- DEGRADATION OF BRUTON'S TYROSINE KINASE (BTK) BY CONJUGATION OF BTK INHIBITORS WITH E3 LIGASE LIGAND AND METHODS OF USE
-
Bifunctional compounds formed by conjugating BTK inhibitor moieties with E3 ligase ligand moieties, which function to recruit targeted proteins to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof.
- -
-
Paragraph 0228-0229
(2021/11/06)
-
- AMINOPYRAZINE COMPOUNDS AS HPK1 INHIBITOR AND THE USE THEREOF
-
Disclosed herein is an aminopyrazine compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising thereof. Also disclosed is a method of treating HPK1 related disorders or diseases by using the compound disclosed herein.
- -
-
Page/Page column 94; 138
(2021/02/26)
-
- INDANE DERIVATIVES FOR USE IN THE TREATMENT OF BACTERIAL INFECTION
-
The invention relates to a compound which is an indane according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, L, M, ?, n, p, and q are as defined herein. The compounds are useful in the treatment of antibacterial infection either as stand alone antibiotics, or in combination with further antibiotics.
- -
-
Paragraph 0393-0395
(2020/04/09)
-
- TRICYCLIC DEGRADERS OF IKAROS AND AIOLOS
-
Tricyclic cereblon binders for the degradation of Ikaros or Aiolos by the ubiquitin proteasome pathway for therapeutic applications are described.
- -
-
Page/Page column 292-293
(2020/10/21)
-
- 1,5,7-TRISUBSTITUTED ISOQUINOLINE DERIVATIVES, PREPARATION THEREOF, AND USE THEREOF IN MEDICINES
-
The present disclosure relates to 1,5,7-trisubstituted isoquinoline derivatives, their preparation and pharmaceutical use. In particular, the present disclosure discloses a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and a preparation method and use thereof. The definitions of the groups in the formula can be found in the specification and claims.
- -
-
Paragraph 0240; 0242
(2020/08/30)
-
- SMARCA DEGRADERS AND USES THEREOF
-
The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same for the modulation of one or more SWI/SNF-related matrix associated actin dependent regulator of chromatin subfamily A (SMARCA) and/or polybromo-1 (PB-1) protein via ubiqitination and/or degradation by compounds. The compounds are bifunctional molecules that link a cereblon-binding moiety to a ligand that binds SMARCA and/or PB1 proteins.
- -
-
Paragraph 00848; 00849
(2020/12/30)
-
- Pyrrolo[2, 3-d] pyrimidine derivatives containing piperidine as well as preparation and application thereof
-
The invention relates to a piperidine-containing pyrrolo[2, 3-d] pyrimidine derivative as shown in a general formula I or a general formula II as well as a use method and a preparation method thereof.The invention also relates to a strong JAK kinase inhibition effect of the compound shown in the general formula I or II, the invention also relates to an application of the compound in preparation of medicines for treating and/or preventing diseases caused by abnormal expression of JAK, and particularly relates to application of the compound in preparation of medicines for treating inflammatory/autoimmune diseases, fibrosis and cancers.
- -
-
-
- INDOLINONE COMPOUNDS FOR USE AS MAP4K1 INHIBITORS
-
The present disclosure is directed to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein ring A, ring C, X1, X2, L1, R1, R2, R3, R4, R5, R6, R7, m and n are as defined herein, which are useful as MAP4K1 inhibitors, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment or prevention of various diseases, conditions and/or disorders mediated by MAP4K1.
- -
-
Page/Page column 55
(2020/05/15)
-
- A Monophosphine Ligand Derived from Anthracene Photodimer: Synthetic Applications for Palladium-Catalyzed Coupling Reactions
-
Herein, we present an air-stable dianthracenyl monophosphine ligand (diAnthPhos) which can be prepared in two steps from commercially available anthracene derivatives. The ligand exhibits excellent efficiency for palladium-catalyzed coupling reactions. In particular, Miyaura borylation of heterocycle-containing electrophiles can be facilitated employing the diAnthPhos ligand with a broad substrate scope and low catalyst loading. The valuable synthetic utility of the new ligand is further demonstrated by a one-pot Miyaura borylation/Suzuki coupling protocol for heteroaryl-containing substrates.
