NZ744870B2 - Fused pyrazole derivatives, preparation method thereof, and use thereof in treatment of cancers, inflammation and immune diseases - Google Patents

Fused pyrazole derivatives, preparation method thereof, and use thereof in treatment of cancers, inflammation and immune diseases

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Publication number
NZ744870B2
NZ744870B2 NZ744870A NZ74487016A NZ744870B2 NZ 744870 B2 NZ744870 B2 NZ 744870B2 NZ 744870 A NZ744870 A NZ 744870A NZ 74487016 A NZ74487016 A NZ 74487016A NZ 744870 B2 NZ744870 B2 NZ 744870B2
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New Zealand
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group
formula
mmol
alkyl
phenoxyphenyl
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NZ744870A
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NZ744870A (en
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Xiangyang Chen
Yucheng Pang
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Beijing Innocare Pharma Tech Co Ltd
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Priority claimed from CN201610066886.9A external-priority patent/CN107021963A/en
Application filed by Beijing Innocare Pharma Tech Co Ltd filed Critical Beijing Innocare Pharma Tech Co Ltd
Publication of NZ744870A publication Critical patent/NZ744870A/en
Publication of NZ744870B2 publication Critical patent/NZ744870B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • 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
    • C07D471/22—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 systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The present invention relates to pyrazole condensed-ring derivatives and preparation method and medicinal application thereof Specifically, the present invention relates to new derivatives shown as the formula (I), medicinal salts thereof or medicinal compositions containing same, and preparation method therefor. The present invention further relates to applications of the derivatives and medicinal salts thereof or medicinal compositions containing the same in preparation of therapeutic agents, especially Bruton tyrosine kinase inhibitor and in preparation of medicines used for treating and/or preventing tumors and immunity-associated diseases. The substituents in formula (I) has the same definition as in description. thod therefor. The present invention further relates to applications of the derivatives and medicinal salts thereof or medicinal compositions containing the same in preparation of therapeutic agents, especially Bruton tyrosine kinase inhibitor and in preparation of medicines used for treating and/or preventing tumors and immunity-associated diseases. The substituents in formula (I) has the same definition as in description.

Description

FUSED PYRAZOLE DERIVATIVES, PREPARATION METHOD THEREOF, AND USE THEREOF IN TREATMENT OF CANCERS, INFLAMMATION AND IMMUNE DISEASES TECHNICAL FIELD The present invention relates to novel fused pyrazole derivatives and their pharmaceutically acceptable salts f or pharmaceutical itions comprising these compounds, and to methods of preparing these compounds. The present invention also relates to use of the fused pyrazole derivatives and their ceutically acceptable salts thereof or the pharmaceutical compositions comprising these compounds in the preparation of therapeutic agents, especially as a Bruton ne kinase inhibitor, and to use of the fused pyrazole derivatives and their pharmaceutically acceptable salts thereof or the pharmaceutical itions in the preparation of ments for treating and/or preventing tumors and inflammatory diseases.
BACKGROUND Bruton tyrosine kinase (BTK) is an important member of Tec tyrosine kinase family, which is present in plasmocytes including B cells, mastocytes and macrophages, and plays a decisive role in the B cell receptor (BCR) mediated signal pathway. When BTK is activated by upstream Src family kinases, it phosphorylates ream phospholipases C (PLC), thereby activating the PI3 and DAG signal pathway. This signal pathway promotes the proliferation, adhesion and survival of cells, and plays an important role in the pment of B cell lymphomas.
By inhibiting the activity of BTK, BTK inhibitors can inhibit the proliferation of B cell lymphoma cells, destroy the adhesion of tumor cells, and promote the apoptosis of tumor cells, so that BTK becomes a drug target of interest in B cells-associated cancers, ally B cell lymphoma and leukemia, for example, non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), and mantle cell lymphoma (MCL), etc. Currently, the only drug with BTK specific inhibition in market is Ibrutinib from Pharmacyclics/JNJ. Ibrutinib is an irreversible small molecule BTK inhibitor, which has icant efficacy on the ent of MCL, CLL, WM, etc., and is safe. Other BTK inhibitors entering clinical trials for targeting cell lymphomas comprise CC-292 from Celgene company, ACP-196 from Acerta company, ONO-4059 from ONO Company, and BGB-3111 from Beigene y, and so on.
In addition to anti-B cell lymphomas and anti-leukemia effects, BTK inhibitors can further inhibit the production of B cell autoantibodies and cytokines. Mutations in BTK can lead to a rare genetic disease – X-Linked Agammaglobulinemia (XLA). Because the function of BTK is inhibited in this disease, resulting in inhibition of the production or maturation of B cells and reduction of the circulating antibodies, the patients are prone to s and even fatal ions.
Pre-clinical animal model studies showed that BTK gene-deficient mice can resist to collageninduced arthritis, and clinical results also demonstrated that Rituxan, an antibody drug for B cell depletion, is efficacious for the ent of immune disorders. Therefore, the BTK inhibitors can also be used for treating autoimmune-related diseases, such as toid tis (RA), systemic lupus erythematosus (SLE), anaphylactic diseases (such as, esophagitis, philic esophagitis), and so on. Currently, there are not yet a BTK specific inhibitor for use in immune es in the market, but several are in clinical stages, for example, CC-292 from Celgene Company, HM-71224 from Hanmi, PRN-1008 from Principia, and a compound from Pharmacyclics.
As BTK plays an important role in a plurality of ing ys, the development of BTK inhibitors has attracted attention from many biopharmaceutical ies. A series of patent applications on BTK tors have been disclosed, including WO2007087068, WO2010126960, 019780, WO2011090760, WO2012135801, WO2012158764, WO2013060098, WO2013081016, 010869, WO2013113097, CN103113375, WO2014068527, WO2014125410, WO2014173289, WO2013118986, WO2015017502, WO2015048689, etc.
However, there is still a need to develop new compounds with better efficacy. With continuous efforts, the inventor designs a compound having the structure of formula (I), and finds that the compounds having such structure exhibit excellent effects and functions.
SUMMARY OF THE INVENTION The present invention is to provide a compound represented by formula (I) or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, mixtures thereof, or a pharmaceutically acceptable salt thereof: wherein: A1, A2 and A3 are each independently selected from the group consisting of CR1 or N; B1 is independently selected from the group consisting of C3-8 cyclic , 3- to 8-membered heterocyclic group, aryl, or heteroaryl, wherein cyclic group, heterocyclic group, aryl or heteroaryl is ally substituted with one or more G1; B2 is independently selected from the group consisting of H, C3-8 cyclic group, 3- to 8- membered heterocyclic group, aryl, or heteroaryl, wherein cyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted with one or more G2; L1 is independently selected from the group consisting of -C0-2 alkyl-, -, -C1-2 alkyl(R5)(OH)-, -C(O)-, -CR5R6O-, 6-, -SCR5R6-, S-, -NR5-, -NR5C(O)-, - C(O)NR5-, -NR5CONR6-, -CF2-, -O-, -S-, -, -NR5S(O)2- or -S(O)2NR5-; L2 is independently selected from the group consisting of -C0-4 alkyl-, -C(O)-, -O-, -NR7-, - NR7C(O)- or -NR7S(O)2-; X is independently selected from the group consisting of C0-4 alkyl, C3-8 cyclic group, 3- to 8- membered heterocyclic group, aryl, or heteroaryl, n alkyl, cyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted with one or more G3; Y is ndently selected from the group consisting of -C(O)-, -NR8C(O)-, -S(O)m- or - NR8S(O)m-; R1 is independently ed from the group consisting of H, D, C0-4 alkyl, halogen or cyano; bond is a double bond or a triple bond; when bond is a double bond, R2, R3 and R4 are each independently selected from the group consisting of H, D, cyano, halogen, alkyl, cyclic group, heterocyclic group, aryl, or heteroaryl, wherein alkyl, cyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted with one or more G4; when bond is a triple bond, R3 and R4 are absent, and R2 is independently selected from the group consisting of H, D, cyano, n, alkyl, cyclic group, heterocyclic group, aryl, or heteroaryl, wherein alkyl, cyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted with one or more G4; wherein R3 and R2 or R3 and R4, together with the carbon atom ed thereto, can form a ring which contains optionally heteroatom(s); R5, R6, R7 and R8 are each independently selected from the group consisting of H, D, C0-8 alkyl, C3-8 cyclic group, 3- to ered heterocyclic group, aryl, or heteroaryl, wherein alkyl, cyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted with one or more G5; G1, G2, G3, G4 and G5 are each independently selected from the group consisting of H, D, halogen, cyano, alkyl, alkenyl, alkynyl, cyclic group, heterocyclic group, aryl, heteroaryl, -OR9, - OC(O)NR9R10, R10, -C(O)NR9R10, -C(O)R9, -NR9R10, O)R10, -NR9C(O)NR10R11, - S(O)mR10 and -NR9S(O)mR10, wherein alkyl, l, alkynyl, cyclic group, cyclic group, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of D, halogen, cyano, C1-8 alkyl, C3-8 cycloalkyl, 3- to 8-membered cyclic group, -OR12, -OC(O)NR12R13, -C(O)OR12, -C(O)NR12R13, -C(O)R12, -NR12R13, -NR12C(O)R13, - NR12C(O)NR13R14, -S(O)mR12, or (O)mR13; R9, R10, R11, R12, R13 and R14 are each independently selected from the group consisting of H, C1-6 alkyl, C1-C6 heteroalkyl, C3-8 cycloalkyl, 3- to 8-membered monocyclic heterocyclic group, monocyclic heteroaryl or monocyclic aryl; and m is 1 or 2.
In an embodiment of the present invention, a nd represented by formula (I) or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, mixtures f and a pharmaceutically acceptable salt thereof is a compound represented by formula (II), or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, mixtures thereof and a pharmaceutically able salt thereof: A2 and A3 are each independently selected from the group consisting of CH or N; B1 is independently selected from the group consisting of C3-8 cyclic group, 3- to 8-membered heterocyclic group, aryl, or heteroaryl, wherein cyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted with one or more G1; B2 is independently ed from the group consisting of H, C3-8 cyclic group, 3- to 8- membered heterocyclic group, aryl, or heteroaryl, wherein cyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted with one or more G2; L1 is independently selected from the group consisting of -C0-2 alkyl-, -CR5R6-, -C1-2 alkyl(R5)(OH)-, -C(O)-, -CR5R6O-, 6-, -SCR5R6-, -CR5R6S-, -NR5-, -NR5C(O)-, - C(O)NR5-, -NR5CONR6-, -CF2-, -O-, -S-, -S(O)m-, -NR5S(O)2- or -S(O)2NR5-; L2 is independently selected from the group consisting of -C0-4 alkyl-, -C(O)-, -O-, -NR7-, - NR7C(O)- or -NR7S(O)2-; X is independently selected from the group consisting of C0-4 alkyl, C3-8 cyclic group, 3- to 8- membered heterocyclic group, aryl, or heteroaryl, wherein alkyl, cyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted with one or more G3; Y is independently selected from the group consisting of -C(O)-, -NR8C(O)-, -S(O)m- or - NR8S(O)m-; bond is a double bond or a triple bond; when bond is a double bond, R2, R3 and R4 are each other independently selected from the group consisting of H, D, cyano, halogen, alkyl, cyclic group, cyclic group, aryl or heteroaryl, wherein alkyl, cyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted with one or more G4; and when bond is a triple bond, R3 and R4 are absent, and R2is ndently selected from the group consisting of H, D, cyano, n, alkyl, cyclic group, heterocyclic group, aryl, or aryl, wherein alkyl, cyclic group, heterocyclic group, aryl or heteroaryl is ally substituted with one or more G4; wherein R3 and R2 or R3 and R4, together with the carbon atom attached thereto, can form a ring which contains optionally heteroatom(s); R5, R6, R7 and R8 are each independently selected from the group consisting of H, D, C0-8 alkyl, C3-8 cyclic group, 3- to 8-membered heterocyclic group, aryl, or heteroaryl, wherein alkyl, cyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted with one or more G5; G1, G2, G3, G4 and G5 are each ndently selected from the group consisting of H, D, halogen, cyano, alkyl, alkenyl, alkynyl, cyclic group, cyclic group, aryl, heteroaryl, -OR9, - OC(O)NR9R10, -C(O)OR10, -C(O)NR9R10, -C(O)R9, -NR9R10, -NR9C(O)R10, O)NR10R11, - S(O)mR10 and -NR9S(O)mR10, wherein alkyl, alkenyl, l, cyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of D, halogen, cyano, C1-8 alkyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclic group, -OR12, -OC(O)NR12R13, -C(O)OR12, -C(O)NR12R13, -C(O)R12, -NR12R13, -NR12C(O)R13, - O)NR13R14, -S(O)mR12, or -NR12S(O)mR13; R9, R10, R11, R12, R13 and R14 are each independently selected from the group consisting of H, C1-6 alkyl, C1-C6 heteroalkyl, C3-8 cycloalkyl, 3- to 8-membered monocyclic cyclic group, monocyclic heteroaryl or monocyclic aryl; and m is 1 or 2.
In another embodiment of the present ion, a compound represented by formula (I) or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, mixtures thereof and a pharmaceutically acceptable salt thereof is a compound represented by a (III), or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, mixtures thereof and a pharmaceutically acceptable salt thereof: (III) wherein: B1 is a phenyl ring or a 6-membered heteroaryl ring; A2, A3, B2, L1, L2, X, Y, bond , R2, R3, R4 and G1 are as defined in claim 1 or 2.
