0.21mmol)溶于乙腈(5mL)和1,4-二氧六环(15mL),然后加入乙酸(13mg,0.21mmol),常温搅拌1h。再加入氰基硼氢化钠(46mg,0.73mmol),40度反应16h。TLC监测反应结束后,加入氨水调节PH为碱性,乙酸乙酯萃取浓缩所得残余物,经反相柱层析纯化(MeCN:H
2O=4:1),冻干得化合物C081(32.02mg,产率13.8%)。
MS m/z(ESI):507.0[M+H]
+
1H NMR(400MHz,DMSO-d
6)δ12.66(br,1H),11.20(s,1H),9.15(s,1H),8.07(s,1H),7.46(d,J=8.3Hz,1H),7.02(d,J=8.5Hz,1H),6.72–6.58(m,1H),4.96(t,J=11.1Hz,2H),3.61(d,J=11.1Hz,2H),3.37(s,1H),3.18(t,J=6.1Hz,2H),3.08(d,J=11.1Hz,2H),2.50(s,1H),2.25–1.83(m,4H),1.45–1.26(m,5H),1.25–1.13(m,2H).
实施例49:制备化合物C082
步骤1:制备2-(1-甲基-1,2,3,6-四氢吡啶-4-基)-5-硝基吡啶-4-胺
向原料2-氯-5-硝基吡啶-4-胺(2000mg,11.52mmol)和1-甲基-1,2,3,6-四氢吡啶(1661.96mg,17.29mmol)混合物中加入1,4-二氧六环(20mL)和水(4mL),然后再依次添加反应物碳酸钾(4777.94mg,34.57mmol)、Pd(dppf)Cl
2(843.17mg,1.15mmol),混合物在氮气保护下,100℃搅拌反应过夜。TLC(二氯甲烷:甲醇=10:1)和LCMS监测反应结束。将反应液倒入水(40mL)中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和食盐水洗涤,无水硫酸钠干燥,浓缩。粗产物通过快速柱层析(二氯甲烷:甲醇=10:1)纯化得2-(1-甲基-1,2,3,6-四氢吡啶-4-基)-5-硝基吡啶-4-胺(1150mg,产率42.6%)。
MS m/z(ESI):=235.0[M+H]
+.
步骤2:制备6-(1-甲基六氢吡啶-4-基)吡啶-3,4-二胺
向原料2-(1-甲基-1,2,3,6-四氢吡啶-4-基)-5-硝基吡啶-4-胺(300mg,1.28mmol)加入乙醇(3mL),然后再依次添加反应物乙酸(0.29mL,5.12mmol)、二氧化铂(290.81mg,1.28mmol),混合物氢气氛围下60℃下搅拌反应过夜。TLC(二氯甲烷:甲醇=5:1)监测反应结束。将反应液过滤,滤液浓缩。通过柱层析(SiO
2,二氯甲烷:甲醇=10/1~4/1)纯化得6-(1-甲基六氢吡啶-4-基)吡啶-3,4-二胺(220mg,产率83.3%)。
MS m/z(ESI):=207.1[M+H]
+.。
步骤3:制备2-环丙基-6-甲氧基-7-[6-(1-甲基六氢吡啶-4-基)-3H咪唑[4,5-c]吡啶-2-基]-1H吡咯[3,2-c]吡啶-3-碳三烯
向原料6-(1-甲基六氢吡啶-4-基)吡啶-3,4-二胺(100mg,0.48mmol)和2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(93.56mg,0.39mmol)混合物中加入DMF溶液(1mL),然后再依次添加反应物焦亚硫酸钠(229.92mg,1.45mmol),混合物在100℃搅拌反应12小时。TLC(二氯甲烷:甲醇=5:1)和LCMS监测反应结束。将反应液倒入水(10mL)中,然后用二氯甲烷萃取,合并有机相。有机相用饱和食盐水洗涤,无水硫酸钠干燥,浓缩。粗产物通过快速柱层析(二氯甲烷:甲醇=4:1)纯化得2-环丙基-6-甲氧基-7-[6-(1-甲基六氢吡啶-4-基)-3H咪唑[4,5-c]吡啶-2-基]-1H吡咯[3,2-c]吡啶-3-碳三烯(120mg,产率57.9%)。
MS m/z(ESI):=428.2[M+H]
+.
步骤4:制备化合物C082
向2-环丙基-6-甲氧基-7-[6-(1-甲基六氢吡啶-4-基)-3H咪唑[4,5-c]吡啶-2-基]-1H吡咯[3,2-c]吡啶-3-碳三烯(120mg,0.28mmol)中加入盐酸/乙醇溶液(10M,5mL),在90℃搅拌反应12小时。LCMS监测反应结束后,浓缩反应混合液,粗产物通过快速HPLC(乙腈:水=30:70)纯化得化合物C082(28.07mg,产率24.2%)。
MS m/z(ESI):=414.2[M+H]
+.
1H NMR(400MHz,DMSO-d
6)δ12.73(br s,1H),8.91(s,1H),8.16-8.23(m,1H),8.07(s,1H),7.54(s,1H),3.71-3.77(m,1H),3.08(br d,J=10.76Hz,2H),2.74-2.83(m,1H),2.39(s,3H),2.34(br t,J=11.38Hz,2H),1.84-1.98(m,4H),1.21-1.30(m,5H).