- Wang, Xin,Liu, Wei-Gang,Tung, Chen-Ho,Wu, Li-Zhu,Cong, Huan
-
supporting information
p. 8158 - 8163
(2019/09/07)
-
- Discovery of Potent and Orally Effective Dual Janus Kinase 2/FLT3 Inhibitors for the Treatment of Acute Myelogenous Leukemia and Myeloproliferative Neoplasms
-
Herein, we describe the design, synthesis, and structure-activity relationships of a series of unique 4-(1H-pyrazol-4-yl)-pyrimidin-2-amine derivatives that selectively inhibit Janus kinase 2 (JAK2) and FLT3 kinases. These screening cascades revealed that 18e was a preferred compound, with IC50 values of 0.7 and 4 nM for JAK2 and FLT3, respectively. Moreover, 18e was a potent JAK2 inhibitor with 37-fold and 56-fold selectivity over JAK1 and JAK3, respectively, and possessed an excellent selectivity profile over the other 100 representative kinases. In a series of cytokine-stimulated cell-based assays, 18e exhibited a higher JAK2 selectivity over other JAK isoforms. The oral administration of 60 mg/kg of 18e could significantly inhibit tumor growth, with a tumor growth inhibition rate of 93 and 85% in MV4-11 and SET-2 xenograft models, respectively. Additionally, 18e showed an excellent bioavailability (F = 58%), a suitable half-life time (T1/2 = 4.1 h), a satisfactory metabolic stability, and a weak CYP3A4 inhibitory activity, suggesting that 18e might be a potential drug candidate for JAK2-driven myeloproliferative neoplasms and FLT3-internal tandem duplication-driven acute myelogenous leukemia.
- Yang, Tao,Hu, Mengshi,Qi, Wenyan,Yang, Zhuang,Tang, Minghai,He, Jun,Chen, Yong,Bai, Peng,Yuan, Xue,Zhang, Chufeng,Liu, Kongjun,Lu, Yulin,Xiang, Mingli,Chen, Lijuan
-
p. 10305 - 10320
(2019/11/19)
-
- Design, synthesis and anti-inflammatory evaluation of novel pyrrolo[2,3-d]pyrimidin derivatives as potent JAK inhibitors
-
Aiming to develop potent JAK inhibitors, two series of 4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives (8a–8p and 11a–11i) were designed and synthesized by coalescing various N-acylpiperidine motifs with baricitinib. The pharmacological results based on enzymatic and cellular assays identified the optimized compound 11e, which exerted over 90% inhibition rates against JAK1 and JAK2, and displayed the most compelling anti-inflammatory efficacy superior to baricitinib by inhibiting NO generation from LPS-induced RAW264.7 macrophages. Importantly, low cytotoxity of 11e was revealed by the IC50 value of 88.2 μM against normal RAW264.7 cells. The binding mode of 11e with JAK1 and JAK2 identified the essential structural bases in accord with SARs analysis. Furthermore, cellular morphology observation and western blot analysis disclosed the ability of 11e to relieve cells inflammatory damage by significantly down-regulating LPS-induced high expression of JAK1, JAK2, as well as pro cytokine IL-1β. Together, 11e was verified as a promising lead for JAK inhibitors for the treatment of inflammatory diseases.
- Jiang, Feng,Zang, Linghe,Miao, Xiuqi,Jia, Fang,Wang, Jie,Zhu, Minglin,Gong, Ping,Jiang, Nan,Zhai, Xin
-
p. 4089 - 4100
(2019/08/06)
-
- Alkenyl compound and its method and use thereof
-
The invention provides a new substituted alkenyl compound, pharmaceutically acceptable salts of the new substituted alkenyl compound, a medicinal preparation of the new substituted alkenyl compound, and application of the new substituted alkenyl compound, the pharmaceutically acceptable salts and the medicinal preparation of the new substituted alkenyl compound in aspects of regulating the activity of protein kinase and regulating the intercellular or intracellular signal response. The invention also relates to a medicament composition containing the compound at the same time, and relates to a method for treating high-proliferative diseases of mammals especially the human by using the medicament composition.
