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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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THELIATINIB


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THELIATINIB

CAS: 1353644-70-8
Chemical Formula: C25H26N6O2

Molecular Weight: 442.523

HMPL-309; HMPL 309; HMPL309; Theliatinib.

  • Originator Hutchison MediPharma
  • Class Antineoplastics; Small molecules
  • Mechanism of Action Epidermal growth factor receptor antagonists

Highest Development Phases

  • Phase I Oesophageal cancer; Solid tumours

Most Recent Events

  • 29 Sep 2017 Efficacy and adverse events data from a phase I trial in Oesophageal cancer released by Hutchison Pharma
  • 13 Mar 2017 Phase-I clinical trials in Oesophageal cancer (First-line therapy) in China (PO) before March 2017 (Hutchison MediPharma pipeline, July 2017)
  • 02 Aug 2016 Hutchison MediPharma plans a phase Ib proof-of-concept trial for Oesophageal cancer, and Head and Neck cancer in China

Theliatinib, also known as HMPL-309, is a novel small molecule, epidermal growth factor receptor tyrosine kinase inhibitor with potential antineoplastic and anti-angiogenesis activities. In vitro studies suggest that Theliatinib is a potent EGFR kinase inhibitor with good kinase selectivity and in vivo data demonstrated broad spectrum anti-tumor activity via oral dosing in multiple xerographs such as A-431, Bcap-37 and Fadu.

PRODUCT PATENT

  • By Zhang, Weihan; Su, Wei-Guo; Yang, Haibin; Cui, Yumin; Ren, Yongxin; Yan, Xiaoqiang

WO2012000356 , covering quinazoline compounds as EGFR inhibitors

https://encrypted.google.com/patents/WO2012000356A1?cl=pt-PT&hl=en&output=html_text

Example 3:

(3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-l-methyl-hexahydropyrrolo [3,4-b]pyrrole-5(lH)-carboxamide

[060] To a solution of Compound 3-a (40 g, 0.138 mol, prepared according to procedures disclosed in WO2010002845), pyridine (40 mL, 0.495 mol) and DMF (anhydrous, 22 mL) in anhydrous THF (500 mL), was added phenyl carbonochloridate 3-b (22 mL, 0.175 mol) dropwise at -10°C. The mixture was stirred at room temperature for 12 hours. The precipitates were filtered and then suspended in saturated NaHC03 solution (500 mL). The solid was filtered, washed with H20 and EtOAc, and dried in vacuum to give compound 3-c (46 g).

A mixture of compound 3-c (1 g, 2.44 mmol) and compound 3-d (369 mg, 2.92 mmol) in dioxane (30mL) was stirred at 70°C for 5 hours, and then cooled to the ambient temperature. The precipitates were filtered, washed with EtOAc, and dried in vacuum to give compound 3 (0.8 g). MS (m/e): 443.4 (M+l)+.

PATENT

https://patents.google.com/patent/WO2010002845A2/en

PATENT

US 9168253

https://patents.google.com/patent/US9168253

Example 3 (3aR,6aR)—N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide

Figure US09168253-20151027-C00004

To a solution of Compound 3-a (40 g, 0.138 mol, prepared according to procedures disclosed in WO2010002845), pyridine (40 mL, 0.495 mol) and DMF (anhydrous, 22 mL) in anhydrous THF (500 mL), was added phenyl carbonochloridate 3-b (22 mL, 0.175 mol) dropwise at −10° C. The mixture was stirred at room temperature for 12 hours. The precipitates were filtered and then suspended in saturated NaHCO3solution (500 mL). The solid was filtered, washed with H2O and EtOAc, and dried in vacuum to give compound 3-c (46 g). A mixture of compound 3-c (1 g, 2.44 mmol) and compound 3-d (369 mg, 2.92 mmol) in dioxane (30 mL) was stirred at 70° C. for 5 hours, and then cooled to the ambient temperature. The precipitates were filtered, washed with EtOAc, and dried in vacuum to give compound 3 (0.8 g). MS (m/e): 443.4 (M+1)+.

PATENT

THELIATINIB BY HUTCHISON

WO-2018099451

The present invention belongs to the field of pharmacy and provides a crystal form of a compound (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, a pharmaceutical composition thereof, and a preparation method therefor and the use thereof.
(FR)La présente invention concerne le domaine de la pharmacie et fournit une forme cristalline d’un composé (3aR,6aR)-N-(4-(3-éthynylphénylamino)-7-méthoxyquinazolin-6-yl)-1-méthyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, une composition pharmaceutique de celui-ci, et son procédé de préparation et son utilisation.

Novel crystalline forms of the compound presumed to be theliatinib , processes for their preparation and compositions comprising them are claimed. Also claimed is their use for treating lung cancer, colon cancer, breast cancer, ovary cancer, prostate cancer, stomach cancer, kidney cancer, liver cancer, brain cancer, esophageal cancer, bone cancer and leukemia.

Hutchison Medipharma is developing theliatinib, a small molecule EGFR tyrosine kinase and AKT cell proliferation pathway inhibitor, for treating cancer, including brain tumor, esophageal tumor and NSCLC; in September 2017, positive preliminary data were presented. Hutchison is also developing epitinib succinate , for treating cancer including glioblastoma.

Binding of epidermal growth factor (EGF) to epidermal growth factor receptor (EGFR) activates tyrosine kinase activity and triggers a response that leads to cell proliferation. Overexpression and/or overactivation of EGFR can lead to uncontrolled cell division, and uncontrolled cell division can be a cause of cancer. Therefore, compounds that inhibit the over-expression and/or over-activation of EGFR are candidates for treating tumors.
Relevant compounds of the present invention (3aR, 6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo [3, 4-b]pyrrole-5(1H)-carboxamide, whose chemical structure is shown in Formula A, has the effect of effectively inhibiting overexpression and/or overactivation of EGFR. Therefore, it can be used for the treatment of diseases associated with overexpression and/or overactivation of EGFR, such as the treatment of cancer.
Before discovering the crystal form of a compound, it is difficult to predict (1) whether a particular compound exists in crystalline form; (2) how an unknown crystal form is made; (3) what the properties of the crystal form would be, such as stability , bioavailability and so on.
Since the properties of the solid depend on the structure and the nature of the compound itself, different solid forms of the compound often exhibit different physical and chemical properties. Differences in chemical properties can be measured, analyzed, and compared using a variety of analytical techniques that ultimately can be used to distinguish these different solid forms. Differences in physical properties, such as solubility and bioavailability, are also important in describing the solid form of the drug compound. Likewise, in the development of pharmaceutical compounds, such as compounds of Formula A, the new crystalline and amorphous forms of the pharmaceutical compounds are also important.

Patent CN102906086A discloses compound (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 4-b]pyrrole-5(1H)-carboxamide and its preparation method.

Experimental part
 
The starting material of the compound of formula A used in the examples was prepared according to CN102906086A
PATENT

Example 3: (3aR, 6aR) -N- (4- (3- ethynyl-phenylamino) -7-methoxy-quinazolin-6-yl) -1-methyl-hexahydro-pyrrolo [3,4-b] pyrrol -5 (IH) – carboxamide

[0102]

Figure CN102906086AD00131

[0103] at -10 ° C, to (40g, 0. 138mol, was prepared in accordance with the operation disclosed in W02010002845) Compound 3-a, pyridine (40mL, O. 495mol) and DMF (anhydrous, 22mL) in dry solution (500 mL) in THF dropwise phenyl chloroformate 3-b (22mL, O. 175mol). The mixture was stirred at room temperature for 12h. The precipitate was filtered off, and then it was suspended in saturated NaHCO3 solution (500mL). The solid was filtered off, washed with H2O and EtOAc, and dried in vacuo to give compound 3_c (46g). Compound 3-c (lg, 2. 44mmol) and the compound 3_d (369mg, 2. 92mmol) in a mixture of two anger dioxane (30mL) was stirred at 70 ° C 5 h, then cooled to ambient temperature. The precipitate was filtered off, washed with EtOAc, and dried in vacuo to give compound 3 (O. 8g). MS (m / e): 443. 4 (M + 1) +.

Theliatinib (HMPL-309)

Theliatinib (HMPL-309) is a novel small molecule, epidermal growth factor receptor tyrosine kinase inhibitor with potential antineoplastic and anti-angiogenesis activities. Theliatinib is being developed as an oral formulation for the treatment of solid tumors like non-small cell lung cancer.

Theliatinib pre-clinical studies were conducted in China. In vitro studies suggest that Theliatinib is a potent EGFR kinase inhibitor with good kinase selectivity and in vivo data demonstrated broad spectrum anti-tumor activity via oral dosing in multiple xerographs such as A-431, Bcap-37 and Fadu. Non-clinical safety studies have indicated that Theliatinib is generally well tolerated in animals.

In November 2012, HMP initiated the first-in-human clinical trials of theliatinib.

Patent Citations (4)

Publication number Priority date Publication date  AssigneeTitle
CN101094840A *2004-12-292007-12-26韩美药品株式会社Quinazoline derivatives for inhibiting cancer cell growth and method for the preparation thereof
CN101619043A *2008-06-302010-01-06和记黄埔医药(上海)有限公司Quinazoline derivant and medical application thereof
WO2010002845A2 *2008-06-302010-01-07Hutchison Medipharma Enterprises LimitedQuinazoline derivatives
CN102311438A *2010-06-302012-01-11和记黄埔医药(上海)有限公司Quinazoline compound
CN106117182A *2016-06-202016-11-16中国药科大学Quinazoline-N-phenethyl tetrahydroisoquinoline compound and preparation method and application thereof

REFERENCES

1: Ren Y, Zheng J, Fan S, Wang L, Cheng M, Shi D, Zhang W, Tang R, Yu Y, Jiao L,
Ni J, Yang H, Cai H, Yin F, Chen Y, Zhou F, Zhang W, Qing W, Su W. Anti-tumor
efficacy of theliatinib in esophageal cancer patient-derived xenografts models
with epidermal growth factor receptor (EGFR) overexpression and gene
amplification. Oncotarget. 2017 Apr 19. doi: 10.18632/oncotarget.17243. [Epub
ahead of print] PubMed PMID: 28472779.

//////THELIATINIB, HMPL-309, HMPL 309, HMPL309, Phase I,  Oesophageal cancer,  Solid tumours

 O=C(N1C[C@]2([H])N(C)CC[C@]2([H])C1)NC3=CC4=C(NC5=CC=CC(C#C)=C5)N=CN=C4C=C3OC

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YINLITINIB


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Figure CN104119350BD00752

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Figure US09556191-20170131-C00087

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YINLITINIB

error EMAIL ME amcrasto@gmail.com

(E)-4-[(4aR,7aS)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrol-6-yl]-N-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]but-2-enamide

(E)-N-(4-((3-Chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxin[2,3-c]pyrrol-6(3H)-yl)but-2-enamide

CAS 1637253-79-2
2-Butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-[(4aR,7aS)-hexahydro-6H-1,4-dioxino[2,3-c]pyrrol-6-yl]-, (2E)-rel
C25 H25 Cl F N5 O4, 513.95

DNT-04110 ; yinlitinib maleate , Guangdong Hec Pharmaceutical

Use for treating proliferative diseases, atherosclerosis and pulmonary fibrosis

Phase I CHINA

NOTE AND USE YOUR JUDGMENT ON DRUG SUBSTANCE, EMAIL ME amcrasto@gmail.com

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Molecular Formula: C25H25ClFN5O4
Molecular Weight: 516.973 g/mol

Yinlitinib methoxy-d3

CAS 1637254-71-7

C25 H22 Cl D3 F N5 O4
2-Butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-(methoxy-d3)-6-quinazolinyl]-4-[(4aR,7aS)-hexahydro-6H-1,4-dioxino[2,3-c]pyrrol-6-yl]-, (2E)-rel
CN 104119350
YINLITINIB MALEATE methoxy-d3
CAS ?
EMAIL ME amcrasto@gmail.com

MAY BE DRUG COMD

Patent ID

Patent Title

Submitted Date

Granted Date

US9556191 AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE THEREOF
2014-04-28
2016-02-11

In March 2015, an IND was filed in China ; in February 2016, approval to conduct a clinical trial was obtained

Guangdong Hec Pharmaceutical is investigating an oral capsule formulation of yinlitinib maleate (DNT-04110), an irreversible pan-ErbB inhibitor, for the potential treatment of solid tumors . In March 2015, an IND was filed in China ; in February 2016, approval to conduct a clinical trial was obtained . In December 2016, a phase I trial was planned in China

Protein kinases (PKs) represent a large family of proteins, which play an important role in the regulation of a wide variety of cellular processes and maintaining control over cellular functions. There are two classes of protein kinases (PKs): the protein tyrosine kinases (PTKs) and the serine-threonine kinases (STKs). The protein tyrosine kinase is an enzyme that catalytically transfers the phosphate group from ATP to the tyrosine residue located at the protein substrate, and has a play in the normal cell growth. Many growth factor receptor proteins operate via the tyrosine kinase, and influence the conduction of signal passage and further regulate the cell growth by this process. However, in some circumstances, these receptors become abnormal due to either mutation or overexpression, which cause the uncontrolled cell multiplication, cause the tumor growth, and finally initiate the well-known disease, i.e., cancer. The growth factor receptor protein tyrosine kinase inhibitor, via the inhibition of the above phosphorylation process, may treat cancers and other diseases characterized by the uncontrolled or abnormal cell growth.

Epidermal growth factor receptor (EGFR), a kind of receptor tyrosine kinases, is a multifunction glycoprotein that is widely distributed on the cell membranes of the tissues of the human body, and is an oncogene analog of avian erythroblastic leukemia viral (v-erb-b). Human EGFR/HER1/ErbB-1 and HER2 (human epidermal growth factor receptor-2)/ErbB-2/Teu/p185, HER3/ErbB-3, HER4/ErbB-4 and the like are grouped into the HER/ErbB family, and belong to protein tyrosine kinases (PTKs). They are single polypeptide chains, and each is encoded respectively by genes located on different chromosomes. EGFR and the like are expressed in the epithelia-derived tumors such as squamous cell carcinoma of head and neck, mammary cancer, rectal cancer, ovarian cancer, prostate carcinoma, non-small cell lung cancer, and the like, which are associated with cell proliferation, metastasis, and the like. Pan-HER tyrosine kinase inhibitor, via the competitive binding to the kinase catalytic sites in the intracellular region against ATP, blocks the autophosphorylation of intramolecular tyrosine, blocks the tyrosine kinase activation, inhibits HER-2 family activation, and therefore inhibits cell cycle progression, accelerates cell apoptosis, and exerts the therapeutic action.

EGFR, after binding to the ligand, forms a dimer with a subgroup of HER family, and then combines with ATP to activate the tyrosine kinase activity of the EGFR itself. Therefore, the autophosphorylation occurs in several tyrosine sites of the intracellular kinase region. Pan-HER tyrosine kinase inhibitor, via simultaneity acting on EGFR and HER2/4, inhibits the activation of HER family, and plays a good role in the tumor growth inhibition.

It is indicated in the study that Pan-HER tyrosine kinase irreversible inhibitor has an inhibition effect on HER2/4, besides it effectively inhibits EGFR. The pharmaceutical drugs of this kind, having an irreversible inhibition to both of HER/ErbB families, not only increase the drug activity, but also reduce the drug resistance, and have a substantial inhibition effect on H1975 cell lines which are resistant to erlotinib.

The pharmaceutical drugs that are now commercially available include selective EGFR tyrosine kinase inhibitor gefitinb (IRESSA®, ZD1839), erlotinib (TARCEVA®, OSI-774), double EGFR/HER2 inhibitor Lapatinib (TYKERB®, GW572016), and the like. These three drugs are all reversible EGF receptor tyrosine phosphorylation kinase inhibitor. It has been found in the study that they have good therapeutic response to some tumors initially. However, several months after the treatment, the disease progression appears again and therefore a natural or secondary drug resistance forms. For example, about half of the patients administered with gefitinib or erlotinib develop resistance to gefitinib or erlotinib, which can not lead to the desired therapeutic effect. And it has been indicated by study that the development of drug resistance to selective EGFR tyrosine kinase inhibitor relates to mutations in EGFR.

The mutations of EGFR gene mostly located in the tyrosing kinase coding domain (TK, exons 18-21) are mainly deletion mutation in exon 19 and point mutation in exon 21, both of which are drug-sensitive, and few are point mutation in exon 18 and insertion mutation in exon 20. T790M mutation recognized as one of the mechanism of drug resistance is a point mutation in exon 20 of EGFR. The presence of a second-site EGFR mutation leads to the substitution of methionine for threonine at position 790 (T790M) and changes in the structure of EGFR, which hinder the binding of EGFR inhibitors to EGFR or greatly increase the affinity between EGFR and ATP, so that ATP affinity back to the level of wild-type EGFR, thus resulting in drug resistance. Further studies shows that the pre-treatment tumor samples with mutations of EGFR contain T790M mutation, which indicates that T790M mutation is not just associated with drug resistance and it may have the carcinogenic potential itself.

Irreversible inhibitor can bind to EGFR tyrosine kinase by covalent bond. Thus, the drugs can act on the entire link of epidermal growth factor signal transduction pathway, and improve efficiency of drug blocking. Many clinical studies show that some irreversible inhibitors in current development can against T790M mutation, and overcome the drug resistance caused by T790M. Meanwhile, listed drug Afatinib (BIBW 2992) and some irreversible inhibitors in clinical development (e.g., Dacomitinib, PF00299804, etc.), can inhibit multiple members of EGFR receptor family, especially to the role of EGFR and HER-2, possibly by blocking collaborative signal pathway activated by homodimer and heterodimer to enhance inhibitory effect (Oncologist, 2009, 14 (11): 1116-1130).

Upon developing the drug having an excellent antineoplastic effect, being able to reduce the drug resistance and having a good tolerance, the present inventors discover a quinazoline derivatives as tyrosine kinase inhibitors having a Pan-HER irreversible inhibition function.

PATENT

https://patents.google.com/patent/US9556191

EXAMPLES Example 1 (E)-N-(4-((3-Chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxin[2,3-c]pyrrol-6(3H)-yl)but-2-enamide

Figure US09556191-20170131-C00087

Step 1) N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine

A solution of N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (10.00 g, 29.8 mmol) and sodium methanolate (2.80 g, 51.8 mmol) in methanol (150 mL) was heated to 70° C. and stirred for 4.0 hours. The reaction mixture was then cooled to 25° C. The resulting mixture was poured into ice water (500 mL), and a yellow solid precipitated out. The mixture was filtered and the filter cake was dried under vacuum to give the title compound as a yellow solid (9.00 g, 86.9%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 349.1 [M+1]+; and 1H NMR (400 MHz, DMSO-d6) δ: 11.60 (s, 1H), 9.55 (s, 1H), 8.08 (dd, J1=6.6 Hz, J2=2.4 Hz, 1H), 7.90 (s, 1H), 7.76-7.71 (m, 1H), 7.58 (s, 1H), 7.55 (t, J=9.4 Hz, 1H), 4.10 (s, 3H).

Step 2) N4-(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine

To a solution of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine (9.00 g, 25.9 mmol) in ethanol (100 mL) were added iron powder (14.50 g, 259.0 mmol) and concentrated hydrochloric acid (3.0 mL) at 25° C. The reaction mixture was heated to 90° C. and stirred for 3.0 hours. Then heating was stopped, and the resulting mixture was adjusted to pH 11 with aqueous sodium hydroxide solution (1 M) while the mixture was still at a temperature of about 60±10° C. The pH-adjusted resulting mixture was then immediately filtered hot to remove iron mud. The filtrate was concentrated in vacuo. The residue was triturated with ethanol (50 mL) and filtered. The filter cake was dried under vacuum to give the title compound as a yellow solid (6.00 g, 73.0%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 319.1 [M+1]+.

Step 3) (E)-4-bromobut-2-enoyl chloride

To a solution of 4-bromocrotonic acid (2.47 g, 15.0 mmol) and DMF (0.05 mL) in DCM (60 mL) was added oxalyl chloride (4.19 g, 33.0 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 3.0 hours, and then concentrated in vacuo. The residue was stored in a refrigerator for the next step.

Step 4) (E)-4-bromo-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)but-2-enamide

To a solution of N4-(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine (4.00 g, 12.6 mmol) and TEA (6.0 mL, 37.8 mmol) in anhydrous tetrahydrofuran (80 mL) was added (E)-4-bromobut-2-enoyl chloride (2.74 g, 15.1 mmol) slowly at 0° C. The reaction mixture was then heated to 25° C. and stirred for 2.0 hours. The resulting mixture was poured into water (100 mL) and extracted with DCM (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was triturated with DCM (30 mL) and filtered. The filter cake was dried under vacuum to give the title compound as a brownish yellow solid (2.00 g, 34.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 465.1 [M+1]+.