实施例50:制备化合物C083
步骤1:制备4-溴-3-(环丙基甲氧基)-2-硝基苯胺
将碳酸钾(2.7g,19.31mmol)加到3-氨基-6-溴-2硝基苯酚(1.5g,6.44mmol)的MeCN(45mL)溶液中,该混合物在室温下搅拌30min。然后将(碘甲基)环丙烷(1.4g,7.72mmol)加到上述反应液中,混合物在80℃下反应16h。反应结束后,向反应混合物中加H
2O(50mL)。用乙酸乙酯萃取混合物。用盐水洗涤合并的有机提取物,然后干燥(无水Na
2SO
4)并减压浓缩。快速色谱法(SiO
2,10-50%乙酸乙酯-石油醚)纯化得4-溴-3-(环丙基甲氧基)-2-硝基苯胺(1.8g,产率97.3%)。
MS m/z:287.2[M+H]
+;
步骤2:制备3-(环丙基甲氧基)-4-(1-甲基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯胺
将K
2CO
3(722mg,5.22mmol)的水溶液(3mL)加到4-溴-3-(环丙基甲氧基)-2-硝基苯胺(500mg,1.74mmol)和1-甲基-1,2,3,6-四氢吡啶-4-硼酸频哪醇酯(776mg,3.48mmol)的1,4二氧六环(27mL)溶液中,然后在N
2下添加Pd(dppf)Cl
2(127mg,0.17mmol),反应混合物在90℃下搅拌2h。反应结束后,加H
2O(30mL)。用乙酸乙酯萃取混合物。用盐水洗涤合并的有机提取物,然后干燥(无水Na
2SO
4)并减压浓缩。通过快速色谱法(SiO
2,0-10%甲醇-二氯甲烷)纯化得3-(环丙基甲氧基)-4-(1-甲基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯胺(400mg,产率75.9%)。
MS m/z:304.1[M+H]
+;
步骤3:制备3-(环丙基甲氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺
将PtO
2(400mg)添加到3-(环丙基甲氧基)-4-(1-甲基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯胺(400mg,1.32mmol)的乙醇(30mL)溶液中,然后在将该混合物在50℃、H
2下搅拌16小时。反应结束后,在减压下过滤并浓缩滤液。通过快速硅胶色谱法(SiO
2,0-10%甲醇-二氯甲烷)纯化粗品得3-(环丙基甲氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(300mg,产率82.6%)。
MS m/z:276.2[M+H]
+;
步骤5:制备2-环丙基-7-(4-(环丙基甲氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈
将3-(环丙基甲氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(300mg,1.09mmol)和2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(316mg,1.31mmol)溶于DMF(8mL)中,混合物在室温下搅拌20分钟,然后加入Na
2S
2O
5(829mg,4.36mmol)。将混合物在90℃搅拌4小时。TLC显示原料反应完全,将反应液倒入冰水中,用饱和碳酸氢钠溶液调至PH=8,有固体析出,将混合物过滤,滤渣用水洗得到粗产物。通过快速色谱法(SiO2,0-10%甲醇-二氯甲烷)纯化得2-环丙基-7-(4-(环丙基甲氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈(130mg,产率24.1%)。
MS m/z:497.2[M+H]
+;
步骤9:制备化合物C083
将2-环丙基-7-(4-(环丙基甲氧基)-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-甲腈(78mg,0.16mmol)和NaI(47mg,0.31mmol)溶于乙腈(15mL)中,然后 加入TMCS(34mg,0.31mmol)。混合物在室温下搅拌16h。反应结束旋干乙腈得到粗品。粗品通过反相制备(梯度:10%MeCN/90%H2O,0.1%NH3.H2O到100%MeCN)纯化得到化合物C083(37.78mg,产率48.94%)。
LCMS(ESI)m/z:483.3[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.40(s,2H),8.04(s,1H),7.35(d,J=8.4Hz,1H),7.04(d,J=8.2Hz,1H),4.44(s,2H),3.13–3.05(m,2H),2.92(d,J=10.6Hz,2H),2.34(d,J=8.2Hz,1H),2.23(s,3H),2.03(t,J=10.6Hz,2H),1.74(dd,J=23.2,12.6Hz,5H),1.31(d,J=5.6Hz,2H),1.16(s,2H),0.60(d,J=7.1Hz,2H),0.39(d,J=4.3Hz,2H).
实施例51:制备化合物C084
步骤1:制备4-溴-3-(2,2-二氟乙氧基)-2-硝基苯胺
室温下,将2-氨基-6-溴-3-硝基苯酚(850mg,3.65mmol)溶于无水乙腈(30mL)中,然后加入1,1-二氟-2-碘乙烷(841mg,4.38mmol),K
2CO
3(1510mg,10.94mmol),升温至80℃反应16h。TLC监测反应结束(石油醚:乙酸乙酯=5:1)显示反应结束,将反应液倒入水(60mL)中淬灭反应。用乙酸乙酯萃取,合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤,浓缩得粗产品。粗品通过柱层析(石油醚:乙酸乙酯=10:1)纯化得4-溴-3-(2,2-二氟乙氧基)-2-硝基苯胺(1g,产率92.3%)。
MS m/z(ESI):297.1[M+H]
+
步骤2:制备4-(4-氨基-2-(2,2-二氟乙氧基)-3-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯
将4-溴-3-(2,2-二氟乙氧基)-2-硝基苯胺(1g,3.37mmol),4-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1267mg,4.1mmol)溶于1,4-二氧六环(27mL)和H
2O(4mL)中,在氮气保护下,分别加入Pd(dppf)Cl
2(249mg,0.34mmol)和K
2CO
3(1.39g,,10.1mmol)。然后再升温到90℃反应2h,得到黑色悬浊液。TLC监测反应结束。然后将反应液倒入水(20mL)中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤浓缩得粗品。粗品通过柱层析(石油醚:乙酸乙酯=10:1)得到4-(4-氨基-2-(2,2-二氟乙氧基)-3-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1g,产率74%)。
MS m/z(ESI):400.1[M+H]
+
步骤3:制备4-(3,4-二氨基-2-(2,2-二氟乙氧基)苯基)哌啶-1-羧酸叔丁酯
将4-(4-氨基-2-(2,2-二氟乙氧基)-3-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1g,2.51mmol)溶于溶剂乙醇(30mL)中,在氮气环境下加入PtO
2(500mg,2.2mmol)。反应体系用氢气置换三次,然后在氢气(15psi)压力下,50℃反应16h。TLC(二氯甲烷/甲醇=10/1)显示反应结束。将反应液通过硅藻土层抽滤,甲醇洗涤。滤液浓缩得4-(3,4-二氨基-2-(2,2-二氟乙氧基)苯基)哌啶-1-羧酸叔丁酯(750mg,产率80%)。
MS m/z(ESI):316.2[M+H]
+
步骤4:制备叔丁基4-(2-(3-氰基-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-4-(2,2-二氟乙氧基)-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸酯
将3-(2,2-二氟乙氧基)-4-(1-甲基哌啶-4-基)苯-1,2-二胺(250mg,0.88mmol)和2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(338mg,1.41mmol)溶于N,N-二甲基甲酰胺(5mL)溶液中,加入焦亚硫酸钠(1.07g,5.64mmol),升温至90℃反应16h。TLC监测反应结束后,反相柱层析纯化(MeCN:H2O=5:1),得叔丁基4-(2-(3-氰基-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶- 7-基)-4-(2,2-二氟乙氧基)-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸酯(600mg,产率50%)。
MS m/z(ESI):593.0[M+H]
+
步骤5:制备2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈
将叔丁基4-(2-(3-氰基-2-环丙基-6-甲氧基-1H-吡咯[3,2-c]吡啶-7-基)-4-(2,2-二氟乙氧基)-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸酯(250mg,0.42mmol)溶于6mL的盐酸1,4-二氧六环,室温反应10分钟。TLC监测反应结束后,加无水乙醚洗涤得2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(200mg,产率99%)。
MS m/z(ESI):493.1[M+H]
+
步骤6:制备2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-氧基-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-碳腈
将化合物2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(250mg,0.5mmol)溶于6mL的乙腈,然后加入碘化钠(123mg,0.82mmol),三甲基氯硅烷(89mg,0.82mmol)45度反应3小时。TLC监测反应结束后,乙酸乙酯萃取浓缩得2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-氧基-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-碳腈(200mg,产率84%)。
MS m/z(ESI):479.0[M+H]
+
步骤7:制备化合物C084
将2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-氧基-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-碳腈(100mg,0.21mmol)溶于15mL的乙腈和5mL的1,4-二氧六环,然后加入乙酸(13mg,0.21mmol),常温搅拌1小时。再加入氰基硼氢化钠(46mg,0.73mmol),40度反应16小时。TLC监测反应结束后,加入氨水调节PH为碱性,乙酸乙酯萃取浓缩得2-环丙基-7-(4-(2,2-二氟乙氧基)-5-(1-((四氢-2H-吡喃-4-基)甲基)哌啶-4-基)-1H苯并[d]咪唑-2-基)-6-氧基-5,6-二氢-1H-吡咯[3,2-c]吡啶-3-碳腈(80mg,粗品)黄色固体。过反相纯化,冻干得到化合物C084(20.78mg,产率17.3%)。
MS m/z(ESI):577.3[M+H]
+
1H NMR(400MHz,DMSO-d
6)δ12.65(s,1H),12.59(s,1H),11.20(s,1H),9.01–8.74(m,1H),8.07(s,1H),7.45(s,1H),7.04(s,1H),6.49(t,J=54.5Hz,1H),4.97(s,2H),3.87(s,2H),3.63(s,1H),3.32(s,3H),3.05(s,4H),2.67(s,2H),2.37–2.13(m,4H),1.99–1.55(s,4H),1.48–1.03(m,4H).