In another embodiment of the present ion, a compound ented by formula (I) or its ers, mesomers, racemates, enantiomers, diastereoisomers, mixtures thereof and a pharmaceutically acceptable salt thereof is a compound represented by formula (IV), or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, es thereof and a pharmaceutically able salt thereof: wherein: Z1 and Z2 are each independently selected from the group consisting of C(Ra), or N; Ra is H or alkyl; n and p are each independently selected from the group consisting of 0, 1 or 2; A2, A3, B1, B2, L1, L2, Y, bond , R2, R3, R4 and G1 are as defined in any one of claims 1-3.
In another embodiment of the present invention, a compound represented by formula (I) or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, mixtures thereof and a pharmaceutically acceptable salt thereof is a compound represented by formula (V), or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, mixtures f and a pharmaceutically acceptable salt thereof: wherein: A2, A3, B1, B2, L1, Y, bond , R2, R3, R4, G1, Z1, Z2, n and p are as defined in any one of claims 1-4.
Representative compounds of the t invention include, but are not limited to: Compound No. Compound ure and Nomenclature 1-(3-(7-(4-(morpholinomethyl)phenyl)-1H-pyrazolo[3,4- c]pyridinyl)piperidinyl)propenone 1-(3-(7-(4-(oxetanoxy)phenyl)-1H-pyrazolo[3,4-c]pyridin yl)piperidinyl)propenone 1-(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridin yl)piperidinyl)propenone (E)(dimethylamino)(3-(7-(4-phenoxyphenyl)-1H- pyrazolo[3,4-c]pyridinyl)piperidinyl)butenone 7-(4-phenoxyphenyl)(1-(ethenylsulfonyl)piperidinyl)-1H- pyrazolo[3,4-c]pyridine 1-(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridin yl)pyrrolidinyl)propenone 1-(4-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridin yl)piperidinyl)propenone N-(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridin yl)phenyl)acrylamide 1-(4-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridin yl)piperazinyl)propenone N-(1-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridin yl)pyrrolidinyl)acrylamide 1-(3-((7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridin yl)amino)pyrrolidinyl)propenone 7-(4-(cyclopentyloxy)phenyl)-1H-pyrazolo[3,4-c]pyridin- -yl)piperidinyl)propenone 1-(4-(7-(4-(pyridinoxy)phenyl)-1H-pyrazolo[3,4-c]pyridin yl)piperidinyl)propenone 1-(4-(7-(2-fluorophenoxyphenyl)-1H-pyrazolo[3,4-c]pyridin- -yl)piperidinyl)propenone 7-(4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4- c]pyridinyl)piperidinyl)propenone 1-(4-(7-(4-(pyrrolidinylmethyl)phenyl)-1H-pyrazolo[3,4- c]pyridinyl)piperidinyl)propenone 1-(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridin yl)piperidinyl)butenone 4-(5-(1-acryloylpyrrolidinyl)-1H-pyrazolo[3,4-c]pyridin yl)-N-(pyridinyl)benzamide 4-(5-(1-(butynoyl)pyrrolidinyl)-1H-pyrazolo[3,4- c]pyridinyl)-N-(pyridinyl)benzamide 1-(3-(7-(4-phenoxyphenyl)-1H-indazolyl)piperidin yl)propenone O O 1-(2-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridin yl)pyrrolidinyl) (22a) (22b) (S)(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridin yl)pyrrolidinyl)propenone 22a and (R)(3-(7-(4- phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidin yl)propenone 22b or their tautomers, mesomers, racemates, enantiomers, diastereoisomers, mixtures thereof and pharmaceutically acceptable salts thereof.
The present ion is further directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound ented by formula (I) or its tautomers, mesomers, racemates, omers, diastereoisomers, mixtures thereof and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
Another aspect of the t invention relates to use of the compound ented by formula (I) or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, es thereof and a pharmaceutically acceptable salt f, or the pharmaceutical composition comprising the same in the ation of Bruton ne kinase inhibitors.
Another aspect of the present invention relates to use of the compound represented by formula (I) or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, mixtures thereof and a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same in the preparation of a medicament for treating and/or preventing tumors, inflammatory diseases, and the like.
The t invention also relates to a method of treating and/or preventing tumors, inflammatory diseases, and the like, comprising administering a therapeutically effective amount of a compound represented by formula (I) or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, mixtures f and a pharmaceutically acceptable salt f, or a pharmaceutical composition comprising the same to a patient in need thereof. r aspect of the present invention relates to a compound represented by formula (I) or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, mixtures thereof and a pharmaceutically acceptable salt thereof for use as a medicament for treating and/or ting tumors, inflammatory diseases, and the like.
DETAILED DESCRIPTION The terms as used in the description and claims have the following gs, unless ise indicated.
The expression "Cx-y" as used herein means the range of carbon atoms, wherein both x and y are an integer. For Example, C3-8 cyclic group means a cyclic group having 3-8 carbon atoms, and -C0-2 alkyl means an alkyl group having 0-2 carbon atoms, wherein -C0 alkyl refers to a single chemical bond.
"Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups having 1-20 carbon atoms, e.g., straight or ed groups having 1-18 carbon atoms, 1- 12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, yl, 1,1- dimethyl-propyl, 1,2-dimethyl-propyl, 2,2-dimethyl-propyl, 1-ethyl-propyl, 2-methyl-butyl, 3- methyl-butyl, n-hexyl, 1-ethylmethyl-propyl, 1,1,2-trimethyl-propyl, 1,1-dimethyl-butyl, 1,2- dimethyl-butyl, methyl-butyl, 1,3-dimethyl-butyl, 2-ethyl-butyl, and any branched isomer thereof, etc. Alkyl can be optionally substituted or unsubstituted.
"Cyclic group" refers to ted or partially unsaturated, mono-cyclic or multi-cyclic hydrocarbon substituents containing 3-12 ring atoms, such as, 3-12, 3-10, or 3-6 ring atoms, or the cyclic group can be a 3-, 4-, 5-, or 6-membered ring. Non-limiting examples of mono-cyclic groups comprise ropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, exadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Cyclic group can be optionally substituted or unsubstituted. ocyclic group" refers to saturated or partially unsaturated, mono-cyclic or multi-cyclic arbon substituents containing 3-20 ring atoms, such as, 3-16, 3-12, 3-10, or 3-6 ring atoms, in which one or more ring atoms are heteroatom(s) selected from the group consisting of en, oxygen and S(O)m (wherein m is an integer from 0 to 2), excluding the case that any ring moiety is -O-O-, -O-S- or - S-S-, and the remainder ring atoms are carbon. Preferably, the heterocyclic group comprises 3-12 ring atoms, of which 1-4 ring atoms are heteroatoms; more ably, the heterocycloalkyl ring contains 3-10 ring atoms; and most ably, the heterocyclic group comprises a 5- or ered ring, wherein 1-4 atoms are heteroatoms, more preferably 1-3 atoms are heteroatoms, and most preferably 1-2 atoms are heteroatoms. Non-limiting examples of monocyclic heterocyclic group comprise pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, sulfomorpholinyl, homopiperazinyl and the like. Multi-cyclic heterocyclic groups comprise those sing spiro-ring, fused-ring, and bridged ring.
"Spiro-heterocyclic group" refers to a 5- to 20-membered, multi-cyclic heterocyclic group wherein a plurality of monocyclic rings shares a common atom (namely, a spiro atom), and wherein one or more ring atoms are heteroatom(s) selected from the group consisting of nitrogen, oxygen, and S(O)m (wherein m is an integer from 0 to 2), and the remainder ring atoms are carbon. The monocyclic rings can contain one or more double bonds, but none of the monocyclic rings has a completely conjugated π- electron system. It is preferably a 6- to 14-membered ring, and more preferably 7- to 10-membered ring. Depending on the number of common spiro-atoms, the spirocycloalkyl groups are fied as mono-spiro heterocyclic groups, bis-spiro heterocyclic groups, or multi-spiro heterocyclic groups, with mono-spirocycloalkyl and bis-spirocycloalkyl preferred. More preferred are 4-/4-membered, embered, 4-/6-membered, 5-/5-membered, or -membered/6-membered piro cycloalkyl groups. Non-limiting examples of spirocycloalkyl groups comprise: and .
"Fused-heterocyclic group" refers to a 5- to 20-membered multi-cyclic heterocyclic group wherein each ring in the system comprises a pair of nt atoms shared with other rings in the system, wherein one or more rings can contain one or more double bonds, but none of the rings comprises a completely conjugated π-electron tem, and wherein one or more ring atoms are heteroatom(s) selected from the group consisting of nitrogen, oxygen, and S(O)m (wherein m is an integer from 0 to 2), and the remainder ring atoms are carbon. It is preferably a 7- to 14-membered ring, and more preferably 7- to 10-membered ring. Depending on the number of the rings, the fused heterocyclic groups are classified as bicyclic, tricyclic, yclic, or polycyclic fused heterocycloalkyl groups, with bicyclic or tricyclic fused heterocyclic groups preferred. More preferred are 5-/5-membered and 5-/6-membered bicyclic fused heterocyclic . miting es of fused heterocyclic groups comprise: and .
The heterocyclic ring can be fused to an aryl, a heteroaryl or a cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclic ring. Non-limiting examples thereof comprise: and the like. The heterocyclic group can be optionally substituted or tituted.
"Aryl" refers to a 6- to 14-membered full carbon mono-cyclic or a fused-polycyclic (i.e., rings sharing a pair of adjacent carbon atoms) group, a clic group (i.e., rings having a pair of adjacent carbon atoms) having conjugated π electron system. It is preferably a 6- to 10-membered aryl, such as, phenyl and naphthyl, and most preferably phenyl. The aryl ring can be fused to a heteroaryl, a heterocyclic or a cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. Non-limiting examples thereof comprise: , .
Aryl can be optionally substituted or unsubstituted. oaryl" refers to a aromatic system having 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms comprise oxygen, sulfur and nitrogen. It is preferably a 5- to 10- membered heteroaryl. More preferably, the heteroaryl is a 5- or ered heteroaryl, such as, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, and the like. The heteroaryl ring can be fused to an aryl, a heterocyclic or a cycloalkyl ring, wherein the ring ed to the parent structure is a heteroaryl ring. Non-limiting examples thereof comprise: and .
Heteroaryl can be optionally substituted or unsubstituted.
"Halogen" refers to fluorine, chlorine, bromine, or iodine.
"Cyano" refers to -CN.
"Optional" or "optionally" means that the event or environment with reference to such term(s) may (but not arily) occur, including the situations that such event or environment occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may be but not necessarily present, including the situations that the heterocyclic group is substituted with the alkyl and that the heterocyclic group is not substituted with the alkyl.
"Substituted" means that one or more hydrogen atoms, preferably up to 5 hydrogen atoms, and more preferably 1-3 en atoms in a group, are each independently substituted with the corresponding number of substituent(s). Apparently, the substituents are merely t in their possible ons, and persons skilled in the art can determine possible or impossible tutions (by experiments or theory) without paying much effort. For example, the binding between an amino or hydroxyl group having free hydrogen and carbon atoms having unsaturated (e.g., olefinic) bond may be unstable.
"Pharmaceutical composition" refers to a e comprising one or more nds as bed herein or a logically/pharmaceutically acceptable salt or prodrug thereof and other chemical components, as well as other components such as, a physiologically/pharmaceutically acceptable carrier and excipient. The pharmaceutical composition aims to promote the administration to a living body and facilitate the absorption of active ingredients, thereby exerting the biological activity.
SYNTHETIC METHOD The present invention r provides a method of preparing the compounds. The compound represented by formula (I) of the present ion can be prepared in according with the following exemplary methods and examples, which should not however be construed as limiting the scope of the present invention in any manner. The ive nds can also be sized by any synthetic technique that is well known by persons skilled in the art, or by a combination of the known s with the methods of the present invention. The product ed in each step can be obtained by any known separation techniques in the art, comprising but not limited to extraction, filtration, distillation, crystallization, chromatography and so on. Starting materials and chemical agents as required by synthesis may be routinely prepared according to tures (available from SciFinder) or commercially available.
The fused pyrazole compounds represented by formula (I) of the present invention can be prepared according to Scheme A: 1) ng a starting material A1 reacted with a precursor g boric acid or borate -L~N-P (wherein L~N-P is a functional group having a protected amino, and P is a protecting group of the amino) via Suzuki coupling reaction to produce A2, or with a precursor bearing an amino L~N-P (wherein L comprises –NH) via Buchwald coupling reaction to produce A2; 2) brominating A2 to produce A3; 3) reacting A3 with a (hetero)aryl boric acid or borate via Suzuki coupling to produce A4; 4) acetylating the amino group in A4 to produce A5; 5) further cyclizing A5 to produce A6; 6) deprotecting the amino group in A6 to produce A7; and 7) derivating the amino group in A7 with a chemical agent containing a functional group capable of reacting with cysteine residue(s) in the binding domain of a kinase ligand (e.g., acryloyl chloride etc.), to produce a target compound A8.