Step 5) (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxin[2,3-c]pyrrol-6(3H)-yl)but-2-enamide

To a solution of (E)-4-bromo-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)but-2-enamide (0.50 g, 1.1 mmol) and diisopropylethylamine (0.6 mL, 3.2 mmol) in N,N-dimethylacetamide (10 mL) was added (4aR,7aS)-hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (0.42 g, 3.2 mmol) at 25° C., and the reaction mixture was then stirred at 25° C. for 5.0 hours. The resulting mixture was poured into water (70 mL) and extracted with DCM (40 mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH (v/v)=20/1) to give the title compound as a brownish yellow solid (0.30 g, 54.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 514.1 [M+1]+; and 1H NMR (400 MHz, DMSO-d6) δ: 10.60 (s, 1H), 9.35 (s, 1H), 8.90 (s, 1H), 8.08 (dd, J1=6.6 Hz, J2=2.4 Hz, 1H), 7.76-7.70 (m, 1H), 7.58 (s, 1H), 7.55 (t, J=8.4 Hz, 1H), 6.75-6.65 (m, 1H), 6.63 (d, J=16.2 Hz, 1H), 4.10 (s, 3H), 3.78 (t, J=6.2 Hz, 4H), 3.26 (t, J=4.4 Hz, 2H), 3.20 (dd, J1=7.8 Hz, J2=2.6 Hz, 2H), 2.20 (d, J=4.6 Hz, 4H).

PATENT

WO2017067447

DIFFERENT COMPD

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017067447

claiming novel crystalline polymorphic forms of a similar EGFR, useful for treating cancer. One of these two compounds is probably yinlitinib maleate , an irreversible pan-ErbB inhibitor, being developed by Guangdong Hec Pharmaceutical , another subsidiary of HEC Pharm , for treating solid tumors; in April 2017, yinlitinib maleate was reported to be in preclinical development

Chinese patent CN 103102344 A (publication number) have disclosed the structure of 4- [ (3-chloro-4-fluorophenyl) amino] -7-methoxy-6- [3- [ (1R, 6S) -2, 5-dioxa-8-azabicyclo [4.3.0] nonan-8-yl] propoxy] quinazoline in example 6 of specification, page 57, and the structure is shown as Formula (II) . The compound of Formula (II) has a high inhibition activity against EGFR, and can be used for treating proliferative disorders.

PATENT

https://patents.google.com/patent/WO2014177038A1/en

InventorYingjun ZhangBing LiuJinlei LiuJiancun ZhangChangchun Zheng

Original AssigneeSunshine Lake Pharma Co., Ltd.

PATENT

CN104119350B

Inventor张英俊刘兵刘金雷张健存郑常春 Original Assignee广东东阳光药业有限公司

https://patents.google.com/patent/CN104119350B/en

Figure CN104119350BD00731

Figure CN104119350BD00741

Figure CN104119350BD00742

Figure CN104119350BD00751

Example 1

[0442] (E) -N- (4- ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) -4- ((4aR, 7aS) – tetrahydro _2H_ [1,4] dioxin burning and [2,3_c] R ratio slightly -6 (3H) – yl) butyric acid amide dilute _2_

[0443]

Figure CN104119350BD00752

[0444] Synthesis Step Shu: N- (3- chloro-4-fluorophenyl) -7-methoxy-6-nitro quinazolin-4-amine

[0445] The N- (3- chloro-4-fluorophenyl) -7-fluoro-6-nitro-quinazolin-4-amine (10 • 0g, 29 • 8mmol) and sodium methoxide (2.80g, 51.8 mmol) was dissolved in methanol (150 mL), the reaction was warmed to 70 ° C 4. Oh. Was cooled to 25 ° C, the reaction mixture was poured into ice-water (500 mL), the precipitated yellow solid was filtered, the filter cake was dried in vacuo to give a yellow solid 9.00g, yield 86.9%.

[0446] MS (. ESI, pos ion) m / z: 349.1 [M + l] +;

[0447] bandit R (400MHz, DMS〇-d6) S: 11 • 60 (s, 1H), 9 • 55 (s, 1H), 8 • 08 (dd, Ji = 6 • 6Hz, J2 = 2.4Hz, lH), 7.90 (s, lH), 7.76-7.71 (m, lH), 7.58 (s, lH), 7.55 (t, J = 9.4Hz, 1H), 4.10 (s, 3H) square

[0448] Synthesis Step 2: n4- (3- chloro-4-fluorophenyl) -7-methoxy-quinazolin-4,6-diamine

[0449] The N- (3- chloro-4-fluorophenyl) -7-methoxy-6-nitro quinazolin-4-amine (9.00g, 25.9mmol) was dissolved in ethanol (100 mL), the was added reduced iron powder (14.5g, 259. Ommol) and concentrated hydrochloric acid (3mL) at 25 ° C, the reaction was warmed to 90 ° C 3.Oh. With 1M aqueous sodium hydroxide solution adjusted to pH 11, filtered hot to remove iron sludge, the mother liquor was concentrated and the residue was purified slurried with ethanol (50 mL), filtered, and the filter cake was dried in vacuo to a yellow solid 6.00g, yield 73.0%.

[0450] MS (ESI, pos ion.) M / z: 319.1 [M + l] + square

[0451] Synthesis Step 3: (E) -4- bromo-but-2-enoyl chloride

The [0452] square ° C Oxalyl chloride (4.19g, 33. Ommol) was slowly added dropwise to a solution containing 4-bromo crotonic acid (2.47g, 15. Ommol) and DMF (0.05mL) in dichloromethane (60 mL) solution of in 3. Oh reaction was stirred at 0 ° C. The reaction solution was concentrated, the residue was stored in a refrigerator until use.

[0453] Synthesis Step 4: (E) -4- bromo–N- (4- ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) butan – 2_ dilute amide

[0454] The N4- (3- chloro-4-fluorophenyl) -7-methoxy-quinazolin-4,6-diamine (4.00g, 12.6mmol) and triethylamine (6.0mL, 37.8mmol ) was dissolved in anhydrous tetrahydro-furan in Misaki (80 mL), cooled to 0 ° C, was slowly added (E) -4- bromo-2-dilute acid chloride (2.748,15.12 dirty 〇1), warmed to 25 ° ( : 2.011 reaction the reaction mixture was poured into water (1001 ^) and extracted with methylene chloride (50mL X 3), the organic phases were combined, dried over anhydrous sodium sulfate filtered, concentrated and the residue with dichloromethane (30 mL). beating purified filtered, the filter cake was dried in vacuo 2.00g tan solid, yield 34.5%.

[0455] MS (ESI, pos ion.) M / z: 465.1 [M + l] + square

[0456] Synthesis Step 5: (E) -N- (4 _ ((3- chloro-4-fluorophenyl) amino) -7_ methoxy-quinazolin-6-yl) _4_ ((4aR, 7aS) – tetrahydro -2H- [1,4] dioxin burning and [2,3_c] P ratio slightly -6 (3H) – yl) butyric acid amide dilute _2_

[0457] The (E) -4- bromo–N- (4- ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) but-2-ene amide (0.50g, 1.08mmol) and diisopropylethylamine (0.6mL, 3.24mmol) was dissolved in dimethylacetamide (10 mL) was added at 25 ° C (4aR, 7aS) – hexahydro–2H- [1,4] dioxane, and [2,3-c] pyrrole (0 • 42g, 3 • 24mmol) 5. Oh reaction was continued under stirring, 25 ° C. The reaction mixture was poured into water (70 mL) and extracted with methylene chloride (40mL X 3), the organic phases were combined, dried over anhydrous sodium sulfate. Filtered, concentrated and the residue purified by column chromatography (CH2Cl2 / MeOH (V / v) = 20/1), to give 0.30g tan solid, yield 54.5%.

[0458] MS (. ESI, pos ion) m / z: 514.1 [M + l] +;

[0459] XH NMR (400MHz, DMS0-d6) 8: 10.60 (s, lH), 9.35 (s, lH), 8.90 (s, lH), 8.08 (dd, Ji = 6.6Hz, J2 = 2.4Hz, 1H ), 7.76-7.70 (m, 1H), 7.58 (s, 1H), 7.55 (t, J = 8.4Hz, 1H), 6.75-6.65 (m, lH), 6.63 (d, J = 16.2Hz, lH) , 4.10 (s, 3H), 3.78 (t, J = 6.2Hz, 4H), 3.26 (t, J = 4.4Hz, 2H), 3.20 (dd, Ji = 7.8Hz, J2 = 2.6Hz, 2H), 2.20 (d, J = 4.6Hz, 4H)

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018095353&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Patent applications WO 2014/177038 and CN 104119350 discloses aminoquinazoline tyrosine kinase inhibitors with irreversible inhibition effect on Pan-HER, wherein the compound (E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D3) -quinazolin-6-yl) -4- ( (4aR, 7aS) -tetra hydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide (i.e. compound (I) ) has an excellent antitumor effect. It can reduce the generation of drug resistance and also have good tolerance.

[0011]
EXPERIMENTAL PART
[0184]
The specific synthetic method for compound (I) (E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D3) -quinazolin-6-yl) -4- ( (4aR, 7aS) -tetra hydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide refers to Example 20 of Patent CN 104119350 A (Application Publication No. ) .
[0185]
EXAMPLES
[0186]
Example 1
[0187]
(E) -N- (4- (3-chloro-4-fluorophenyl) amino) -7- (methyloxy-D3) -quinazolin-6-yl) -4- ( (4aR, 7aS) -t etrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide dimesylate having crystalline form A
[0188]
1. Preparation of dimesylatesulfonate having crystalline form A
[0189]
(E) -N- (4- (3-Chloro-4-fluorophenyl) amino) -7- (methyloxy-D3) -quinazolin-6-yl) -4- ( (4a R, 7aS) -tetrahydro-2H- [l, 4] dioxino [2, 3-c] pyrrole-6 (3H) -yl) butyl-2-enamide (1.032 g, 2.0 mmol) was added to acetone (80 mL) , the mixture was heated to reflux for 30 minutes and filtered. The filtrate was refluxed, and mesylate (0.481 g, 5.0 mmol) was added. The resulting mixture was refluxed overnight. A part of solvent was evaporated under reduced pressure, then the temperature of the residue was gradually cooled to room temperature and maintained at this temperature overnight. The resulting mixture was filtered with suction. The filter cake was washed with acetone and dried at 50 ℃ for 8 hours in vacuo to give a white solid (1.15 g, 81.3%) .
PATENT

Example 6

[00221] N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(tetrahvdro-2H-n,41dioxinor2,3-clpyrrol-6(3H -vn propoxy quinazolin-4-amine

Figure imgf000074_0001

[00222] Step Ubenzyl 3,4-dihvdroxypyrrolidine-l -carboxylate

Figure imgf000074_0002

To a solution of N- carbobenzoxy-3-pyrroline ( 1.00 g, 4.92 mmol, 1.0 eq) in acetone (20 mL) was added NMO ( 1.0 g, 7.38 mmol, 1.5 eq) followed by Os04 (cat. 10 mg in 1 mL ‘PrOH). The mixture was stirred for 3 h. To this, saturated NaHS03aqueous solution (5 mL) was added, and the mixture was stirred for another 0.5 h. The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (EtOAc) to give the compound as colorless oil (1.16 g, 100 %).

[00223] Step 2) benzyl tetrahvdro-2H-n.41dioxino[2.3-c1pyrrole-6(3H)- carboxylate

Figure imgf000074_0003

A mixture of NaOH aqueous solution (35 w/w %, 21 mL, aq.), C1CH2CH2C1 (21 mL), benzyl 3,4-dihydroxypyrrolidine-l -carboxylate (1.16 g, 4.9 mmol, 1.0 eq) and TBAB (0.31 g, 0.98 mmol, 0.2 eq) was heated at 55 °C for 48h in a round-bottom flask. The reaction mixture was cooled to room temperature and poured into water (50 mL), extracted with EtOAc (50 mL). The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (20 mLx3). The combined organic phases were dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo and the residue was purified with a silica gel column chromatography ( 1 : 1 (v/v) PE/EtOAc) to give the product as colorless oil (0.50 g, 39 %).

[00224] Step 3) hexahvdro-2H-n.41dioxinor2.3-clpyrrole

Figure imgf000074_0004

To a solution of benzyl tetrahydro-2H-[l ,4]dioxino[2,3-c] pyrrole-6(3H)-carboxylate (0.46 g, 1 .94 mmol) in MeOH (20 mL) was added two drops of HC02H followed by 20 % Pd(OH)2 (50mg). The reaction mixture was stirred under H2 for 4h at rt and was filtered. The filtrate was concentrated in vacuo to give the crude product, which was used for the next step without further purification.

[00225] Step 4) N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(tetrahvdro-2H-n,41 dioxinor2,3-clpyrrol-6(3H) -yl)propoxy)quinazolin-4-amine

Figure imgf000075_0001

A mixture of hexahydro-2H-[ l ,4]dioxino[2,3-c]pyrrole (1.0 eq), N-(3-chloro-4-fluorophenyI)-6- (3-chloropropoxy)-7-methoxyquinazolin-4-amine (710 mg, 1.8 mmol, 0.95 eq), 2C03 (524 mg, 3.8 mmol, 2.0 eq) and KI (16 mg, 0.095 mmol, 0.05 eq) in DMF (12 mL) was heated at 60 °C for 3 h and cooled to room temperature. The reaction mixture was quenched with water (10 mL) and diluted with EtOAc (20 mL). The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (20 mLx3). The combined organic phases were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20: 1 (v/v) CH2Cl2/CH3OH) to give the crude product, which was recrystallized from CH2C12/PE to afford the title compound as a grayish-white solid (230 mg, 25.00 %), HPLC:99.1 1 % . The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 489.9 (M+1 );’H NMR (400 MHz, CDC13) δ: 2.09 (2H, m), 2.74 (4H, m), 2.99 (2H, dd, = 3.3, 10.4 Hz), 3.56 (2H, m), 3.80 (2H, m), 3.99 (3H, s), 4.12 (2H, t, J = 3.5 Hz), 4.22 (2H, t, J = 6.8 Hz), 7.14 (1 H, t, J = 8.8 Hz), 7.23 (1 H, s), 7.29 ( 1 H, d, J = 15.8 Hz), 7.60 (1 H, m), 7.89 (1 H, dd, J = 2.5, 6.5 Hz), 8.63 (1 H, s) ppm.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014177038&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example 1

[00192] (^-N 4 (3-Chloro -fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4 (4aR,7a5)-tetrahydro-2H-[ l,4]dioxino[2,3-c]pyrrol-6(3H)

[00193] Step 1) N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine

A solution of N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (10.00 g, 29.8 mmol) and sodium methanolate (2.80 g, 51.8 mmol) in methanol (150 mL) was heated to 70 °C and stirred for 4.0 hours. The reaction mixture was then cooled to 25 °C. The resulting mixture was poured into ice water (500 mL), and a yellow solid precipitated out. The mixture was filtered and the filter cake was dried under vacuum to give the title compound as a yellow solid (9.00 g, 86.9%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z : 349.1 [M+l]+; and ‘H NMR (400 MHz, DMSO-<&) δ: 11.60 (s, 1H), 9.55 (s, 1H), 8.08 (dd, Jx = 6.6 Hz, J2 = 2.4 Hz, 1H), 7.90 (s, 1H), 7.76-7.71 (m, 1H), 7.58 (s, 1H), 7.55 (t, J = 9.4 Hz, lH ), 4.10 (s, 3H).

[00194] Step 2) N4-(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine

To a solution of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine (9.00 g, 25.9 mmol) in ethanol (100 mL) were added iron powder (14.50 g, 259.0 mmol) and concentrated hydrochloric acid (3.0 mL) at 25 °C. The reaction mixture was heated to 90 °C and stirred for 3.0 hours. Then heating was stopped, and the resulting mixture was adjusted to pH 11 with aqueous sodium hydroxide solution (1 M) while the mixture was still at a temperature of about 60 ± 10 °C. The pH-adjusted resulting mixture was then immediately filtered hot to remove iron mud. The filtrate was concentrated in vacuo. The residue was triturated with ethanol (50 mL) and filtered. The filter cake was dried under vacuum to give the title compound as a yellow solid (6.00 g, 73.0%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z : 319.1 [M+l]+.

[00195] Step 3) (£)-4-bromobut-2-enoyl chloride

To a solution of 4-bromocrotonic acid (2.47 g, 15.0 mmol) and DMF (0.05 mL) in DCM (60 mL) was added oxalyl chloride (4.19 g, 33.0 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 3.0 hours, and then concentrated in vacuo. The residue was stored in a refrigerator for the next step.

[00196] Step 4) (ii)-4-bromo-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)but-2-enamide

To a solution of N4-(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine (4.00 g, 12.6 mmol) and TEA (6.0 mL, 37.8 mmol) in anhydrous tetrahydrofuran (80 mL) was added (E)-4-bromobut-2-enoyl chloride (2.74 g, 15.1 mmol) slowly at 0 °C. The reaction mixture was then heated to 25 °C and stirred for 2.0 hours. The resulting mixture was poured into water (100 mL) and extracted with DCM (50 mL x 3). The combined organic phases were dried over anhydrous NaaSOzi, filtered and concentrated in vacuo. The residue was triturated with DCM (30 mL) and filtered. The filter cake was dried under vacuum to give the title compound as a brownish yellow solid (2.00 g, 34.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z : 465.1 [M+l]+.

[00197] Step 5) (^-N 4 (3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl) (4aR,7aS)-tetrahydro-2H-[l,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enamide

To a solution of (iT)-4-bromo-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)but-2-enamide (0.50 g, 1.1 mmol) and diisopropylethylamine (0.6 mL, 3.2 mmol) in N^V-dimethylacetamide (10 mL) was added (4aR,7aS)-hexahydro-2H-[l,4]dioxino[2,3-c]pyrrole (0.42 g, 3.2 mmol) at 25 °C, and the reaction mixture was then stirred at 25 °C for 5.0 hours. The resulting mixture was poured into water (70 mL) and extracted with DCM (40 mL x 3). The combined organic phases were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2 MeOH (v/v) = 20/1) to give the title compound as a brownish yellow solid (0.30 g, 54.5%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z : 514.1 [M+l]+; and lH NMR (400 MHz, DMSO-t/tf) δ: 10.60 (s, 1H), 9.35 (s, 1H) , 8.90 (s, 1H), 8.08 (dd, Jx = 6.6 Hz, J2 = 2.4 Hz, 1H), 7.76-7.70 (m, 1H), 7.58 (s, 1H), 7.55 (t, J = 8.4 Hz, 1H ), 6.75-6.65 (m, 1H), 6.63(d, J = 16.2 Hz, 1H), 4.10 (s, 3H), 3.78 (t, J= 6.2 Hz, 4H), 3.26 (t, J = 4.4 Hz, 2H), 3.20 (dd, Jx = 7.8 Hz, J2 = 2.6 Hz, 2H), 2.20 (d, J= 4.6 Hz, 4H).