实施例52:制备化合物C085
步骤1:制备3-乙氧基-4-(1-乙基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯胺
将4-溴-3-乙氧基-2-硝基苯胺(500mg,1.92mmol),1-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)-1,2,3,6-四氢吡啶(545mg,2.3mmol)溶于1,4-二氧六环(18mL)和H
2O(2mL)中,在氮气保护下,分别加入Pd(dppf)Cl
2(139mg,0.19mmol)和K
2CO
3(795mg,5.76mmol)。然后再升温到90℃ 反应2h,得到黑色悬浊液。TLC监测反应结束。然后将反应液倒入水(20mL)中,然后用乙酸乙酯萃取,合并有机相。有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤浓缩得粗品。粗品通过柱层析(二氯甲烷:无水甲醇=15:1)得到3-乙氧基-4-(1-乙基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯胺(300mg,产率53.6%)。
MS m/z(ESI):292.2[M+H]
+
步骤2:制备3-乙氧基-4-(1-乙基哌啶-4-基)苯-1,2-二胺
将3-乙氧基-4-(1-乙基-1,2,3,6-四氢吡啶-4-基)-2-硝基苯胺(300mg,1.03mmol)溶于溶剂乙醇(10mL)中,在氮气环境下加入PtO
2(200mg,0.88mmol)。反应体系用氢气置换三次,然后在氢气(15psi)压力下,50℃反应16h。TLC(二氯甲烷/甲醇=10/1)显示反应结束。将反应液通过硅藻土层抽滤,甲醇洗涤。滤液浓缩得3-乙氧基-4-(1-乙基哌啶-4-基)苯-1,2-二胺(250mg,产率92%)。
MS m/z(ESI):264.2[M+H]
+
步骤3:制备2-环丙基-7-(4-乙氧基-5-(1-乙基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈
将3-乙氧基-4-(1-乙基哌啶-4-基)苯-1,2-二胺(250mg,0.95mmol)和2-环丙基-7-甲酰基-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(228mg,0.95mmol)溶于N,N-二甲基甲酰胺(6mL)溶液中,加入焦亚硫酸钠(722mg,3.8mmol),升温至90℃反应16h。TLC监测反应结束后,反相柱层析纯化(MeCN:H2O=5:1),得2-环丙基-7-(4-乙氧基-5-(1-乙基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(28mg,产率6%)。
MS m/z(ESI):485.1[M+H]
+
步骤4:制备化合物C085
将2-环丙基-7-(4-乙氧基-5-(1-乙基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-6-甲氧基-1H-吡咯[3,2-c]吡啶-3-碳腈(28mg,0.058mmol)溶于(4mL)的乙腈,然后加入碘化钠(17mg,0.116mmol),三甲基氯硅烷(12mg,0.116mmol)45℃反应3h。TLC监测反应结束后,乙酸乙酯萃取浓缩所得残余物经HPLC制备纯化得C085(7.83mg,产率23.8%)。
MS m/z(ESI):471.3[M+H]
+
1H NMR(400MHz,DMSO-d6)δ12.39(s,2H),8.23(s,2H),8.04(s,1H),7.34(s,1H),7.04(d,J=8.2Hz,1H),4.66(s,2H),3.08(s,2H),2.33(s,1H),2.18(s,4H),1.72(s,4H),1.45(t,J=7.0Hz,3H),1.34(s,2H),1.15(s,2H),1.07(t,J=7.3Hz,3H).
实施例53:制备化合物C086
步骤1:制备7-溴-2-环丙基-3-碘-6-甲氧基-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯[3,2-c]吡啶
向7-溴-2-环丙基-3-碘-6-甲氧基-1H-吡咯[3,2-c]吡啶(6g,15.31mmol)的无水DMF(60mL)溶液中分批加入60%的NaH(1.22g,30.62mmol)。将混合物在0℃下搅拌1小时。向混合物中逐滴添加(2-(氯甲氧基)乙基)三甲基硅烷(3.83g,22.97mmol),并将所得混合物在室温下再搅拌2小时。反应结束后,向反应液中加水(300mL),并用EA萃取混合液。用水、盐水冲洗合并的有机层,用无水硫酸钠干燥,并在减压下浓缩。通过快速色谱法(SiO
2,0-50%乙酸乙酯:石油醚)纯化得7-溴-2-环丙基-3-碘-6-甲氧基-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯[3,2-c]吡啶(7g,产率87.5%)。
MS m/z(ESI):522.9[M+H]
+;
步骤2:制备7-溴-2-环丙基-6-甲氧基-3-(三氟甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯[3,2-c]吡啶
将Pd
2(dba)
3(422mg,0.46mmol)加到7-溴-2-环丙基-3-碘-6-甲氧基-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯[3,2-c]吡啶(2g,3.84mmol)和CuI(22g,115.16mmol)的DMF(150mL)溶液中,然后在N2下加入SM2(22g,115.16mmol),该混合物在100℃下搅拌0.5h。反应结束后,将混合物过滤。向滤液中加H
2O(50mL)并用乙酸乙酯萃取,用盐水洗涤合并的有机提取物,然后干燥(无水硫酸钠)并减压浓缩。通过快速色谱法(SiO
2,10-50%乙酸乙酯-己烷)纯化得到7-溴-2-环丙基-6-甲氧基-3-(三氟甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯[3,2-c]吡啶(1.0g,产率56.2%)。
MS m/z(ESI):464.9[M+H]
+;
步骤3:制备(E)-2-环丙基-6-甲氧基-7-苯乙烯基-3-(三氟甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯[3,2-c]吡啶
将(E)-苯乙烯基硼酸(954mg,6.54mmol)加到7-溴-2-环丙基-6-甲氧基-3-(三氟甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯[3,2-c]吡啶(1g,2.15mmol)和K
2CO
3(891mg,6.45mmol)的1,4-二氧六环(20mL)和H
2O(2mL)混合溶液中,然后在N
2下加入Pd(PPh
3)
4(248mg,0.22mmol),该混合物在100℃下搅拌1小时。反应结束后,加H
2O(100mL),并用乙酸乙酯(3x30mL)提取混合物。用盐水洗涤合并的有机提取物,然后干燥(无水硫酸钠)并减压浓缩。通过快速色谱法(SiO
2,10-50%乙酸乙酯-石油醚)纯化得到(E)-2-环丙基-6-甲氧基-7-苯乙烯基-3-(三氟甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯[3,2-c]吡啶(300mg,产率30%)。
MS m/z(ESI):489.1[M+H]
+;
步骤4:制备2-环丙基-6-甲氧基-3-(三氟甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯[3,2-c]吡啶-7-甲醛
将(E)-2-环丙基-6-甲氧基-7-苯乙烯基-3-(三氟甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯[3,2-c]吡啶(200mg,0.41mmol)溶解于DCM(100mL)中,反应混合物在-78℃,O