Scheme A: Coupling Brominating Coupling Acetylating ating Deprotecting Amidating Functional group A6 can also be prepared according to Scheme B: subjecting B2 to o Buchwald coupling reaction to produce B3, followed by acetylation, cyclization, and coupling to e an intermediate A6.
Scheme B: tion Coupling ation Cyclization Coupling A6 can also be prepared according to Scheme C: subjecting C1 or C1’ to iodization or bromination, followed by cyclization to produce C3. In ance with the requirements of synthesis, an iodine-containing C3 is subject to a coupling reaction with a (hetero)aryl boric acid (or borate) via Suzuki coupling, following by a second coupling reaction with ((RO)2B-)L~N-P, to produce A6; or a e-containing C3 is subject to a first coupling reaction with ((RO)2B-)L~NP , followed by a second coupling reaction with a (hetero)aryl boric acid (or borate), to produce A6.
Scheme C: Iodization ation Coupling Coupling Bromi zation EXAMPLES The compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by the exemplary methods as bed in the following examples and the associated publications referenced by persons skilled in the art. However, these examples are not to limit the scope of the present invention.
The structure of compounds are identified by nuclear magnetic resonance (NMR) or mass spectrum (MS). NMR measurements are conducted on a Bruker AVANCE-400 or Varian Oxford- 300 NMR instrument, using DMSO-d6, CDC13, CD3OD as solvent, tetramethylsilane (TMS) as an internal standard, and a chemical shift of 10-6ppm.
MS ements are conducted on an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, Model: 62100) or a Shimadzu SQD (ESI) mass ometer (manufacturer: Shimadzu, Model: 2020).
HPLC measurements are conducted on an Agilent 1200 DAD high pressure liquid chromatograph (Sunfirc C18, 150 × 4.6mm, 5 μm chromatographic column), and Waters 2695- 2996 high pressure liquid chromatograph i C18 150 × 4.6mm, 5 μm chromatographic column).
The used silica gel plate is Qingdao Haiyang GF254 silica gel plate. The silica gel plate has a specification of 0.15 mm - 0.2 mm when used in the thin layer chromatography (TLC), and a specification of 0.4 mm-0.5 mm during the separation and purification of product by thin layer chromatography.
Column chromatography usually employs Qingdao Haiyang 200-300 mesh silica gel as carrier.
The known starting materials of the present invention can be prepared by or in accordance with the methods known in the art, or commercially available from ABCR GmbH&Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio, Beijing Ouhe Chemical Company, and so on.
The reactions in the examples are d out under an argon or en atmosphere unless otherwise indicated.
Argon or en atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a 1L volume.
Hydrogen atmosphere means that the on flask is connected to a en balloon having a 1L volume.
Pressurized hydrogenation reaction is carried out by using a GCD-500G high-purity hydrogen generator and 00 medium-pressure hydrogenation ment ble from Beijing Jiawei Kechuang Technology Co., Ltd.
Hydrogenation reaction is usually carried out by vacuuming the reactor and ng it with hydrogen, and the aforesaid steps are ed three times.
Microwave reaction is conducted on a CEM Discover-SP-type microwave reactor.
The reaction temperature in the examples is room temperature ranging from 20ºC to 30ºC unless otherwise ted.
The reaction progress in the examples is monitored with thin layer chromatography (TLC).
The developer system used in the reaction comprises: A: dichloromethane and methanol system; and B: petroleum ether and ethyl acetate system, wherein the volumetric ratio of solvents is adjusted in accordance with the polarity of compounds.
The eluent system in column chromatography and the developer system in thin layer chromatography for use in the purification of compounds comprise: A: dichloromethane and methanol system; and B: petroleum ether and ethyl acetate system, wherein the volumetric ratio of solvents is ed in accordance with the polarity of compounds, and a small amount of triethylamine and an acidic or alkaline reagent may be added for adjustment.
EXAMPLE 1 1-(3-(7-(4-(morpholinomethyl)phenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidinyl)prop- 2-enone Step 1 Step 2 Step 3 Step 4 Step 5 Step 6 Step 7 Step 8 Step 1 Tert-butyl 5-aminomethyl-5',6'-dihydro-[2,3'-dipyridyl]-1'(2'H)-carboxylate Compound 6-chloromethylpyridinamine 1a (568 mg, 4.0 mmol), tert-butyl 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)-5,6-dihydropyridine-1(2H)-carboxylate (1.22 g, 4.0 mmol), cesium ate (3.8 g, 12 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane adduct (146 mg, 0.2 mmol), 1,4-dioxane (30 mL), and water (7 mL) were mixed, degassed, and heated to reflux under nitrogen for 16 hrs. The e was cooled to room temperature and concentrated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 20/1 to 2/1) to e the target compound tert-butyl 5-aminomethyl-5',6'-dihydro-[2,3'-dipyridyl]-1'(2'H)- carboxylate 1b (401 mg, yellow oil), yield: 34%.
MS m/z (ESI):290[M+1] Step 2 utyl 3-(5-aminomethylpyridinyl)piperidincarboxylate Compound tert-butyl 5-aminomethyl-5',6'-dihydro-[2,3'-dipyridyl]-1'(2'H)-carboxylate 1b (401 mg, 0.45 mmol), Pd/C (106 mg), and ethanol (100 mL) were mixed, degassed, and stirred under hydrogen atmosphere at room temperature for 16 hrs. The mixture was filtered and concentrated to remove solvent under reduced pressure to give the crude target product utyl 3-(5-aminomethylpyridinyl)piperidincarboxylate 1c (400 mg, yellow oil) which was used for the next reaction without further cation.
MS m/z (ESI):292[M+1] Step 3 Tert-butyl 3-(5-aminobromomethylpyridinyl)piperidincarboxylate Compound tert-butyl 3-(5-aminomethylpyridinyl)piperidincarboxylate 1c (400 mg, crude), N-bromosuccinimide (244 mg, 1.4 mmol), and dichloromethane (5 mL) were mixed at 0°C, and then stirred at 0°C for 1 hr. Saturated sodium bicarbonate (10 mL) was added and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated to remove solvent under reduced pressure. The residue was purified by column tography on silica gel (petroleum ether/ethyl acetate= 6/1) to give a target product tert-butyl minobromo methylpyridinyl)piperidincarboxylate 1d (290 mg, brown oil), yield: two-step 57%.
MS m/z (ESI):370[M+1] Step 4 Tert-butyl 3-(5-aminomethyl(4-(morpholinomethyl)phenyl)pyridinyl)piperidin carboxylate Compound utyl 3-(5-aminobromomethylpyridinyl)piperidincarboxylate 1d (300 mg, 0.81 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenmethyl)morpholine (295 mg, 0.97 mmol), cesium carbonate (792 mg, 2.4 mmol), [1,1'- bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane adduct (50 mg, 0.2 mmol), 1,4-dioxane (15 mL), and water (5 mL) were mixed, degassed, and heated to reflux under en for 16 hrs. The mixture was cooled to room temperature and concentrated to remove solvent under reduced pressure. The e was purified by column chromatography on silica gel (petroleum ethyl acetate= 20/1 to 1/1) to produce a target compound tert-butyl 3-(5-aminomethyl (4-(morpholinomethyl)phenyl)pyridinyl)piperidincarboxylate 1e (300 mg, yellow oil), yield: MS m/z (ESI):467[M+1] Step 5 utyl 3-(5-acetamidomethyl(4-(morpholinomethyl)phenyl)pyridinyl)piperidin- 1-carboxylate Compound tert-butyl 3-(5-aminomethyl(4-(morpholinomethyl)phenyl)pyridin yl)piperidincarboxylate 1e (300 mg, 0.64 mmol), acetic anhydride (130 mg, 1.3 mmol), and anhydrous toluene (20 mL) were mixed, heated to 100ºC under stirring for 14 hrs. The mixture was cooled to room temperature and concentrated to remove solvent under reduced pressure to give a target crude product tert-butyl 3-(5-acetamidomethyl(4-(morpholinomethyl)phenyl)pyridin- 2-yl)piperidincarboxylate 1f (350 mg, yellow viscous oil) which was directly used in the next reaction without further cation.
MS m/z (ESI):509[M+1] Step 6 Tert-butyl 3-(7-(4-(morpholinomethyl)phenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidin carboxylate A mixture of tert-butyl 3-(5-acetamidomethyl(4-(morpholinomethyl)phenyl)pyridin eridincarboxylate 1f (350 mg, crude), acetic anhydride (208 mg, 2.0 mmol), potassium e (87 mg, 0.88 mmol), and e (20 mL) was heated to 78ºC. Isoamyl nitrite (117 mg, 1.0 mmol) was added immediately and the resulting mixture was stirred for 18 hrs. The mixture was cooled to room temperature and concentrated to remove t under reduced pressure. The residue was dissolved in a mixture of water (5 mL), and ethanol (15 mL) and lithium hydroxide monohydrate (100 mg) was added. The mixture was stirred at room temperature for 2 hrs and concentrated to remove solvent under reduced pressure. The residue was dispersed in water (10 mL), and extracted with ethyl acetate (50 mL×3). The c phases were combined, dried over anhydrous sodium e, filtered to remove the desiccant, and concentrated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 1/1 to 1/2) to give a target product tert-butyl 3-(7-(4- (morpholinomethyl)phenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidincarboxylate 1g (130 mg, yellow solid), yield: two-step 40%.
MS m/z (ESI):478[M+1] Step 7 -(piperidinyl)-1H-pyrazolo[3,4-c]pyridinyl)phenmethyl)morpholine Compound tert-butyl 3-(7-(4-(morpholinomethyl)phenyl)-1H-pyrazolo[3,4-c]pyridin yl)piperidincarboxylate 1g (130 mg, 0.27 mmol), trifluoroacetic acid (3 mL), and dichloromethane (3 mL) were mixed and stirred at room temperature for 14 hrs. Saturated sodium bicarbonate solution (30 mL) was added, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/methanol = 10/1) to give a target product 4-(4-(5-(piperidinyl)-1H-pyrazolo[3,4-c]pyridinyl)phenmethyl)morpholine 1h (100 mg, yellow viscous oil), yield: 98%.
MS m/z (ESI):378[M+1] Step 8 1-(3-(7-(4-(morpholinomethyl)phenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidinyl)prop- 2-enone Compound 4-(4-(5-(piperidinyl)-1H-pyrazolo[3,4-c]pyridinyl)phenmethyl)morpholine 1h (0.15 g, 0.40 mmol), yl chloride (91 mg, 0.56 mmol), solid sodium bicarbonate (86 mg, 0.86 mmol), water (5 mL), and ydrofuran (15 mL) were mixed and d at room temperature for 2 hrs. The mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/methanol = 10/1) to give a target t 1-(3-(7- rpholinomethyl)phenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidinyl)propenone 1 (20 mg, white solid), yield: 23%.
MS m/z (ESI):432[M+1] 1H NMR (400 MHz, CD 3OD) δ 8.30 - 8.22 (m, 3H), 7.77 (dd, J = 8.3, 2.3 Hz, 2H), 7.73 (d, J = 10.0 Hz, 1H), 4.79 (m, 0.5H), 4.52 (m, 2.5H), 4.17 (m, 1H), 4.01 (m, 2H), 3.84 (m, 2H), 3.53 (dd, J = 13.3, 11.0 Hz, 1H), 3.36 (m, 2H), 3.29 - 2.98 (m, 3H), 2.93 - 2.78 (m, 1H), 2.19 (s, 3H), 2.15 (s, 1H), 2.08 (s, 1H), 1.95 (d, J = 3.3 Hz, 1H), 1.78 - 1.62 (m, 1H).
EXAMPLE 2 1-(3-(7-(4-(oxetanoxy)phenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidinyl)propen- 1-one e 2 was synthesized following the procedures in Example 1, except that 4-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)phenmethyl)morpholine was replaced with 4,4,5,5- tetramethyl(4-(oxetanoxy)phenyl)-1,3,2-dioxaborolane in Step 4.
MS m/z (ESI):405[M+1] 1H NMR (400 MHz, CDCl 3) δ 11.04 (s, 1H), 8.15 (d, J = 6.9 Hz, 1H), 8.00 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 12.8 Hz, 1H), 6.98 - 6.82 (m, 2H), 6.68 (dd, J = 16.6, 10.7 Hz, 1H), 6.31 (t, J = .1 Hz, 1H), 5.69 (dd, J = 27.8, 10.4 Hz, 1H), 5.31 (s, 1H), 5.09 - 4.98 (m, 2H), 4.89 - 4.74 (m, 2.5H), 4.70 (d, J = 11.4 Hz, 0.5H), 4.29 (d, J = 12.3 Hz, 0.5H), 4.05 (d, J = 13.3 Hz, 0.5H), 3.51 (t, J = 12.1 Hz, 0.5H), 3.20 (dd, J = 29.8, 16.8 Hz, 2H), 2.83 (t, J = 12.3 Hz, 0.5H), 2.22 (d, J = 11.2 Hz, 1H), 2.14 - 1.97 (m, 1H), 1.89 (s, 1H), 1.71 (s, 1H).
EXAMPLE 3 1-(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidinyl)propenone Step 1 Example 3a was synthesized following the procedures described in Steps 1-7 of e 1, except that 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenmethyl)morpholine was replaced with (4-phenoxyphenyl) boric acid in Step 4.