- -
-
-
- Synthesis of 1 - (N - Boc - 4 - piperidyl) - 4 - pyrazole boric acid frequency alcohol ester
-
The invention discloses a method for synthesis of 1-(N-Boc-4-piperidine)-4-pyrazoleboronic acid pinaol ester. According to the method, N-Boc-4-piperidone serves as the raw material and reacts with hydrazine hydrate, N-Boc-4-piperidine hydrazine is generated through reduction, then dehydration condensation reaction is conducted between N-Boc-4-piperidine hydrazine and 2-halogenate malonaldehyde so that a 1-(N-Boc-4-piperidine)-4-chlorine/bromine pyrazol midbody can be obtained effectively, and in the presence of metallic nickel, metallic nickel catalytic coupling reaction ester forming is conducted on the midbody under a mild condition to obtain the 1-(N-Boc-4-piperidine)-4-pyrazoleboronic acid pinaol ester. The whole process is easy to operate, conditions are mild, and untralow-temperature reaction is not needed; meanwhile, required raw materials are cheap and easy to obtain, reproducibility is high, and the method is suitable for industrialized large-scale production.
- -
-
-
- 2,4-DISUBSTITUTED PHENYLENE-1,5-DIAMINE DERIVATIVES AND APPLICATIONS THEREOF, AND PHARMACEUTICAL COMPOSITIONS AND PHARMACEUTICALLY ACCEPTABLE COMPOSITIONS PREPARED THEREFROM
-
The present invention provides a class of 2,4-substituted phenylene-1,5-diamine derivatives, having an inhibiting effect on EGFR tyrosine kinases, and pharmaceutically acceptable salt, stereoisomer, solvate or prodrug of said derivatives. See the description for the definition of each group in the formula. In addition, the present invention also discloses pharmaceutical compositions, pharmaceutically acceptable compositions and applications thereof.
- -
-
Paragraph 0309; 0311
(2017/01/31)
-
- Compounds used as JAK inhibitor, and use of compounds
-
The invention provides compounds used as a JAK inhibitor, and a use of the compounds, and concretely provides compounds (represented by formula (I)) with JAK inhibition activity or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and a medicinal composition including the compounds. The invention also discloses a use of the compounds or the medicinal composition thereof in the preparation of medicines used for treating autoimmune diseases or proliferative diseases.
- -
-
Paragraph 0509; 0510; 0511; 0512
(2017/08/27)
-
- Crizotinib intermediate, preparation method and crizotinib preparation method
-
The invention relates to a crizotinib intermediate, a preparation method and a crizotinib preparation method, in particular to an intermediate of crizotinib which has the structure of a formula (CZT-5) as shown in the description and the structure of a formula (CZT-9) as shown in the description, a preparation method of the intermediate and a preparation method of a crizotinib with the structure of a formula (CZT-11). The method provided by the invention has the characteristics of short route, high yield, easiness in acquisition of raw materials, high reaction selectivity and the like, chiral resolution is not required in a synthetic process, the utilization rate of the raw materials is increased, the path costs are low, and therefore, the method can meet requirements of large-scale industrial production.
- -
-
Paragraph 0062; 0063; 0064; 0065'; 0066
(2017/08/28)
-
- Synthetic method of bis-4-(1H-pyrazol-1-yl) piperidine-1-tert-butyl formate and application thereof
-
The invention discloses a synthetic method of bis-4-(1H-pyrazol-1-yl) piperidine-1-tert-butyl formate and an application thereof. The bis-4-(1H-pyrazol-1-yl) piperidine-1-tert-butyl formate is prepared through a methyl sulfonylation reaction, a hydrocarbylation reaction, a Grignard reaction and a Suzuki coupling reaction by taking cheap and easily available N-Boc-4-hydroxyl piperidine as a raw material. The synthetic method is simple, the process is easy to control, and the yield of the prepared bis-4-(1H-pyrazol-1-yl) piperidine-1-tert-butyl formate is 86.7%; bis-4-(1H-pyrazol-1-yl) piperidine-1-tert-butyl formate can be used as a standard substance to detect and monitor synthesis of crizotinib. The synthetic method disclosed by the invention is suitable for synthesizing bis-4-(1H-pyrazol-1-yl) piperidine-1-tert-butyl formate and the synthesized substance is used for detecting and monitoring synthesis of crizotinib.