3环境下搅拌20min。反应结束后,用二甲基硫淬灭反应溶液。在减压下除去溶剂。通过TLC(PE:EA=20:1)纯化粗品,得到2-环丙基-6-甲氧基-3-(三氟甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯[3,2-c]吡啶-7-甲醛(100mg,产率58.9%)。
MS m/z(ESI):415.2[M+H]
+;
步骤5:制备2-(2-环丙基-6-甲氧基-3-(三氟甲基)-5,6-二氢-1H-吡咯[3,2-c]吡啶-7-基)-4-乙氧基-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑
将2-环丙基-6-甲氧基-3-(三氟甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡咯[3,2-c]吡啶-7-甲醛(58mg,0.14mmol)和3-乙氧基-4-(1-甲基哌啶-4-基)苯-1,2-二胺(52mg,0.21mmol)溶于DMF(5mL)中,混合物在室温下搅拌20min,然后加入Na
2S
2O
5(106mg,0.56mmol)。将混合物在90℃下搅拌4h。TLC显示原料反应完全,将反应液倒入冰水中,用碳酸氢钠水溶液调节pH至碱性,有固体析出,将混合物过滤,滤渣用水洗得2-(2-环丙基-6-甲氧基-3-(三氟甲基)-5,6-二氢-1H-吡咯[3,2-c]吡啶-7-基)-4-乙氧基-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑(15mg,产率20.8%)。
MS m/z(ESI):514.3[M+H]
+;
步骤6:制备化合物C086
将NaI(9mg,0.06mmol)加到2-(2-环丙基-6-甲氧基-3-(三氟甲基)-5,6-二氢-1H-吡咯[3,2-c]吡啶-7-基)-4-乙氧基-5-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑(15mg,0.03mmol)的MeCN溶液(5mL)中。然后在0℃下添加TMSCl(7mg,0.19mmol)。混合物在室温下搅拌16小时。反应结束后,加H
2O(100mL),并用乙酸乙酯(3x30mL)提取混合物。用饱和食盐水洗涤合并的有机提取物,然后干燥(无水硫酸钠)并减压浓缩。得到粗产物通过TLC纯化(二氯甲烷:甲醇=10:1)得到化合物C086(6.32mg,产率42.2%)。
MS m/z(ESI):500.2[M+H]
+;
1H NMR(400MHz,DMSO-d6)δ12.38(s,1H),11.20(s,1H),8.25(s,1H),7.82(s,1H),7.35(d,J= 8.2Hz,1H),7.03(d,J=8.3Hz,1H),4.67(q,J=6.9Hz,2H),3.05(s,1H),2.98(d,J=11.9Hz,2H),2.31(d,J=12.6Hz,4H),2.16(t,J=11.1Hz,2H),1.75(dt,J=25.0,12.8Hz,4H),1.46(t,J=7.0Hz,3H),1.33–1.25(m,2H),1.03(q,J=5.0Hz,2H).
其他本发明所述化合物,可参考如上示例化合物制备方法制备得到。
生物学活性测定
实验例1:对HPK1酶及GLK酶的抑制活性的测定
(1)测试仪器及试剂
(2)实验条件示例
激酶反应条件:
制备1x激酶反应缓冲液:
名称 | 储液浓度 | 体积 | 终浓度 |
Tris | 1M(25x) | 240μL | 40mM |
MgCl 2 | 1M(50x) | 120μL | 20mM |
BSA | 7.5%(75x) | 80μL | 0.10% |
DTT | 1M(500x) | 3μL | 0.5mM |
ddH 2O | 5557μL |
化合物激酶活性检测:
1.在稀释板中用DMSO对化合物进行4倍稀释,化合物起始浓度为1-10uM。
2.将化合物50倍稀释到1x激酶反应缓冲液中,在振荡器上震荡20分钟。
3.用1x的酶反应缓冲液配制准备2x激酶。
4.向反应板中每孔加入2μl激酶(步骤3中配制)。
5.向每孔加入1μl在缓冲液中稀释好的化合物,用封板膜封住板子1000g离心30秒,室温放置10分钟。
6.用1x的酶反应缓冲液配制4x MBP Protein和ATP(ATP终浓度10μM)混合液,向反应板 中加入1μl 4x MBP Protein/ATP混合液。
7.用封板膜封住板子1000g离心30秒,室温反应60分钟。
8.转移4μL ADP-Glo到384反应板中1000rpm/min,离心1min,25℃孵育40min。
9.转移8μL Detection溶液到384反应板中1000rpm/min,离心1min,25℃孵育40min。
10.使用Biotek多功能读板机读取RLU(Relative luminescence unit)信号。信号强度用于表征激酶的活性程度。
(3)数据处理
计算每孔的抑制率,抑制率计算公式如下:
计算IC
50并绘制化合物的抑制曲线:
利用以下非线性拟合公式来得到化合物的IC
50(半数抑制浓度):用Graphpad7.0软件进行数据分析。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)*Hill Slope))
X:化合物浓度log值;Y:抑制率(%inhibition)。
(4)实验结果
本发明化合物对HPK1酶/GLK酶的抑制活性和选择性:
本发明的化合物的HPK1IC
50(nM)范围在0.01-500nM,优选0.01-300nM,更优选0.01-100nM,其中一些化合物是不大于60nM,一些化合物是不大于50nM,一些化合物是不大于40nM,一些化合物是不大于30nM,一些化合物是不大于20nM,一些化合物是不大于10nM,一些化合物是不大于5nM,说明本发明化合物对HPK1具有良好的抑制活性,在治疗由HPK1介导的疾病方面有较好的应用潜力。再则,本发明化合物对HPK1具有良好的抑制活性,且一些化合物对HPK1相对于 MAP4K3的选择性在3倍以上、一些化合物是约5倍以上、一些化合物是约8倍或更高,一些化合物是约10倍或更高,一些化合物是约20倍或更高,一些化合物是约30倍或更高,一些化合物是约50倍或更高,说明本发明涉及的化合物具有较好的安全性,说明本发明化合物在治疗由HPK1介导的疾病方面有较好的应用潜力。
实验例2:小鼠体内PK研究
实验条件
以雄性C57小鼠为受试动物,单次给药后测定化合物血药浓度并评估药代动力学行为,实验操作:
1.试验动物(balb/c小鼠)适应性饲养3天,随机分组,并于给药前禁食过夜。
2.称取适量化合物,采用适当的溶剂将化合物溶解,得到目标浓度的给药溶液。试验前留取部分制剂溶液进行含量测定,确定实际给药制剂含量。
3.根据分组和试验设计对试验动物按预设剂量进行给药,给药方式为灌胃和静脉注射。
4.完成给药的时间计为0min,之后按照预设的时间点进行血样采集,采血方式通常为眼眶静脉丛采血或尾尖采血,采集的全血置于预含抗凝剂的采血管中,批量于离心机3000g离心,分离取上清血浆于新的EP管中,置于-20℃保存。
5.所有血样完成采集后,送至生物分析实验室,有分析人员采用空白血浆配制标准曲线和质控,并将冻存的待测血浆样品化冻。
6.分析人员按照预先开发好的方法和样本处理步骤,处理标准曲线,质控及待测样本。通常采用蛋白沉淀法处理样本。完成分析批的样品前处理后,使用LCMS进行样本分析,获得待测样本的血浆药物浓度。
数据处理.:采用药动学计算软件WinNonlin计算药动学参数。
实验结果
表2.本发明化合物的PK测试结果
根据表2所示,本发明化合物的口服AUC
0-t值较高,表现出较高的口服暴露量,具有良好的药代动力学特性。
以上对本发明所提供的HPK1抑制剂及其应用进行了详细的介绍。
本文中应用了具体实施例对本发明的原理及实施方式进行了阐述,以上实施例的说明只是用于帮助理解本发明的方法及其中心思想。应当指出,对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护。