MS m/z (ESI):371[M+1] 1H NMR (400 MHz, CD 3OD) δ 8.35 - 8.28 (m, 1H), 8.10 (d, J = 8.7 Hz, 2H), 7.78 (d, J = 12.2 Hz, 1H), 7.52 - 7.40 (m, 2H), 7.23 (dd, J = 7.8, 4.2 Hz, 3H), 7.18 - 7.09 (m, 2H), 3.68 (d, J = 10.1 Hz, 1H), 3.47 (d, J = 11.6 Hz, 3H), 3.22 - 3.09 (m, 1H), 2.26 (d, J = 12.9 Hz, 1H), 2.17 - 1.92 (m, Step 1 nd 7-(4-phenoxyphenyl)(piperidinyl)-1H-pyrazolo[3,4-c]pyridine 3a (0.13 g, 0.40 mmol), acryloyl chloride (34 mg, 0.37 mmol), solid sodium bicarbonate (63 mg, 0.75 mmol), water (5 mL), and tetrahydrofuran (15 mL) were mixed and stirred at room temperature for 2 hrs.
The mixture was extracted with ethyl acetate 3). The organic phases were combined, dried over ous sodium e, filtered to remove the desiccant, and trated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/methanol = 10/1) to give a target t 3 1-(3-(7-(4-phenoxyphenyl)-1H- pyrazolo[3,4-c]pyridinyl)piperidinyl)propenone (120 mg, white solid), yield: 83%.
MS m/z (ESI):425[M+1] 1H NMR (400 MHz, CDCl 3) δ 10.81 (brs, 1H), 8.18 (s, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.49 (s, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.21 (t, J = 6.9 Hz, 3H), 7.13 (d, J = 7.9 Hz, 2H), 6.68 (d, J = 7.0 Hz, 1H), 6.38 - 6.26 (m, 1H), 5.69 (dd, J = 25.2, 10.5 Hz, 1H), 4.84 (s, 0.5H), 4.71 (d, J = 11.9 Hz, 0.5H), 4.30 (d, J = 13.5 Hz, 0.5H), 4.05 (d, J = 12.8 Hz, 0.5H), 3.57 - 3.48 (m, 0.5H), 3.28 - 3.12(m, 2H), 2.84 - 2.74(m, 0.5H), 2.25 - 2.16(m, 1H), 2.11 - 2.0(s, 1H), 1.95 - 1.85(m, 1H), 1.75 - 1.65(m, EXAMPLE 4 (E)(dimethylamino)(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridin yl)piperidinyl)butenone N N Compound 7-(4-phenoxyphenyl)(piperidinyl)-1H-pyrazolo[3,4-c]pyridine 3a (100 mg, 0.28 mmol), (E)(dimethylamino)butenic acid (53 mg, 0.32 mmol), 2-(7-azobenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate (154 mg, 0.41 mmol), triethylamine (82 mg, 0.81 mmol), and N,N-dimethylformamide (15 mL) were mixed and stirred at room temperature for 3 hrs. The mixture was desolventized under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/methanol = 30/1 to 10/1) to give a target product (E)(dimethylamino)(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidin yl)butenone 4 (45 mg, white solid), yield: 33%.
MS m/z (ESI):482[M+1] 1H NMR (300 MHz, DMSO-d 6) δ 13.55 (brs, 1H), 8.26 (s, 3H), 7.60 (s, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.31 - 7.06 (m, 5H), 6.59 (s, 2H), 4.48 (s, 1H), 4.23 (s, 1H), 3.13 - 2.97 (m, 5H), 2.21 (s, 7H), 2.08 - 1.96 (m, 1H), 1.88 (d, J = 13.2 Hz, 1H), 1.70 - 1.50 (m, 1H).
EXAMPLE 5 7-(4-phenoxyphenyl)(1-(ethenylsulfonyl)piperidinyl)-1H-pyrazolo[3,4-c]pyridine Compound 7-(4-phenoxyphenyl)(piperidinyl)-1H-pyrazolo[3,4-c]pyridine 3a (100 mg, 0.27 mmol), roethanesulfonyl chloride (52 mg, 0.32 mmol), triethylamine (82 mg, 0.81 mmol), and dichloromethane (3 mL) were mixed and stirred for at room temperature for 1 hr. The mixture was concentrated to remove solvent under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ethyl acetate = 1/1 to 1/3) to give a target product 7-(4-phenoxyphenyl)(1-(ethenylsulfonyl)piperidinyl)-1H-pyrazolo[3,4-c]pyridine 5 (20 mg, white solid), yield: 16%.
MS m/z (ESI):461[M+1] 1H NMR (400 MHz, CDCl 3) δ 8.21 (s, 1H), 8.01 (d, J = 8.3 Hz, 2H), 7.59 (s, 1H), 7.43 (dd, J = 8.4, 7.5 Hz, 2H), 7.22 (dd, J = 7.9, 6.4 Hz, 3H), 7.17 - 7.09 (m, 2H), 6.51 (dd, J = 16.7, 9.9 Hz, 1H), 6.27 (d, J = 16.6 Hz, 1H), 6.05 (d, J = 9.9 Hz, 1H), 3.95 - 3.86 (m, 1H), 3.75 - 3.79 (m, 1H), 3.20 - 3.10 (m, 2H), 2.90 - 2.75 (m, 1H), 2.20 - 2.09 (m, 1H), 1.99 - 1.85 (m, 2H), 1.65 - 1.50(m, EXAMPLE 6 1-(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidinyl)propenone Step 1 Step 2 Step 3 Step 4 Step 5 Step 6 Step 7 Step 8 Step 1 6-chloroiodomethylpyridinamine Compound 6-chloromethylpyridinamine 6a (6.75 g, 47.3 mmol), N-iodosuccinimide (12.95 g, 57.6 mmol), and N,N-dimethylformamide (100 mL) were mixed at 0°C and stirred at room temperature for 15 hrs. Next, water (100 ml) was added, and the mixture was extracted with ethyl acetate (150 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated to remove solvent under d pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate= 10/1) to give a target t 6-chloroiodomethylpyridinamine 6b (6.5 g, yellow solid), yield: MS m/z (ESI):269[M+1] Step 2 6-chloromethyl(4-phenoxyphenyl)pyridine amine Referring to the procedure for 1e of Example 1, 1,6-chloroiodomethylpyridinamine 6b (3.0 g, 11.2 mmol) was used as starting material to give a target product 6-chloromethyl (4-phenoxyphenyl)pyridine amine 6c (3.5 g, yellow , yield: 100%.
MS m/z (ESI):311[M+1] Step 3 N-(6-chloromethyl(4-phenoxyphenyl)pyridine acetamide Referring to the ure for 1f of Example 1, 6-chloromethyl(4- phenoxyphenyl)pyridinamine 6c (3.5 g, 11.2 mmol) was used as starting material to give a target product N-(6-chloromethyl(4-phenoxyphenyl)pyridinyl)acetamide 6d (4.0 g, yellow solid), yield: 100%.
MS m/z (ESI):353[M+1] Step 4 -chloro(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridine Referring to the procedure for 1g of Example 1, N-(6-chloromethyl(4- phenoxyphenyl)pyridine yl)acetamide 6d (3.4 g, 9.6 mmol) was used as starting material to give a target product 5-chloro(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridine 6e (1.5 g, yellow solid), yield: 40%.
MS m/z (ESI):322[M+1] Step 5 utyl 3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)-2,5-dihydro-1H- pyrrolecarboxylate Referring to the procedure for 1b of Example 1, ro(4-phenoxyphenyl)-1H- pyrazolo[3,4-c]pyridine 6e (850 mg, 2.64 mmol), and utyl 3-(4,4,5,5-tetramethyl-1,3,2- orolanyl)-2,5-dihydro-1H-pyrrolecarboxylate (1.95 g, 6.6 mmol) were used as starting materials to give a target product tert-butyl 3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridin yl)-2,5-dihydro-1H-pyrrolecarboxylate 6f (700 mg, yellow solid), yield: 58%.
MS m/z (ESI):455[M+1] Step 6 Tert-butyl 3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidine carboxylate Referring to the procedure for 1c of Example 1, tert-butyl 3-(7-(4-phenoxyphenyl)-1H- pyrazolo[3,4-c]pyridinyl)-2,5-dihydro-1H- pyrrolecarboxylate 6f (700 mg, 1.54 mmol) was used as starting material to give a target product tert-butyl 3-(7-(4-phenoxyphenyl)-1H- pyrazolo[3,4-c]pyridinyl) pyrrolidinecarboxylate 6g (270 mg, yellow solid), yield: 39%.
MS m/z (ESI):457[M+1] Step 7 7-(4-phenoxyphenyl)(pyrrolidinyl)-1H-pyrazolo[3,4-c]pyridine Referring to the procedure for 1h of Example 1, tert-butyl 3-(7-(4-phenoxyphenyl)-1H- pyrazolo[3,4-c]pyridinyl)pyrrolidinecarboxylate 6g (250 mg, 0.327 mmol) was used as starting material to give a target product tert-butyl 7-(4-phenoxyphenyl)(pyrrolidinyl)-1H- pyrazolo[3,4-c]pyridine 6h (95 mg, yellow solid), yield: 82%.
MS m/z (ESI):357[M+1] Step 8 1-(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidinyl)propenone Referring to the procedure for 1 of Example 1, 1,7-(4-phenoxyphenyl)(pyrrolidinyl)- 1H-pyrazolo[3,4-c]pyridine 6h (95 mg, 0.267 mmol) was used as starting material to give a target product 1-(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidinyl)propen one 6 (45 mg, yellow solid), yield: 82%.
MS m/z (ESI):411[M+1] 1H NMR (400 MHz, CDCl 3) δ 10.86 (brs, 1H), 8.18 (s, 1H), 7.99 (t, J = 9.3 Hz, 2H), 7.50 (d, J = 8.2 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.20 (dd, J = 11.5, 8.7 Hz, 3H), 7.15 - 7.09 (m, 2H), 6.58 - 6.36 (m, 2H), 5.71 (ddd, J = 14.7, 10.0, 2.3 Hz, 1H), 4.20 - 4.07 (m, 1H), 4.00 - 3.60 (m, 4H), 2.58 - 2.30 (m, 2H).
EXAMPLE 7 1-(4-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidinyl)propenone O Example 7 was synthesized ing the procedures in e 6, except that tert-butyl 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-2,5-dihydro-1H-pyrrolecarboxylate was replaced with utyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-5,6-dihydropyridine-1(2H)- carboxylate in Step 5.
MS m/z (ESI):371[M+1] 1H NMR (400 MHz, DMSO-d 6) δ s, 1H), 8.23 (s, 1H), 8.09 - 8.08(m, 2H), 7.57 - 7.44(m, 3H), 7.23 - 7.11(m, 5H), 6.90 - 6.84 (m, 1H), 6.13(d, J = 12.8 Hz, 1H), 5.68 (d, J = 10.4 Hz, 1H), 4.62 - 4.59 (m, 1H), 4.23 - 4.19 (m, 1H), 3.02 - 3.12(m, 2H), 2.83 - 2.77(m, 1H), 2.02 - 1.99(m, 2H), 1.76 - 1.70 (m, 2H).
EXAMPLE 8 N-(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)phenyl)acrylamide Step 1 Step 2 Step 1 4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)aniline Referring to the procedure for 1b of Example 1, 5-chloro(4-phenoxyphenyl)-1H- pyrazolo[3,4-c]pyridine (100 mg, 0.34 mmol), and (3-aminophenyl)boric acid 6e (51 mg, 0.37 mmol) were used as starting materials to give a target product 3-(7-(4-phenoxyphenyl)-1H- pyrazolo[3,4-c]pyridinyl)aniline 8b (80 mg, grey solid), yield: 68%.
MS m/z (ESI):379[M+1] Step 1 N-(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)phenyl)acrylamide Referring to the procedure for 1 of Example 1, 3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4- dinyl)aniline 8b (80 mg, 0.21 mmol) was used as ng material to give N-(3-(7-(4- phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)phenyl)acrylamide 8 (13 mg, yellow solid), yield: MS m/z (ESI):433[M+1] 1H NMR (400 MHz, DMSO-d 6) δ 13.82 (s, 1H), 10.28 (s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.23 - 8.19 (m, 3H), 7.89 - 7.79 (m, 2H), 7.49 - 7.43 (m, 3H), 7.25 - 7.15 (m, 5H), 6.50 - 6.46 (m, 1H), 6.31 - 6.27 (m, 1H), 5.79 - 5.77 (m, 1H).