- -
-
Paragraph 0016; 0018; 0019
(2017/08/29)
-
- Preparation method of crizotinib intermediate
-
The invention discloses a synthetic method of anti-tumor molecular targeted drug crizotinib, belongs to the field of pharmaceuticals, and relates to a synthetic method of a crizotinib intermediate. The method comprises two reduction processes: a bromination reaction process comprises the following reaction steps: a reduction process I: carrying out reduction reaction on a (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-nitropyridine compound and sodium dithionate under a mechanical chemical condition to generate (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-aminopyridine; a reduction process II: dissolving the (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-nitropyridine compound into an organic solvent, carrying out catalytic hydrogenation and reduction treatment to generate (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-aminopyridine; the bromination reaction process comprises a step of carrying out reaction between the compound and potassium hydrogen persulfate as well as bromate to obtain the crizotinib intermediate. The process is low in cost, the raw materials are easy to purchase, the operation is simple, convenient and safe, and the yield is high; moreover, the process is suitable for large-scale production.
- -
-
-
- Alkynyl compound and its method and use thereof
-
The invention provides a novel substituted alkynyl compound and its pharmaceutically acceptable salt and medicinal preparation, and a use of the novel substituted alkynyl compound and its pharmaceutically acceptable salt and medicinal preparation in adjustment of protein kinase activity and intercellular or intracellular signal response. The invention also relates to a pharmaceutical composition containing the novel substituted alkynyl compound and a method for treating high-proliferative diseases of mammals especially such as human by the pharmaceutical composition.
- -
-
-
- Design, synthesis and biological evaluation of 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine derivatives as c-Met inhibitors
-
Five novel 1H-pyrrolo[2,3-b]pyridine or 1H-pyrazolo[3,4-b]pyridine derivatives, with a methylene, sulfur, sulfoxide or cyclopropyl group as a linker, were designed, synthesized and biologically evaluated against c-Met and ALK. The development of these methods of compound synthesis may provide an important reference for the construction of novel 7-azaindole and 7-azaindazole derivatives with a single atom linker. The enzyme assay and cell assay in vitro showed that compound 9 displayed strong c-Met kinase inhibition with IC50 of 22.8 nM, moderate ALK kinase inhibition, and strong cell inhibition with MKN-45 IC50 of 329 nM and EBC-1 IC50 of 479 nM. In order to find the better candidate compounds, compounds 8, 9 and 10 have been selected as tool compounds for further optimization.
- Liu, Na,Wang, Yanfen,Huang, Gongchao,Ji, Conghui,Fan, Wei,Li, Haitao,Cheng, Ying,Tian, Hongqi
-
p. 146 - 158
(2016/03/12)
-
- CRIZOTINIB FOR USE IN THE TREATMENT OF CANCER
-
The present invention relates to the use of ROS kinase inhibitors for treating abnormal cell growth in mammals. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS by administration of crizotinib.
- -
-
-
- AMINOPYRIDINE DERIVATIVES AS TAM FAMILY KINASE INHIBITORS
-
Provided herein are aminopyridine derivatives and pharmaceutical compositions that are useful as TAM family kinase inhibitors.
- -
-
Page/Page column 81-82
(2015/06/11)
-
- PROTEIN KINASE INHIBITORS
-
A compound of formula (I), wherein R3, R4, G, B, M, and Z are as defined in the claims, and pharmaceutically acceptable salts thereof are disclosed. The compounds of formula (I) possess utility as FGFR inhibitors and are useful in the treatment of a condition, where FGFR kinase inhibition is desired, such as cancer.
- -
-
Paragraph 0137
(2015/02/18)
-
- Boryl substitution of functionalized aryl-, heteroaryl- and alkenyl halides with silylborane and an alkoxy base: expanded scope and mechanistic studies
-
A transition-metal-free method has been developed for the boryl substitution of functionalized aryl-, heteroaryl- and alkenyl halides with a silylborane in the presence of an alkali-metal alkoxide. The base-mediated boryl substitution of organohalides with a silylborane was recently reported to provide the corresponding borylated products in good to high yields, and exhibit good functional group compatibility and high tolerance to steric hindrance. In this study, the scope of this transformation has been extended significantly to include a wide variety of functionalized aryl-, heteroaryl- and alkenyl halides. In particular, the boryl substitution of (E)- and (Z)-alkenyl halides proceeded smoothly to afford the corresponding alkenyl boronates in good to high yields with retention of the configuration using modified reaction conditions. The results of the mechanistic studies suggest that this boryl substitution proceeds via a carbanion-mediated mechanism.