////////////DNT-04110,  yinlitinib maleate , Guangdong Hec Pharmaceutical, PHASE 1, CHINA, yinlitinib

Fc1ccc(cc1Cl)Nc2ncnc3cc(OC)c(cc23)NC(=O)/C=C/CN4C[C@H]5OCCO[C@H]5C4

Fc1ccc(cc1Cl)Nc2ncnc3cc(OC([2H])([2H])[2H])c(cc23)NC(=O)/C=C/CN4C[C@H]5OCCO[C@H]5C4

SIMILAR COMPDS

1
Canertinib [INN:BAN]
267243-28-7
2D chemical structure of 267243-28-7
MW: 485.9445  –
2
Canertinib dihydrochloride [USAN]
289499-45-2
2D chemical structure of 289499-45-2
MW: 558.8663
3
Dacomitinib [USAN:INN]
1110813-31-4
2D chemical structure of 1110813-31-4
MW: 469.9455
4
439081-18-2
2D chemical structure of 439081-18-2
MW: 485.9445
5
Afatinib [USAN:INN]
850140-72-6
2D chemical structure of 850140-72-6
MW: 485.9445

BMS-986195


img
BMS-986195
  • Molecular FormulaC20H23FN4O2
  • Average mass370.421 Da
  • CAS: 1912445-55-6
1H-Indole-7-carboxamide, 5-fluoro-2,3-dimethyl-4-[(3S)-3-[(1-oxo-2-butyn-1-yl)amino]-1-piperidinyl]-
4-[(3S)-3-(2-Butynoylamino)-1-piperidinyl]-5-fluor-2,3-dimethyl-1H-indol-7-carboxamid
(S)-4-(3-(2-Butynoylamino)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide
(S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimeth -lH-indole-7-carboxamide
  • Originator Bristol-Myers Squibb
  • Class Anti-inflammatories; Antirheumatics
  • Mechanism of Action Agammaglobulinaemia tyrosine kinase inhibitors

Highest Development Phases

  • Phase I Rheumatoid arthritis

Most Recent Events

  • 30 Jan 2018 Bristol-Myers Squibb completes a phase I trial in Rheumatoid arthritis (In volunteers, In adults, Combination therapy) in USA (PO) (NCT03262740)
  • 10 Nov 2017 Bristol-Myers Squibb completes a phase I drug-drug interaction trial in Healthy volunteers (NCT03131973)
  • 03 Nov 2017 Safety, pharmacokinetic, and pharmacodynamic data from a pharmacokinetic trial in healthy volunteers presented at the 81st American College of Rheumatology and the 52nd Association of Rheumatology Health Professionals Annual Scientific Meeting (ACR/ARHP-2017)
  • Image result for BMS-986195

BMS-986195 is a potent, covalent, irreversible inhibitor of Bruton’s tyrosine kinase (BTK), a member of the Tec family of non-receptor tyrosine kinases essential in antigen-dependent B-cell signaling and function. BMS-986195 is more than 5000-fold selective for BTK over all kinases outside of the Tec family, and selectivity ranges from 9- to 1010-fold within the Tec family. BMS-986195 inactivated BTK in human whole blood with a rapid rate of inactivation (3.5×10-4 nM-1·min-1) and potently inhibited antigen-dependent interleukin-6 production, CD86 expression and proliferation in B cells (IC50 <1 nM) without effect on antigen-independent measures in the same cells.

Bristol-Myers Squibb is developing BMS-986195, an oral candidate for the treatment of rheumatoid arthritis. A phase I clinical trial in healthy adult volunteers is ongoing.

Image result

Structure of BMS986195.
Credit: Tien Nguyen/C&EN

Presented by: Scott H. Watterson, principal scientist at Bristol-Myers Squibb

Target: Bruton’s tyrosine kinase (BTK)

Disease: Autoimmune diseases such as rheumatoid arthritis

Reporter’s notes: Completing another set of back-to-back presentations on the same target, Watterson revealed another BTK inhibitor also in Phase II clinical trials. Chemists made BMS-986195 in seven steps, and the molecule showed high levels of BTK inactivation in mice. The team aimed to develop an effective compound that required low doses and that had low metabolic degradation.

Patent

WO 2016065226

Inventor Saleem AhmadJoseph A. TinoJohn E. MacorAndrew J. TebbenHua GongQingjie LiuDouglas G. BattKhehyong NguScott Hunter WattersonWeiwei GuoBertrand Myra Beaudoin

Original Assignee Bristol-Myers Squibb Company

https://patents.google.com/patent/WO2016065226A1/en

PATENT

WO 2018045157

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=E81EF2BDB127473D100AAA55455FC42B.wapp1nA?docId=WO2018045157&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

otein kinases, the largest family of human enzymes, encompass well over 500 proteins. Btk is a member of the Tec family of tyrosine kinases, and is a regulator of early B-cell development, as well as mature B-cell activation, signaling, and survival.

B-cell signaling through the B-cell receptor (BCR) leads to a wide range of biological outputs, which in turn depend on the developmental stage of the B-cell. The magnitude and duration of BCR signals must be precisely regulated. Aberrant BCR-mediated signaling can cause dysregulated B-cell activation and/or the formation of pathogenic auto-antibodies leading to multiple autoimmune and/or inflammatory diseases. Mutation of Btk in humans results in X-linked agammaglobulinaemia (XLA). This disease is associated with the impaired maturation of B-cells, diminished immunoglobulin production, compromised T-cell-independent immune responses and marked attenuation of the sustained calcium signal upon BCR stimulation.

Evidence for the role of Btk in allergic disorders and/or autoimmune disease and/or inflammatory disease has been established in Btk-deficient mouse models. For example, in standard murine preclinical models of systemic lupus erythematosus (SLE), Btk deficiency has been shown to result in a marked amelioration of disease progression. Moreover, Btk deficient mice are also resistant to developing collagen-induced arthritis and are less susceptible to Staphylococcus-induced arthritis.

A large body of evidence supports the role of B-cells and the humoral immune system in the pathogenesis of autoimmune and/or inflammatory diseases. Protein-based therapeutics (such as Rituxan) developed to deplete B-cells, represent an important approach to the treatment of a number of autoimmune and/or inflammatory diseases.

Because of Btk’s role in B-cell activation, inhibitors of Btk can be useful as inhibitors of B-cell mediated pathogenic activity (such as autoantibody production).

Btk is also expressed in mast cells and monocytes and has been shown to be important for the function of these cells. For example, Btk deficiency in mice is associated with impaired IgE -mediated mast cell activation (marked diminution of T F-alpha and other inflammatory cytokine release), and Btk deficiency in humans is associated with greatly reduced TNF-alpha production by activated monocytes.

Thus, inhibition of Btk activity can be useful for the treatment of allergic disorders and/or autoimmune and/or inflammatory diseases including, but not limited to: SLE, rheumatoid arthritis, multiple vasculitides, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, type I diabetes, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and warm agglutinin diseases, Evan’s syndrome, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), sarcoidosis, Sjogren’s syndrome, peripheral neuropathies (e.g., Guillain-Barre syndrome), pemphigus vulgaris, and asthma.

In addition, Btk has been reported to play a role in controlling B-cell survival in certain B-cell cancers. For example, Btk has been shown to be important for the survival of BCR-Abl-positive B-cell acute lymphoblastic leukemia cells. Thus inhibition of Btk activity can be useful for the treatment of B-cell lymphoma and leukemia.

In view of the numerous conditions that are contemplated to benefit by treatment involving modulation of protein kinases, it is immediately apparent that new compounds capable of modulating protein kinases such as Btk and methods of using these compounds should provide substantial therapeutic benefits to a wide variety of patients.

WO 2016/065226 discloses indole carboxamide compounds useful as Btk inhibitors, including (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide (Example 223), which has the structure:

Also disclosed is multistep synthesis process for preparing (S)-4-(3-(but-2-ynamido) piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide.

There are difficulties associated with the adaptation of the multistep synthesis disclosed in WO 2016/065226 to larger scale synthesis, such as production in a pilot plant or a manufacturing plant for commercial production. Further, there is a continuing need to find a process that has few synthesis steps, provides higher yields, and/or generates less waste.

Applicants have discovered a new synthesis process for the preparation of (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide that has fewer synthesis steps and/or provides higher yields than the process disclosed in WO 2016/065226. Furthermore, this process contains no metal-catalyzed steps, no genotoxic intermediates, and is adaptable to large scale manufacturing.

EXAMPLE 1

(S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide

Step 1 : Preparation of Methyl (S)-2-amino-4-(3-((tert-butoxycarbonyl)amino)piperidin-l-yl)-5-fluorobenz

To a 250 mL ChemGlass reactor were charged methyl 2-amino-4,5-difluoro-benzoate (11.21 g, 59.90 mmol), tert-butyl N-[(3S)-3-piperidyl]carbamate (10 g, 49.930 mmol), potassium phosphate, dibasic (10.44 g, 59.94 mmol), and dimethyl sulfoxide (100 mL, 1400 mmol). The resulting thin slurry was heated to 95 to 100 °C and agitated at this temperature for 25 hours. The mixture was cooled to 50 °C. Methanol (100 mL) was added and followed by slow addition of water (50 mL). The mixture was aged at 50 °C for 30 minutes to result in a thick white slurry. Additional water (150 mL) was slowly charged to the above mixture and agitated at 50 °C for 1 hour. The slurry was cooled to 20 °C in 1 hour and aged at this temperature for 4 hours. The slurry was filtrated. The wet cake washed with 25% MeOH in water (30 mL), water (100 mL) and dried under vacuum at 60 °C for 24 h. Methyl (S)-2-amino-4-(3-((tert-butoxycarbonyl)amino) piperidin-l-yl)-5-fluorobenzoate was obtained as a white solid (7 g, yield: 72.5%). ¾ MR (400MHz, METHANOLS) δ 7.34 (d, J=14.6 Hz, 1H), 6.27 (d, J=7.3 Hz, 1H), 3.83-3.71 (s, 3H), 3.68-3.57 (m., 1H), 3.50 -3.40 (m 1H), 3.39 -3.31 (m, 1H), 3.31-3.26 (m, 1H), 2.86-2.70 (m, 1H), 2.64 (t, J=10.0 Hz, 1H), 1.97-1.84 (m, 1H), 1.84-1.74 (m, 1H), 1.73-1.61 (m, 1H), 1.44 (s, 9H), 1.38 (m, 1H). LC-MS [M+H] 368.

Step 2: Preparation of Methyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate

To a reactor were charged methyl (S)-2-amino-4-(3-((tert-butoxycarbonyl)amino) piperidin-l-yl)-5-fluorobenzoate (5.0 g), DPPOH (diphenyl phosphate, 6.81 g, 2 eq) and 3-hydroxybutanone (1.2 eq, 1.44 g), followed by addition of isopropyl acetate (100 mL, 20 mL/g). The mixture was allowed to warm up to 70 to 75 °C, resulting in a yellow solution. The solution was stirred at 70 to 75 °C for 30 h to complete the cyclization.

Water (2 mL) was added and the mixture was aged at 70 °C over 24 h to remove the Boc group. The mixture was cooled to room temperature. Next, aqueous 20% K3PO4 solution (50 mL) was added and the mixture was stirred for 15 min. The organic layer was separated and washed with water (50 mL). The organic layer was then concentrated under vacuum (200 Torr) to -50 mL. The resulting slurry was stirred at 50 °C for 2 h and then heptane (100 mL) was added over 1 h. The mixture was cooled to room

temperature, stirred for 20 h, and then filtered. The cake was washed with heptane (50 mL). Methyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate, DPPOH salt was obtained as a light yellow solid. The wet-cake was added to a reactor. Isopropyl acetate (100 mL) was added, followed by addition of aqueous K3PO4 solution (4 g in water 50 mL). The mixture was stirred at room temperature for -half-hour, resulting in a two phase clear solution (pH >10 for aqueous). The organic layer was separated and washed with water (50 mL), and then concentrated under vacuum to a volume of 15 mL. The resulting slurry was stirred at room temperature for 4 h, then heptane (75 mL) was added over 1 h. The mixture was aged at room temperature for 24 h, then concentrated to a volume to -50 mL. The slurry was filtered. The cake was washed with heptane 20 mL and dried under vacuum at 50 °C for 24 h. Methyl (S)-4-(3- aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate was obtained as a light yellow solid (2.76 g, yield: 69%). ¾ NMR (400MHz, DMSO-d6) δ 10.64 (s, 1H), 7.33 (d, J=13.7 Hz, 1H), 3.89 (s, 3H), 3.14 (br. m., 1H), 3.07-2.90 (m, 2H), 2.84 (br. m., 1H), 2.70 (br. m., 1H), 2.35 (s, 3H), 2.33 (s, 3H), 1.87 (br. m., 1H), 1.67 (br. m., 3H). LC-MS: M+H= 320.

Alternative Preparation

Step 2: Preparation of ethyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate trifluoroacetic acid salt

To a reactor were charged ethyl (S)-2-amino-4-(3-((tert-butoxycarbonyl)amino) piperidin-l-yl)-5-fluorobenzoate (1.0 g, limiting reagent), DPPOH (diphenyl phosphate, 1.97 g, 3.0 eq) and 3-hydroxybutanone (1.4 eq, 0.32 g), followed by addition of toluene (20 mL, 20 mL/g). The mixture was allowed to warm up to 80-90 °C, resulting in a yellow solution. The solution was stirred at 80-90 °C for 10 h to complete the

cyclization. Water (0.4 mL, 0.4 ml/g) was added and the mixture was aged at 80-90 °C for 8 hours. The mixture was cooled to room temperature. Next, aqueous 20% K3PO4 solution (15 mL, 15 mL/g) was added and the mixture was stirred for 0.5 hour. The organic layer was separated and the aqueous layer was washed with toluene (7.5 mL, 7.5 mL/g). To combined organic layers water (10 mL, 10 mL/g) was added and the mixture was stirred for 0.5 hour. The organic layer was separated. To the organic layer water (10 mL, 10 mL/g) was added and the mixture was stirred for 0.5 hour. The organic layer was separated. The organic layer was concentrated under vacuum (100 Torr) to 8 mL (8 ml/g). Following concentration the reaction mixture was cooled to 20-25 °C and MTBE (20 mL, 20 mL/g) was added. Trifluoroacetic acid (1.2 eq., 0.36 g) was slowly added to make the salt maintaining temperature at 20-25 °C. The resulting slurry was aged for 4 hours and then filtered. The filtered solids are washed with MTBE (8 mL, 8 mL/g) and the cake

was dried under vacuum at 50 °C. (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate trifluoroacetic acid salt was obtained as a white to tan crystalline material (85% yield, 1.0 g). ¾ NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.16-7.88 (m, 2H), 7.37 (d, 7=13.6 Hz, 1H), 4.38 (q, 7=7.1 Hz, 2H), 3.18-3.01 (m, 3H), 2.96 (br s, 1H), 2.35 (s, 6H), 2.30 (s, 1H), 2.12 (br d, 7=9.3 Hz, 1H), 1.78 (br s, 2H), 1.45-1.31 (m, 4H), 1.10 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 165.1, 165.1, 158.4, 158.1, 135.4, 134.7, 134.6, 132.2, 128.8, 128.2, 126.9, 126.8, 118.7, 115.7, 110.6, 110.3,108.7, 108.6, 106.6, 106.5, 83.5, 79.8, 60.5, 54.9, 51.7, 48.7, 47.2, 28.4, 26.8, 23.6, 14.2, 11.1, 10.2

Step 3A: Preparation of (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide

A 40 mL vial was charged with methyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate (1.5 g, 4.70 mmol), followed by the addition of N,N-dimethylformamide (12.0 mL, 8.0 mL/g). The vial was purged with N2. Formamide (1.49 mL, 37.6 mmol) was added followed by sodium methoxide solution in methanol (35 wt%, 1.29 mL, 3.76 mmol). The resulting solution was heated at 50 °C over 8 hours. The reaction mixture was cooled down to room temperature and the reaction was quenched with water (12.0 mL, 8.0 mL/g). 2-methyltetrahydrofuran (30 mL, 20 mL/g) was added to the mixture. The mixture was shaken vigorously. The layers were separated and the aqueous layer was extracted with 2-methyltetrahydrofuran (15 mL, 10 mL/g) two more times. Organic extracts were then washed with brine and water (15 mL each, 10 mL/g). The organic layer was evaporated. Solids were dried in vacuo at 60 °C to afford (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide as a yellow solid (1.04 g, 69% yield). ¾ NMR (500MHz, DMSO-d6) δ 10.60 (br. s.,

1H), 7.91 (br. s., 1H), 7.40 (d, 7=14.0 Hz, 1H), 7.32 (br. s., 1H), 3.10 (br. s., 1H), 2.98 (br. s., 2H), 2.82 (br. s., 1H), 2.68 (br. s., 1H), 2.34 (br. s., 3H), 2.30 (br. s., 3H), 1.88 (br. s., 1H), 1.67 (br. s., 2H), 1.45 (br. s., 2H), 1.05 (br. s., 1H). LCMS [M+H] 305.24.

Step 3B: Alternative Preparation of (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide

A 100 mL Hastelloy high pressure EasyMax reactor was charged with methyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate (1.5 g, 4.70 mmol), followed by addition of 7 N ammonia solution in methanol (45.0 mL, 30.0 mL/g) followed by addition of l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (1.33 g, 9.39 mmol). The reactor was sealed and purged with N2 three times. The reactor was then heated to 80 °C for 24 hrs. The reaction mixture was cooled to room temperature and the vessel contents were purged with N2 three times. Volatiles were concentrated to ~6 mL (4 mL/g) and water (24 mL, 16 mL/g) was added. The yellow precipitate was collected and filtered. The precipitate was washed with methanol/water mixture (20:80 v/v, 6 mL, 4 mL/g), and then water (18 mL, 12 mL/g). The solids were dried in vacuo at 60 °C to afford (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide as a yellow crystalline material (0.93 g, 62% yield). ¾ MR (500MHz, DMSO-de) δ 10.60 (br. s., 1H), 7.91 (br. s., 1H), 7.40 (d, J=14.0 Hz, 1H), 7.32 (br. s., 1H), 3.10 (br. s., 1H), 2.98 (br. s., 2H), 2.82 (br. s., 1H), 2.68 (br. s., 1H), 2.34 (br. s., 3H), 2.30 (br. s., 3H), 1.88 (br. s., 1H), 1.67 (br. s., 2H), 1.45 (br. s., 2H), 1.05 (br. s., 1H). LCMS [M+H] 305.24.

Alternative Preparation:

Step 3C: Preparation of (,S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide 2-butynoic acid salt

Ethyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate trifluoroacetic acid salt (1.0 g, limiting reagent) and formamide (5 mL, 5 mL/g) were added to a nitrogen inerted reactor. The temperature was maintained at 20-25 °C. To the reactor was added a solution of 20 wt% potassium t-butoxide in THF. The reaction mixture was allowed to sit for 6 hours. To reaction mixture was added Me-THF (15 mL, 15 mL/g) and 12.5 wt % aqueous NaCl (5 mL, 5 mL/g). The reaction mixture was stirred for 0.5 hour. The organic layer was separated, 5 wt% aqueous NaCl (1 mL, 1 mL/g) and 0.25 N aqueous NaOH (4 mL, 4 mL/g) were added, and then stirred for 0.5 hour. The organic layer was separated and 5 wt% aqueous NaCl (5 mL, 5 mL/g) was added, the mixture was stirred for 0.5 hour, and organic phase was separated. The rich organic phase was dried distillation at a pressure of 100 mtorr with Me-THF to obtain KF in 1.5-4wt% range at 5 mL Me-THF volume. The volume was adjusted to 15 mL Me-THF by adding Me-THF (10 mL, 10 mL/g) and EtOH (4 mL, 4 mL/g). Next, 2-butynoic acid (1.0 eq., 0.19 g) was added and the mixture was agitated for 10 hrs. The resulting slurry was filtered. The cake was washed with Me-THF (10 mL, 10 mL/g) and dried under vacuum at 75 °C to afford (,S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide 2-butynoic acid salt (0.7 g, 80% yield) as white crystalline powder. ¾ NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.98 (br s, 1H), 7.50-7.32 (m, 2H), 3.32 (br d, J=8.6 Hz, 2H), 3.21 (br t, J=10.5 Hz, 1H), 3.13-2.89 (m, 3H), 2.32 (d, J=5.1 Hz, 5H), 2.11 (br d, J=10.9 Hz, 1H), 1.81-1.67 (m, 4H), 1.55-1.28 (m, 1H).

