cas 479633-63-1, 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine

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Identification of N-Phenyl-7 H-pyrrolo[2,3- d]pyrimidin-4-amine Derivatives as Novel, Potent, and Selective NF-κB Inducing Kinase (NIK) Inhibitors for the Treatment of Psoriasis
A series of N-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives with NF-κB inducing kinase (NIK) inhibitory activity were obtained through structure-based drug design and synthetic chemistry. Among them, 4-(3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-4-morpholinophenyl)-2-(thiazol-2-yl)but-3-yn-2-ol (12f) was identified as a highly potent NIK inhibitor, along with satisfactory selectivity. The pharmacokinetics of 12f and its ability to inhibit interleukin 6 secretion in BEAS-2B cells were better than compound 1 developed by Amgen. Oral administration of different doses of 12f in an imiquimod-induced psoriasis mouse model showed effective alleviation of psoriasis, including invasive erythema, swelling, skin thickening, and scales. The underlying pathological mechanism involved attenuation of proinflammatory cytokine and chemokine gene expression, and the infiltration of macrophages after the treatment of 12f. This work provides a foundation for the development of NIK inhibitors, highlighting the potential of developing NIK inhibitors as a new strategy for the treatment of psoriasis.
Zhu, Yuqin,Ma, Yuxiang,Zu, Weidong,Song, Jianing,Wang, Hua,Zhong, You,Li, Hongmei,Zhang, Yanmin,Gao, Qianqian,Kong, Bo,Xu, Junyu,Jiang, Fei,Wang, Xinren,Li, Shuwen,Liu, Chenhe,Liu, Haichun,Lu, Tao,Chen, Yadong
p. 6748 - 6773
(2020)
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PROCESS AND INTERMEDIATES FOR PREPARING A JAK1 INHIBITOR
The present invention is related to processes for preparing itacitinib, or a salt thereof, and related synthetic intermediates related thereto.
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(2022/03/02)

PROCESS AND INTERMEDIATES FOR PREPARING A JAK INHIBITOR
The present invention is related to processes for preparing ruxolitinib, or a salt thereof, and related synthetic intermediates related thereto.
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(2022/03/04)

Preparation method of key intermediate of JAK inhibitor
The invention discloses a preparation method of a key intermediate of a JAK inhibitor. The preparation method comprises the following steps: step a, protecting an amino group of a raw material 4-chloro-7H-pyrrole-[2.3-d]-pyrimidine to synthesize 4-chloro-
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Paragraph 0043-0045; 0050-0052; 0057-0059

(2021/09/04)

Selective JAK1 inhibitor compound as well as preparation method and application thereof
The invention provides a heterocyclic compound serving as a JAK1 inhibitor and synthesis and use methods, and particularly provides a compound shown as a formula (I), a preparation method of the compound and application of the compound serving as a JAK1 i
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Paragraph 0069-0074

(2021/01/30)

COMPOUND HAVING TRKA INHIBITORY ACTIVITY AND PHARMACEUTICAL COMPOSITION, FOR PREVENTING OR ALLEVIATING PAIN, CONTAINING SAME AS ACTIVE INGREDIENT
The present invention relates to a compound having TrkA inhibitory activity and a pharmaceutical composition for preventing or treating pain containing the same as an active ingredient. The compound provided in one aspect of the present invention has excellent TrkA inhibitory activity and exhibits excellent pain inhibitory effects in an animal model of pain after a surgery, and thus can be effectively used as an analgesic.
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Paragraph 0074

(2021/05/13)

PROCESS FOR PREPARATION OF ABROCITINIB
The present invention relates to crystalline abrocitinib characterized by X-ray powder diffraction (XRPD) spectrum having peak reflections at about 12.9, 14.7, 19.4, 23.2 and 25.2 ±0.2 degrees 2 theta, and process for its preparation. The present invention relates to amorphous solid dispersion comprising abrocitinib or salt thereof together with at least one pharmaceutically acceptable carrier and process for its preparation.
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Paragraph 0107

(2021/01/23)

TRICYCLIC JANUS KINASE 1 INHIBITORS, AND COMPOSITIONS AND METHODS THEREOF
Provided are novel class of therapeutics that are safe and effective inhibitors of Janus kinase 1 and pharmaceutical composition and methods of preparation and use thereof in the treatment of various diseases and disorders (e. g., inflammatory diseases, immune-mediated diseases or cancer).
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Paragraph 00199; 00288

(2020/05/28)

A class of pyrrolopyrimidine derivatives, and synthesis method thereof
The invention discloses a class of pyrrolopyrimidine derivatives, wherein the pyrrolopyrimidine derivative has a structural general formula represented by a formula (I). The invention also discloses asynthesis method of the compound represented by the for
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Paragraph 0070-0073

(2020/05/29)

PROCESS FOR PREPARATION OF TOFACITINIB AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
The present invention relates to an improved process for preparation of tofacitinib (I) and pharmaceutically acceptable salt thereof. (I)
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Page/Page column 10