Claims (25)
- 式(I)所示的化合物或其药学上可接受的盐、或其立体异构体、或其protac嵌合物,其中R 1选自氢或-C 1-8烷基,所述的-C 1-8烷基任选被至少一个取代基R 1d取代;R 1d独立地是氢、氨基、卤素、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO 2;X选自NH或N-C 1-8烷基;R 2选自氢、羧基、氰基、硝基、卤素原子、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、-OR 2a、-SO 2R 2a、-SO 2NR 2aR 2b、-COR 2a、-CO 2R 2a、-CONR 2aR 2b、-POR 2aR 2b、-NR 2aR 2b、-NR 2aCOR 2b、-NR 2aCONR 2bR 2c、-NR 2aCO 2R 2b、-NR 2aSO 2NR 2bR 2c、-NR 2aSO 2R 2b,所述的-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R 2d取代;R 2a、R 2b、和R 2c各自独立地是氢、羟基、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基,所述-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个取代基R 2e取代;或者(R 2a和R 2b)、(R 2b和R 2c)、或(R 2c和R 2a)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R 2e取代;R 2d和R 2e各自独立地是氢、氨基、卤素、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO 2、-OR 2f、-SO 2R 2f、-SO 2NR 2fR 2g、-COR 2f、-CO 2R 2f、-CONR 2fR 2g、-NR 2fR 2g、-NR 2fCOR 2g、-NR 2fCONR 2gR 2h、-NR 2fCO 2R 2f、-NR 2fSO 2NR 2gR 2h、或-NR 2fSO 2R 2g,所述-C 1- 8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个选自卤素、-C 1-8烷基、-OR 2i、-NR 2iR 2j、环烷基、杂环基、芳基、或杂芳基的取代基取代;R 2f、R 2g、R 2h、R 2i、和R 2j各自独立地是氢、-C 1-8烷基、C 1-8烷氧基-C 1-8烷基-、-C 2-8烯基、-C 2- 8炔基、环烷基、杂环基、芳基、或杂芳基;R 3选自氢、羟基、羧基、氰基、硝基、卤素原子、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、-OR 3a、-SR 3a、-SO 2R 3a、-SO 2NR 3aR 3b、-COR 3a、-CO 2R 3a、-CONR 3aR 3b、-POR 3aR 3b、-NR 3aR 3b、-NR 3aCOR 3b、-NR 3aCONR 3bR 3c、-NR 3aCO 2R 3b、-NR 3aSO 2NR 3bR 3c、-NR 3aSO 2R 3b,所述的-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R 3d取代;R 3a、R 3b、和R 3c各自独立地是氢、羟基、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基,所述-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个取代基R 3e取代;或者(R 3a和R 3b)、(R 3b和R 3c)、或(R 3c和R 3a)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R 3e取代;R 3d和R 3e各自独立地是氢、氨基、卤素、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO 2、-OR 3f、-SO 2R 3f、-SO 2NR 3fR 3g、-COR 3f、-CO 2R 3f、-CONR 3fR 3g、 -NR 3fR 3g、-NR 3fCOR 3g、-NR 3fCONR 3gR 3h、-NR 3fCO 2R 3f、-NR 3fSO 2NR 3gR 3h、或-NR 3fSO 2R 3g,所述-C 1- 8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个R 3k取代基取代;或者(R 3f和R 3g)、(R 3g和R 3h)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R 3k取代;每个R 3k独立地选自卤素、-C 1-8烷基、-OR 3i、-NR 3iR 3j、环烷基、杂环基、芳基、或杂芳基,所述的-C 1-8烷基、环烷基、杂环基、芳基、或杂芳基任选地被至少一个选自氢、-C 1-8烷基、C 1-8烷氧基-C 1-8烷基-、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基的取代基取代;R 3f、R 3g、R 3h、R 3i、和R 3j各自独立地是氢、-C 1-8烷基、C 1-8烷氧基-C 1-8烷基-、-C 2-8烯基、-C 2- 8炔基、环烷基、杂环基、芳基、或杂芳基;X 1、X 2、X 3、X 4各自独立的选自N或C,前提是已满足化合价理论(即,所得化合价在化学上是可能的);R 4选自氢、羟基、氨基、氧代基、羧基、氰基、硝基、卤素原子、-C 1-8烷基、-C 2-8烯基、-C 2- 8炔基、环烷基、杂环基、芳基、杂芳基、-OR 4a、-SR 4a、-SO 2R 4a、-SO 2NR 4aR 4b、-COR 4a、-CO 2R 4a、-CONR 4aR 4b、-POR 4aR 4b、-NR 4aR 4b、-NR 4aCOR 4b、-NR 4aCONR 4bR 4c、-NR 4aCO 2R 4b、-NR 4aSO 2NR 4bR 4c、-NR 4aSO 2R 4b,所述的-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R 4d取代;R 4a、R 4b、和R 4c各自独立地是氢、羟基、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基,所述-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个取代基R 4e取代;或者(R 4a和R 4b)、(R 4b和R 4c)、或(R 4c和R 4a)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R 4e取代;R 4d和R 4e各自独立地是氢、氨基、卤素、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO 2、-OR 4f、-SO 2R 4f、-SO 2NR 4fR 4g、-COR 4f、-CO 2R 4f、-CONR 4fR 4g、-NR 4fR 4g、-NR 4fCOR 4g、-NR 4fCONR 4gR 4h、-NR 4fCO 2R 4f、-NR 4fSO 2NR 4gR 4h、或-NR 4fSO 2R 4g,所述-C 1- 8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个R 4k取代基取代;每个R 4k独立地选自卤素、-C 1-8烷基、-OR 4i、-NR 4iR 4j、环烷基、杂环基、芳基、或杂芳基,所述的-C 1-8烷基、环烷基、杂环基、芳基、或杂芳基任选地被至少一个选自氢、-C 1-8烷基、C 1-8烷氧基-C 1-8烷基-、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基的取代基取代;R 4f、R 4g、R 4h、R 4i、和R 4j各自独立地是氢、-C 1-8烷基、C 1-8烷氧基-C 1-8烷基-、-C 2-8烯基、-C 2- 8炔基、环烷基、杂环基、芳基、或杂芳基;n是0、1、2、3或4,前提是已满足化合价理论(即,所得化合价在化学上是可能的)。