Step 4A: Preparation of (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide

To Reactor-1 was charged N,N-dimethylformamide (DMF, 12.77 kg, 13.5 L). Reactor-1 was purged with N2 to inert. (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide (3.0 kg, 1.0 equiv) was charged followed by 2-butynoic acid (0.854 kg, 1.04 equiv). Reactor-1 was rinsed with DMF (1.42 kg, 1.5 L). The mixture was sparged with N2 for 20 min. Triethylamine (2.99 kg, 3.0 equiv) was charged followed by a DMF rinse (1.42 kg, 1.5 L). TBTU (O-(Benzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium tetrafluorob orate, 3.256 kg, 1.04 equiv) was charged followed by a DMF rinse (1.42 kg, 1.5 L). The reaction mixture was agitated for 1.5 h at 20 °C. MeTHF (46.44 kg, 60 L) was charged to the batch. The reaction was quenched with LiCl (20 wt%, 26.76 kg, 24 L) at 20 °C. The bottom aqueous layer was discharged as waste. The organic layer was washed with 2N HCl solution (24.48 kg, 24 L), 10 wt% sodium bicarbonate solution (25.44 kg, 24 L) and deionized water (24.0 kg, 24 L). THF (26.61 kg, 30 L) was charged into Reactor-1. The rich organic stream in MeTHF/TFIF was polish filtered. The stream was distilled down to 15 L at 75-100 Torn Constant volume distillation was carried out at 15 L with THF feed (39.92 kg, 45 L). The stream was heated to 60 °C for 1 hr and cooled to 50 °C. MTBE (33.30 kg, 45 L) was charged slowly over 2 h. The slurry was aged at 50 °C for 4 h and cooled to 20 °C over 2 h, and aged at 20 °C for >2 h. The 1st drop slurry was filtered and was rinsed with MTBE (8.88 kg, 12 L) twice. Wet cake was dried under vacuum 60 to 70 °C at 25 mbar overnight (>15 h). Reactor-1 was thoroughly cleaned with IPA. The dry cake was charged into Reactor-1 followed by the charge of IPA (47.10 kg, 60 L). The batch was heated to 60 °C to achieve full dissolution and cooled to 40 °C. Rich organic (24 L) was transferred to Reactor-2 for crystallization. The stream was distilled at 24 L constant volume and 100 mbar using remaining rich organic from reactor-1 as distillation feed. Following distillation completion, the batch was heated to 60 °C, aged at 60 °C for 2 h, cooled to 20 °C over 2 h, and aged at 20 °C over 2 h. The slurry was filtered. IPA (1.18 kg) was used to rinse the reactor and washed the cake. The wet cake was dried under vacuum at 70 °C and 25 mbar for >15 h. The dry cake (2.196 kg, 63.2% yield) was discharged as an off-white crystalline solid. ¾ NMR (400MHz, DMSO-d6): δ 10.62 (s, 1H), 8.48 (d, J= 7.1 Hz, 1H), 7.91 (s, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.33 (s, 1H), 3.88 (m, 1H), 3.11 (t, J= 8.0 Hz, 1H), 3.0 (m, 1H), 2.96 (m, 1H), 2.78 (t, J= 10.0 Hz, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 1.92 (s, 3H), 1.86 (m, 1H), 1.31 (m, 1H), 1.70 (m, 2H); 13C NMR (400 MHz, DMSO-d6): δ 168.2, 153.2, 151.9, 134.4, 133.2, 132.1, 126.5, 112.3, 108.4, 106.0, 82.3, 75.7, 56.9, 51.9, 46.3, 29.7, 24.4, 11.1, 10.2, 3.0; LC-MS: M+H= 371.2.

Step 4B: Alternative preparation of (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimeth -lH-indole-7-carboxamide

To Reactor-1 was charged N,N-dimethylformamide (DMF 4.5 mL, 4.5 mL/g). Reactor-1 was purged with N2 to inert. (,S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide 2-butynoic acid salt (1.0 g, limiting reagent) was charged followed by 2-butynoic acid (0.065g, 0.3 equiv.). The mixture was inerted with N2 for 20 min. N-methylmorpholine (0.78 g, 3.0 equiv) was charged. Next,

diphenylphosphinic chloride (0.79 g, 1.3 equiv) was charged over 0.5 h while maintaining the reaction temperature at 20-25 °C. The reaction mixture was agitated for 1.5 hour at 20 °C. Me-THF (14 mL, 14 mL/g) was charged to the reaction mixture. The reaction was quenched with the addition of aqueous NaCl (12.5 wt%, 6 mL, 6 mL/g) at 20 °C. The bottom aqueous layer was discharged as waste. Aqueous NaCl (12.5 wt%, 6 mL, 6 mL/g) at 20 °C was added to the organic layer, stirred for 0.5 hour and the bottom aqueous layer was discharged to waste. Deionized water (6 mL, 6 mL/g) was charged to the organic layer, stirred for 0.5 hour and the bottom aqueous layer was discharged to waste. THF (8 mL, 8 mL/g) was charged into Reactor-1 and the mixture was

concentrated under vacuum to remove Me-THF and water, and reconstituted in 4 L/kg of THF. The mixture was heated to 60 °C and stirred for 1 hour; the temperature was reduced to 50 °C and MTBE (12 mL, 12 mL/g) was added. The mixture was aged for 4 hours while maintaining the temperature of 50 °C and then cooled to room temperature. The solids were filtered and washed with MTBE (6.5 mL, 6.5 mL/g). The solids of crude were dried at 70 °C under vacuum for 12 hours.

Crude (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide was charged to Reactor-2, followed by THF (12 mL, 12 mL/g). The mixture was stirred for 0.5 hour. The solution was polish filtered. The solution was concentrated under vaccuum to remove THF and reconstituted in EtOH (7 mL, 7 mL/g). (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide seeds (0.01 g, 0.01 g/g) were added, the mixture was heated to 60 °C and aged for 2 hours, n-heptane (21 mL, 21 mL/g) was added slowly over 4 hours. The mixture was aged for additional 2 hours at 60 °C, followed by cooldown to room temperature. The slurry was filtered, washed with n-heptane (6 mL, 6 mL/g), and dried under vacuum at 70 °C for 12 hours. The dry cake (0.68 g, 71% yield) was discharged as an off-white crystalline solid. ¾ NMR (400MHz, DMSO-d6): δ 10.62 (s, 1H), 8.48 (d, J= 7.1 Hz, 1H), 7.91 (s, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.33 (s, 1H), 3.88 (m, 1H), 3.11 (t, J= 8.0 Hz, 1H), 3.0 (m, 1H), 2.96 (m, 1H), 2.78 (t, J= 10.0 Hz, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 1.92 (s, 3H), 1.86 (m, 1H), 1.31 (m, 1H), 1.70 (m, 2H); 13C MR (400 MHz, DMSO-d6): δ 168.2, 153.2, 151.9, 134.4, 133.2, 132.1, 126.5, 112.3, 108.4, 106.0, 82.3, 75.7, 56.9, 51.9, 46.3, 29.7, 24.4, 11.1, 10.2, 3.0; LC-MS: M+H= 371.2.

Applicants have discovered a new synthesis process for the preparation of (S)-4- (3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide which offers significant advantages.

The new synthesis process utilizes fewer synthesis steps (4 vs 8) than the process disclosed in WO 2016/065226.

Additionally, the process of the present invention provided (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide at an overall

yield of 22% (step 1 : 73.%, step 2: 69%, step 3 : 69%, step 4: 63%). In comparison, (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide was prepared according to the process of WO 2016/065226, which provided (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide at an overall yield of 2.9% yield (step 1 : 91%, step 2: 71%, step 3 : 35%, step 4: 88%, step 5: 80%, step 6: 29%, step 7: 99%, step 8: 63%).

Furthermore, the process of the present invention does not include any transition metal-catalyzed steps, no genotoxic intermediates, and is adaptable to large scale manufacturing. In comparison, the process disclosed in WO 2016/065226 employed lead (Pb) in process step (8) and included a potentially genotoxic hydrazine intermediate in process step 8.

The process of the present invention has an estimated manufacturing cycle time of approximately 6 months versus a estimated manufacturing cycle time of approximately 12 months for the process disclosed in WO 2016/065226.

REFERENCE

http://acrabstracts.org/abstract/bms-986195-is-a-highly-selective-and-rapidly-acting-covalent-inhibitor-of-brutons-tyrosine-kinase-with-robust-efficacy-at-low-doses-in-preclinical-models-of-ra-and-lupus-nephritis/

/////////////////BMS-986195, Phase I,  Rheumatoid arthritis, BMS

NC(=O)c2cc(F)c(c1c(C)c(C)nc12)N3CCC[C@@H](C3)NC(=O)C#CC

VNRX-5133 from VENATORX PHARMACEUTICALS


 img
str1
VNRX-5133
CAS: 1613268-23-7
Chemical Formula: C19H28BN3O5
Molecular Weight: 389.26
3-(2-((1r,4r)-4-((2-aminoethyl)amino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
 ( R)-3-( 2-( trans-4-( 2-aminoethylamino)cvclohexyl)acetamido)-2-hvdroxy-3-,4-dihydro-2H-benzo[el [l,21oxaborinine-8-carboxylic acid
Image result for VNRX-5133
  • Originator VenatoRx Pharmaceuticals
  • Developer  National Institute of Allergy and Infectious Diseases; VenatoRx Pharmaceuticals
  • Class Antibacterials; Cephalosporins; Small molecules
  • Mechanism of Action Beta lactamase inhibitors; Cell wall inhibitors

Highest Development Phases

  • Phase I Bacterial infections

Most Recent Events

  • 19 Mar 2018 VenatoRx Pharmaceuticals plans phase III pivotal trials in mid-2018
  • 03 Jan 2018 VNRX 5133 receives Fast Track designation for Bacterial infections (complicated urinary tract infections and complicated intra-abdominal infections) [IV-infusion] in USA
  • 03 Jan 2018 VNRX 5133 receives Qualified Infectious Disease Product status for Intra-abdominal infections in USA
  • clip
  • https://cen.acs.org/articles/96/web/2018/03/Drug-structures-made-public-New-Orleans.html

str4Credit: Tien Nguyen/C&EN

Presented by: Christopher J. Burns, president and chief executive officer of VenatoRx Pharmaceuticals

Target: β-lactamase enzymes, enzymes that inactivate β-lactam-based antibiotics enabling bacteria to resist their attacks

Disease: Gram-negative bacterial infections

Reporter’s notes: Another story with humble beginnings, this time with Burns and two colleagues sitting in a Panera Bread, with an idea. They wanted to offer a new compound in the class of β-lactam antibiotics, drugs which are “well-liked” by doctors, Burns said, and make up 60% of all antibiotic prescriptions. However, bacteria have developed defenses against these compounds in the form of β-lactamases, or as Burns dubbed them, “PAC-men.” These enzymes can chew up 1000 β-lactams per second, he said. VNRX-5133 was active against both serine-β-lactamases and metallo-β-lactamases in enzyme assays. It is being developed in combination with the antibiotic cefepime. VNRX-5133 fends off the PAC-men’s attacks, allowing cefepime to combat infection. The compound has gone through Phase I clinical trials and will be skipping ahead to Phase III later this year.

PATENT

WO 2014089365

Applicants: VENATORX PHARMACEUTICALS, INC [US/US]; 30 Spring Mill Drive Malvern, PA 19355 (US)
Inventors: BURNS, Christopher, J.; (US).
DAIGLE, Denis; (US).
LIU, Bin; (US).
MCGARRY, Daniel; (US).
PEVEAR, Daniel C.; (US).
TROUT, Robert E. Lee; (US)

https://patents.google.com/patent/WO2014089365A1/en

Christopher J. Burns, Ph.D.
President and Chief Executive Officer

Dr. Burns is Co-Founder, President and Chief Executive Officer of VenatoRx. He brings over 25 years of corporate and R&D experience within both major (RPR/Aventis) and specialty (ViroPharma, Protez…https://www.venatorx.com/leadership/

Antibiotics are the most effective drugs for curing bacteria-infectious diseases clinically. They have a wide market due to their advantages of good antibacterial effect with limited side effects. Among them, the beta-lactam class of antibiotics (for example, penicillins,

cephalosporins, and carbapenems) are widely used because they have a strong bactericidal effect and low toxicity.

[0004] To counter the efficacy of the various beta-lactams, bacteria have evolved to produce variants of beta-lactam deactivating enzymes called beta-lactamases, and in the ability to share this tool inter- and intra-species. These beta-lactamases are categorized as “serine” or “metallo” based, respectively, on presence of a key serine or zinc in the enzyme active site. The rapid spread of this mechanism of bacterial resistance can severely limit beta-lactam treatment options in the hospital and in the community.

EXAMPLE 15 : ( R)-3-( 2-( trans-4-( 2-aminoethylamino)cvclohexyl)acetamido)-2-hvdroxy-3-,4-dihydro-2H-benzo[el [l,21oxaborinine-8-carboxylic acid

Step 1 : Synthesis of (R)-3-(2-(trans-4-(2-(tert-butoxycarbonylamino)ethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e] [ 1 ,2]oxaborinine-8-carboxylic acid.

[00240] To (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][l,2]oxaborinine-8-carboxylic acid (Example 6, 15 mg) in MeOH (2 mL) was added tert-butyl 2-oxoethylcarbamate (20 mg). Pd/C (10% by weight, 10 mg) was added and the reaction mixture was stirred under ¾ balloon overnight. The reaction mixture was filtrated and the solvent was then removed under reduced pressure and the residue was carried on to the next step without further purification. ESI-MS m/z 490.1 (MH)+.

Step 2: Synthesis of (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][l,2]oxaborinine-8-carboxylic acid.

[00241] To (R)-3-(2-(trans-4-(2-(tert-butoxycarbonylamino)ethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][l,2]oxaborinine-8-carboxylic acid (20 mg) in a flask was added 1 mL 4N HC1 in dioxane. The resulting reaction mixture was stirred at RT for 2hr. The solvent was removed in vacuo and the residue was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 390 (MH)+.

Step 2: (R)-3-(2-(trans-4-((2-aminoethylamino)methyl)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e] [ 1 ,2]oxaborinine-8-carboxylic acid

[00229] Prepared from 3-[2-(2-{4-[(2-tert-Butoxycarbonylamino-ethylamino)-methyl]-cyclohexyl}-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester and BC13 following the procedure described in Step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 404 (MH)+.

/////////////////////////////VNRX-5133; VNRX5133; VNRX 5133, phase 1, VenatoRx Pharmaceuticals, BACTERIAL INFECTIONS, Christopher J. Burns

 NCCN[C@@H]1CC[C@@H](CC(NC2B(O)OC(C(C(O)=O)=CC=C3)=C3C2)=O)CC1

GDC 0575


str1

BAZRWWGASYWYGB-SNVBAGLBSA-N.png

GDC 0575

GDC-0575
CAS:  1196541-47-5

C16 H20 Br N5 O, 378.27

(R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-indol-3-yl)cyclopropanecarboxamide

N-[4-[(3R)-3-Amino-1-piperidinyl]-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]cyclopropanecarboxamide

Cyclopropanecarboxamide, N-[4-[(3R)-3-amino-1-piperidinyl]-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-

ARRY-575; GDC-0575; RG 7741; RO 6845979,
  • AK 687476
  • ARRY 575
  • GDC 0575
  • RG 7741

Image result for gdc 0575

GDC-0575, also known as ARRY-575 and RG7741, is a potent and selective CHK1 inhibitor.

GDC-0575 is a highly selective small-molecule Chk-1 inhibitor invented by Array and licensed to Genentech.  Genentech is responsible for all clinical development and commercialization activities. Array received an upfront payment of $28 million and is eligible to receive clinical and commercial milestone payments up to $380 million and up to double-digit royalties on sales.

Chk-1 is a protein kinase that regulates the tumor cell’s response to DNA damage often caused by treatment with chemotherapy. In response to DNA damage, Chk-1 blocks cell cycle progression in order to allow for repair of damaged DNA, thereby limiting the efficacy of chemotherapeutic agents. Inhibiting Chk-1 in combination with chemotherapy can enhance tumor cell death by preventing these cells from recovering from DNA damage. GDC‑0575 is designed to enhance the efficacy of some chemotherapeutic agents.  GDC-0575 is currently advancing in a Phase 1 trial in patients with lymphoma or solid tumors.

  • Originator Array BioPharma
  • Developer Genentech
  • Class Antineoplastics; Small molecules
  • Mechanism of Action Checkpoint kinase 1 inhibitors

Highest Development Phases

  • Phase I Lymphoma; Solid tumours

Most Recent Events

  • 11 Jan 2018 Genentech completes a phase I trial in Lymphoma (Late-stage disease, Metastatic disease, Second-line therapy or greater, Combination therapy, Monotherapy) in France and USA (PO) (NCT01564251)
  • 05 Dec 2017 GDC 0575 is still in phase I trials for Solid tumours and lymphoma in USA and France (Genentech pipeline, December 2017) (NCT01564251)
  • 04 Nov 2017 No recent reports of development identified for phase-I development in Lymphoma in France (PO)

 Array BioPharma

PATENTS

U.S. Patent, 8,841,304

U.S. Patent 8,178,131,

PAPER

Org. Process Res. Dev. 201721664– 668 

Highly Regioselective and Practical Synthesis of 5-Bromo-4-chloro-3-nitro-7-azaindole

 Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
 Department of Pharma Technical Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, CH-4070 Basel, Switzerland
Org. Process Res. Dev.201721 (4), pp 664–668
DOI: 10.1021/acs.oprd.7b00060
Abstract Image

We report an efficient and highly regiocontrolled route to prepare a functionalized 7-azaindole derivative—5-bromo-4-chloro-3-nitro-7-azaindole—from readily available parent 7-azaindole featuring a highly regioselective bromination of the 4-chloro-3-nitro-7-azaindole intermediate. In addition to the high efficiency and excellent control of regioisomeric impurities, the process is operationally simple by isolating each product via direct crystallization from the reaction mixture with no liquid–liquid extractions or distillation steps needed. We demonstrated the route on >50 kg scale and 46% overall yield to provide the target product in 97% purity by HPLC, which can serve as a useful building block for the preparation of a series of 3,4,5-substituted-7-azaindole derivatives.

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.7b00060/suppl_file/op7b00060_si_001.pdf

-Bromo-4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine (1)(10)

Into ………….. afford 5-bromo-4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine 1 as a tan solid (66.4 kg, 96.2 wt %, 90% yield, 96.9 A % HPLC; unreacted starting material 5: 0.99 A% HPLC; impurity 8: 0.95 A% HPLC): mp 269 °C dec; 1H NMR (300 MHz, DMSO-d6) δ 13.68 (s, 1H), 8.93 (s, 1H), 8.66 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 146.9, 146.4, 133.9, 133.2, 12

PATENT

WO 2010118390

https://patents.google.com/patent/WO2010118390A1/und

PATENT

WO 2015027090

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015027090

PATENT

WO 2015027092

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015027092&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example 1: Preparation of (i?)-5-bromo-4-(3-amino)piperidin-l-yl)-3- (cyclopropanecarboxamido)-lH-pyrrolo[2,3-&]pyridine:

[0096] Step 1 : Preparation of (i?)-5-bromo-4-(3-(/ert-butoxycarbonylamino)piperidin-l-yl)-3-nitro-lH-pyrrolo[2,3-6]pyridine:

[0097] To an inerted 10 L jacket reactor, equipped with a mechanic stirrer, a nitrogen/vacuum manifold, a thermocouple, and a condenser, were charged 2-methyl-2-butanol (3.30 L), 5-bromo-4-chloro-3-nitro-lH-pyrrolo[2,3-6]pyridine (330 g, 1.00 equiv), (R)-tert-butyl piperidin-3-ylcarbamate (456 g, 2.00 equiv), and N-methylmorpholine (115 g, 1.00 equiv). The reaction mixture was stirred at 85 °C for 48 h and cooled to 20 °C. The mixture was then washed with 15 wt % citric acid aqueous solution (3.30 kg) and water (3.30 kg). The majority of 2-methyl-2-butanol was distilled off under vacuum at 50 °C. Acetonitrile was added to bring the mixture back to its original volume. Continuous distillation was conducted until a total of 10.3 kg of acetonitrile was added. Water (3.20 kg) was slowly charged to the suspension over approximately 1 h at 55 °C. The slurry was slowly cooled to 20 °C over 4 h. The resulting solid was collected by filtration and washed with a 1 : 1 (v/v) mixture of acetonitrile and water (1.60 L). The product was dried in a vacuum oven under nitrogen at 70 °C to provide 358 g (69% yield) of (i?)-5-bromo-4-(3-(ter/-butoxycarbonylamino)piperidin-l-yl)-3-nitro-lH-pyrrolo[2,3-6]pyridine as a yellow solid. !H NMR (600 MHz, DMSO-i/6): δ 13.12 (s, 1H), 8.60 (s, 1H), 8.39 (s, 1H), 6.80 (d, J= 6.8 Hz, 1H), 3.49 (m, 1H), 3.34 (m, 2H), 3.22 (t, J = 11.2 Hz, 1H), 3.00 (t, J = 10.2 Hz, 1H), 1.88 (dd, J = 12.3, 2.8 Hz, 1H), 1.74 (m, 2H), 1.38 (m, 1H), 1.34 (s, 9H). 13C NMR (150 MHz, DMSO-<¾): δ 154.8, 148.9, 148.2, 147.9, 130.6, 128.5, 113.8, 109.6, 77.6, 54.7, 48.9, 47.3, 30.0, 28.1 (3C), 24.2. HRMS-ESI (m/z): [M + H]+ calcd for C17H23BrN504, 440.0928; found, 440.0912.