EXAMPLE 9 1-(4-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperazinyl)propenone Step 1 Step 2 Step 3 Step 4 Step 1 -chloro(4-phenoxyphenyl)(tetrahydro-2H-pyranyl)-1H-pyrazolo[3,4-c]pyridine Compound 5-chloro(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridine 9a (500 mg, 1.56 mmol), 3,4-dihydro-2H-pyrane (393 mg, 4.68 mmol), and dichloromethane (20 mL) were mixed at 0°C, and then p-toluenesulfonic acid (50 mg, 0.29 mmol) was added. The mixture was d at room ature for 15 hrs. A saturated solution of sodium bicarbonate (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL×3). The c phases were combined, dried over anhydrous sodium e, filtered to remove the desiccant, and concentrated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate= 5/1) to give a target product 5-chloro(4-phenoxyphenyl) (tetrahydro-2H-pyranyl)-1H-pyrazolo[3,4-c]pyridine 9b (350 mg, pale yellow solid), yield: MS m/z (ESI): 406[M+1] Step 2 tert-butyl 4-(7-(4-phenoxyphenyl)(tetrahydro-2H-pyranyl)-1H-pyrazolo[3,4-c]pyridin- -yl)piperazine carboxylate Compound ro(4-phenoxyphenyl)(tetrahydro-2H-pyranyl)-1H-pyrazolo[3,4- c]pyridine 9b (350 mg, 0.864 mmol), tert-butylpiperazinecarboxylate (344 mg, 1.73 mmol), cesium carbonate (562 mg, 1.73 mmol), (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'- biphenyl)[2-(2-aminoethylphenyl)] palladium (II) chloride methyl tert-butyl ether adduct (68 mg, 0.09 mmol), and 1,4-dioxane (20 mL) were mixed, degassed, and heated in microwave at 150°C under nitrogen for 5 hrs. The mixture was cooled to room temperature, and concentrated to remove solvent under reduced pressure. The e was purified by column chromatography on silica gel (dichloromethane/methanol = 20/1), to produce a target compound utyl 4-(7-(4- yphenyl)(tetrahydro-2H-pyranyl)-1H-pyrazolo[3,4-c]pyridinyl)piperazine carboxylate 9c (50 mg, yellow oil), yield: 18%.
MS m/z (ESI):556[M+1] Step 3 7-(4-phenoxyphenyl)(piperazinyl)-1H-pyrazolo[3,4-c]pyridine Compound tert-butyl 4-(7-(4-phenoxyphenyl)(tetrahydro-2H-pyranyl)-1H- pyrazolo[3,4-c]pyridinyl)piperazinecarboxylate 9c (50 mg, 0.0899 mmol), and dichloromethane (3 mL) were mixed, and then a solution of hydrogen chloride in ethanol (4 M, 1 mL, 4 mmol) was added. The mixture was stirred at room temperature for 14 hrs, and concentrated to remove solvent under reduced pressure to give a target product 7-(4-phenoxyphenyl) (piperazinyl)-1H-pyrazolo[3,4-c]pyridine 9d (crude, pale yellow solid) which was directly used in the next reaction without further purification.
MS m/z (ESI):372[M+1] Step 4 1-(4-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperazinyl)propenone Referring to the procedure for 1 of Example 1, 7-(4-phenoxyphenyl)(piperazinyl)-1H- lo[3,4-c]pyridine 9d ) was used as the starting material to give 1-(4-(7-(4- phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperazinyl)propenone 9 (10 mg, nearly white solid), yield: two-step 26%.
MS m/z (ESI):426[M+1] 1H NMR (400 MHz, CDCl 3) δ 10.62 (s, 1H),8.02 (t, J = 18.6 Hz, 3H), 7.42(t, J = 7.9 Hz, 2H), 7.16 (dd, J = .2 Hz, 5H), 6.89 (s, 1H), 6.66 (dd, J =16.8,10.5 Hz, 1H), 6.47 - 6.29 (m, 1H), 5.78 (d, J = 10.6 Hz, 1H), 3.89 (d, J =51.8 Hz, 4H), 3.61 (d, J = 30.3 Hz, 4H).
EXAMPLE 10 N-(1-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidinyl)acrylamide Example 10 was synthesized following the procedures in Example 9, except that tert-butyl piperazinecarboxylate was replaced with tert-butyl pyrrolidinyl carbamate in Step 2.
MS m/z (ESI):426[M+1] 1H NMR (400 MHz, CDCl 3) δ 10.42 (s, 1H), 7.99 (d, J = 8.7 Hz, 3H), 7.41 (t, J = 8.0 Hz, 2H), 7.16 (dt, J = 8.6, 7.7 Hz, 4H), 6.57 (s, 1H), 6.35 (dd, J = 16.9, 1.2 Hz, 1H), 6.21 - 5.84 (m, 2H), .68 (dd, J = 10.3, 1.2 Hz, 1H), 4.80 (s, 1H), 3.92 - 3.56 (m, 4H), 2.43 (dd, J = 13.5, 6.5 Hz, 1H), 2.13 (d, J = 4.8 Hz, 1H). 1-(3-((7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)amino)pyrrolidinyl)prop enone Example 11 was synthesized following the procedures in Example 9, except that tert-butyl piperazinecarboxylate was replaced with tert-butyl 3-aminopyrrolidinecarboxylate in Step 2.
MS m/z 426[M+1] 1H NMR (400 MHz, CD 3OD) δ 8.07 - 7.93 (m, 2H), 7.43 (t, J = 8.0 Hz, 2H), 7.24 - 7.06 (m, 4H), 6.65 (ddd, J = 27.4, 24.5, 16.1 Hz, 2H), 6.29 (ddd, J = 16.9, 7.6, 2.0 Hz, 1H), 5.75 (ddd, J = 16.4, 10.4, 1.9 Hz, 1H), 4.61 - 4.44 (m, 1H), 4.09 (dd, J = 10.6, 6.1 Hz, 1H), 3.99 - 3.85 (m, 1H), 3.78 (dt, J = 15.1, 6.9 Hz, 1H), 3.63 (ddd, J = 25.3, 14.2, 6.2 Hz, 2H), 2.25 (m, 3H).
EXAMPLE 12 1-(4-(7-(4-(pyridinoxy)phenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidinyl)propen- 1-one NH2 NH2 NH2 N N N Br Cl N Step 1第一步 N Step 2第二步 N Step 3第三步 Boc Boc N 12a 12b 12c Boc NH2 NH N Step 5 Step 6 Step 4 第五步 N 第四步 第六步 N N Boc O Boc O 12e 12f N N NH NH N Step 7第七步 Step 8第八步 N N N N Boc O HN O O 12g O 12h 12 Example 12 was synthesized following the procedures in Example 1, except that tert-butyl 3- ,5-tetramethyl-1,3,2-dioxaborolanyl)-5,6-dihydropyridine-1(2H)-carboxylate was replaced with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3,6-dihydropyridine- 1(2H)-carboxylate in Step 1, and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)phenmethyl)morpholine was replaced with 4,4,5,5-tetramethyl(4-(oxetanoxy)phenyl)- 1,3,2-dioxaborolane in Step 4.
MS m/z (ESI):417[M+1] 1H NMR (400 MHz, DMSO-d 6) δ 13.62 (s, 1H), 8.21 (s, 1H), 8.02 (d, J = 7.0 Hz, 2H), 7.51 (s, 1H), 7.08 (d, J = 8.7 Hz, 2H), 6.88 (dd, J = 16.7, 10.5 Hz, 1H), 6.13 (dd, J = 16.7, 2.5 Hz, 1H), .69 (dd, J = 10.4, 2.5 Hz, 1H), 4.93 (dd, J = 7.1, 4.5 Hz, 1H), 4.61 (d, J = 12.4 Hz, 1H), 4.21 (d, J = 12.6 Hz, 1H), 3.23 (t, J = 12.2 Hz, 1H), 3.09 (s, 1H), 2.80 (s, 1H), 1.99 (dd, J = 8.5, 5.5 Hz, 4H), 1.83 - 1.55 (m, 8H).
EXAMPLE 13 1-(4-(7-(4-(pyridinoxy)phenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidinyl)propen- 1-one Br O N O N 第一步Step 1 Br Step 2第二步 O 第三步Step 3 O N OH O 13a 13b 13c 13d NHAc NH N N Step 4第四步 O N Step 5 O N O N 第五步 O N Step 6第六步 O O 13e 13f N NH N 第七步Step 7 N HN O N 13g 13 Step 1 2-(4-bromophenoxy)pyridine Compound 4-bromophenol 13a (5.00 g, 28.9 mmol), 2-bromopyridine (4.60 g, 28.9 mmol), copper powder (184 mg, 2.89 mmol), cuprous iodide (550 mg, 2.89 mmol), potassium carbonate (11.9 g, 86.7 mmol), and N-methylpiperidinone (30 mL) were mixed and heated to 150°C under stirring for 15 hrs. The mixture was cooled to room temperature, and then water (90 mL) was added.
The mixture was extracted with romethane (80 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the ant, and concentrated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate= 5/1) to give a target product 2-(4-bromophenoxy)pyridine 13b (2.60 g, pale yellow oil), yield: 36%.
MS m/z (ESI): 250, 252[M+1] Step 2 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy)pyridine nd romophenoxy)pyridine 13b (1.3 g, 5.24 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-di(1,3,2-dioxaborolanyl) (1.59 g, 6.28 mmol), potassium acetate (1.03 g, 10.50 mmol), bis(diphenylphosphine)ferrocene]palladium dichloride (380 mg, 0.524 mmol), and 1,4-dioxane (70 mL) were mixed, degassed, and heated at 90°C under nitrogen for 15 hrs. The mixture was cooled to room temperature, and concentrated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl e= 10/1), to produce a target compound 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)phenoxy)pyridine 13c (1.30 g, yellow oil), yield: 79%.
MS m/z (ESI): 298[M+1] Steps 3 to 7 1-(4-(7-(4-(pyridinoxy)phenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidinyl)propen- 1-one 13 was prepared following the procedures described in Steps 4 to 8 of Example 12, except that 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenmethyl)morpholine and tert-butyl 3- (5-aminobromomethylpyridinyl)piperidincarboxylate were replaced with 2-(4- ,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy)pyridine and tert-butyl 4-(5-amino bromomethylpyridinyl)piperidincarboxylate in Step 3.
MS m/z 426[M+1] 1H NMR (400 MHz, CD 3OD) δ 8.19 (s, 1H), 8.06 (d, J = 7.0 Hz, 2H), 7.59 (s, 1H), 7.41 (dd, J = 15.1, 8.2 Hz, 1H), 7.25 (d, J = 8.5 Hz, 2H), 6.88 (dt, J = 19.0, 8.5 Hz, 4H), 6.24 (dd, J = 16.8, 1.4 Hz, 1H), 5.77 (d, J = 10.7 Hz, 1H), 4.77 (d, J = 13.0 Hz, 1H), 4.30 (d, J = 13.1 Hz, 1H), 3.38 (s, 1H), 3.21 (s, 1H), 2.93 (t, J = 12.6 Hz, 1H), 2.14 (s, 2H), 1.91 (s, 2H).
EXAMPLE 14 1-(4-(7-(2-fluorophenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidinyl)prop enone F O Br F O F F O O N 第一步Step 1 Br Step 2第二步 O 第三步Step 3 F O OH O 14a 14b 14c 14d NHAc NH N N Step 4第四步 O N O N Step 6 F O 第五步Step 5 第六步 F O O O 14e 14f N NH N 第七步Step 7 N HN F O F O 14g 14 Step 1 1-bromofluorophenoxybenzene Compound robromophenol 14a (3.00 g, 15.7 mmol), phenylboronic acid (3.82 g, 31.4 mmol), cupric acetate (2.85 g, 15.7 mmol), triethylamine (4.8 g, 47.1 mmol), molecular sieve (5 g), and dichloromethane (120 mL) were mixed and stirred at room temperature for 15 hrs. The mixture was filtered to remove the molecular sieve, and desolventized under d pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate= 5/1) to give a target product 1-bromofluorophenoxybenzene 14b (3.30 g, white solid), yield: 78%. 1H NMR (400 MHz, CDCl 3) δ 7.48 (t, J = 8.3 Hz, 1H), 7.41 (t, J = 7.9 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.80 (dd, J = 9.8, 2.7 Hz, 1H), 6.73 (dd, J = 8.8, 2.7 Hz, 1H).
Step 2 2-(2-fluorophenoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Following the synthetic procedures for 12c in Example 12, 1-bromofluoro phenoxybenzene (3.30 g, 12.3 mmol) was used as ng material to produce luoro phenoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 13c (1.40 g, pale yellow solid), yield: 1H NMR (400 MHz, CDCl 3) δ 7.73 - 7.67 (m, 1H), 7.40 (t, J = 7.9 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 7.8 Hz, 2H), 6.78 (dd, J = 8.3, 2.2 Hz, 1H), 6.64 (dd, J = 10.7, 2.2 Hz, 1H), 1.37 (s, 12H).
Steps 3 to 7 1-(4-(7-(2-fluorophenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidinyl)prop enone 14 was prepared following the procedures described in Steps 4 to 8 of Example 12, except that 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenmethyl)morpholine and tert-butyl 3- (5-aminobromomethylpyridinyl)piperidincarboxylate were replaced with 2-(2-fluoro- 4-phenoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and utyl 4-(5-aminobromo methylpyridinyl)piperidincarboxylate in Step 3.
MS m/z (ESI):443[M+1] 1H NMR (400 MHz, CD 3OD) δ 8.17 (s, 1H), 7.75 (t, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.25 (t, J = 7.4 Hz, 1H), 7.21 - 7.11 (m, 2H), 7.01 (dd, J = 8.5, 2.0 Hz, 1H), 6.89 (ddd, J = 27.5, 14.2, 6.4 Hz, 2H), 6.23 (dd, J = 16.8, 2.0 Hz, 1H), 5.77 (dd, J = 10.7, 1.9 Hz, 1H), 4.76 (d, J = 12.5 Hz, 1H), 4.29 (d, J = 14.0 Hz, 1H), 3.35 (d, J = 11.0 Hz, 1H), 3.21 (t, J = 11.8 Hz, 1H), 2.92 (t, J = 12.7 Hz, 1H), 2.13 (s, 2H), 1.89 (td, J = 12.2, 5.3 Hz, 2H).