(2020/09/27)

PREPARATION METHOD FOR AND INTERMEDIATE OF PYRROLO SIX-MEMBERED HETEROAROMATIC RING DERIVATIVE
Disclosed are an intermediate of a pyrrolo six-membered heteroaromatic ring derivative as a JAK inhibitor and a preparation method therefor, and a method for preparing a pyrrolo six-membered heteroaromatic ring derivative using the intermediate. The metho
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Paragraph 0108-0110

(2019/10/23)

Optimization of novel reversible Bruton's tyrosine kinase inhibitors identified using Tethering-fragment-based screens
Since the approval of ibrutinib for the treatment of B-cell malignancies in 2012, numerous clinical trials have been reported using covalent inhibitors to target Bruton's tyrosine kinase (BTK) for oncology indications. However, a formidable challenge for
Hopkins, Brian T.,Bame, Eris,Bell, Noah,Bohnert, Tonika,Bowden-Verhoek, Jon K.,Bui, Minna,Cancilla, Mark T.,Conlon, Patrick,Cullen, Patrick,Erlanson, Daniel A.,Fan, Junfa,Fuchs-Knotts, Tarra,Hansen, Stig,Heumann, Stacey,Jenkins, Tracy J.,Marcotte, Douglas,McDowell, Bob,Mertsching, Elisabeth,Negrou, Ella,Otipoby, Kevin L.,Poreci, Urjana,Romanowski, Michael J.,Scott, Daniel,Silvian, Laura,Yang, Wenjin,Zhong, Min
p. 2905 - 2913
(2019/05/29)

Discovery of potent Pan-Raf inhibitors with increased solubility to overcome drug resistance
Despite various applications of kinase inhibitors in oncology and inflammatory diseases, the emergence of resistance still remains the major barrier to achieve long-term remission in cancer treatment. With the aim of overcoming the resistance induced by type IIB BRaf V600E selective inhibitor vemurafenib, and further ameliorating the antiproliferative activity, a novel type IIA Pan-Raf inhibitors Ia–Io based on pyrrolo[2,3-d] pyrimidine scaffold were designed and evaluated in this work. Herein, we tried to improve the cellular potency of the target compounds by increasing their solubility. Among them, Il, with the solubility of 0.107 mg/mL, demonstrated favorable cellular activity against vemurafenib-resistant carcinoma cells including BRafWT phenotypic melanoma SK-MEL-2 and BRafV600E phenotypic colorectal cancer HT-29 cell lines. Based on the well solubility, Il exhibited good metabolic stability compared to sorafenib and showed favorable pharmacokinetic profiles in rats. As for the biological mechanism research, Il had the similar P-ERK kinase inhibitory activity in A375 and SK-Mel-2 cells as our previously lead P-2. Il may become a good candidate compound to overcome the resistance associated with vemurafenib.
Wang, Lu,Zhang, Yanmin,Zhang, Qing,Zhu, Gaoyuan,Zhang, Zhimin,Duan, Chunqi,Lu, Tao,Tang, Weifang
p. 243 - 255
(2018/12/11)

4-chloro pyrrolo[2,3-d]pyrimidine substituted compound and synthetic method thereof
The invention relates to a method for synthesizing 4-chloro pyrrolo[2,3-b] pyridine. The method mainly comprises three steps: 1) carrying out p-toluenesulfonyl chloride protection on a 4-chloro pyrrolo[2,3-d]pyrimidine compound; 2) reacting the 4-chloro p
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Paragraph 0034-0037; 0040-0043; 0046-0049; 0052-0055

(2019/12/02)

METHOD OF MANUFACTURING 4-CHLORO-7H-PYRROLO[2,3-d]PYRIMIDINE
The present invention discloses a method of manufacturing 4-chloro-7H-pyrrolo[2,3-d]pyrimidine comprising the steps: a) Preparing ethyl 2-cyano-4,4-dimethoxybutanoate by coupling ethyl 2- cyanoacetate and 2-bromo-1,1-dimethoxyethane; b) Preparing 6-amino-5-(2,2- dimethoxyethyl)pyrimidin-4-ol by adding formamidine to ethyl 2-cyano-4,4-dimethoxybutanoate; c) Converting 6-amino-5-(2,2-dimethoxyethyl)pyrimidin-4-ol to 7H-pyrrolo[2,3-d]pyrimidin-4-ol; and d) Converting the 7H-pyrrolo[2,3-d]pyrimidin-4-ol to 4-chloro-7H-pyrrolo[2,3-d]pyrimidine. The method offers increased yield, less by-products and a decrease in waste compared to methods known as being state of the art.
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(2018/03/06)

PREPARATION METHOD FOR PYRROLE SIX-MEMBERED HETEROARYL RING DERIVATIVE AND INTERMEDIATE THEREOF
The present invention relates to preparation method for pyrrole six-membered heteroaryl ring derivative and intermediate thereof. Specifically, the present invention relates to a preparation method for pyrrole six-membered heteroaryl ring derivative, inte
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Page/Page column 26