[0098] Steps 2 and 3: Preparation of (i?)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin- 1 -yl)-3 -(cyclopropanecarboxamido)- 1 H-pyrrolo[2,3 -&]pyridine:

[0099] To an inerted 1 L pressure reactor were charged (i?)-5-bromo-4-(3-(tert-

butoxycarbonylamino)piperidin-l-yl)-3-nitro-lH-pyrrolo[2,3-6]pyridine (75.0 g, 1.00 equiv), 1% Pt + 2% V/C (11.3 g, 15 wt %), N-methylmorpholine (29.3 g, 1.70 equiv), and 2-MeTHF (750 mL). The reaction mixture was stirred at 50 °C at 5 bar of hydrogen for a minimum of 2 h. Cyclopropanecarbonyl chloride (26.7 g, 1.50 equiv) was charged into the reactor over 10 min at 15 °C. The reaction mixture was stirred at 25 °C for 1 h and filtered through Celite. The cake was washed with 2-MeTHF (150 mL). The filtrate was washed with 15 wt % aqueous ammonium chloride solution (450 mL) and water (450 mL) and then distilled in vacuo to 1/3 of it’s original volume. Toluene was added to bring the solution back to its original volume. Continuous vacuum distillation was conducted at 55 °C while adding toluene until the 2-MeTHF was below 2 wt %. The resulting solid was isolated by filtration, washed with toluene and dried in a vacuum oven at 40 °C overnight to give 69.8 g (69% corrected yield) of (i?)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-l-yl)-3-(cyclopropanecarboxamido)-lH-pyrrolo[2,3-6]pyridine (1 :1 toluene solvate) as an off-white solid. 1H NMR (600 MHz, THF-i 8, 4 °C): δ 10.76 (s, 1H), 9.72 (s, 1H), 8.15 (s, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.18-7.08 (m, 5H), 6.41 (d, J = 7.8 Hz, 1H), 3.82 (m, 1H), 3.60 (m, 1H), 3.44 (t, J = 10.6 Hz, 1H), 3.30 (dd, J= 10.6, 3.9 Hz, 1H), 3.03 (d, J = 10.9 Hz, 1H), 2.29 (s, 3H), 2.08 (m, 1H), 1.89 (m, 2H), 1.66 (m, 1H), 1.37 (s, 9H), 1.36 (m, 1H), 0.95-0.80 (m, 4H). 13C NMR (150 MHz, THF-ci8, 4 °C): δ 170.0, 155.8, 149.0, 147.8, 147.6, 138.4, 129.6 (2C), 128.9 (2C), 126.0, 116.6, 115.6, 111.9, 108.8, 78.5, 55.8, 50.2, 49.1, 31.8, 28.6 (3C), 26.3, 21.5, 15.8, 7.70, 7.56. HRMS-ESI (m/z): [M + H]+ calcd for C21H29BrN503, 478.1448; found, 478.1431.

[00100] Step 4: Preparation of (i?)-5-bromo-4-(3-amino)piperidin-l-yl)-3-(cyclopropanecarboxamido)- 1 H-pyrrolo [2,3 -6]pyridine :

[00101] To an inerted 1 L jacket reactor, equipped with a mechanic stirrer, a nitrogen/vacuum manifold, a thermocouple, and a condenser, were charged (i?)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-l-yl)-3-nitro-lH-pyrrolo[2,3-0]pyridine (1 : 1 toluene solvate) (30.0 g, 1.00 equiv), tetrahydrofuran (180 mL, 6.00 mL/g), followed by 4.5 M sulfuric acid (36.1 mL, 3.00 equiv). The reaction mixture was stirred at 50 ± 5 °C for 2 h and then cooled to 20 °C. An aqueous piperazine solution (42.4 g dissolved in 190 mL of water) was added slowly at 25 °C followed by addition of 15.0 mL of sat’d brine. The aqueous bottom layer was removed. The resulting solution was stirred at 20 °C for 5 min. Water (22.0 mL) was added. Continuous distillation was conducted at 50 °C by adjusting the feed rate of ethanol to match the distillation rate until a total of 260 mL of ethanol was added. Water (340 mL) was added at 50 °C over 1 h. The resulting solid was isolated by filtration, washed with 20% ethanol in water (2 x 60 mL) and dried in a vacuum oven at 50 °C overnight to give 16.4 g (78% corrected yield) of (i?)-5-bromo-4-(3-amino)piperidin-l-yl)-3-(cyclopropanecarboxamido)-l H-pyrrolo [2,3 -b]pyridine as a light yellow solid. (Note: The proton ( H) and carbon- 13 ( C) spectra of freebase product are very broad. Therefore, the spectra shown below are of freebase converted to a bis-HCl salt.) 1H NMR (300 MHz, DMSC ): δ 11.98 (br, 1H), 9.78 (s, 1H), 8.44 (br, 3H), 8.25 (s, 1H), 7.45 (d, J = 2.4 Hz, 1H), 3.57 (m, 1H), 3.43 (m, 1H), 3.41 (m, 1H), 3.28 (m, 1H), 3.14 (m, 1H), 2.15 (m, 1H), 1.90 (penta, J = 6.5 Hz, 1H), 1.81 (m, 1H), 1.72 (m, 1H), 1.52 (m, 1H), 0.83 (m, 4H). 13C NMR (75 MHz, DMSO- 6): 5 172.9, 149.5, 145.9, 145.1, 121.9, 114.2, 113.1, 107.8, 53.8, 51.1, 47.5, 28.6, 24.37, 14.7, 7.55, 7.45. HRMS-ESI (m/z): [M + H]+ calcd for C16H21BrN50, 378.0924; found, 378.0912.

[00102] Example 2:

[00103] Alternatively, the compound (i?)-5-bromo-4-(3-(fer/-butoxycarbonylamino)piperidin- 1 -yl)-3 -(cyclopropanecarboxamido)- 1 H-pyrrolo [2,3 -£]pyridine can be prepared from 5-bromo-4-chloro-3-nitro-lH-pyrrolo[2,3-b]pyridine and (^)-tert-butyl piperidin-3-ylcarbamate via a through process without isolating (i?)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-l-yl)-3-nitro-lH-pyrrolo[2,3-6]pyridine. The changes to existing procedure are shown as below: The solution of (i?)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin- 1 -yl)-3 -nitro- 1 H-pyrrolo [2,3 -6]pyridine was hydrogenated directly in 2-methyl-2-butanol after aqueous washes with 15 wt % citric acid aqueous solution (10.0 g/g) and water (10.0 g/g). The solution concentration in 2-methyl-2-butanol was determined by HPLC weight assay.

PATENT

WO 2016138458

CHK1 is a serine/threonine kinase that regulates cell-cycle progression and is a main factor in DNA-damage response within a cell. CHK1 inhibitors have been shown to sensitize tumor cells to a variety of genotoxic agents, such as chemotherapy and radiation. U.S. Pat. No. 8,178,131 discusses a number of inhibitors of CHK1, including the compound (i?)-N-(4-(3-aminopiperidin-l-yl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (Compound 1), which is being investigated in clinical trials for the treatment of various cancers.

Compound 1

PATENT

U.S. Patent Application, 20160200723

Example 1 Preparation of (R)-5-bromo-4-(3-amino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine

Step 1: Preparation of (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridine

To an inserted 10 L jacket reactor, equipped with a mechanic stirrer, a nitrogen/vacuum manifold, a thermocouple, and a condenser, were charged 2-methyl-2-butanol (3.30 L), 5-bromo-4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine (330 g, 1.00 equiv), (R)-tert-butyl piperidin-3-ylcarbamate (456 g, 2.00 equiv), and N-methylmorpholine (115 g, 1.00 equiv). The reaction mixture was stirred at 85° C. for 48 h and cooled to 20° C. The mixture was then washed with 15 wt % citric acid aqueous solution (3.30 kg) and water (3.30 kg). The majority of 2-methyl-2-butanol was distilled off under vacuum at 50° C. Acetonitrile was added to bring the mixture back to its original volume. Continuous distillation was conducted until a total of 10.3 kg of acetonitrile was added. Water (3.20 kg) was slowly charged to the suspension over approximately 1 h at 55° C. The slurry was slowly cooled to 20° C. over 4 h. The resulting solid was collected by filtration and washed with a 1:1 (v/v) mixture of acetonitrile and water (1.60 L). The product was dried in a vacuum oven under nitrogen at 70° C. to provide 358 g (69% yield) of (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridine as a yellow solid. 1H NMR (600 MHz, DMSO-d6): δ 13.12 (s, 1H), 8.60 (s, 1H), 8.39 (s, 1H), 6.80 (d, J=6.8 Hz, 1H), 3.49 (m, 1H), 3.34 (m, 2H), 3.22 (t, J=11.2 Hz, 1H), 3.00 (t, J=10.2 Hz, 1H), 1.88 (dd, J=12.3, 2.8 Hz, 1H), 1.74 (m, 2H), 1.38 (m, 1H), 1.34 (s, 9H). 13C NMR (150 MHz, DMSO-d6): δ 154.8, 148.9, 148.2, 147.9, 130.6, 128.5, 113.8, 109.6, 77.6, 54.7, 48.9, 47.3, 30.0, 28.1 (3C), 24.2. HRMS-ESI (m/z): [M+H]+ calcd for C17H23BrN5O4, 440.0928. found, 440.091

Steps 2 and 3: Preparation of (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine

To an inserted 1 L pressure reactor were charged (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridine (75.0 g, 1.00 equiv), 1% Pt+2% V/C (11.3 g, 15 wt %), N-methylmorpholine (29.3 g, 1.70 equiv), and 2-MeTHF (750 mL). The reaction mixture was stirred at 50° C. at 5 bar of hydrogen for a minimum of 2 h. Cyclopropanecarbonyl chloride (26.7 g, 1.50 equiv) was charged into the reactor over 10 min at 15° C. The reaction mixture was stirred at 25° C. for 1 h and filtered through Celite. The cake was washed with 2-MeTHF (150 mL). The filtrate was washed with 15 wt % aqueous ammonium chloride solution (450 mL) and water (450 mL) and then distilled in vacuo to ⅓ of it’s original volume. Toluene was added to bring the solution back to its original volume. Continuous vacuum distillation was conducted at 55° C. while adding toluene until the 2-MeTHF was below 2 wt %. The resulting solid was isolated by filtration, washed with toluene and dried in a vacuum oven at 40° C. overnight to give 69.8 g (69% corrected yield) of (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine (1:1 toluene solvate) as an off-white solid. 1H NMR (600 MHz, THF-d8, 4° C.): δ 10.76 (s, 1H), 9.72 (s, 1H), 8.15 (s, 1H), 7.90 (d, J=2.4 Hz, 1H), 7.18-7.08 (m, 5H), 6.41 (d, J=7.8 Hz, 1H), 3.82 (m, 1H), 3.60 (m, 1H), 3.44 (t, J=10.6 Hz, 1H), 3.30 (dd, J=10.6, 3.9 Hz, 1H), 3.03 (d, J=10.9 Hz, 1H), 2.29 (s, 3H), 2.08 (m, 1H), 1.89 (m, 2H), 1.66 (m, 1H), 1.37 (s, 9H), 1.36 (m, 1H), 0.95-0.80 (m, 4H). 13C NMR (150 MHz, THF-d8, 4° C.): δ 170.0, 155.8, 149.0, 147.8, 147.6, 138.4, 129.6 (2C), 128.9 (2C), 126.0, 116.6, 115.6, 111.9, 108.8, 78.5, 55.8, 50.2, 49.1, 31.8, 28.6 (3C), 26.3, 21.5, 15.8, 7.70, 7.56. HRMS-ESI (m/z): [M+H]+ calcd for C21H29BrN5O3, 478.1448. found, 478.1431.

Step 4: Preparation of (R)-5-bromo-4-(3-amino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine

To an inserted 1 L jacket reactor, equipped with a mechanic stirrer, a nitrogen/vacuum manifold, a thermocouple, and a condenser, were charged (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridine (1:1 toluene solvate) (30.0 g, 1.00 equiv), tetrahydrofuran (180 mL, 6.00 mL/g), followed by 4.5 M sulfuric acid (36.1 mL, 3.00 equiv). The reaction mixture was stirred at 50±5° C. for 2 h and then cooled to 20° C. An aqueous piperazine solution (42.4 g dissolved in 190 mL of water) was added slowly at 25° C. followed by addition of 15.0 mL of sat′d brine. The aqueous bottom layer was removed. The resulting solution was stirred at 20° C. for 5 min. Water (22.0 mL) was added. Continuous distillation was conducted at 50° C. by adjusting the feed rate of ethanol to match the distillation rate until a total of 260 mL of ethanol was added. Water (340 mL) was added at 50° C. over 1 h. The resulting solid was isolated by filtration, washed with 20% ethanol in water (2×60 mL) and dried in a vacuum oven at 50° C. overnight to give 16.4 g (78% corrected yield) of (R)-5-bromo-4-(3-amino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine as a light yellow solid. (Note: The proton (1H) and carbon-13 (13C) spectra of freebase product are very broad. Therefore, the spectra shown below are of freebase converted to a bis-HCl salt.)1H NMR (300 MHz, DMSO-d6): δ 11.98 (br, 1H), 9.78 (s, 1H), 8.44 (br, 3H), 8.25 (s, 1H), 7.45 (d, J=2.4 Hz, 1H), 3.57 (m, 1H), 3.43 (m, 1H), 3.41 (m, 1H), 3.28 (m, 1H), 3.14 (m, 1H), 2.15 (m, 1H), 1.90 (penta, J=6.5 Hz, 1H), 1.81 (m, 1H), 1.72 (m, 1H), 1.52 (m, 1H), 0.83 (m, 4H). 13C NMR (75 MHz, DMSO-d6): δ 172.9, 149.5, 145.9, 145.1, 121.9, 114.2, 113.1, 107.8, 53.8, 51.1, 47.5, 28.6, 24.37, 14.7, 7.55, 7.45. HRMS-ESI (m/z): [M+H]+ calcd for C16H21BrN5O, 378.0924. found, 378.0912.

Example 2

Alternatively, the compound (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine can be prepared from 5-bromo-4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine and (R)-tert-butyl piperidin-3-ylcarbamate via a through process without isolating (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridine. The changes to existing procedure are shown as below: The solution of (R)-5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridine was hydrogenated directly in 2-methyl-2-butanol after aqueous washes with 15 wt % citric acid aqueous solution (10.0 g/g) and water (10.0 g/g). The solution concentration in 2-methyl-2-butanol was determined by HPLC weight assay.

PAPER

An Efficient Through-Process for Chk1 Kinase Inhibitor GDC-0575

 Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
 Department of Pharma Technical Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, CH-4070 Basel, Switzerland
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00388

Abstract

Abstract Image

We report an efficient route to prepare Chk1 kinase inhibitor GDC-0575 from 5-bromo-4-chloro-3-nitro-7-azaindole featuring a sequence of nucleophilic aromatic substitution, hydrogenative nitro-reduction, and a robust, high-yielding end-game involving deprotection–crystallization steps. The developed route was demonstrated on 10 kg scale in 30% overall yield to provide the target API in >99.8 A % HPLC purity.

(R)-5-Bromo-4-(3-amino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine (GDC-0575)

To ………….. to give (R)-5-bromo-4-(3-amino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine as a light yellow solid (5.1 kg, 76% yield, 99.9 A % by HPLC analysis).
Both 1H and 13C spectra of GDC-0575 freebase are very broad.
Therefore, the spectra shown below are of freebase converted to a bis-HCl salt: mp = 267 °C;
1H NMR (300 MHz, DMSO-d6): δ 11.98 (br, 1H), 9.78 (s, 1H), 8.44 (br, 3H), 8.25 (s, 1H), 7.45 (d, J = 2.4 Hz, 1H), 3.57 (m, 1H), 3.43 (m, 1H), 3.41 (m, 1H), 3.28 (m, 1H), 3.14 (m, 1H), 2.15 (m, 1H), 1.90 (penta, J = 6.5 Hz, 1H), 1.81 (m, 1H), 1.72 (m, 1H), 1.52 (m, 1H), 0.83 (m, 4H);
13C NMR (75 MHz, DMSO-d6): δ 172.9, 149.5, 145.9, 145.1, 121.9, 114.2, 113.1, 107.8, 53.8, 51.1, 47.5, 28.6, 24.37, 14.7, 7.55, 7.45;
HRMS–ESI (m/z): [M + H]+ calcd for C16H21BrN5O, 378.0924; found, 378.0912.

REFERENCES

1: Duan W, Gao L, Aguila B, Kalvala A, Otterson GA, Villalona-Calero MA. Fanconi
anemia repair pathway dysfunction, a potential therapeutic target in lung cancer.
Front Oncol. 2014 Dec 19;4:368. doi: 10.3389/fonc.2014.00368. eCollection 2014.
PubMed PMID: 25566506; PubMed Central PMCID: PMC4271581.

Publications

GDC-0575 / Cancer

07/01/2011

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics

Single-Agent Inhibition of Chk1 Is Antiproliferative in Human Cancer Cell Lines In Vitro and Inhibits Tumor Xenograft Growth In Vivo

K. D. Davies, et al.

GDC-0575 / Cancer

04/05/2011

American Association for Cancer Research Annual Meeting

Chk1 inhibition and Wee1 inhibition combine synergistically to inhibit cellular proliferation

K. D. Davies, et al.

GDC-0575 / Cancer

03/11/2011

International Symposium on Targeted Anticancer Therapies

Preclinical characterization of ARRY-575: A potent, selective, and orally bio-available small molecule inhibitor of Chk1

M. J. Humphries, et al.

///////// GDC0575,  GDC 0575, ARRY-575, GDC-0575, RG 7741, RO 6845979, AK 687476, ARRY 575, GDC 0575, RG 7741, PHASE 1

O=C(Nc1cnc2ncc(Br)c(c12)N3CCC[C@@H](N)C3)C4CC4

AVOID CONFUSING

GLXC-11762   WRONG  COMPD 2097938-64-0

N ATOM MISSING IN RING

Empesertib , BAY 1161909


img

2D chemical structure of 1443763-60-7

Empesertib , BAY 1161909, Mps1-IN-5,  (-)-BAY-1161909

CAS 1443763-60-7
Chemical Formula: C29H26FN5O4S
Molecular Weight: 559.6164

[a]D20 : -78.9° (in DMSO). WO 2014198647

UNII-02Y3Z2756M
(αR)-4-Fluoro-N-[4-[2-[[2-methoxy-4-(methylsulfonyl)phenyl]amino][1,2,4]triazolo[1,5-a]pyridin-6-yl]phenyl]-α-methylbenzeneacetamide

(R)-2-(4-fluorophenyl)-N-(4-(2-((2-methoxy-4-(methylsulfonyl)phenyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)propanamide

(2R)-2-(4-Fluorophenyl)-N-(4-(2-((4-(methanesulfonyl)-2-methoxyphenyl)amino)(1,2,4)triazolo(1,5-a)pyridin-6-yl)phenyl)propanamide

Benzeneacetamide, 4-fluoro-N-(4-(2-((2-methoxy-4-(methylsulfonyl)phenyl)amino)(1,2,4)triazolo(1,5-a)pyridin-6-yl)phenyl)-alpha-methyl-, (alphaR)-

PHASE 1, BAYER, CANCER

PRODUCT PATENT, WO2013087579, https://www.google.com/patents/WO2013087579A1

Image result

SYNTHESIS, 

WO 2014198647

Analytical UPLC-MS was performed as follows:

Method A: System: UPLC Acquity (Waters) with PDA Detector und Waters ZQ mass spectrometer; Column: Acquity BEH C18 1 .7μηη 2.1 x50mm; Temperature: 60° C; Solvent A: Water + 0.1 % formic acid; Solvent B: acetonitrile; Gradient: 99 % A – 1 % A (1 .6 min) -> 1 % A (0.4 min) ; Flow: 0.8 mL/min; Injection Volume: 1 .0 μΐ (0.1 mg-1 mg/ml_ sample concentration); Detection: PDA scan range 210-400 nm – Fixed and ESI (+), scan range 170-800 m/z

LC-MS methods:

Method 1 :

Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1 .8 μ 50 x 1 mm; Eluent A: 1 I Wasser + 0.25 ml 99%ige Formic acid, Eluent B: 1 I Acetonitril + 0.25 ml 99%ige Formic acid; Gradient: 0.0 min 90% A → 1 .2 min 5% A→ 2.0 min 5% A Ofen: 50° C; Flow: 0.40 ml/min; UV-Detection: 208 – 400 nm.

1H-NMR (300 MHz, DMSO-d6), δ [ppm] = 1 .39 (3H), 3.16 (3H), 3.83 (1 H), 3.95 (3H), 7.08-7.20 (2H), 7.34-7.45 (3H), 7.51 (1 H), 7.63-7.77 (5H), 7.92 (1 H), 8.48 (1 H), 8.64 (1 H), 9.1 1 (1 H), 10.19 (1 H).

[a]D20 : -78.9° (in DMSO).