- Yamamoto, Eiji,Ukigai, Satoshi,Ito, Hajime
-
p. 2943 - 2951
(2015/06/17)
-
- 5-(1H-Pyrazol-4-yl)-1H-Pyrrolo[2,3-b]Pyridine Derivatives as Kinase Inhibitors
-
The present application relates to novel 5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine derivatives of formula (I), as protein kinase inhibitors. The invention particularly relates to compounds of formula (I), preparation of compounds and pharmaceutical compositions thereof. The invention further relates to prodrugs, derivatives, polymorphs, pharmaceutically acceptable salts and compositions comprising the said novel 5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine compounds and their derivatives and their use in the treatment of various disorders.
- -
-
Paragraph 0140; 0141; 0160; 0161
(2015/07/15)
-
- Iridium-catalyzed C-H borylation of heteroarenes: Scope, regioselectivity, application to late-stage functionalization, and mechanism
-
A study on the iridium-catalyzed C-H borylation of heteroarenes is reported. Several heteroarenes containing multiple heteroatoms were found to be amenable to C-H borylation catalyzed by the combination of an iridium(I) precursor and tetramethylphenanthroline. The investigations of the scope of the reaction led to the development of powerful rules for predicting the regioselectivity of borylation, foremost of which is that borylation occurs distal to nitrogen atoms. One-pot functionalizations are reported of the heteroaryl boronate esters formed in situ, demonstrating the usefulness of the reported methodology for the synthesis of complex heteroaryl structures. Application of this methodology to the synthesis and late-stage functionalization of biologically active compounds is also demonstrated. Mechanistic studies show that basic heteroarenes can bind to the catalyst and alter the resting state from the olefin-bound complex observed during arene borylation to a species containing a bound heteroarene, leading to catalyst deactivation. Studies on the origins of the observed regioselectivity show that borylation occurs distal to N-H bonds due to rapid N-H borylation, creating an unfavorable steric environment for borylation adjacent to these bonds. Computational studies and mechanistic studies show that the lack of observable borylation of C-H bonds adjacent to basic nitrogen is not the result of coordination to a bulky Lewis acid prior to C-H activation, but the combination of a higher-energy pathway for the borylation of these bonds relative to other C-H bonds and the instability of the products formed from borylation adjacent to basic nitrogen.
- Larsen, Matthew A.,Hartwig, John F.
-
p. 4287 - 4299
(2014/04/03)
-
- A novel approach for the synthesis of Crizotinib through the key chiral alcohol intermediate by asymmetric hydrogenation using highly active Ir-Spiro-PAP catalyst
-
A novel approach for the synthesis of Crizotinib (1) is described. In addition, new efficient procedures have been developed for the preparation of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (2) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) piperidine-1-carboxylate (4), the key intermediates required for the synthesis of Crizotinib.
- Qian, Jian-Qiang,Yan, Pu-Cha,Che, Da-Qing,Zhou, Qi-Lin,Li, Yuan-Qiang
-
p. 1528 - 1531
(2014/03/21)
-
- PROCESS FOR THE PREPARATION OF PYRAZOLE SUBSTITUTED AMINOHETEROARYL COMPOUNDS
-
The present invention relates to an improved process for the preparation of pyrazole substituted aminoheteroaryl compounds. More particularly, the present invention provides highly pure 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4- yl)pyridin-2-amine, its intermediates and preparation thereof. The process of the present invention is simple, convenient, does not use expensive chemicals and avoids use of tedious purification techniques. Invention also provides process intermediates, useful not only in the synthesis, but also useful for providing desired compound with high purity.
- -
-
Page/Page column 20
(2014/02/16)
-
- SUBSTITUTED PYRIDOPYRAZINES AS NOVEL SYK INHIBITORS
-
Provided are pyridopyrazine compounds of formula (1), pharmaceutical compositions thereof and methods of use therefore, wherein R1, R2, R3, R4 and m are as defined in the specification.
- -
-
Paragraph 0333; 0334
(2014/05/08)
-
- ALKYNYL COMPOUNDS AND METHODS OF USE
-
The present invention provides novel substituted alkynyl compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
- -
-
-
- Inhibitors of nedd8-activating enzyme
-
The invention relates to an administration unit comprising crystalline form I of {(1 S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate (I-216) hydrochloride salt and to a packaging comprising the administration unit according to the invention.