(2019/03/26)

Piperidine-containing pyrrolopyrimidine compound and preparation method and application thereof
The invention discloses a piperidine-containing pyrrolopyrimidine compound and a preparation method and application thereof. The piperidine-containing pyrrolopyrimidine compound adopts the structure shown in the general formula (I) or (II). The invention
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Paragraph 0101; 0108-0111

(2018/04/01)

For the prevention and treatment of various autoimmune diseases of the new compound
Disclosed is an isoxazole derivative that inhibits the activity of the Janus kinases (JAKs), the structure thereof as presented in formula I, formula II, formula IX, and formula XI. The substituent groups in the formulas are described in the description. Also disclosed are the pharmaceutical composition of the compound and a related use in medicine preparation.
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Paragraph 0080; 0081; 0082

(2018/04/20)

An Efficient Method for Synthesis of Tofacitinib Citrate
An efficient and mild synthetic method was developed for tofacitinib citrate from 3-amino-4-methylpyridine and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine. The related reactions were systematically optimized. Sodium hydride instead of potassium tert-butoxide employed in the methoxycarbonylation reaction of compound 9 made the reaction proceed effectively to present compound 8 in a better yield. The replacement of benzaldehyde with benzyl bromide simplified the protection process of amino group. Red-Al provided a cost-effective method for the reduction of amides. The introduction of tosyl group into compound 10 enhanced the nucleophilic substitution of 10 with compound 4 dramatically. Thus, under the optimized conditions, tofacitinib citrate was obtained in 13.3% yield (based on compound 9) with a purity of 99.9%, much better than the reported yield 8.6%. This cost-effective and environmental friendly process is more suitable for scale-up production.
Zhi, Shuang,Liu, Dengke,Liu, Ying,Liu, Bingni,Wang, Donghua,Chen, Ligong
p. 1259 - 1263
(2016/07/29)

PYRROLOPYRIMIDINE DERIVATIVES AS NR2B NMDA RECEPTOR ANTAGONISTS
Disclosed are chemical entities of formula I: [INSERT CHEMICAL FORMULA HERE] wherein X, Y, Z, R1, R3, R4, R5 and R6 are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of formula I, and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of formula I.
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Paragraph 0258

(2016/04/09)

3,3-DIFLUORO-PIPERIDINE DERIVATIVES AS NR2B NMDA RECEPTOR ANTAGONISTS
Disclosed are chemical entities of Formula (I): wherein X, Y, Z, R1, R3, R4 and R5 are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of Formula (I), and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of Formula (I).
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Paragraph 0152

(2016/09/22)

Crystalline form of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine
The invention discloses a Tofacitinib midbody, i.e. a new crystalline form of N-methyl-N-((3R,4R)-4-methyl-1-benzyl-3-piperidyl)-7H-pyrrolo[2,3-D]pyrimidine-4-amine, a preparation method thereof, and a method of preparing Tofacitinib by using a midbody of
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Paragraph 0037

(2016/10/10)

PIPERIDINE INHIBITORS OF JANUS KINASE 3
The present invention relates to a new piperidine inhibitors of Janus Kinase 3 activity, pharmaceutical compositions thereof, and methods of use there-of.
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Page/Page column 49

(2010/11/05)

Compounds and Compositions as Protein Kinase Inhibitors
The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly di
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Page/Page column 9

(2008/12/07)

PYRROLO[2,3-D]PYRIMIDINE DERIVATIVES; THEIR INTERMEDIATES AND SYNTHESIS
This invention relates to methods and intermediates useful for the synthesis of pyrrolo [2,3-d] pyrimidine compounds. Specifically novel synthetic methods and intermediates for the synthesis of 3- {(3R, 4R)-4-methyl-(7H-pyrrolo[2,3-d] pyrimidin-4-yl)-amino}-piperidin-1-yl)-3-oxo-propionitrile and its corresponding citrate salt are disclosed.
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Page/Page column 21

(2010/11/25)

DEAZAPURINES USEFUL AS INHIBITORS OF JANUS KINASES
The present invention relates to compounds of formula (I): useful as inhibitors of protein kinases, particularly of JAK family kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the
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Page/Page column 61-62

(2008/06/13)

Pyrrolopyrimidines useful as inhibitors of protein kinase
The present invention relates to compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, c
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Page/Page column 25

(2008/06/13)

COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly di
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Page/Page column 23-24

(2008/06/13)

COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of Abl, Bcr-Abl, Bmx, BTK, b-RAF, c RAF, CSK, cSRC, Fes, FGFR3, Flt3, IKKα, IKKβ, JNK1α1, JNK2α2, Lck, Met, MKK4, MKK6, p70S6K, PAK2, PDGFRα, PKA, PKCα, PKD2, ROCK-II, Ros, Rsk1, SAPK2α, SAPK2β, SAPK3, SAPK4, SGK, Syk, Tie2 and TrkB kinases.
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Page/Page column 24; 31; 33-34

(2008/06/13)