- 根据权利要求1所述的化合物,其中R 4选自氢、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、-OR 4a、-SR 4a、-SO 2R 4a、-SO 2NR 4aR 4b、-COR 4a、-CO 2R 4a、-CONR 4aR 4b、-POR 4aR 4b、-NR 4aR 4b、-NR 4aCOR 4b、-NR 4aCO 2R 4b、-NR 4aSO 2R 4b,所述的-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R 4d取代;R 4a、R 4b和R 4d是如式(I)所定义的。
- 根据权利要求2所述的化合物,其中R 4选自环烷基、杂环基、芳基、杂芳基,所述的环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R 4d取代;进一步的,R 4是任选地被至少一个取代基R 4d取代的环,所述的环是选自C 3-10环烷基、包含一个或两个独立地选自氮、氧或任选氧化的硫中的杂原子的4、5、6、或7元杂环基、或包含一或二或 三个独立地选自氧、氮或硫中的杂原子的7至12元稠合的杂环基;进一步的,R 4是任选地被至少一个取代基R 4d取代的是包含一个或两个独立地选自氮、氧的杂原子的4-7元单环杂环基或7-9元稠合杂环基;
- 根据权利要求2所述的化合物,其中R 4是H、-C 1-8烷基、-OR 4a、-NR 4aR 4b、-SR 4a、-NR 4aSO 2R 4b,所述的-C 1-8烷基任选被至少一个取代基R 4d取代;R 4a、R 4b各自独立地是氢或者-C 1-8烷基(优选-C 1-6烷基,更优选甲基、乙基、异丙基或正丙基、 ),或环烷基(优选单环-C 3-8环烷基,更优选环丙基、环丁基、环戊基或环己基),或杂环基(优选四氢呋喃基、氮杂环丁烷基、吡咯烷基、哌啶基),所述-C 1-8烷基、环烷基和杂环基各自任选地被至少一个取代基R 4e取代;R 4d、R 4e各自独立地是是氢、卤素(优选氟、氯,更优选氟)、环烷基(优选C 3-6环烷基,更优选C 3环烷基)、杂环基、芳基、-CONR 4fR 4g、-CO 2R 4f、或-NR 4fR 4g,所述的环烷基、杂环基、芳基各自任选地被至少一个R 4k取代基取代;R 4k选自卤素(优选氟、氯、溴,更优选氟)、-C 1-8烷基(优选-C 1-6烷基,更优选甲基);R 4f、R 4g各自独立地是氢、或-C 1-8烷基(优选-C 1-6烷基,更优选甲基);进一步的,R 4是H、-C 1-8烷基、-OR 4a;R 4a是-C 1-8烷基、环烷基,且所述-C 1-8烷基、环烷基各自任选地被至少一个取代基R 4e取代;R 4e是卤素、环烷基,所述环烷基任选地被至少一个R 4k取代基取代;R 4k独立地选自卤素、-C 1-8烷基;进一步的,
- 根据权利要求1所述的化合物,其中n是1,R 4是如权利要求3-5中任一项所定义的,所述的R 4在X 2或者X 3位上。
- 根据权利要求1所述的化合物,其中n是2,第一个R 4是如权利要求3-5中任一项所定义的,第二个R 4是如权利要求6所定义的;第一个R 4在X 2位上,第二个R 4在X 1或者X 3位上,或者第一个R 4在X 3位上,第二个R 4在X 2或者X 4位上。
- 根据权利要求1所述的化合物,其中n是3,第一个R 4是如权利要求3-5中任一项所定义的,第二个和第三个R 4是如权利要求6所定义的;第一个R 4在X 2位上,第二个R 4在X 1位上,第三个R 4在X 3位上。或者第一个R 4在X 3位上,第二个R 4在X 2位上,第三个R 4在X 4位上。
- 根据权利要求1所述的化合物,所述化合物是通式(II)所示的化合物或其药学上可接受的盐、或其立体异构体、或其protac嵌合物,其中R 1选自氢或-C 1-8烷基,所述的-C 1-8烷基任选被至少一个取代基R 1d取代;R 1d独立地是氢、氨基、卤素、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO 2;X选自NH或N-C 1-8烷基,优选NH;R 2选自氢、羧基、氰基、硝基、卤素原子、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、-OR 2a、-SO 2R 2a、-SO 2NR 2aR 2b、-COR 2a、-CO 2R 2a、-CONR 2aR 2b、-POR 2aR 2b、-NR 2aR 2b、-NR 2aCOR 2b、-NR 2aCONR 2bR 2c、-NR 2aCO 2R 2b、-NR 2aSO 2NR 2bR 2c、-NR 2aSO 2R 2b,所述的-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R 2d取代;R 2a、R 2b和R 2c各自独立地是氢、羟基、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基,所述-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个取代基R 2e取代;或者(R 2a和R 2b)、(R 2b和R 2c)、或(R 2c和R 2a)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R 2e取代;R 2d和R 2e各自独立地是氢、氨基、卤素、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO 2、-OR 2f、-SO 2R 2f、-SO 2NR 2fR 2g、-COR 2f、-CO 2R 2f、-CONR 2fR 2g、-NR 2fR 2g、-NR 2fCOR 2g、-NR 2fCONR 2gR 2h、-NR 2fCO 2R 2f、-NR 2fSO 2NR 2gR 2h、或-NR 2fSO 2R 2g,所述-C 1- 8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个选自卤素、-C 1-8烷基、-OR 2i、-NR 2iR 2j、环烷基、杂环基、芳基、或杂芳基的取代基取代;R 2f、R 2g、R 2h、R 2i和R 2j各自独立地是氢、-C 1-8烷基、C 1-8烷氧基-C 1-8烷基-、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基;R 3选自氢、羟基、羧基、氰基、硝基、卤素原子、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、-OR 3a、-SR 3a、-SO 2R 3a、-SO 2NR 3aR 3b、-COR 3a、-CO 2R 3a、-CONR 3aR 3b、-POR 3aR 3b、-NR 3aR 3b、-NR 3aCOR 3b、-NR 3aCONR 3bR 3c、-NR 3aCO 2R 3b、-NR 3aSO 2NR 3bR 3c、-NR 3aSO 2R 3b,所述的-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R 3d取代;R 3a、R 3b和R 3c各自独立地是氢、羟基、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基,所述-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个取代基R 3e取代;或者(R 3a和R 3b)、(R 3b和R 3c)、或(R 3c和R 3a)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R 