Determination of enantiomeric purity by analytical chiral HPLC:

Column: Chiralcel OD-RH 150×4.6; Flow: 1 .00 mL/min; Solvent: A: Water with 0.1 % formic acid, B: Acetonitrile; Solvent mixture: 40% A + 60% B. Run Time: 30 min. Retention Time: 12.83 min; UV 254 nm; Enantiomeric Ratio: <1 % : > 99%.

Empesertib, also known as BAY1161909, is an orally bioavailable, selective inhibitor of the serine/threonine monopolar spindle 1 (Mps1) kinase, with potential antineoplastic activity. Upon administration, the Mps1 kinase inhibitor BAY1161909 binds to and inhibits the activity of Mps1. This causes inactivation of the spindle assembly checkpoint (SAC), accelerated mitosis, chromosomal misalignment, chromosomal missegregation, mitotic checkpoint complex destabilization, and increased aneuploidy. This leads to the induction of cell death in cancer cells overexpressing Mps1.

BAY-1161909 is an oral dual specificity protein kinase TTK inhibitor in early clinical trials at Bayer for the treatment of advanced malignancies in combination with paclitaxel.

Bayer and INSERM are developing BAY-1161909 , presumed to be the lead from monopolar spindle-1 inhibitors, including Mps-BAY-2b and Mps-BAY-2c, for the oral treatment of cancer; in July 2016, BAY-1161909 was reported to be in phase I clinical trial.

Mps-1 (Monopolar Spindle 1 ) kinase (also known as Tyrosine Threonine Kinase, TTK). Mps-1 is a dual specificity Ser/Thr kinase which plays a key role in the activation of the mitotic checkpoint (also known as spindle checkpoint, spindle assembly checkpoint) thereby ensuring proper chromosome segregation during mitosis [Abrieu A et al., Cell, 2001 , 106, 83-93]. Every dividing cell has to ensure equal separation of the replicated chromosomes into the two daughter cells. Upon entry into mitosis, chromosomes are attached at their kinetochores to the microtubules of the spindle apparatus. The mitotic checkpoint is a surveillance mechanism that is active as long as unattached kinetochores are present and prevents mitotic cells from entering anaphase and thereby completing cell division with unattached chromosomes [Suijkerbuijk SJ and Kops GJ, Biochemica et Biophysica Acta, 2008, 1786, 24- 31 ; Musacchio A and Salmon ED, Nat Rev Mol Cell Biol., 2007, 8, 379-93]. Once all kinetochores are attached in a correct amphitelic, i.e. bipolar, fashion with the mitotic spindle, the checkpoint is satisfied and the cell enters anaphase and proceeds through mitosis. The mitotic checkpoint consists of a complex network of a number of essential proteins, including members of the MAD (mitotic arrest deficient, MAD 1 -3) and Bub (Budding uninhibited by benzimidazole, Bub 1 -3) families, the motor protein CENP-E, Mps-1 kinase as well as other components, many of these being over-expressed in proliferating cells (e.g. cancer cells) and tissues [Yuan B et al., Clinical Cancer Research, 2006, 12, 405-10]. The essential role of Mps-1 kinase activity in mitotic checkpoint signalling has been shown by shRNA-silencing, chemical genetics as well as chemical inhibitors of Mps-1 kinase [Jelluma N et al., PLos ONE, 2008, 3, e2415; Jones MH et al., Current Biology, 2005, 15, 160-65; Dorer RK et al., Current Biology, 2005, 15, 1070-76; Schmidt M et al., EMBO Reports, 2005, 6, 866-72].

There is ample evidence linking reduced but incomplete mitotic checkpoint function with aneuploidy and tumorigenesis [Weaver BA and Cleveland DW, Cancer Research, 2007, 67, 10103-5; King RW, Biochimica et Biophysica Acta, 2008, 1786, 4-14]. In contrast, complete inhibition of the mitotic checkpoint has been recognised to result in severe chromosome missegregation and induction of apoptosis in tumour cells [Kops GJ et al., Nature Reviews Cancer, 2005, 5, 773-85; Schmidt M and Medema RH, Cell Cycle, 2006, 5, 159-63; Schmidt M and Bastians H, Drug Resistance Updates, 2007, 10, 162-81]. Therefore, mitotic checkpoint abrogation through pharmacological inhibition of Mps-1 kinase or other components of the mitotic checkpoint represents a new approach for the treatment of proliferative disorders including solid tumours such as carcinomas and sarcomas and leukaemias and lymphoid malignancies or other disorders associated with uncontrolled cellular proliferation.

Different compounds have been disclosed in prior art which show an inhibitory effect on Mps-1 kinase:

WO 2009/024824 A1 discloses 2-Anilinopurin-8-ones as inhibitors of Mps-1 for the treatment of proliferate disorders. WO 2010/124826 A1 discloses substituted imidazoquinoxaline compounds as inhibitors of Mps-1 kinase. WO 2011 /026579 A1 discloses substituted aminoquinoxalines as Mps-1 inhibitors.

Substituted triazolopyndine compounds have been disclosed for the treatment or prophylaxis of different diseases:

WO 2008/025821 A1 (Cellzome (UK) Ltd) relates to triazole derivatives as kinase inhibitors, especially inhibitors of ITK or PI3K, for the treatment or prophylaxis of immunological, inflammatory or allergic disorders. Said triazole derivatives are exemplified as possessing an amide, urea or aliphatic amine substituent in position 2.

WO 2009/047514 A1 (Cancer Research Technology Limited) relates to [1 ,2,4]- triazolo-[1 ,5-a]-pyridine and [1 ,2,4]-triazolo-[1 ,5-c]-pyrimidine compounds which inhibit AXL receptor tyrosine kinase function, and to the treatment of diseases and conditions that are mediated by AXL receptor tyrosine kinase, that are ameliorated by the inhibition of AXL receptor tyrosine kinase function etc., including proliferative conditions such as cancer, etc.. Said compounds are exemplified as possessing a substituent in the 5-position and a substituent in the 2-position.

WO 2009/010530 A1 discloses bicyclic heterorayl compounds and their use as phosphatidyli nositol (PI) 3-kinase. Among other compounds also substituted triazolopyridines are mentioned.

WO 2009/027283 A1 discloses triazolopyridine compounds and their use as ASK (apoptosis signal-regulating kinase) inhibitors for the treatment of autoimmune diseases and neurodegenerative diseases. WO 2010/092041 A1 (Fovea Pharmaceuticals SA) relates to [1 ,2,4]-triazolo- [1 ,5-a] -pyridines, which are said to be useful as selective kinase inhibitors, to methods for producing such compounds and methods for treating or ameliorating kinase-mediated disorder. Said triazole derivatives are exemplified as possessing a 2-chloro-5-hydroxyphenyl substituent in the 6- position of the [1 ,2,4]-triazolo-[1 ,5-a]-pyridine.

WO 2011 /064328 A1 , WO 2011 /063907 A1 , and WO 2011 /063908 A1 (Bayer Pharma AG) relate to [1 ,2,4]-triazolo-[1 ,5-a]-pyridines and their use for inhibition of Mps-1 kinase.

WO 2011 /064328 A1 discloses com ounds of fomula S2:

Figure imgf000005_0001

S2

in which

R1 is an aryl- or heteroaryl- group; wherein the aryl- or heteroaryl- group can be substituted inter alia with -N(H)C(=0)R6 or -C(=0)N(H)R6 ; in which R6represents a hydrogen or a Ci-C6-alkyl- group; the Ci-C6-alkyl- group optionally being substituted with halo-, hydroxyl-, d-C3-alkyl, R70-. WO 2011 /064328 A1 does not disclose compounds of the present invention as defined below.

WO 2011 /063907 A1 discloses compounds of fomula S1 :

Figure imgf000005_0002

S1

in which

R1 is an aryl group which is substituted at least one time; whereas the at least one substituent inter alia can be -N(H)C(=0)R6 or -C(=0)N(H)R6 ; in which R6represents a group selected from C3-C6-cycloalkyl, 3- to 10-membered heterocyclyl-, aryl-, heteroaryl-, -(CH2)q-(C3-C6-cycloalkyl), -(CH2)q-(3- to 10- membered heterocyclyl), -(CH2)q-aryl, or -(CH2)q-heteroaryl, wherein R6 is optionally substituted, and q is 0, 1 , 2 or 3;

R2 represents a substituted or unsubstituted aryl- or heteroaryl- group;

R3 and R4 inter alia can be hydrogen; and

R5 represents a substituted or unsubstituted Ci-C6-alkyl group.

WO 2011 /063908 A1 discloses com ounds of fomula S3:

Figure imgf000006_0001

S3

in which

R1 is an aryl group which is substituted at least one time; whereas the at least one substituent inter alia can be -N(H)C(=0)R6 or -C(=0)N(H)R6 ; in which R6inter alia represents a group selected from C3-C6-cycloalkyl, 3- to 10- membered heterocyclyl-, aryl-, heteroaryl-, -(CH2)q-(C3-C6-cycloalkyl), -(CH2)q– (3- to 10-membered heterocyclyl), -(CH2)q-aryl, and -(CH2)q-heteroaryl, wherein R6 is optionally substituted, and q is 0, 1 , 2 or 3;

R2 represents a substituted or unsubstituted aryl- or heteroaryl- group;

R3 and R4 inter alia can be hydrogen; and

R5 is hydrogen.

There are patent applications which are related to [1 ,2,4]-triazolo-[1 ,5-a]- pyridines and their use for inhibition of Mps-1 kinase, but which have not been published at the time of filing of this patent application: Subject matter of the EP patent applications No. 11167872.8, and No. 11167139.2 as well as of the patent application PCT/EP2011 /059806 are com ounds of fomula S4:

Figure imgf000007_0001

S4

in which

R1 represents inter alia a phenyl- group which is substituted at least one time; whereas the at least one substituent inter alia can be -N(H)C(=0)R6; in which R6inter alia can be -(CH2)q-aryl, wherein R6 is optionally substituted, and q is 0, 1 , 2 or 3;

R2 represents a substituted or unsubstituted aryl- or heteroaryl- group;

R3 and R4 inter alia can be hydrogen; and

R5 is hydrogen. However, the state of the art described above does not specifically disclose the substituted triazolopyridine compounds of general formula (I) of the present invention, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, as described and defined herein, and as hereinafter referred to as “compounds of the present invention”, or their pharmacological activity.

The above mentioned patent applications which are related to [1 ,2,4]-triazolo- [1 ,5-a] -pyridines mainly focus on the effectiveness of the compounds in inhibiting Mps-1 kinase, expressed by the half maximal inhibitory concentration (IC50) of the compounds. For example, in WO 2011 /063908 A1 the effectiveness in inhibiting Mps-1 kinase was measured in an Mps-1 kinase assay with a concentration of 10 μΜ adenosine triphosphate (ATP).

The cellular concentration of ATP in mammals is in the millimolar range. Therefore it is important that a drug substance is also effective in inhibiting Mps-1 kinase in a kinase assay with a concentration of ATP in the millimolar range, e.g. 2 mM ATP, in order to potentially achieve an antiproliferative effect in a cellular assay. In addition, as one of ordinary skill in the art knows, there a many more factors determining the druglikeness of a compound. The objective of a preclinical development is to assess e.g. safety, toxicity, pharmacokinetics and metabolism parameters prior to human clinical trials. One important factor for assessing the druglikeness of a compound is the metabolic stability. The metabolic stability of a compound can be determined e.g. by incubating the compound with a suspension of liver microsomes from e.g. a rat, a dog and/or a human (for details see experimental section). Another important factor for assessing the druglikeness of a compound for the treatment of cancer is the inhibition of cell proliferation which can be determined e.g. in a HeLa cell proliferation assay (for details see experimental section). Surprisingly it was found, that the compounds of the present invention are characterized by :

– an IC50 lower than or equal to 1 nM (more potent than 1 nM) in an Mps-1 kinase assay with a concentration of 10 μΜ ATP, and

– an IC50 lower than 10 nM (more potent than 10 nM) in an Mps-1 kinase assay with a concentration of 2 mM ATP, and – a maximum oral bioavailability (Fmax) in rat that is higher than 50 % determined by means of rat liver microsomes as described below, and

– a maximum oral bioavailability (Fmax) in dog that is higher than 45 % determined by means of dog liver microsomes as described below, and

– a maximum oral bioavailability (Fmax) in human that is higher than 45 %, determined by means of human liver microsomes as described below, and

– an IC50 lower than 600 nM in a HeLa cell proliferation assay as described below. Hence, the compounds of the present invention have surprising and advantageous properties. These unexpected findings give rise to the present selection invention. The compounds of the present invention are purposively selected from the above mentioned prior art due to their superior properties. In particular, said compounds of the present invention may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by Mps-1 kinase, such as, for example, haemotological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

PATENT

WO2013087579

https://www.google.com/patents/WO2013087579A1

 
Inventors Volker SchulzeDirk KosemundAntje Margret WengnerGerhard SiemeisterDetlef STÖCKIGTMichael Bruening
Applicant Bayer Intellectual Property GmbhBayer Pharma Aktiengesellschaft

Synthesis of Examples

Compounds of the present invention

Example01.01

(2 ?)-2-(4-fluorophenyl)-N-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl]propanamide

Figure imgf000139_0001

To a stirred suspension of Int08.011 (6.0 g) in DMF (48 mL) and dichloromethane (96 mL) was added sodium bicarbonate (3.69 g), (2/?)-2-(4- fluorophenyl)propanoic acid (2.71 g) and HATU (8.36 g). The mixture was stirred at room temperature for 4 h. Water was added, and the mixture was stirred for 30 minutes. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with ethyl acetate to give 7,44 g of the title compound. 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.40 (d, 3H), 3.16 (s, 3H), 3.84 (q, 1H), 3.96 (s, 3H), 7.09 – 7.18 (m, 2H), 7.36 – 7.44 (m, 3H), 7.51 (dd, 1H), 7.63 – 7.76 (m, 5H), 7.92 (dd, 1H), 8.48 (d, 1H), 8.60 (s, 1H), 9.10 (d, 1 H), 10.16 (s, 1H).

[a]D20 : -77.0° (in DMSO).

Column: Chiralcel OD-RH 150×4.6; Flow: 1.00 mL/min; Solvent: A: Water with 0.1 % formic acid, B: Acetonitrile; Solvent mixture: 40% A + 60% B. Run Time: 30 min. Retention Time: 12.83 min; UV 254 nm; Enantiomeric Ratio: <1% : > 99%. Racemate01.01.r

Figure imgf000140_0001

Starting with Int01.05 and Int03.02, Racemate01.01.r was prepared analogously to the procedure for the preparation of Int08.020.

Racemate01.02.r

PATENT

WO2014009219

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014198647&recNum=63

Analytical UPLC-MS was performed as follows:

Method A: System: UPLC Acquity (Waters) with PDA Detector und Waters ZQ mass spectrometer; Column: Acquity BEH C18 1 .7μηη 2.1 x50mm; Temperature: 60° C; Solvent A: Water + 0.1 % formic acid; Solvent B: acetonitrile; Gradient: 99 % A – 1 % A (1 .6 min) -> 1 % A (0.4 min) ; Flow: 0.8 mL/min; Injection Volume: 1 .0 μΐ (0.1 mg-1 mg/ml_ sample concentration); Detection: PDA scan range 210-400 nm – Fixed and ESI (+), scan range 170-800 m/z

LC-MS methods:

Method 1 :

Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1 .8 μ 50 x 1 mm; Eluent A: 1 I Wasser + 0.25 ml 99%ige Formic acid, Eluent B: 1 I Acetonitril + 0.25 ml 99%ige Formic acid; Gradient: 0.0 min 90% A → 1 .2 min 5% A→ 2.0 min 5% A Ofen: 50° C; Flow: 0.40 ml/min; UV-Detection: 208 – 400 nm.

Preparation of compound A1

Route I

(2/?)-2-(4-fluorophenyl)-N-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]-amino}[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)phenyl]propanamide

To a stirred suspension of Int08.011 (6.0 g) in DMF (48 mL) and dichloromethane (96 mL) was added sodium bicarbonate (3.69 g), (2/?)-2-(4-fluorophenyl)propanoic acid (2.71 g) and HATU (8.36 g). The mixture was stirred at room temperature for 4 h. Water was added, and the mixture was stirred for 30 minutes. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with ethyl acetate to give 7.44 g of the title compound.

1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.40 (d, 3H), 3.16 (s, 3H), 3.84 (q, 1 H), 3.96 (s, 3H), 7.09 – 7.18 (m, 2H), 7.36 – 7.44 (m, 3H), 7.51 (dd, 1 H), 7.63 – 7.76 (m, 5H), 7.92 (dd, 1 H), 8.48 (d, 1 H), 8.60 (s, 1 H), 9.10 (d, 1 H), 10.16 (s, 1 H).

[a]D20 : -77.0° (in DMSO).

Determination of enantiomeric purity by analytical chiral HPLC:

Column: Chiralcel OD-RH 150×4.6; Flow: 1.00 mL/min; Solvent: A: Water with 0.1 % formic acid, B: Acetonitrile; Solvent mixture: 40% A + 60% B. Run Time: 30 min. Retention Time: 12.83 min; UV 254 nm; Enantiomeric Ratio: <1% : > 99%.

Intermediate Int08.01 1

6-(4-aminophenyl)-N-[2-methoxy-4-(methylsulfonyl)phenyl][ 1 ,2,4]-triazolo[1 ,5-a]pyridin-2-amine

To a stirred suspension of Int08.010 (12.3 g) in dichloromethane (40 mL) was added TFA (46 mL). The mixture was stirred at room temperature for 16 h. Further TFA was added (1 mL) and the mixture was stirred at room temperature for 5 h. A saturated solution of potassium carbonate was added until pH 9 was reached. The mixture was extracted with dichloromethane and methanol (10:1 mixture). The solution was dried (sodium sulfate) and the solvent was removed in vacuum. The residue was triturated with ethanol to give 9.2 g of the title compound.

1H-NMR (300MHz, DMSO-d6): δ [ppm]= 3.16 (s, 3H), 3.95 (s, 3H), 5.30 (s, 2H), 6.63 (d, 2H), 7.38 – 7.46 (m, 3H), 7.51 (dd, 1 H), 7.61 (d, 1 H), 7.84 (dd, 1 H), 8.48 (d, 1 H), 8.55 (s, 1 H), 8.93 (d, 1 H).

Intermediate Int08.010

ieri-butyl [4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[ 1 ,2,4]-triazolo[1 ,5-a]pyridin-6-yl)phenyl]carbamate

To a stirred suspension of Int01.03 (4.0 g) in toluene (250 mL) and NMP (25 mL) was added Int03.02 (8.31 g), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1 ,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(ll) methyl-tert-butylether adduct (1.08 g), X-Phos (0.64 g) and powdered potassium phosphate (16.6 g). The flask was degassed twice and backfilled with argon. The mixture was heated to reflux for 16 h.

The reaction mixture was filtered through a microfilter and the solvent was removed in vacuum. The residue was triturated with dichloromethane to give 12.3 g of the title compound.

1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.46 (s, 9H), 3.16 (s, 3H), 3.96 (s, 3H), 7.43 (d, 1 H), 7.48 – 7.59 (m, 3H), 7.63 – 7.72 (m, 3H), 7.92 (dd, 1 H), 8.48 (d, 1 H), 8.58 (s, 1 H), 9.06 – 9.12 (m, 1 H), 9.46 (s, 1 H).

Intermediate Int01.03.

ieri-butyl [4-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)phenyl]carbamate

To a stirred solution of Int01.02 (5.82 g) in 1 -propanol (400 mL) was added 2M potassium carbonate solution (41 mL), {4-[(tert-butoxycarbonyl) amino] phenyl} boronic acid (8.6 g), triphenylphosphine (150 mg) and PdCl2(PPh3)2 (1.9 g). The mixture was heated to reflux for 4 h, the solvent was removed in vacuum, water (150 mL) was added and the mixture was extracted with ethyl

acetate (500 mL). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was triturated with DCM to give the title compound as a white solid. Yield: 7.2 g. 1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.37 – 1.55 (m, 9H), 5.99 (s, 2H), 7.36 (dd, 1 H), 7.48 – 7.55 (m, 2H), 7.55 – 7.62 (m, 2H), 7.69 (dd, 1 H), 8.78 (dd, 1 H), 9.44 (s, 1 H).

Intermediate Int01.02

6-Bromo[1 ,2,4]triazolo[1 ,5-a]pyridin-2-amine

Hydroxylammonium chloride (39.8 g) was suspended in methanol (200 mL) and ethanol (190 mL) and Hiinig Base (59 mL) was added at r.t. The mixture was heated to 60°C, Int01.01 (30 g) was added portionwise, and the mixture was stirred at 60 °C for 2h. The solvent was removed in vacuum and water (150 mL) was added. A solid was collected by filtration and was washed with water and dried in vacuum.