EXAMPLE 15 1-(4-(7-(4-(3-fluorophenoxyl)phenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidinyl)prop- 2-enone O was prepared following the ures of Example 14, except that 3-fluorobromophenol and phenylboronic acid were ed with p-bromophenol and m-fluorophenylboronic acid in Step 1.
MS m/z (ESI):443[M+1] 1H NMR (400 MHz, CD 3OD) δ 8.38 (s, 1H), 8.22 (dd, J = 5.0, 1.3 Hz, 1H), 8.13 (d, J = 7.7 Hz, 2H), 7.99 - 7.82 (m, 2H), 7.42 (d, J = 8.6 Hz, 2H), 7.23 (dd, J = 6.8, 5.4 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.87 (dd, J = 16.8, 10.7 Hz, 1H), 6.25 (dd, J = 16.8, 2.0 Hz, 1H), 5.79 (dd, J = 10.7, 2.0 Hz, 1H), 4.81 (d, J = 13.4 Hz, 1H), 4.35 (d, J = 13.4 Hz, 1H), 3.38 (d, J = 12.9 Hz, 2H), 2.94 (s, 1H), 2.18 (s, 2H), 1.99 - 1.84 (m, 2H).
EXAMPLE 16 1-(4-(7-(4-(pyrrolidinylmethyl)phenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidin yl)propenone 16 was prepared following the procedures bed in Steps 4 to 8 of Example 13, except that 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy)pyridine was replaced with 1-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzyl)pyrrolidine as starting material.
MS m/z (ESI):416[M+1] 1H NMR (400 MHz, CD 3OD) δ 8.20 (s, 1H), 8.07 (d, J = 8.0 Hz, 2H), 7.69 - 7.57 (m, 3H), 6.85 (dd, J = 16.8, 10.7 Hz, 1H), 6.24 (dd, J = 16.8, 1.9 Hz, 1H), 5.77 (dd, J = 10.6, 1.9 Hz, 1H), 4.76 (d, J = 12.9 Hz, 1H), 4.30 (d, J = 13.5 Hz, 1H), 3.98 (s, 2H), 3.36 (d, J = 14.7 Hz, 1H), 3.20 (ddd, J = 15.4, 7.7, 3.7 Hz, 1H), 3.00 - 2.80 (m, 5H), 2.13 (t, J = 9.9 Hz, 2H), 2.04 - 1.81 (m, 6H).
EXAMPLE 17 1-(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)piperidinyl)butynone 17 was prepared following the procedures of Example 4, except that (E) hylamino)butenic acid was replaced with butynoic acid.
MS m/z (ESI):416[M+1] 1H NMR (400 MHz, CD 3OD) δ 8.19 (d, J = 7.0 Hz, 1H), 8.07 (t, J = 8.6 Hz, 2H), 7.62 (d, J = .3 Hz, 1H), 7.43 (t, J = 7.9 Hz, 2H), 7.20 (dd, J = 8.2, 4.1 Hz, 3H), 7.12 (d, J = 8.2 Hz, 2H), 4.69 (t, J = 9.3 Hz, 1H), 4.54 - 4.41 (m, 1H), 3.61 - 3.52 (m, 0.5H), 3.28 (s, 0.5H), 3.24 - 3.16 (m, 0.5H), 3.15 - 2.95 (m, 1H), 2.91 - 2.86 (m, 0.5H), 2.23 - 2.18 (m, 1H), 2.15 - 1.88 (m, 5H), 1.80 - 1.58 (m, EXAMPLE 18 4-(5-(1-acryloylpyrrolidinyl)-1H-pyrazolo[3,4-c]pyridinyl)-N-(pyridinyl) benzamide N N 18 O N O N NH2 NH Cl N Cl N Cl N Cl N I 第一步Step 1 O 第二步Step 2 第三步 O Step 4第四步 O Step 3 O O 18a 18b 18c O 18d N N NH NH Boc N N N Boc N N Boc N Step 5第五步 O Step 6第六步 OH Step 7第七步 O O 18e 18f 18g N N N NH NH NH Boc N N H 第八步 HN N N Step 9 N Step 8 H H N N 第九步 N O N O N O N 18h 18i 18 Steps 1 to 5 Tert-butyl 3-(7-(4-(methoxycarbonyl)phenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidine carboxylate 18f was prepared following the procedures described in Steps 2 to 6 of Example 6, except that (4-phenoxyphenyl) boric acid was replaced with methyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl) benzoate in Step 1.
MS m/z (ESI):423[M+1] Step 6 1-(tert-butoxycarbonyl)pyrrolidinyl)-1H-pyrazolo[3,4-c]pyridinyl) c acid Compound tert-butyl 3-(7-(4-(methoxycarbonyl)phenyl)-1H-pyrazolo[3,4-c]pyridin yl)pyrrolidinecarboxylate 18f (422 mg, 1.0 mmol), m hydroxide (52 mg, 10.0 mmol), water (10 mL), and ydrofuran (10 mL) were mixed and stirred at room temperature for 14 hrs. The reaction solution was adjusted to pH= 6 with 1 M diluted hydrochloric acid, and extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated to remove solvent under reduced pressure to give a target product 4-(5-(1-(tert-butoxycarbonyl)pyrrolidinyl)-1H-pyrazolo[3,4- c]pyridinyl)benzoic acid 18g (300mg, crude), which was directly used in the next reaction without further purification.
MS m/z (ESI):409[M+1] Step 7 Tert-butyl 3-(7-(4-(pyridinylcarbamoyl)phenyl)-1H-pyrazolo[3,4-c]pyridin yl)pyrrolidinecarboxylate Compound 4-(5-(1-(tert-butoxycarbonyl)pyrrolidinyl)-1H-pyrazolo[3,4-c]pyridinyl) benzoic acid 18g (204 mg, 0.5 mmol), triethylamine (194 mg, 3.0 mmol), and dichloromethane (20 mL) were mixed, and then 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphoric acid-2,4,6-trioxide (477 mg, 1.5 mmol) was added. The e was stirred at room temperature for 14 hrs, and then a ted solution of sodium bicarbonate (10 mL) was added. The reaction mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/methanol = 20/1) to give a target product tert-butyl 3-(7-(4-(pyridin ylcarbamoyl)phenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidinecarboxylate 18h (80 mg, yellow , yield: 33%.
MS m/z (ESI):485[M+1] Step 8 N-(pyridinyl)(5-(pyrrolidinyl)-1H-pyrazolo[3,4-c]pyridinyl) benzamide Following the tic procedure for 1h of Example 1, tert-butyl 4-(pyridin ylcarbamoyl)phenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidinecarboxylate (80 mg, 0.17 mmol) was used as starting material to produce N-(pyridinyl)(5-(pyrrolidinyl)-1H- lo[3,4-c]pyridinyl)benzamide 18i (50 mg, crude).
MS m/z (ESI):385[M+1] Step 9 4-(5-(1-acryloylpyrrolidinyl)-1H-pyrazolo[3,4-c]pyridinyl)-N-(pyridin yl)benzamide Following the synthetic procedure for 1 of Example 1, N-(pyridinyl)(5-(pyrrolidin yl)-1H-pyrazolo[3,4-c]pyridinyl)benzamide 18i (50 mg, 0.13 mmol) was used as starting material to produce a target product 4-(5-(1-acryloylpyrrolidinyl)-1H-pyrazolo[3,4-c]pyridin yl)-N-(pyridinyl)benzamide 18 (12 mg, yellow solid), yield: 12%.
MS m/z 439[M+1] 1H NMR (400 MHz,CDCl 3) δ 11.13 (s, 1H), 9.69 (s, 1H), 8.66 - 8.56 (m, 1H), 8.36 (s, 1H), 8.30 - 8.14 (m, 3H), 7.96 (s, 1H), 7.80 (s, 1H), 7.57 (t, J = 10.6 Hz, 1H), 7.23 (s, 1H), 6.93 - 6.79 (m, 1H), 6.51 (tdd, J = 16.8, 12.4, 8.0 Hz, 2H), 5.78 - 5.66 (m, 1H), 4.22 - 4.05 (m, 1H), 4.03 - 3.60 (m, 4H), 2.46 (dt, J = 32.0, 7.5 Hz, 2H).
EXAMPLE 19 4-(5-(1-(butynoyl)pyrrolidinyl)-1H-pyrazolo[3,4-c]pyridinyl)-N-(pyridin yl)benzamide Step 1 Compound N-(pyridinyl)(5-(pyrrolidinyl)-1H-pyrazolo[3,4-c]pyridin yl)benzamide 18i (384 mg, 1.0 mmol), butynoyl chloride (113 mg, 1.1 mmol), solid sodium bicarbonate (232 mg, 3.0 mmol), water (4 mL), and tetrahydrofuran (16 mL) were mixed and stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/methanol = 20/1) to give a target product 1-(butynacyl)pyrrolidinyl)-1H-pyrazolo[3,4-c]pyridinyl)-N-(pyridin yl)benzamide 19 (72 mg, white solid), yield: 16%.
MS m/z (ESI):439[M+1] 1H NMR (400 MHz, CD 3OD) δ 8.53 (t, J = 7.4 Hz, 2H), 8.47 (d, J = 5.8 Hz, 1H), 8.43 - 8.33 (m, 4H), 8.03 (d, J = 7.8 Hz, 1H), 7.94 (d, J = 8.9 Hz, 1H), 7.71 (t, J = 6.9 Hz, 1H), 4.28 (dd, J = 10.9, 7.4 Hz, 0.5H), 3.95 (m, 4H), 3.66 - 3.56 (m, 0.5H), 2.63 - 2.36 (m, 2H), 2.06 (d, J = 20.4 Hz, EXAMPLE 20 1-(3-(7-(4-phenoxyphenyl)-1H-indazolyl)piperidinyl)propenone Br Br N N NH Step 1第一步 I Step 2第二步 Step 3第三步 Br Step 4第四步 Br I NH2 NH2 20a 20b 20c 20d N N N NH NH NH B Step 6第六步 BocN Step 7 第七步 BocN O O O 20e 20f 20g N N NH NH Step 8第八步 HN Step 9第九步 N O O 20h 20 O OTf N Step 5第五步 N Boc Boc 20i 20j Step 1 4-bromoiodomethylaniline Compound 4-bromomethylaniline 20a (5 g, 26.87 mmol), N-iodosuccinimide (6.05 g, 26.87 mmol), p-toluenesulfonic acid (0.5 g, 2.91 mmol), and acetonitrile (100 mL) were mixed at room ature and stirred for 3 hrs, and then saturated sodium bicarbonate (50 mL) was added.
The mixture was extracted with ethyl acetate (50 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated to remove t under reduced re. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 5/1) to give a target product 4-bromoiodomethylaniline 20b (3.5 g, white solid), yield: 42%.
MS m/z 312, 314[M+1] Step 2 -bromoiodo-1H-indazole Compound 4-bromoiodomethylaniline 20b (3.5 g, 11.2 mmol), acetic acid (45 mL), and water (2.1 mL) were mixed at room temperature, and then sodium nitrite (851 mg, 12.3 mmol) was added. The mixture was stirred at room temperature for another 1 hr, and then water (200 mL) was added. The mixture was adjusted to pH = 9 by using a saturated solution of sodium bicarbonate, and extracted with ethyl acetate (200 mL×2). The c phases were combined, and concentrated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ethyl acetate= 5/1) to give a target product 5-bromoiodo-1H- indazole 20c (2.5 g, brown solid), yield: 69%.
MS m/z (ESI):323, 325[M+1] Step 3 -bromo(4-phenoxyphenyl)-1H-indazole nd 5-bromoiodo-1H-indazole 20c (2.0 g, 6.2 mmol), (4-phenoxyphenyl)boric acid (1.46 g, 6.8mmol), cesium carbonate (4.04 g, 12.4 mmol), [1,1'- bis(diphenylphosphine)ferrocene]palladium dichloride (453 mg, 0.62 mmol), 1,4-dioxane (50 mL), and water (10 mL) were mixed, degassed, and heated at 100°C under en for 12 hrs. The mixture was cooled to room temperature, and then water (100 mL) was added. Next, the mixture was extracted with ethyl e (100 mL×2). The c phases were combined, and desolventized under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/methanol = 30/1), to produce a target compound 5-bromo(4- phenoxyphenyl)-1H-indazole 20d (1.6 g, white solid), yield: 71%.
MS m/z(ESI):365, 367[M+1] Step 4 7-(4-phenoxyphenyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-indazole Compound 5-bromo(4-phenoxyphenyl)-1H-indazole 20d (730 mg, 2 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(1,3,2-dioxaborolanyl) (1.22g, 4.0 mmol), potassium acetate (589 mg, 6 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (146 mg, 0.2 mmol), and 1,4-dioxane (20 mL) were mixed, degassed, and heated at 90°C under en for 12 hrs. The mixture was cooled to room temperature, and concentrated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate= 5/1), to produce a target nd 7-(4-phenoxyphenyl)(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)-1H-indazole 20e (480 mg, white solid), yield: 34%.