3e取代;R 3d和R 3e各自独立地是氢、氨基、卤素、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO 2、-OR 3f、-SO 2R 3f、-SO 2NR 3fR 3g、-COR 3f、-CO 2R 3f、-CONR 3fR 3g、-NR 3fR 3g、-NR 3fCOR 3g、-NR 3fCONR 3gR 3h、-NR 3fCO 2R 3f、-NR 3fSO 2NR 3gR 3h、或-NR 3fSO 2R 3g,所述-C 1- 8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个R 3k取代基取代;或者(R 3f和R 3g)、(R 3g和R 3h)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R 3k取代;每个R 3k独立地选自卤素、-C 1-8烷基、-OR 3i、-NR 3iR 3j、环烷基、杂环基、芳基、或杂芳基,所述的-C 1-8烷基、环烷基、杂环基、芳基、或杂芳基任选地被至少一个选自氢、-C 1-8烷基、C 1-8烷氧基-C 1-8烷基-、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基的取代基取代;R 3f、R 3g、R 3h、R 3i、和R 3j各自独立地是氢、-C 1-8烷基、C 1-8烷氧基-C 1-8烷基-、-C 2-8烯基、-C 2- 8炔基、环烷基、杂环基、芳基、或杂芳基;X 1、X 2、X 3、X 4各自独立的选自N或C,前提是已满足化合价理论(即,所得化合价在化学上是可能的);R 5选自氢、羟基、氨基、氧代基、羧基、氰基、硝基、卤素原子、-C 1-8烷基、-C 2-8烯基、-C 2-8 炔基、环烷基、杂环基、芳基、杂芳基、-OR 5a、-SR 5a、-SO 2R 5a、-SO 2NR 5aR 5b、-COR 5a、-CO 2R 5a、-CONR 5aR 5b、-POR 5aR 5b、-NR 5aR 5b、-NR 5aCOR 5b、-NR 5aCONR 5bR 5c、-NR 5aCO 2R 5b、-NR 5aSO 2NR 5bR 5c、-NR 5aSO 2R 5b,所述的-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R 5d取代;R 5a、R 5b、和R 5c各自独立地是氢、羟基、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基,所述-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个取代基R 5e取代;或者(R 5a和R 5b)、(R 5b和R 5c)、或(R 5c和R 5a)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R 5e取代;R 5d和R 5e各自独立地是氢、氨基、卤素、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO 2、-OR 5f、-SO 2R 5f、-SO 2NR 5fR 5g、-COR 5f、-CO 2R 5f、-CONR 5fR 5g、-NR 5fR 5g、-NR 5fCOR 5g、-NR 5fCONR 5gR 5h、-NR 5fCO 2R 5f、-NR 5fSO 2NR 5gR 5h、或-NR 5fSO 2R 5g,所述-C 1- 8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个R 5k取代基取代;每个R 5k独立地选自卤素、-C 1-8烷基、-OR 5i、-NR 5iR 5j、环烷基、杂环基、芳基、或杂芳基,所述的-C 1-8烷基、环烷基、杂环基、芳基、或杂芳基任选地被至少一个选自氢、-C 1-8烷基、C 1-8烷氧基-C 1-8烷基-、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基的取代基取代;R 5f、R 5g、R 5h、R 5i、和R 5j各自独立地是氢、-C 1-8烷基、C 1-8烷氧基-C 1-8烷基-、-C 2-8烯基、-C 2- 8炔基、环烷基、杂环基、芳基、或杂芳基;s是0、1、2或3,前提是已满足化合价理论(即,所得化合价在化学上是可能的);Cy1选自环烷基、杂环基、芳基或杂芳基,它们各自任选地被t个R 6取代;R 6选自氢、羟基、氨基、氧代基、羧基、氰基、硝基、卤素原子、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、-OR 6a、-SR 6a、-SO 2R 6a、-SO 2NR 6aR 6b、-COR 6a、-CO 2R 6a、-CONR 6aR 6b、-POR 6aR 6b、-NR 6aR 6b、-NR 6aCOR 6b、-NR 6aCONR 6bR 6c、-NR 6aCO 2R 6b、-NR 6aSO 2NR 6bR 6c、-NR 6aSO 2R 6b,所述的-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R 6d取代;R 6a、R 6b和R 6c各自独立地是氢、羟基、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基,所述-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个取代基R 6e取代;或者(R 6a和R 6b)、(R 6b和R 6c)、或(R 6c和R 6a)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R 6e取代;R 6d和R 6e各自独立地是氢、氨基、卤素、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO 2、-OR 6f、-SO 2R 6f、-SO 2NR 6fR 6g、-COR 6f、-CO 2R 6f、-CONR 6fR 6g、-NR 6fR 6g、-NR 6fCOR 6g、-NR 6fCONR 6gR 6h、-NR 6fCO 2R 6f、-NR 6fSO 2NR 6gR 6h、或-NR 6fSO 2R 6g,所述-C 1- 8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个R 6k取代基取代;每个R 6k独立地选自卤素、-C 1-8烷基、-OR 6i、-NR 6iR 6j、环烷基、杂环基、芳基、或杂芳基,所述的-C 1-8烷基、环烷基、杂环基、芳基、或杂芳基任选地被至少一个选自氢、-C 1-8烷基、C 1-8烷氧基-C 1-8烷基-、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基的取代基取代;R 6f、R 6g、R 6h、R 6i和R 6j各自独立地是氢、-C 1-8烷基、C 1-8烷氧基-C 1-8烷基-、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基;t是0、1、2、3或4,前提是已满足化合价理论(即,所得化合价在化学上是可能的)。
- 根据权利要求10所述的化合物,其中s是0、1或2,R 5选自氢、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、-OR 5a、-SR 5a、-SO 2R 5a、-SO 2NR 5aR 5b、-COR 5a、-CO 2R 5a、-CONR 5aR 5b、-POR 5aR 5b、-NR 5aR 5b、-NR 5aCOR 5b、--NR 5aCO 2R 5b、-NR 5aSO 2R 5b,所述的-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R 5d取代;R 5a、R 5b和R 5d是如式(II)所定义的。