- -
-
-
- ALKENYL COMPOUNDS AND METHODS OF USE
-
The present invention provides novel substituted alkenyl compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
- -
-
-
- 5-(1H-PYRAZOL-4-YL)-1H-PYRROLO[2,3-b]PYRIDINE DERIVATIVES AS KINASE INHIBITORS
-
The present application relates to novel 5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine derivatives of formula (I), as protein kinase inhibitors. The invention particularly relates to compounds of formula (I), preparation of compounds and pharmaceutical compositions thereof. The invention further relates to prodrugs, derivatives, polymorphs, pharmaceutically acceptable salts and compositions comprising the said novel 5-(1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine compounds and their derivatives and their use in the treatment of various disorders.
- -
-
Page/Page column 28; 36
(2014/03/21)
-
- PROTEIN KINASE INHIBITORS
-
A compound of formula (I), wherein R3, R4, G, B, M, and Z are as defined in the claims, and pharmaceutically acceptable salts thereof are disclosed. The compounds of formula (I) possess utility as FGFR inhibitors and are useful in the treatment of a condition, where FGFR kinase inhibition is desired, such as cancer.
- -
-
Page/Page column 31; 32
(2013/04/25)
-
- Synthesis and biological evaluation of 2-amino-5-aryl-3-benzylthiopyridine scaffold based potent c-Met inhibitors
-
A series of 2-amino-N-benzylpyridine-3-carboxnamides, 2-amino-N- benzylpyridine-3-sulfonamides and 2-amino-3-benzylthiopyridines against c-Met were designed by means of bioisosteric replacement and docking analysis. Optimization of the 2-amino-3-benzylthiopyridine scaffold led to the identification of compound (R)-10b displaying c-Met inhibition with an IC 50 up to 7.7 nM. In the cytotoxic evaluation, compound (R)-10b effectively inhibited the proliferation of c-Met addictive human cancer cell lines (IC50 from 0.19 to 0.71 μM) and c-Met activation-mediated cell metastasis. At a dose of 100 mg/Kg, (R)-10b evidently inhibited tumor growth (45%) in NIH-3T3/TPR-Met xenograft model. Of note, (R)-10b could overcome c-Met-activation mediated gefitinib-resistance, which indicated its potential use for drug combination. Taken together, 2-amino-3-benzylthiopyridine scaffold was first disclosed and exhibited promising pharmacological profiles against c-Met, which left room for further exploration.
- Zhang, Dengyou,Zhang, Xiaowei,Ai, Jing,Zhai, Yun,Liang, Zhongjie,Wang, Ying,Chen, Yi,Li, Chunpu,Zhao, Fei,Jiang, Hualiang,Geng, Meiyu,Luo, Cheng,Liu, Hong
-
p. 6804 - 6820
(2013/10/22)
-
- Discovery of 1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5] cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide (MK-8033): A specific c-Met/Ron dual kinase inhibitor with preferential affinity for the activated state of c-Met
-
This report documents the first example of a specific inhibitor of protein kinases with preferential binding to the activated kinase conformation: 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one 11r (MK-8033), a dual c-Met/Ron inhibitor under investigation as a treatment for cancer. The design of 11r was based on the desire to reduce time-dependent inhibition of CYP3A4 (TDI) by members of this structural class. A novel two-step protocol for the synthesis of benzylic sulfonamides was developed to access 11r and analogues. We provide a rationale for the observed selectivity based on X-ray crystallographic evidence and discuss selectivity trends with additional examples. Importantly, 11r provides full inhibition of tumor growth in a c-Met amplified (GTL-16) subcutaneous tumor xenograft model and may have an advantage over inactive form kinase inhibitors due to equal potency against a panel of oncogenic activating mutations of c-Met in contrast to c-Met inhibitors without preferential binding to the active kinase conformation.
- Northrup, Alan B.,Katcher, Matthew H.,Altman, Michael D.,Chenard, Melissa,Daniels, Matthew H.,Deshmukh, Sujal V.,Falcone, Danielle,Guerin, David J.,Hatch, Harold,Li, Chaomin,Lu, Wei,Lutterbach, Bart,Allison, Timothy J.,Patel, Sangita B.,Reilly, John F.,Reutershan, Michael,Rickert, Keith W.,Rosenstein, Craig,Soisson, Stephen M.,Szewczak, Alexander A.,Walker, Deborah,Wilson, Kevin,Young, Jonathan R.,Pan, Bo-Sheng,Dinsmore, Christopher J.