Yield: 19.3 g of the title compound.

1H-NMR (300MHz, DMSO-d6): δ [ppm] = 6.10 (s, 2H), 7.28 (dd, 1 H), 7.51 (dd, 1 H), 8.88 (dd, 1 H).

Intermediate Int01.01

Eth l [(5-bromopyridin-2-yl)carbamothioyl]carbamate

Ethoxycarbonylisothiocyanate (16.7 g) was added to a stirred solution of 2-amino-5-brompyridine (20 g) in dioxane (200 mL). The mixture was stirred for 2h at r.t. A white solid precipitated. Hexane (20 mL) was added and the white solid was collected by filtration.

Yield: 30.4 g of the title compound.

1H-NMR (300MHz, DMSO-d6): δ [ppm] = 1 .22 (t, 3H), 4.19 (q, 2H), 8.08 (dd, 1 H), 8.49 (d, 1 H), 8.57 (br. d, 1 H), 1 1 .37 – 12.35 (m, 2H).

Intermediate Int03.02

1 -bromo-2-methoxy-4-(methylsulfonyl)benzene

To a stirred solution of Int03.01 (265 mg) in chloroform (10 mL) was added 3-chlorobenzenecarboperoxoic acid (mCPBA) (890 mg). The mixture was stirred at room temperature for 1 h. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 252 mg of the title compound.

1H-NMR (300MHz, DMSO-d6): δ [ppm] = 3.22 (s, 3H), 3.93 (s, 3H), 7.39 (dd, 1 H), 7.50 (d, 1 H), 7.84 (d, 1 H).

Intermediate Int03.01

1 -bromo-2-methoxy-4-(methylsulfanyl)benzene

To a stirred solution of 1 -bromo-4-fluoro-2-methoxybenzene (4.0 g) in DMF (40 mL) was added sodium methanethiolate (2.76 g). The mixture was stirred at room temperature for 30 minutes and at 85 °C for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 280 mg of the title compound.

1H-NMR (400MHz, DMSO-d6): δ [ppm] = 2.46 (s, 3H), 3.82 (s, 3H), 6.74 (dd, 1 H), 6.91 (d, 1 H), 7.44 (d, 1 H).

Intermediate Int03.00

1 -bromo-2-methoxy-4-(methylsulfanyl)benzene (alternative procedure)

To a stirred solution of 1 -bromo-4-fluoro-2-methoxybenzene (10.0 g) in DMF (100 mL) was added sodium methanethiolate (4.44 g). The mixture was stirred at 65°C for 2 h. The mixture was cooled to 0°C and methyl iodide (4.55 mL) was added. The mixture was stirred at room temperature for 1 h and further sodium methanethiolate (4.44 g) was added. The mixture was stirred at 65 °C for 1 h. The mixture was cooled to 0°C and methyl iodide (4.55 mL) was added. The mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 6.2 g of the title compound as a 2:1 mixture with the starting material. The mixture was used for the next step without purification.

Route II

(2/?)-2-(4-fluorophenyl)-N-[4-(2-{[2-methoxy-4-(methylsulfonyl)ph

amino}[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)phenyl]propanamide

To a stirred suspension of Int21.06 (550 mg) in toluene (18 mL) was added potassium fluoride (260 mg) and powdered potassium phosphate (842 mg) and the flask was degassed twice and backfilled with argon. The mixture was stirred for 15 minutes at r.t.. Int21.03 (350 mg), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (81 mg) and palladium acetate (22 mg) were added and the flask was degassed twice and backfilled with argon. The mixture was heated to 85 °C for 3 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave a solid that was triturated with a mixture of dichloromethane and hexane to give 452 mg of the title compound.

1H-NMR (300 MHz, DMSO-d6), δ [ppm] = 1 .39 (3H), 3.16 (3H), 3.83 (1 H), 3.95 (3H), 7.08-7.20 (2H), 7.34-7.45 (3H), 7.51 (1 H), 7.63-7.77 (5H), 7.92 (1 H), 8.48 (1 H), 8.64 (1 H), 9.1 1 (1 H), 10.19 (1 H).

[a]D20 : -78.9° (in DMSO).

Determination of enantiomeric purity by analytical chiral HPLC:

Column: Chiralcel OD-RH 150×4.6; Flow: 1 .00 mL/min; Solvent: A: Water with 0.1 % formic acid, B: Acetonitrile; Solvent mixture: 40% A + 60% B. Run Time: 30 min. Retention Time: 12.83 min; UV 254 nm; Enantiomeric Ratio: <1 % : > 99%.

Intermediate Int21.06

(2R)-2-(4-fluorophenyl)-N-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]propanamide

To a stirred solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (1.0 g) in DMF (45 mL) and dichloromethane (90 mL) was added sodium bicarbonate (766 mg), Int09.03 (844 mg) and HATU (2.6 g). The mixture was stirred at room temperature for 4 h. Water was added, and the mixture was stirred for 30 minutes. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica-gel chromatography gave 1.53 g of the title compound.

1H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.23 (12H), 1.37 (3H), 3.74-3.87 (1 H), 7.06-7.16 (2H), 7.31 -7.42 (2H), 7.51 -7.61 (4H), 10.12 (1 H).

Intermediate Example Int21.05

(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)boronic acid

To a stirred solution of (4-aminophenyl)boronic acid hydrochloride (2.00 g) in DMF (42 mL) was added sodium bicarbonate (2.9 g), (2R)-2-(4-

fluorophenyl)propanoic acid (2.04 g) and HATU (6.58 g). The mixture was stirred at room temperature for 72 h. Water (140 mL) was added, and the mixture was stirred for 2 h. The white precipitate was collected by filtration and was washed with water and was dried in vacuum to give 2.86 g of the title compound.

1H-NMR (300 MHz, DMSO-d6), δ [ppm] = 1.39 (3H), 3.84 (1 H), 7.08-7.21 (2H), 7.35-7.44 (2H), 7.52 (2H), 7.69 (2H), 7.88 (2H), 10.07 (1 H).

Intermediate Int09.03

2/?)-2-(4-fluorophenyl)propanoic acid

To a stirred solution of Int09.02 (23.6 g) in refluxing ethyl acetate (250ml_) was added a solution of (1S)-1 -phenylethanamine (17.35 g) in ethyl acetate. The mixture was allowed to cool down to room temperature within 1 h. A white solid was collected by filtration, was washed with ethyl acetate and dried in vacuum to give 27.5 g of a solid. The solid was recrystallized from 400 mL refluxing ethyl acetate. The mixture was allowed to cool down to room temperature. A white solid was collected by filtration, was washed with ethyl acetate and dried in vacuum to give 18.3 g of a solid. The solid was twice recrystallized from refluxing ethyl acetate (350 mL; 300 mL). A white solid was collected by filtration, was washed with ethyl acetate and dried in vacuum to give 10.51 g of a solid. The solid was dissolved in water, hydrochloric acid (c=2.0 M) was added until pH 5 was reached and the reaction mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum to give 5.6 g of the title product. The crude product was used without further purification.

1H-NMR (300MHz, DMSO-d6): δ [ppm] = 1.31 (d, 3H), 3.66 (q, 1 H), 7.05 – 7.16 (m, 2H), 7.24 – 7.33 (m, 2H), 12.28 (br. s., 1 H).

[a]D20 : -79.3° (in DMSO)

Determination of enantiomeric purity by analytical chiral HPLC:

Column: Chiralcel OJ-H 150×4.6; Flow: 1.00 mL/min; Solvent: A: Hexane, B: 2-propanol with 0.1 % formic acid; Solvent mixture: 80% A + 20% B. Run Time: 30 min. Retention Time: 3.41 min; UV 254 nm; Enantiomeric Ratio: 99.8% : 0.2%.

Intermediate Int09.02

Rac-2- 4-fluorophenyl)propanoic acid

To a stirred solution of Int09.01 (18.9 g) in ethanol (200 mL) was added a solution of potassium hydroxide (35 g), dissolved in water (200 mL). The mixture was stirred at 0 °C for 4 h. Hydrochloric acid (c=4.0 M) was added until pH 5 was reached and the reaction mixture was extracted with ethyl acetate. The organic phase was separated and the solvent was removed in vacuum to give 15.64 g of the title product. The crude product was used without further purification.

1H-NMR (300MHz, DMSO-d6): δ [ppm] = 1.31 (d, 3H), 3.66 (q, 1 H), 7.05 – 7.15 (m, 2H), 7.24 – 7.33 (m, 2H), 12.30 (s, 1 H).

Intermediate Int09.01

Rac-meth l 2-(4-fluorophenyl)propanoate

To a stirred solution of diisopropylamine (13.0 g) in tetrahydrofurane (160 mL) was added a solution of n-butyllithium in hexane (51.4 mL; c= 2.5 M) at -78 °C. The solution was stirred at 0 °C for 15 minutes. The solution was cooled to -78 °C and a solution of methyl (4-fluorophenyl)acetate (18.0 g), dissolved in tetrahydrofurane (40 mL) was added. The solution was stirred at -78 °C for 30 minutes. Methyl iodide (10.0 mL) was added at -78 °C, and the solution was allowed to warm up to 0 °C within 1 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 18.9 g of the title compound.

1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.34 (d, 3H), 3.55 (s, 3H), 3.79 (q, 1 H), 7.08 – 7.15 (m, 2H), 7.25 – 7.32 (m, 2H).

Intermediate Int21.03

6-chloro-N-[2-methoxy-4-(methylsulfonyl)phenyl][1 ,2,4]triazolo[1 ,5-a]pyridin-2-amine

To a stirred suspension of Int21.02 (0.7 g) in toluene (28 mL) was added Int03.02 (1.27 g), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1 ,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(ll) methyl-tert-butylether adduct (343 mg), X-Phos (202 mg) and powdered potassium phosphate (3.09 g). The flask was degassed twice and backfilled with argon. The mixture was heated to reflux for 3 h. Further chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1 ,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(ll) methyl-tert-butylether adduct (30 mg) and X-Phos (19 mg) were added and the mixture was heated to reflux

for 15 h. The solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated ethyl acetate to give 1.0 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.16 (3H), 3.95 (3H), 7.42 (1 H), 7.50 (1 H), 7.62-7.69 (2H), 8.41 (1 H), 8.70 (1 H), 9.17 (1 H).

Intermediate Int21.02

6-chloro[1 ,2,4]triazolo[1 ,5-a]pyridin-2-amine

Hydroxylammonium chloride (4.4 g) was suspended in methanol (35 mL) and ethanol (35 mL) and Hiinig Base (10.2 mL) was added at r.t. The mixture was heated to 60° C, Int21.01 (4.4 g) was added portionwise, and the mixture was stirred at 60 °C for 2h. The solvent was removed in vacuum and water (150 mL) was added. A solid was collected by filtration and was washed with water and dried in vacuum.

Yield: 2.0 g of the title compound.

1H-NMR (300 MHz, DMSO-d6): δ [ppm] = 6.09 (2H), 7.28-7.37 (1 H), 7.39-7.49

(1 H), 8.84 (1 H).

Intermediate Int21.01

Eth l [(5-chloropyridin-2-yl)carbamothioyl]carbamate

Ethoxycarbonylisothiocyanate (3.37 g) was added to a stirred solution of 2-amino-5-cloropyridine (3.0 g) in dioxane (100 mL). The mixture was stirred at r.t. for 14 h. The solvent was removed in vacuum. The solid was dissolved in dichloromethane and methanol (100 : 1 ), filtered and the solvent was removed in vacuum to give a solid that was recystallized from ethyl acetate to give 4.4 g of the title compound.

1H-NMR (400 MHz, CHLOROFORM-d): δ [ppm] = 1.35 (3H), 4.31 (2H), 7.71 (1 H), 8.03 (1 H), 8.34 (1 H), 8.83 (1 H), 12.09 (1 H).

PATENT

WO-2017216025

Novel crystalline polymorphic forms of (2R)-2-(4-fluorophenyl)-N-[4-(2-{[2- methoxy-4-(methylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl]propan-amide 4-toluenesulfonate (empesertib), and crystalline (2R)-2-(4-fluorophenyl)-N-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl]propanamide 4- toluenesulfonate monohydrate, composition comprising them and their preparation methods are claimed. Also claims their use for treating various cancers. It is disclosed that empesertib is a potent Mps-1 kinase inhibitor.

MPS-1 INHIBITORS

The present invention covers crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy^-imethylsulfonyljphenyllaminojll^^ltriazololl^-olpyridin-e-yljphenyllpropan-amide 4-toluenesulfonate, and crystalline (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate monohydrate, as compounds per se, a method of preparing said crystalline, anhydrous compound, pharmaceutical compsitions and pharmaceutical combinations comprising said crystalline, anhydrous compound, and uses of said crystalline, anhydrous compound in the treatment or prophylaxis of cancer, in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer, and/or gastric cancer.

BACKGROUND OF THE INVENTION

(2R)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]-amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide is known to be a very potent inhibitor of Mps-1 kinase.

WO 2013/087579 Al discloses the compound, data showing its pharmaceutical activity, and a method for the preparation of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide.

WO 2014/009219 Al discloses an improved method for the preparation of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propan-amide.

WO 2014/195408 Al discloses pharmaceutical compositions comprising (2 ?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propan-amide mainly in amorphous form.

Surprisingly and unexpectedly, it was observed that a crystalline form of the anhydrous 4-toluenesulfonate salt of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)-phenyl]amino}[l,2,4]triazolo[l,5-o]pyridin-6-yl)phenyl]propanamide shows superior properties in terms of its pharmacological usability compared to the free base (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide or other salts thereof.

In accordance with a first aspect, the present invention thus covers crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]-amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate, of formula (I) :

(I),

hereinafter also referred to as the “anhydrous tosylate salt” or “anhydrous 4-toluenesulfonate salt”,

Example 1 : Preparation of crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenvnamino}fl,2,41triazolofl,5-a1pyridin-6-vDphenyllpropanamide 4-toluene-sulfonate : method 1 (without seeding)

Without seeding:

10 g (17.9 mmol) of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]-amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide were suspended in 2-butanone (100 ml) and heated to 65°C 4.08 g (21.4 mmol) 4-toluenesulfonic acid monohydrate in 2-butanone (20 ml) were added at 65°C. The suspension dissolved and the product precipitated from solution. The mixture was stirred for 21h at 65°C. The mixture was cooled to 20°C over 2h. After 2h stirring at 20°C the precipitate was isolated by suction filtration and washed two times with 100 ml 2-butanone (each). The product was dried in vacuum (approximately 60 mbar) at 50°C for 7h. 12.4 g (95 % of theory) were isolated.

Example 3 : Preparation of crystalline (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyllannino}[l,2,41triazolo[l,5-alpyriclin-6-yl)phenyllpropanamide 4; toluene-sulfonate monohydrate: method 1 : without seeding

10 g (17.9 mmol) of (2/?)-2-(4-fluorophenyl)-W-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]-amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide were suspended in 2-butanone (100 ml) and water (2.4 ml) and heated to 65°C. 4.08 g (21.4 mmol) 4-toluenesulfonic acid monohydrate in 2-butanone (20 ml) were added at 65°C. The suspension dissolved and the product precipitated from solution. The mixture was stirred for 21h at 65°C and then cooled to 20°C within 2h. After 2h stirring at 20°C the precipitate was isolated by suction filtration and washed two times with 100 ml 2-butanone (each). The product was dried in vacuum (approximately 60 mbar) at 50°C for 7h. 11.4 g (85 % of theory) were isolated.

Thermogravimetry showed a wheight loss of 2.2 weight-% while heating from 32.6°C to 100°C.

lH-N MR(DMSO-d6): δ = 1.43 (3H), 2.29 (3H), 3.20 (3H), 3.87 (1H), 4.00 (3H), 4.40-4.95 (broad signal, water) 7.09-7.21 (4H), 7.41-7.50 (5H), 7.55 (1H), 7.69-7.78 (5H), 7.97 (1H), 8.51 (1H), 8.67 (1H), 9.15 (1H), 10.21 (1H) ppm.

REFERENCES

1. Combinations for the treatment of cancer comprising a Mps-1 kinase inhibitor and a mitotic inhibitor
By Wengner, Antje Margret; Siemeister, Gerhard
From PCT Int. Appl. (2014), WO 2014198645 A1 20141218.

2. Preparation of prodrug derivatives of substituted triazolopyridine monopolar spindle 1 kinase inhibitors and their use for the treatment of cancer
By Schulze, Volker; Lerchen, Hans-Georg; Bierer, Donald; Wengner, Antje Margret; Siemeister, Gerhard; Lienau, Philip; Krenz, Ursula; Kosemund, Dirk; Stoeckigt, Detlef; Bruening, Michael; et al
From PCT Int. Appl. (2014), WO 2014198647 A2 20141218.

3. Pharmaceutical compositions comprising substituted triazolopyridine compds.
By Schulze, Volker; Bruening, Michael; Stoeckigt, Detlef
From PCT Int. Appl. (2014), WO 2014195408 A1 20141211.

4. Combinations comprising inhibitors of Mps-1 kinase and anti-apoptotic protein of the Bcl-2 family for the treatment of cancer
By Siemeister, Gerhard; Bader, Benjamin; Wengner, Antje; Mumberg, Dominik; Schulze, Volker; Kroemer, Guido; Vitale, Ilio; Jemaa, Mohamed
From PCT Int. Appl. (2014), WO 2014020043 A1 20140206.

5. Method for preparing substituted triazolopyridines as Mps-1 kinase inhibitors
By Schulze, Volker; Mais, Franz-Josef
From PCT Int. Appl. (2014), WO 2014009219 A1 20140116.

6. Preparation of triazolopyridine derivatives for use as TTK inhibitors
By Schulze, Volker; Kosemund, Dirk; Wengner, Antje Margret; Siemeister, Gerhard; Stoeckigt, Detlef; Bruening, Michael
From PCT Int. Appl. (2013), WO 2013087579 A1 20130620.

///////////BAY1161909, BAY-1161909, BAY 1161909, Empesertib, Mps1-IN-5,  (-)-BAY-1161909, PHASE 1

 O=C(NC1=CC=C(C2=CN3C(C=C2)=NC(NC4=CC=C(S(=O)(C)=O)C=C4OC)=N3)C=C1)[C@H](C)C5=CC=C(F)C=C5

PH 46A


str1str1SCHEMBL14669646.png

PH 46A

cas  1421332-97-9

C27 H24 O3, 396.48

Benzoic acid, 4-[[(1S,2S)-2,3-dihydro-1-hydroxy[2,2′-bi-1H-inden]-2-yl]methyl]-, methyl ester
Methyl 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1’H-[2,2′-biinden]-2-yl)methyl)benzoate
str1
FREE ACID CAS  1380445-03-3, Benzoic acid, 4-[[(1S,2S)-2,3-dihydro-1-hydroxy[2,2′-bi-1H-inden]-2-yl]methyl]-
str1
N-Methyl-(D)-Glucamine salt (NMDG)
1380445-04-4
C26 H22 O3 . C7 H17 N O5
D-Glucitol, 1-deoxy-1-(methylamino)-, 4-[[(1S,2S)-2,3-dihydro-1-hydroxy[2,2′-bi-1H-inden]-2-yl]methyl]benzoate (1:1)
PH46A, belonging to a class of 1,2-Indane dimers, has been developed by  Trino Therapeutics Ltd research group as a potential therapeutic agent for the treatment of inflammatory and autoimmune diseases
The new chiral chemical entity PH46A, 6-(methylamino)hexane-1,2,3,4,5-pentanol 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2-biinden]-2-yl)methyl)benzoate, was previously synthesized research group(1X) and shown to have potential therapeutic activity in the areas of inflammation and autoimmune diseases, including inflammatory bowel disease.(2X) PH46A recently completed a first-in-man Phase I clinical trial study.(3X)
  1. 1X  FramptonC.-S.ZhangT.ScalabrinoG.FrankishN.SheridanH. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 201268o323 DOI: 10.1107/S0108270112031265

  2. 2X FrankishN.SheridanH. J. Med. Chem. 2012555497 DOI: 10.1021/jm300390f

  3. 2X TherapeuticsT. A study to assess the safety and tolerability of PH46A in healthy volunteers, to measure drug levels in these subjects and to determine the effect of food on the drug’s absorption. BioMed Central: ISRCTN Registry, EudraCT: 2013-003717-17, 2014.
PH 46A
  • Originator Trino Therapeutics
  • Class Anti-inflammatories; Benzoates; Indans; Muscle relaxants; Small molecules
  • Mechanism of Action Mast cell stabilisers
  • Orphan Drug Status No
  • New Molecular Entity Yes

Highest Development Phases

  • Phase I Ulcerative colitis

Most Recent Events

  • 31 Aug 2014 Trino Therapeutics completes a phase I trial in Ulcerative colitis (In volunteers) in United Kingdom (ISRCTN90725219)
  • 07 Feb 2014 Phase-I clinical trials in Ulcerative colitis (in volunteers) in United Kingdom (PO)
  • 04 Jun 2012 Pharmacodynamics data from a preclinical trial in Ulcerative colitis released by Trino Therapeutics

Cytokines can be produced by various cell populations and have been shown to augment or limit immune responses to pathogens and influence the autoimmune response. One family of cytokines, which uses the common receptor gamma chain (cc), a component of receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21, has been classically defined as growth and survival factors.