- 根据权利要求11所述的化合物,其中:R 5是H、-C 1-8烷基、-OR 5a、-NR 5aR 5b、-SR 5a、-NR 5aSO 2R 5b,所述的-C 1-8烷基任选被至少一个取代基R 5d取代;R 5a、R 5b各自独立地是氢或者-C 1-8烷基(优选-C 1-6烷基,更优选甲基、乙基、异丙基或正丙基、 ),或环烷基(优选单环-C 3-8环烷基,更优选环丙基、环丁基、环戊基或环己基),所述-C 1-8烷基和环烷基各自任选地被至少一个取代基R 5e取代;R 5d、R 5e各自独立地是是氢、卤素(优选氟、氯,更优选氟)、环烷基(优选C 3-6环烷基,更优选C 3环烷基)、杂环基、芳基、-CONR 5fR 5g、-CO 2R 5f、或-NR 5fR 5g,所述的环烷基、杂环基、芳基各自任选地被至少一个R 5k取代基取代;R 5k选自卤素(优选氟、氯、溴,更优选氟)、-C 1-8烷基(优选-C 1-6烷基,更优选甲基);R 5f、R 5g各自独立地是氢、或-C 1-8烷基(优选-C 1-6烷基,更优选甲基);进一步的,R 5选自
- 根据权利要求10所述的化合物,其中Cy1选自环烷基、杂环基、芳基或杂芳基,它们各自任选地被t个R 6取代,t是0、1或2,并且R 6是如式(II)所定义的。
- 根据权利要求10所述的化合物,其中Cy1在X 2位上,当s是1,R 5在X 1或者X 3位上;当s是2,第一个R 5在X 1位上,第二个R 5在X 3位上。
- 根据权利要求10所述的化合物,其中Cy1在X 3位上,当s是1,R 5在X 2或者X 4位上。当s是2,第一个R 5在X 2位上,第二个R 5在X 4位上。
- 根据权利要求1-19中任一项所述的化合物,其中:R 3是氢、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基,所述的-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基或杂芳基各自任选被至少一个取代基R 3d取代;其中R 3d是氢、氨基、卤素、-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、杂芳基、氧代基、-CN、-NO 2、-OR 3f、-SO 2R 3f、-SO 2NR 3fR 3g、-COR 3f、-CO 2R 3f、-CONR 3fR 3g、-NR 3fR 3g、-NR 3fCOR 3g、-NR 3fCONR 3gR 3h、-NR 3fCO 2R 3f、-NR 3fSO 2NR 3gR 3h、或-NR 3fSO 2R 3g,所述-C 1-8烷基、-C 2-8烯基、-C 2-8炔基、环烷基、杂环基、芳基、或杂芳基各自任选地被至少一个选自卤素、-C 1-8烷基、-OR 3i、或-NR 3iR 3j的取代基取代,或者(R 3f和R 3g)、(R 3g和R 3h)与它们所连接的一个或多个原子一起形成3至12元环,所述环包含0、1、2或3个独立地选自氮、氧或硫中的杂原子作为一个或多个环成员,所述环任选地被至少一个取代基R 3k取代;R 3f、R 3g、R 3h、R 3i、R 3j和R 3k各自独立地是氢、-C 1-8烷基,优选-C 1-6烷基,更优选甲基或乙基;进一步的,R 3选自
- 根据权利要求1-20中任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其protac嵌合物,所述化合物选自说明书中表1所列的化合物。
- 一种药物组合物,其包含权利要求1-20中任一项所述的化合物或其药学上可接受的盐或其立体异构体,或其protac嵌合物,及药学上可接受的药用载体。
- 一种药物组合物,其包含权利要求1-20中任一项所述的化合物或其药学上可接受的盐,或其立体异构体,或其protac嵌合物,及一种或多种治疗活性成分。
- 根据权利要求1-20中任一项所述的化合物或其药学上可接受的盐、或其立体异构体、或其protac嵌合物在制备用于治疗和/或预防HPK1介导的疾病及相关疾病的药物中的应用,其中所述HPK1介导的疾病及相关疾病包括但不限于,肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、乳腺癌、乳腺导管癌、头颈癌、子宫内膜癌、宫体癌、直肠癌、肝癌、肾癌、肾盂癌、食管癌、食管腺癌、神经胶质瘤、前列腺癌、甲状腺癌、女性生殖系统癌症、原位癌、淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、口腔癌、咽癌、多发性骨髓瘤、白血病、非霍奇金淋巴瘤、大肠绒毛腺瘤、黑色素瘤、细胞瘤和肉瘤,骨髓增生异常综合症。
- 一种用于预防和/或治疗HPK1介导的疾病和相关疾病的方法,其包括对受试者给予治疗有效量的如权利要求1-20中任一项所述的化合物或其药学上可接受的盐、或其立体异构体、或其protac嵌合物,其中所述HPK1介导的疾病及相关疾病包括但不限于,肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、乳腺癌、乳腺导管癌、头颈癌、子宫内膜癌、宫体癌、直肠癌、肝癌、肾癌、肾盂癌、食管癌、食管腺癌、神经胶质瘤、前列腺癌、甲状腺癌、女性生殖系统癌症、原位癌、 淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、口腔癌、咽癌、多发性骨髓瘤、白血病、非霍奇金淋巴瘤、大肠绒毛腺瘤、黑色素瘤、细胞瘤和肉瘤,骨髓增生异常综合症。
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WO2013097601A1 (en) * | 2011-12-30 | 2013-07-04 | Abbvie Inc. | Bromodomain inhibitors |
CN110402248A (zh) * | 2017-03-15 | 2019-11-01 | 豪夫迈·罗氏有限公司 | 作为hpk1抑制剂的氮杂吲哚类 |
WO2020092621A1 (en) * | 2018-10-31 | 2020-05-07 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds as hpk1 inhibitors |
WO2020092528A1 (en) * | 2018-10-31 | 2020-05-07 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity |
US20200172539A1 (en) * | 2018-11-15 | 2020-06-04 | Pfizer Inc. | Azalactam Compounds as HPK1 Inhibitors |
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WO2013097601A1 (en) * | 2011-12-30 | 2013-07-04 | Abbvie Inc. | Bromodomain inhibitors |
CN110402248A (zh) * | 2017-03-15 | 2019-11-01 | 豪夫迈·罗氏有限公司 | 作为hpk1抑制剂的氮杂吲哚类 |
WO2020092621A1 (en) * | 2018-10-31 | 2020-05-07 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds as hpk1 inhibitors |
WO2020092528A1 (en) * | 2018-10-31 | 2020-05-07 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity |
US20200172539A1 (en) * | 2018-11-15 | 2020-06-04 | Pfizer Inc. | Azalactam Compounds as HPK1 Inhibitors |
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