MS m/z (ESI):413[M+1] Step 5 Tert-butyl 5-(((trifluoromethyl)sulfonyl)oxo)-3,6-dihydropyridine-1(2H)-carboxylate Compound tert-butyl 3-carbonylpiperidincarboxylate 20i (10 g, 50 mmol) was dissolved in tetrahydrofuran (200 mL) under nitrogen protection and cooled to -78°C, and then a solution of lithium di-isopropyl amide in tetrahydrofuran (2 M, 30mL) was added. The mixture was stirred at the aforesaid temperature for 1 hr, and then N-phenyl-bis(trifluoromethanesulfonimide) (19.6 g, 55 mmol) was added. Next, the mixture was lly warmed to room temperature and stirred for another 3 hrs. The reaction was ed with water (5 mL). The reaction mixture was poured into water (300 mL), and extracted with ethyl acetate (300 mL×2). The organic phases were combined and trated to remove solvent under reduced pressure to give a target product tert-butyl 5- (((trifluoromethyl)sulfonyl)oxo)-3,6-dihydropyridine-1(2H)-carboxylate 20j (4.8 g, brown oil), yield: 29%. 1H NMR (400 MHz, CDCl 3) δ 5.97-5.89 (m, 1H), 4.07-4.00 (m, 2H), 3.52-3.44 (m, 2H), 2.34- 2.26 (m, 2H), 1.48 (s, 9H).
Step 6 utyl 5-(7-(4-phenoxyphenyl)-1H-indazolyl)-3,6-dihydropyridine-1(2H)-carboxylate nd 7-(4-phenoxyphenyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H- indazole 20e (2.3 g, 5.58 mmol), tert-butyl 5-(((trifluoromethyl)sulfonyl)oxo)-3,6- dihydropyridine-1(2H)-carboxylate 20j (2.8 g, 8.37 mmol), cesium carbonate (3.6 g, 11.16 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (408 mg, 0.2 mmol), 1,4-dioxane (80 mL), and water (16 mL) were mixed, degassed, and heated at 100°C under nitrogen for 12 hrs. The mixture was cooled to room ature and concentrated to remove solvent. The residue was sed in water (50 mL) and extracted with ethyl acetate (300 mL×2). The organic phases were combined, and concentrated to remove t under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/methanol = 20/1), to produce a target compound tert-butyl 5-(7-(4-phenoxyphenyl)-1H-indazolyl)-3,6-dihydropyridine-1(2H)- carboxylate 20f (2.2 g, white solid), yield: 85%.
MS m/z (ESI):468[M+1] Step 7 Tert-butyl 3-(7-(4-phenoxyphenyl)-1H-indazolyl)piperidincarboxylate Compound tert-butyl 5-(7-(4-phenoxyphenyl)-1H-indazolyl)-3,6-dihydropyridine-1(2H)- carboxylate 20f (1.4 g, 2.99 mmol), Pd-C (400mg), and methanol (30 mL) were mixed, degassed, and stirred at room ature under hydrogen atmosphere for 16 hrs. The mixture was filtered, and concentrated to remove solvent under d pressure to produce a target product tert-butyl 3-(7-(4-phenoxyphenyl)-1H-indazolyl)piperidincarboxylate 20g (1.3 g, brown oil), yield: MS m/z (ESI): 470[M+1] Step 8 7-(4-phenoxyphenyl)(piperidinyl)-1H-indazole Compound tert-butyl 3-(7-(4-phenoxyphenyl)-1H-indazolyl)piperidincarboxylate 20g (1.1 g, 2.3 mmol) was dissolved in a solution of hydrogen chloride in ethyl acetate (1 M, 25 mL, mmol), and stirred at room temperature for 12 hrs. The mixture was concentrated to remove solvent under reduced re to produce a target product 7-(4-phenoxyphenyl)(piperidin yl)-1H-indazole 20h (1.1 g, yellow , yield 100%.
MS m/z 370[M+1] Step 9 1-(3-(7-(4-phenoxyphenyl)-1H-indazolyl)piperidinyl)propenone Compound 7-(4-phenoxyphenyl)(piperidinyl)-1H-indazole 20h (500 mg, 1.23 mmol), acryloyl chloride (111 mg, 1.23 mmol), solid sodium bicarbonate (210 mg, 2.46 mmol), water (12.5 mL), and tetrahydrofuran (12.5 mL) were mixed and stirred at room temperature for 2 hrs. The mixture was extracted with ethyl e (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated to remove solvent under reduced pressure. The residue was purified by column tography on silica gel (dichloromethane/methanol = 20/1) to give a target product 1-(3-(7-(4-phenoxyphenyl)-1H- indazolyl)piperidinyl)propenone 20 (20 mg, white solid), yield: 40%.
MS m/z (ESI):424[M+1] 1H NMR (400 MHz, CDCl 3) δ 8.10 (s, 1H), 7.68 - 7.62 (m, 2H), 7.60 (s, 1H), 7.42 (dd, J = 8.3, 7.6 Hz, 2H), 7.35 (s, 1H), 7.19 (d, J = 8.2 Hz, 3H), 7.13 (dd, J = 8.6, 0.9 Hz, 2H), 6.65 (d, J = .6 Hz, 1H), 6.33 (d, J = 16.9 Hz, 1H), 5.77 - 5.64 (m, 1H), 4.86 (dd, J = 45.3, 12.8 Hz, 1H), 4.22 - 4.06 (m, 1H), 3.27 - 3.11 (m, 1H), 2.91 (d, J = 10.6 Hz, 1H), 2.80 - 2.68 (m, 1H), 2.21 (d, J = 13.2 Hz, 1H), 1.98 - 1.81 (m, 2H), 1.75 - 1.63 (m, 1H).
EXAMPLE 21 1-(2-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidinyl)propenone O O O O O NH2 O O O Step 1第一步 Step 2第二步 O O O 21a 21b 21c O N O O N N O OH O O O O 第三步Step 3 O O 第四步Step 4 N 第五步Step 5 N O N Boc O 21d 21e 21f 21g N N 第六步Step 6 Step 7第七步 Step 8第八步 N N O O O O O O 21h 21i N N NH NH NH Boc Boc H N N N 第九步 N N Step 9 Step 10第十步 O O O 21j 21k 21l 第十一步Step 11 O O Step 1 Ethyl 3-carbonyl(4-phenoxyphenyl)propionate A mixture of 1-(4-phenoxyphenyl)ethanone 21a (4.24 g, 20 mmol), sodium hydride (60%, 2.0 g, 50 mmol), and toluene (30 mL) was heated to 90°C, and then compound diethyl carbonate (5.9 g, 50 mmol) was added. The reaction mixture was stirred at reflux for 45 min. The e was cooled to room temperature, and ed with a saturated ammonium chloride solution to neutral and extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the ant, and concentrated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 100/1) to give a target product ethyl 3-carbonyl(4- phenoxyphenyl) nate 21b (4.0 g, white solid), yield: 50%.
MS m/z (ESI):283[M-1] Step 2 Ethyl (Z)amino(4-phenoxyphenyl)acryloyl acid ester Compound ethyl 3-carbonyl(4-phenoxyphenyl) propionate 21b (2.84 g, 10.0 mmol), ammonium formate (3.15 g, 50.0 mmol), molecular sieve (2.0 g), and ethanol (50 mL) were mixed and heated to reflux for 16 hrs. The mixture was cooled to room ature and filtered. The te was concentrrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to give a target product ethyl (Z)amino(4-phenoxyphenyl)acryloyl acid ester 21c (1.8 g, white solid), yield: 64%.
MS m/z (ESI):284[M+1] Step 3 Tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidinecarboxylate Compound (tert-butoxy carbonyl)proline 21d (5 g, 23 mmol), methoxymethyl amine hydrochloride (2.5 g, 25 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (9.7 g, 25 mmol), diisopropyl ethyl amine (11.5 mL, 69 mmol), and dichloromethane (100 mL) were mixed and stirred at room ature for 15 hrs. The mixture was desolventized under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), and washed with saturated saline. The organic phase was desolventized under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate= 5/1 to 1/1) to give a target product tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine- oxylate 21e (5.7 g, ess oil), yield: 96%. 1H NMR (400 MHz, CDCl 3) δ 4.78 - 4.57 (m, 1H), 3.77 (d, J = 25.5 Hz, 3H), 3.59 (m, 1H), 3.54 - 3.38 (m, 1H), 3.22 (s, 3H), 2.20 (m, 1H), 1.93 (m, 3H), 1.46 (d, J = 17.8 Hz, 9H).
Step 4 tert-butyl 2-(butynacyl)pyrrolidinecarboxylate Compound utyl 2-(methoxy(methyl)carbamoyl)pyrrolidinecarboxylate 21e (3.5 g, 13.5mmol) was dissolved in tetrahydrofuran (100 mL). The mixture was cooled to -78°C, and then a propynyl magnesium bromide solution (0.5 M, 54 mL, 27 mmol) was dropwise added. After completion of addition, the mixture was gradually warmed to room temperature and stirred for another 15 hrs. After the completion of reaction, a ted ammonium chloride solution was added to quench the reaction. The mixture was desolventized under reduced pressure. The residue was diluted with ethyl e (200 mL), and washed with saturated saline. The c phase was desolventized under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to give a target product tert-butyl 2-(but ynacyl)pyrrolidinecarboxylate 21f (2.45 g, colorless oil), yield: 78%. 1H NMR (400 MHz, CDCl 3) δ 4.33 (ddd, J = 13.9, 8.7, 4.8 Hz, 1H), 3.55 (d, J = 6.7 Hz, 2H), 2.33 - 2.12 (m, 1H), 2.04 (d, J = 2.2 Hz, 3H), 2.03 - 1.80 (m, 3H), 1.46 (d, J = 19.1 Hz, 9H).
Step 5 Ethyl 6-(1-(tert-butoxy carbonyl)pyrrolidinyl)methyl(4-phenoxyphenyl)nicotine acid ester Compound ethyl (Z)amino(4-phenoxyphenyl)acryloyl acid ester 21c (980 mg, 3.5 mmol), tert-butyl 2-(butynacyl)pyrrolidinecarboxylate 21f (907 mg, 3.8 mmol), ammonium acetate (267 mg, 3.5 mmol), and ethanol (30 mL) were mixed and heated with stirring at 100°C for 15 hrs. After the completion of reaction, the mixture was cooled to room ature, and concentrated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 5/1) to give a target product ethyl 6- (1-(tert-butoxycarbonyl)pyrrolidinyl)methyl(4-phenoxyphenyl)nicotine acid ester 21g (540 mg, yellow solid), yield: 31%.
MS m/z (ESI):503[M+1] Step 6 6-(1-(tert-butoxycarbonyl)pyrrolidinyl)methyl(4-phenoxyphenyl)nicotinicacid nd ethyl 6-(1-(tert-butoxycarbonyl)pyrrolidinyl)methyl(4- yphenyl)nicotine acid ester 21g (140 mg, 0.28 mmol), sodium hydroxide (1.1 g, 28 mmol), water (5 mL), and l (8 mL) were mixed, heated to 88°C, and stirred for 15 hrs. After the completion of reaction, the reaction mixture was adjusted by hydrochloric acid to pH = 3, and extracted with ethyl acetate (100 mL). The organic phase was concentrated to remove solvent under d pressure, and the residue was purified by column chromatography on silica gel (dichloromethane/methanol = 20/1) to give a target t 6-(1-(tert-butoxycarbonyl)pyrrolidin- 2-yl)methyl(4-phenoxyphenyl)nicotinic acid 21h (130 mg, colorless oil), yield: 90%.
MS m/z (ESI):475[M+1] Step 7 tert-butyl 2-(5-aminomethyl(4-phenoxyphenyl)pyridinyl)pyrrolidinecarboxylate Compound 6-(1-(tert-butoxycarbonyl)pyrrolidinyl)methyl(4- phenoxyphenyl)nicotinic acid 21h (130 mg, 0.27 mmol), diphenylphosphoryl azide (98 mg, 0.324 mmol), triethylamine (36 mg, 0.324 mmol), and acetonitrile (10 mL) were mixed and heated with stirring at 90°C under Ar atmosphere for 5 hrs. The mixture was cooled to room ature, and then water was added (2 mL). The mixture was heated for 1 hr at 90°C under Ar atmosphere. After the tion of reaction, the on mixture was concentrated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 1/1) to give a target product tert-butyl 2-(5-aminomethyl(4-phenoxyphenyl)pyridin- 2-yl)pyrrolidinecarboxylate 21i (60 mg, colorless oil), yield: 60%.
MS m/z 446[M+1] Step 8 Tert-butyl 2-(5-acetamidomethyl(4-phenoxyphenyl)pyridinyl)pyrrolidine carboxylate Compound tert-butyl 2-(5-aminomethyl(4-phenoxyphenyl)pyridinyl)pyrrolidine carboxylate 21i (80 mg, 0.18 mmol), acetic anhydride (37 mg, 0.36 mmol), and toluene (10 mL) were mixed and heated with stirring at 90°C for 15 hrs. The reaction was cooled to room ature, and concentrated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate= 5/1) to give a target product tert-butyl 2-(5-acetamidomethyl(4-phenoxyphenyl)pyridinyl)pyrrolidine carboxylate 21j (44 mg, ess oil), yield: 50%.