-
p. 2294 - 2310
(2013/06/04)
-
- CRIZOTINIB FOR USE IN THE TREATMENT OF CANCER
-
The present invention relates to the use of ROS kinase inhibitors for treating abnormal cell growth in mammals. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS by administration of crizotinib.
- -
-
-
- SUBSTITUTED IMIDAZOPYRIDAZINES AND BENZIMIDAZOLES AS INHIBITORS OF FGFR3
-
The present invention relates to substituted imidazopyridazines and substituted benzimidazoles, as well as pharmaceutical compositions comprising the same, which are FGFR3 inhibitors useful in the treatment of cancer and other diseases.
- -
-
Page/Page column 29
(2012/07/13)
-
- 7-AMINOFUROPYRIDINE DERIVATIVES
-
Compounds of Formula 1, as shown below and defined herein: pharmaceutically acceptable salts thereof, synthesis, intermediates, formulations, and methods of disease treatment therewith, including treatment of cancers, such as tumors driven at least in part by TAK1 or for which an appropriate TAK1 inhibitor is effective. This Abstract is not limiting of the invention.
- -
-
Page/Page column 37
(2011/09/15)
-
- FUSED BICYCLIC KINASE INHIBITORS
-
Compounds of Formula I, as shown below and defined herein: pharmaceutically acceptable salts thereof, synthesis, intermediates, formulations, and methods of disease treatment therewith, including treatment of cancers, such as but not limited to tumors driven at least in part by at least one of RON, MET, IR, IGF-1 R, or ALK. This Abstract is not limiting of the invention.
- -
-
Page/Page column 41-42
(2011/12/02)
-
- Fit-for-purpose development of the enabling route to crizotinib (PF-02341066)
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A robust six-step process for the synthesis of crizotinib, a novel c-Met/ALK inhibitor currently in phase III clinical trials, has been developed and used to deliver over 100 kg of API. The process includes a Mitsunobu reaction, a chemoselective reduction of an arylnitro group, and a Suzuki coupling, all of which required optimization to ensure successful scale-up. Conducting the Mitsunobu reaction in toluene and then crystallizing the product from ethanol efficiently purged the reaction byproduct. A chemoselective arylnitro reduction and subsequent bromination reaction afforded the key intermediate 6. A highly selective Suzuki reaction between 6 and pinacol boronate 8, followed by Boc deprotection, completed the synthesis of crizotinib 1.
- De Koning, Pieter D.,McAndrew, Douglas,Moore, Robert,Moses, Ian B.,Boyles, David C.,Kissick, Kyle,Stanchina, Corey L.,Cuthbertson, Timothy,Kamatani, Asayuki,Rahman, Leera,Rodriguez, Rick,Urbina, Armando,Sandovalnee Accacia, Alison,Rose, Peter R.
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experimental part
p. 1018 - 1026
(2011/12/21)
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- Discovery of a 5 H-benzo[4,5]cyclohepta[1,2-b ]pyridin-5-one (MK-2461) inhibitor of c-Met kinase for the treatment of cancer
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c-Met is a transmembrane tyrosine kinase that mediates activation of several signaling pathways implicated in aggressive cancer phenotypes. In recent years, research into this area has highlighted c-Met as an attractive cancer drug target, triggering a number of approaches to disrupt aberrant c-Met signaling. Screening efforts identified a unique class of 5H-benzo[4,5] cyclohepta[1,2-b]pyridin-5-one kinase inhibitors, exemplified by 1. Subsequent SAR studies led to the development of 81 (MK-2461), a potent inhibitor of c-Met that was efficacious in preclinical animal models of tumor suppression. In addition, biochemical studies and X-ray analysis have revealed that this unique class of kinase inhibitors binds preferentially to the activated (phosphorylated) form of the kinase. This report details the development of 81 and provides a description of its unique biochemical properties.