MS m/z (ESI):488[M+1] Step 9 Tert-butyl 2-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidine carboxylate A mixture of utyl 2-(5-acetamidomethyl(4-phenoxyphenyl)pyridin yl)pyrrolidinecarboxylate 21j (44 mg, 0.09 mmol), acetic anhydride (28 mg, 0.27 mmol), potassium acetate (12 mg, 0.12 mmol), and benzene (20 mL) was heated to 78°C, and isoamyl nitrite was immediately added (17 mg, 0.14 mmol). The mixture was stirred for 18 hrs, and then cooled to room temperature. The mixture was desolventized under reduced pressure. The residue was ved in a mixture of water (5 mL), and ethanol (15 mL), and then lithium hydroxide monohydrate (100 mg) was added and stirred at room temperature for 2 hrs. The mixture was trated to remove solvent under reduced pressure, and the residue was dispersed in water (10 mL). The mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated to remove t under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 1/1 to 1/2) to give a target t tert-butyl 2-(7-(4- phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidinecarboxylate 21k (10 mg, yellow solid), yield: 24%.
MS m/z (ESI):457[M+1] Step 10 henoxyphenyl)(pyrrolidinyl)-1H-pyrazolo[3,4-c]pyridine Compound tert-butyl 2-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidine carboxylate 20k (10 mg, 0.02 mmol), dichloromethane (5 mL), and a solution of en chloride in ethanol (4 M, 1 mL, 4 mmol) were mixed and stirred at room temperature for 2 hrs. The mixture was desolventized under reduced pressure to produce a target product 7-(4-phenoxyphenyl) (pyrrolidinyl)-1H-pyrazolo[3,4-c]pyridine 21l (5 mg, crude). The product was directly used in the next reaction without further purification.
MS m/z (ESI):357[M+1] Step 11 1-(2-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidinyl)propenone Compound henoxyphenyl)(pyrrolidinyl)-1H-pyrazolo[3,4-c]pyridine 20l (5 mg, crude), acryloyl de (2 mg, 0.02 mmol), solid sodium bicarbonate (20 mg, 0.24 mmol), water (10 mL), and tetrahydrofuran (20 mL) were mixed and stirred at room temperature for 2 hrs. The mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated to remove solvent under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/methanol = 20/1) to give a target product 7-(4-phenoxyphenyl)-1H- pyrazolo[3,4-c]pyridinyl)pyrrolidinyl)propenone 21 (1 mg, white solid), yield: 17%.
MS m/z (ESI):411[M+1] 1H NMR (400 MHz, CD 3OD) δ 8.19 (d, J = 12.2 Hz, 1H), 8.03 (dd, J = 12.4, 8.7 Hz, 2H), 7.53 (d, J = 4.5 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.25 - 7.17 (m, 2H), 7.13 (d, J = 8.3 Hz,1.5H), 6.80 (dd, J = 16.8, 10.5 Hz, 0.5H), 6.39 (dd, J = 16.9, 10.1 Hz, 0.5H), 6.24 (m, 1H), 5.79 (dd, J = 10.4, 1.9 Hz, 0.5H), 5.53 (dd, J = 10.3, 2.0 Hz, 0.5H), 5.46 (s, 1H), 5.36 (t, J = 4.7 Hz, 0.5H), 4.09 (d, J = 6.3 Hz, 0.5H), 4.00 - 3.85 (m, 1H), 3.82 - 3.74 (m, 0.5H), 2.49 (m, 1H), 2.23 (m, 2H), 2.11 - 1.98 (m, 2H).
EXAMPLE 22 (S)(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidinyl)propen one 22a and (R)(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidin yl)propenone 22b Compound 1-(3-(7-(4-phenoxyphenyl)-1H-pyrazolo[3,4-c]pyridinyl)pyrrolidin yl)propenone 6 (1.34 g) was resolved by chiral preparative liquid chromatography (chiral column: CHIRALCEL OD-H; gauge: 0.46 cm I.D. × 15 cm L; mobile phase: n-hexane/ethanol = 70/30; flow rate: 1.0 mL/min; temperature: 35°C) to give two optical isomers (one component with a retention time of 7.428 min, 0.61 g; and the other component with a retention time of 10.601 min, 0.70 g). The two optical isomers correspond to 22a and 22b, respectively, but the absolute configurations thereof were not yet identified.
BTK ENZYME ACTIVITY TESTING An in vitro kinase assay is used to evaluate the effect of the inventive compounds on Bruton tyrosine kinase (BTK) activity.
The experimental method is generally bed as follows: In vitro activity of BTK is measured by detecting ADP produced in a kinase reaction with an ADP-Glo™ kinase assay kit from a Company. In the kinase assay, the kinase consumes ATP to phosphorylate the substrate, while ing ADP. ADP-Glo reagent then terminates the kinase reaction and completely consumes the remaining ATP. Finally, a kinase ion reagent is added to convert generated ADP into new ATP. Luciferase in the ion reagent is capable of catalyzing fluorescein with the participation of ATP and O2 to produce oxidized fluorescein, AMP, and generate light m, thereby converting a chemical signal into an optical signal (Luminecence). The intensity of optical signal is positively ated with the production of ADP in the kinase reaction, so that the activity of kinase BTK can be thereby tatively determined.
All assays are conducted at a constant temperature of 23°C, using a Corning 3674 Type white 384-welll plate; the BTK kinase (full length with His-Tag) is expressed and purified internally by the company; the substrate of kinase is polypeptide (4:1 Glu,Tyr) (from Chem) and ATP (from ; and a microplate reader EnVision (Perkin Elmer) is used for reading an optical signal.
The assay buffer includes 40 mM Tris-HCl (pH 7.5), 10 mM MgCl2 (Sigma), 2 mM MnCl2 ), 0.05 mM DTT (Sigma), and 0.01% BSA (Sigma); the BTK kinase is diluted with the assay buffer to a concentration of 1.6 ng/uL as a kinase reaction solution; and the substrate reaction solution comprises 0.2 mg/mL polypeptide substrate and 50 uM ATP.
Compound’s IC50 is calculated from 10 concentration points by the following . The compound is dissolved and diluted in 100% DMSO to a tration of 1 mM, followed by a serial 3X dilution with DMSO to a m concentration of 0.05 uM. Each tration stock is further diluted 40X with the assay buffer. To a 384-well assay plate are added 1 uL of a series of compound solutions and 2 uL of the kinase reaction solution, followed by mixing homogeneously, and incubating in the dark at room temperature. After in the dark for 30 min, 2 uL of the substrate reaction solution is added to allowed the total reaction volume to 5uL. The reaction mixture is incubated in the dark at room ature in the dark for another 60 min. An equal volume of 5 uL ADP-Glo™ reagent is then added to terminate the reaction. The resulting mixture is homogeneously mixed, and stands at room temperature for 40 min. Finally, 10 uL of the kinase detection reagent is added, stands at room temperature for 30 min, and then a value is read on Envision.
Percent inhibition is calculated based on the following equation: Inhibition % = [1 - (RLUcompound - RLUmin) / (RLUmax - RLUmin)] X 100 wherein RLUcompound is the luminescence reading at a given concentration of compound, RLUmin is the luminescence reading in the absence of kinase, and RLUmax is the scence reading in the absence of compound. IC50 of the compound is calculated by using a XLfit program in Excel.
Compound No. M) Compound No. IC50(nM) 1 B 2 B 3 A 4 A A 6 A 7 A 8 A 9 A 10 A 11 A 12 A 13 A 14 A A 16 C 17 B 18 A 19 B 20 A 21 A 22a A 22b A A﹤100nM; B = 100 to 500nM; C﹥500nM Conclusion: the compounds of the present invention exhibit a icant inhibitory effect on the activity of Bruton tyrosine kinase.

Claims (9)

1. A compound represented by formula (IV) or formula (V), B2 G1 B1 G1 B1 N A3 H R2 A2 Z1 n R4 N A3 n a a Z2 Y Z2 R3 Z1 R3 Y A2 L2 p R4 (IV) R2 (V) or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, mixtures thereof， or a pharmaceutically acceptable salt thereof: wherein: A2 and A3 are each independently ed from the group consisting of CR1 and B1 is independently selected from the group consisting of C3-8 cyclic group, 3- to 8-membered heterocyclic group, aryl, and heteroaryl, n the cyclic group, cyclic group, aryl or heteroaryl is optionally tuted with one or more G1; B2 is independently selected from the group consisting of C3-8 cyclic group, 3- to 8-membered heterocyclic group, aryl and heteroaryl, wherein the cyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted with one or more G2; L1 is independently selected from the group consisting of -C1-2 alkyl-, -CR5R6-, - C1-2 alkyl (R5)(OH)-, -C(O)-, -NR5-, -NR5C(O)-, -C(O)NR5-, -CF2-, -O-, -S-, -S(O)m-, -NR5S(O)2- and -S(O)2NR5-; L2 is independently selected from the group consisting of -C1-4 , -C(O)-, -O-, -NR7-, -NR7C(O)- and -NR7S(O)2-; Z1 and Z2 are each independently selected from the group ting of - and –N-; Ra is H or alkyl; Y is independently selected from the group consisting of -C(O)-, -NR8C(O)-, - S(O)m- and -NR8S(O)m-; R1 is independently selected from the group consisting of H, D, C1-4 alkyl, halogen and cyano; bond is a double bond or a triple bond; when bond is a double bond, R2, R3 and R4 are each independently selected from the group consisting of H and D; and when bond is a triple bond, R3 and R4 are absent, and R2 is independently selected from the group consisting of H, D, and C1- 2 alkyl; R5, R6, R7 and R8 are each independently selected from the group consisting of H, D, C1-8 alkyl, C3-8 cyclic group, 3- to 8-membered heterocyclic group, aryl, and heteroaryl, wherein the alkyl, cyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted with one or more G5; G1, G2, and G5 are each independently selected from the group consisting of H, D, halogen, cyano, alkyl, l, alkynyl, cyclic group, cyclic group, aryl, aryl, -OR9, NR9R10, R10, -C(O)NR9R10, -C(O)R9, -NR9R10, - NR9C(O)R10, -NR9C(O)NR10R11, -S(O)mR10 and O)mR10, wherein the alkyl, alkenyl, alkynyl, cyclic group, heterocyclic group, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of D, halogen, cyano, C1-8 alkyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclic group, -OR12, NR12R13, -C(O)OR12, -C(O)NR12R13, -C(O)R12, -NR12R13, -NR12C(O)R13, - NR12C(O)NR13R14, -S(O)mR12, and -NR12S(O)mR13; R9, R10, R11, R12, R13 and R14 are each independently selected from the group consisting of H, C1-6 alkyl, C1-C6 heteroalkyl, C3-8 cycloalkyl, 3- to 8-membered monocyclic heterocyclic group, monocyclic heteroaryl and monocyclic aryl; n and p are each independently selected from the group consisting of 0, 1 and 2; m is 1 or 2.
2. The compound represented by formula (IV) or formula (V) or its tautomers, mesomers, racemates, enantiomers, reoisomers, mixtures thereof or a pharmaceutically acceptable salt thereof of claim 1, wherein the compound is: N N NH NH O O N N O N N O N , O , N N O , N N NH NH S O N N N N O , O , N N O O O , O , N N NH NH HN N N O O O , O , O N N N NH O , N N N NH O O , N N O , N N N NH F O F O , N N O , N N N N O O , N N N O , N N NH H N N O N H , N N O N , O N N O , O O , N N N O , or N N O .
3. A ceutical composition comprising a therapeutically effective amount of a compound represented by formula (IV) or formula (V) or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, mixtures thereof or a pharmaceutically acceptable salt thereof of claim 1, and a pharmaceutically acceptable carrier, diluent, or excipient.
4. Use of the compound represented by formula (IV) or formula (V) or its tautomers, rs, racemates, enantiomers, diastereoisomers, mixtures thereof or a pharmaceutically acceptable salt thereof of claim 1 or claim 2, in the preparation of a medicament which ts Bruton tyrosine kinase (BTK).
5. Use of the compound represented by formula (IV) or formula (V) or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, mixtures thereof or a pharmaceutically acceptable salt thereof of claim 1 or claim 2, in the preparation of a medicament for treating and/or preventing tumors and matory diseases. N N
6. A compound represented by a formula of O or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, mixtures thereof or a ceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a therapeutically effective amount of N N a compound represented by a formula of O or its ers, rs, racemates, enantiomers, diastereoisomers, mixtures thereof or a ceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. N N
8. Use of a compound represented by a formula of O or its tautomers, mesomers, racemates, enantiomers, diastereoisomers, mixtures thereof or a pharmaceutically acceptable salt thereof, in the preparation of a medicament which inhibits Bruton tyrosine kinase (BTK). N N
9. Use of a nd represented by a formula of O or its tautomers, mesomers, racemates, omers, diastereoisomers, mixtures thereof or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating and/or preventing tumors and inflammatory diseases.
NZ744870A 2016-01-29 2016-12-28 Fused pyrazole derivatives, preparation method thereof, and use thereof in treatment of cancers, inflammation and immune diseases NZ744870B2 (en)

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CN201610066886.9 2016-01-29
CN201610066886.9A CN107021963A (en) 2016-01-29 2016-01-29 Pyrazole fused ring analog derivative, its preparation method and its application in treating cancer, inflammation and immunity disease
PCT/CN2016/112625 WO2017128917A1 (en) 2016-01-29 2016-12-28 Parazole condensed-ring derivatives and preparation method thereof and application thereof in treatment of cancers, inflammation and immune diseases

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