- Katz, Jason D.,Jewell, James P.,Guerin, David J.,Lim, Jongwon,Dinsmore, Christopher J.,Deshmukh, Sujal V.,Pan, Bo-Sheng,Marshall, C. Gary,Lu, Wei,Altman, Michael D.,Dahlberg, William K.,Davis, Lenora,Falcone, Danielle,Gabarda, Ana E.,Hang, Gaozhen,Hatch, Harold,Holmes, Rachael,Kunii, Kaiko,Lumb, Kevin J.,Lutterbach, Bart,Mathvink, Robert,Nazef, Naim,Patel, Sangita B.,Qu, Xianlu,Reilly, John F.,Rickert, Keith W.,Rosenstein, Craig,Soisson, Stephen M.,Spencer, Kerrie B.,Szewczak, Alexander A.,Walker, Deborah,Wang, Wenxian,Young, Jonathan,Zeng, Qinwen
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p. 4092 - 4108
(2011/08/06)
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- Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK)
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Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.
- Cui, J. Jean,Tran-Dubé, Michelle,Shen, Hong,Nambu, Mitchell,Kung, Pei-Pei,Pairish, Mason,Jia, Lei,Meng, Jerry,Funk, Lee,Botrous, Iriny,McTigue, Michele,Grodsky, Neil,Ryan, Kevin,Padrique, Ellen,Alton, Gordon,Timofeevski, Sergei,Yamazaki, Shinji,Li, Qiuhua,Zou, Helen,Christensen, James,Mroczkowski, Barbara,Bender, Steve,Kania, Robert S.,Edwards, Martin P.
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p. 6342 - 6363
(2011/11/05)
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- 4, 6-DISUBSTITUTED 2-AMINO-PYRIMIDINES AS HISTAMINE H4 RECEPTOR MODULATORS
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The present invention relates to substituted heterocyclic compounds of Formula (I) or pharmaceutically acceptable salts or N-oxides or quaternary ammonium salts thereof wherein constituent members are provided hereinwith, as well as their compositions and methods of use, which are histamine H4 receptor inhibitors/antagonists useful in the treatment of histamine H4 receptor-associated conditions or diseases or disorders including, for example, inflammatory diseases or disorders, pruritus, and pain.
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Page/Page column 68-69
(2010/07/09)
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- SUBSTITUTED PYRROLO[2,3-B]-PYRIDINES AND-PYRAZINES
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Compounds of Formula I, as shown below and defined herein:(I) pharmaceutically acceptable salts, synthesis, intermediates, formulations, and methods of disease treatment therewith, including cancers mediated at least in part by Ron and/or Met.
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Page/Page column 30-31
(2010/07/10)
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- C-MET PROTEIN KINASE INHIBITORS
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The present invention relates to compounds of formula (I) useful in the inhibition of c-Met protein kinase. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of proliferative disorders
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Page/Page column 54-55
(2010/05/13)
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- AZAINDOLE DERIVATIVES AS KINASE INHIBITORS
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This invention relates to compounds of the general formula (I) in which the variable groups are as defined herein, and to their preparation and use.
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Page/Page column 85-86
(2010/07/02)
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- ORGANIC COMPOUNDS
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Compounds of formula (I) in free or salt or solvate form, where T1, T2, X, Ra, Rb, R8 and R9 have the meanings as indicated in the specification, are useful for treating inflammatory or obstructive airways, pulmonary hypertension, pulmonary fibrosis, liver fibrosis, muscle diseases and systemic skeletal disorders. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.
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Page/Page column 146
(2009/09/04)
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- QUINOXALINE DERIVATIVES AS INHIBITORS OF THE TYROSINE KINASE ACTIVITY OF JANUS KINASES
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The present invention relates to quinoxaline compound of the formula (I): wherein R1 is carbocyclyl or heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R7; R2 is carbocyclyl or heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 R8; R3, R4, R5 and R6 are each independently hydrogen or R9; and R7, R8 and R9 are each independently selected from organic and inorganic substituents, their use in therapy of diseases, in particular diseases mediated by the tyrosine kinase activity of Janus kinases, including JAK-2 and JAK-3 kinases
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Page/Page column 52
(2009/01/24)
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- Method of Treating Abnormal Cell Growth
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The present invention relates to the use of (R)-3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, a novel c-Met/HGFR inhibitor, for treating abnormal cell growth in mammals. In particular, the invention provides methods of treating mammals suffering from cancer.
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