IL-2 production can induce an immune response by promoting the proliferation and generation of CD4+ Thl, CD4+ Th2 and CD8+ CTL effector cells. Many of the immunosuppressive drugs used in the treatment of autoimmune diseases and organ transplant rejection, such as corticosteroids and immune suppressive drugs (ciclosporin, tacrolimus) work by inhibiting the production of IL-2 by antigen -activated T cells. Others (sirolimus) block IL-2R signalling, thereby preventing the clonal expansion and function of antigen-selected T cells [ref: Opposing functions of IL-2 and IL-7 in the regulation of immune responses Shoshana D. Katzman, Katrina . Hoyer, Hans Dooms, Iris K. Gratz, Michael D. Rosenblum, Jonathan S. Paw, Sara H. Isakson, Abul K. Abbas. Cytokine 56 (201 1) 1 16-121]

In contrast IL-2 can inhibit the immune response by promoting the survival and functionality of natural (thymic) regulatory T-cells (Tregs), promoting the generation of induced (peripheral) Tregs and inhibiting the generation of CD4+ Thl 7 effector cells [ref: IL-2 and autoimmune disease. Anneliese Schimpl , A., Berberich, I, Kneitz, B., Kramer, S., Santner-Nanan, B., Wagner, S., Wolf, M., Hunig, T. Cytokine & Growth Factor Reviews 13 (2002) 369-378]. Interleukin-2/IL-2R deficiency with time leads to multiorgan inflammation and the formation of autoantibodies of various specificities. Depending on the genetic background, death occurs within a few weeks to a few months, mostly from autoimmune hemolytic anemia or inflammatory bowel disease (IBD) [ref. Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 1993;75:253-61]. IL-2 signalling has been shown to be important in both the initiation and regulation of immune responses. In these dual and opposing roles, IL-2 acts to balance immune response, both driving immune cell activation and subsequent reduction. The potential clinical applicability of either augmenting or inhibiting signals mediated by IL-2 is significant and includes cancer, autoimmune inflammatory diseases, organ transplantation and HIV.

Inflammatory bowel disease (IBD) is an autoimmune inflammatory disease that consists of two idiopathic inflammatory diseases, ulcerative colitis (UC) and Crohn’s disease (CD). The greatest distinction between UC and CD is the range of inflamed bowel tissue. Inflammation in CD is discontinuously segmented, known as regional enteritis, while UC is superficial inflammation extending proximally and continuously from the rectum. At present, the exact cause of IBD is unknown. The disease seems to be related to an exaggerated mucosal immune response to infection of the intestinal epithelium because of an imbalance of pro- inflammatory and immune- regulatory molecules. The inheritance patterns of IBD suggest a complex genetic component of pathogenesis that may consist of several combined genetic mutations. Currently no specific diagnostic test exists for IBD, but as an understanding of pathogenesis is improved so will the corresponding testing methods. Treatment of IBD consists of inducing and maintaining remission. IBD patients may be maintained on remission by use of a 5-aminosalycilate. However, while the use of aminosalycilates in UC provides considerable benefit, both in inducing remission in mild to moderate disease and in preventing relapse, the usefulness of these drugs to maintain remission in CD is questionable and is no longer recommended. The mainstay of treatment of active disease is a corticosteroid, commonly used for limited periods to return both UC and CD patients to remission, though budesonide, designed for topical administration with limited systemic absorption, has no benefit in maintaining remission. Alternatives, such as the immunosuppressive drugs azathioprine and mercaptopurine, together with methotrexate and cyclosporine have limited efficacy and the capability of inducing grave adverse effects. Anti- TNFa antibodies, such as infliximab and adalimubab, may be used in those patients unresponsive to standard immunosuppressive therapy. However, many patients fail to respond to anti-TNFa therapy, either due to their particular phenotype or by the production of autoantibodies.

Inventors Helen SheridanNeil Frankish
Applicant Venantius Limited

PATENTS

WO 2013014660

https://encrypted.google.com/patents/WO2013014660A1?cl=en

Compound 6: The N-Methyl-(D)-Glucamine salt (NMDG) of compound 2.

Figure imgf000035_0001

Compound 6 physiochemical properties:

Appearance: Off-white solid

Molecular Weight: 577 (free acid: 382)

Molecular Formula: C33H39O8N (free acid: C26H2203)

Melting Point: 165-167 °C

Compound 6: [a]D:-76.5 (sample concentration: 200 mg/10 ml in Water)

Mass (Da): ES+ only [NMDG+Na] was visible

Elemental analysis: Calc: C (68.61), H (6.80), N (2.42), O (22.16). Found: C (68.44), H

(6.80), N (2.50), 0 (21.98) δΗ(400 MHz, DMSO-d6): 2.48 (3H, apparent s, NCH3), 2.65 (1H, d, J=13.56 Hz, HCH), 2.84-

3.02 (4H, m), 3.16 (1H, d, J= 13.60 Hz, HCH), 3.40-3.70 (7H, m), 3.85-3.92 (l H, m), 5.06 (1H, s, CH-OH), 5.93 (1H, broad s, CH- OH), 6.41 (1H, f, .CH=C), 6.80 (2H, d, J=7.92 Hz, Ar-H), 7.06-7.41 (8H, m, Ar-H), 7.64 (2H, d, J=7.80 Hz, Ar-H).

6c(100 MHz, DMSO): 33.8 (CH3), 37.9 (CH2), 38.2 (CH2), 39.5 (CH2), 51.6 (CH2-N), 55.8

(quat. C), 63.5 (CH2-0), 69.0 (CH-O), 70.3 (CH-O), 70.6 (CH-O), 71.3 (CH-O), 81.1 (CH-OH), 120.1 (tert. C), 123.4 (tert. C), 123.7 (tert. C), 124.3 (tert. C), 124.4 (tert. C), 126.1 (tert. C), 126.3 (tert. C), 127.0 (tert. C), 127.5 (tert. C), 2 x 128.5 (2 x tert. C), 2 x 129.1 (2 x tert. C), 140,4 (quat. C), 141.1 (quat. C), 142.9 (quat. C), 144.5 (quat. C), 145.2 (quat. C), 154.3 (quat. C), 170.4 (C=0).

Synthesis of methyl 4- (lS,2S)-l-hvdroxy-2,3-dihvdro-lHJ’H-f2,2′-biinden1-2-yl)methyl) benzoate (17):

Figure imgf000042_0002

To a solution of 4-(((15,25)-l-hydroxy-2,3-dihydro-lH, l’H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) and K2C03 (72 mg, 0.52 mmol) in DMF (2.5 mL), was added Mel (148 mg, 1.04 mmol) and then stirred at room temperature for 4 h. The reaction mixture was diluted with 1.5 N HCI (50 mL) and extracted with ethyl acetate (3 x 25 mL). The organic layer was washed with 10 % aq. NaHC03 (25 mL), brine (25 mL), dried over anhydrous Na2S04 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20 % ethyl acetate in chloroform as an eluent to yield 62 mg (59 %) of the title compound as an off white solid.

LCMS (-OH): observed 379.2, calculated 396.17, molecular formula C27H2403

Purity (HPLC): 97 %.

Ή NMR (400 MHz, CDC13): 6 2.84 (1H, d, J = 13.28 Hz, ¾), 3.00 (1H, d, J = 15.64 Hz, CH2), 3.05 (1H, d, J = 15.56 Hz, CPb), 3.27 (lH, d, J = 13.32 Hz, CH ), 3.45 (1H, d, J = 22.52 Hz, CH2), 3.57 (1H, d, J = 22.60 Hz, CH2), 3.89 (3H, s, OCH3), 5.25 (1H, s, CHQH), 6.47 (1H, s, CH=C), 6.96 (2H, d, J = 8.24 Hz, Ar-H), 7.17 (1H, dt, J = 2.04, 9.88 Hz, Ar-H), 7.24-7.33 (5H, m, Ar-H), 7.43 (2H, d, J = 7.60 Hz, Ar-H), 7.83 (2H, dd, J = 1.76, 6.60 Hz, Ar-H).

PATENT

WO 2013174916

PATENT

US 9260376

US 20150141506

PH 46A (S,S & R,R) racemic

Melting point 141–143 °C. 1H NMR (400 MHz, CDCl3) δH (ppm) 6.99 (d, J = 7.72 Hz, 2H), 7.46 (d, J = 7.04 Hz, 2H), 7.20–7.31 (m, 6H), 6.97 (d, J = 7.80 Hz, 2H), 6.50 (s, 1H), 5.29 (d, J = 24.16 Hz, 1H), 3.91 (s, 3H), 3.60 (d, J = 22.68 Hz, 1H), 3.48 (d, J = 22.88 Hz, 1H), 3.28 (d, J = 13.24 Hz, 1H), 3.06 (d, J = 15.64 Hz, 1H), 3.51 (d, J = 16.00 Hz, 1H), 2.86 (d, J = 13.28 Hz, 1H). 13C NMR (100 MHz, CDCl3) δC (ppm) 166.9, 152.3, 144.1, 143.9, 143.4, 142.4, 140.0, 2 × 129.8, 2 × 128.6, 128.1, 128.0, 127.5, 126.6, 126.0, 124.4, 123.9, 123.6, 123.2, 120.2, 82.4, 55.5, 51.6, 39.6, 38.2, 38.0. HRMS (ESI) m/z calculated for C27H24O3 (M + Na)+ , 419.1606; found, 419.1618. Achiral HPLC: Zorbax C18 XDB (150 x 4.6 mm), 20:80:0.1 (v:v:v) water:MeOH:TFA, 1.0 mL/min, 254 nm, RT: 4.31 min. Chiral HPLC: Chiralpak IC, 90:10:0.1 (v:v:v) heptane:IPA:TFA, 1.0 mL/min, 210 nm, RT: 7.98 min & 9.38 min.

PH 46A

1H NMR (400 MHz, dmso-d6) δH (ppm): 7.70 (d, J = 8.4 Hz, 2H, Ar–H), 7.34–7.40 (m, 2H, Ar–H), 7.14–7.25 (m, 5H, Ar–H), 7.07 (t, J = 14.4 Hz, 1H, Ar–H), 6.97 (d, J = 8.4 Hz, 2H, Ar–H), 6.39 (s, 1H, CH = C), 5.85 (d, J = 7.2 Hz, 1H, CHOH), 5.06 (d, J = 6.8 Hz, 1H, CHOH), 3.77 (s, 3H, CH3), 3.56 (d, J = 23.2 Hz, 1H, CH2), 3.42 (d, J = 23.2 Hz, 1H, CH2), 3.20 (d, J = 13.6 Hz, 1H, CH2), 2.96 (s, 2H, CH2), 2.73 (d, J = 13.6 Hz, 1H, CH2).

Figure

clip

Image result for PH46A

https://www.sciencedirect.com/science/article/pii/S0040403916301332

Investigation of the Stereoselective Synthesis of the Indane Dimer PH46A, a New Potential Anti-inflammatory Agent

Celtic Catalysts Ltd, NovaUCD, Belfield, Dublin 4, Ireland
Trino Therapeutics Ltd, The Tower, Trinity Technology & Enterprise Campus, Dublin 2, Ireland
§ Drug Discovery Group, School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute (TBSI), Trinity College, Dublin 2, Ireland
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00258
Publication Date (Web): November 27, 2017
Copyright © 2017 American Chemical Society
*E-mail: hsheridn@tcd.ie.
Abstract Image

PH46A, belonging to a class of 1,2-Indane dimers, has been developed by our research group as a potential therapeutic agent for the treatment of inflammatory and autoimmune diseases. The initial synthetic route to PH46A gave a low overall yield, due in large part to the generation of undesired diastereoisomer 5 and the unwanted enantiomer (R,R)-8 during the synthesis. The aim of this work was to carry out a comprehensive investigation into the stereoselective synthesis of PH46A. Significant progress was made on the ketone reduction step, where the use of triisobutylaluminum [TiBA, Al(iBu)3] afforded high selectivity for the target diastereoisomer (rac)-6, compared to the unfavorable ratio obtained using a previous process. This enabled a multikilo scale synthesis of PH46A in a GMP environment. Further, a brief proof-of-principle investigation was carried out using an achiral phase transfer catalyst (PTC) for alkylation at the methine carbon of the parent indanone.

Patent ID

Patent Title

Submitted Date

Granted Date

US2015141506 INDANE DIMERS FOR USE IN THE TREATMENT OF AUTOIMMUNE INFLAMMATORY DISEASE
2013-05-23
2015-05-21
US9260376 COMPOUNDS FOR USE IN THE TREATMENT OF IMMUNE RELATED INFLAMMATORY DISEASE
2012-07-20
2014-04-17

///////////////////////PH46A, PH 46A, phase 1, trino

O=C(OC)c1ccc(cc1)C[C@]3(Cc2ccccc2[C@H]3O)C4=Cc5ccccc5C4

AD 35


str1

AD 35

IND-120499

MF C24 H27 N3 O3
Molecular Weight, 405.49
Spiro[cyclopropane-1,5′-[5H-1,3]dioxolo[4,5-f]isoindol]-7′(6′H)-one, 6′-[2-[1-(2-pyridinylmethyl)-4-piperidinyl]ethyl]-

6′-[2-[1-(2-Pyridinylmethyl)-4-piperidinyl]ethyl]spiro[cyclopropane-1,5′-[5H-1,3]dioxolo[4,5-f]isoindol]-7′(6’H)-one

1531586-58-9 CAS FREE FORM

1531586-64-7  PHOSPHATE

1531586-62-5  HYDROCHLORIDE

Zhejiang Hisun Pharmaceutical Co Ltd

Image result for Zhejiang Hisun Pharmaceutical Co Ltd

AD-35 is known to be a neuroprotectant, useful for treating Alzheimer’s diseases.

Zhejiang Hisun Pharmaceutical is developing an oral tablet formulation of AD-35, for treating Alzheimers disease . By August 2017, the phase I multiple doses trial had been completed in the US and would be completed in China soon

CAS 1531586-64-7  PHOSPHATE

6′-[2-[1-(Pyridin-2-ylmethyl)piperidin-4-yl]ethyl]spiro[cyclopropane-1,5′-[1,3]dioxolo[4,5-f]isoindol]-7′(6’H)-one phosphate

 Molecular Formula C24 H27 N3 O3 . H3 O4 P
 Molecular Weight 503.4847

With the rapid growth of the elderly population, the number of people suffering from Alzheimer’s disease (Alzheimer’s disease) also will be increased dramatically.Alzheimer’s disease is also known as Alzheimer-type dementia (Alzheimer type dementia), or the Alzheimer type senile dementia (senile dementia of the Alzheimer type). At present, although the prevalence of this disease on a global scale is still unknown, but according to the latest report from the US Alzheimer’s Association (the Alzheimer’s Association), and in 2011 the United States there are about 540 million people suffer from Alcatel the number of Alzheimer’s disease, and in 2050, in the United States suffering from the disease will increase to about 13.5 million. Therefore, the development of better efficacy and fewer side effects of new drugs to treat the disease it is a priority.

Alzheimer’s disease is the most common form of senile dementia, it has become the sixth leading cause of death of Americans, and 65 years and the fifth leading cause of death in Americans over 65 years. Although scientists have this disease carried out extensive and in-depth research, but so far, the exact cause of the disease remains unclear. Alzheimer’s disease is a progressive disease that continues to kill nerve cells, destroying nerve connections in the brain, resulting in brain tissue is damaged, leading to patients gradually lose memory, consciousness and judgment, and cause mood disorders and behavioral disorders in patients.

Alzheimer’s is an irreversible disease, and now there is no any drug can prevent the disease, and no drugs can cure the disease or slow the disease process. Drugs currently used to treat the disease can only alleviate or ameliorate symptoms of the disease. These drugs are FDA approved for use in the United States a total of five, four of which are acetylcholinesterase (acetylcholinesterase) inhibitors. Acetylcholine (acetylcholine) is a neurotransmitter, a chemical released by nerves, if produced in the brain acetylcholine system, i.e. damaged cholinergic system, it can result in associated with Alzheimer’s disease memory disorders; and acetylcholinesterase function is to catalyze the hydrolysis of acetylcholine, acetylcholine is decomposed. Because Alzheimer’s disease is accompanied

Attenuation of acetylcholine activity, thus inhibiting acetylcholinesterase is one way to treat this disease. As described above, in the present 5 treatment of Alzheimer’s disease drugs in clinical use, there are four acetylcholinesterase inhibitors, including acetylcholinesterase inhibitors such as donepezil (donepezil), tacrine (tacrine ), rivastigmine (rivastigmine), and galantamine (galantamine), wherein donepezil (Sugimoto et al US4895841 and 5100901;.. Pathi et al WO 2007077443;. Parthasaradhi et al WO 2005003092;. Dubey et al WO 2005076749; Gutman . et al WO 200009483;… Sugimoto et al J. Med Chem 1995, 38, 481) is a first-line treatment of Alzheimer’s disease drugs. However, donepezil and the other four drugs can only improve the patient’s symptoms, and this is the only improvement of symptoms is short, only lasting about 6-12 months, and the patient response rates to these drugs only about 50% (Alzheimer’s Association, 201 1 Alzheimer ‘Disease Facts and Figures, Alzheimer’s & Dementia, 201 1, 7 (2), 208). The present invention provides a new class of inhibitors of acetylcholinesterase, which is dioxole between a new class of derivatives of benzo, is more effective than donepezil and fewer side effects in the treatment of Alzheimer’s disease drug.

PATENT

WO 2014005421

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014005421&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example 42: 6- [2- [l- (2-Pyridylmethyl) -4-piperidinyl] ethyl] spiro [[1,3] dioxolo [4,5-f ] Isoindole-7, Γ-cyclopropane-5-one (Compound No. 1-29)

To the reaction flask was added 24.3 g (0.069 mol) of compound 11-5, 36.5 g (0.26 mol) of potassium carbonate, 243 ml of ethanol, 6.1 ml (0.044 mole) of triethylamine, heated to about 50 ° C, 0.049 mol) of 2-chloromethylpyridine hydrochloride was maintained at about 50 ° C for 5 hours. The reaction was complete and 750 ml of water was added. The solid was precipitated, filtered and the cake was washed with water and dried to give 17.8 g of compound 1-29. Rate: 63.4%. ‘HNMR (CDC13 . 3 ): [delta] 1.26 (dd, 2H, J = 6.1, 7.6 Hz), 1.35 (brs,. 3 H), 1.49-1.57 (m, 4H), 1.72 (D, 2H, J = 8.6Hz) (T, 2H, J = 7.9 Hz), 3.64 (s, 2H), 6.03 (s, 2H), 2.09 (t, 2H, J = 10.4 Hz), 2.89 (d, 2H, J = 10.7 Hz) , 7.42 (s, 1 H), 7.15 (dd, 1 H, J = 5.2, 6.7 Hz), 7.24 (s, 1 H), 7.41 (d, 1 H, J = 7.7 Hz), 7.64 (td, H, J = 7.6, 1.8 Hz), 8.55 (D,. 1 H, J = 4.2 Hz); the MS (ESI): m / Z 406 [m + H] + .

Example 46: 6- [2- [l- (2-Pyridylmethyl) -4-piperidinyl] ethyl] spiro [[1,3] dioxolo [4,5-f ] Isoindole-7, Γ-cyclopropane] -5-one hydrochloride (Compound No. 1-33)

To the reaction flask was added 5 g (0.012 mol) of compound 1-29 and 25 ml of ethanol, heated at 50 ° C

(0.012 mol) of concentrated hydrochloric acid was added, and 1 g of activated charcoal was added to decolorize for 20 minutes. The filtrate was cooled to room temperature and 50 ml of isopropyl ether was added dropwise. The solid was precipitated, stirred for 1 hour, The ether cake was washed with ether and dried to give 5 g of compound 1-33 in a yield of 91.7%. Ethanol / isopropyl ether can be re-refined, the yield of about 90%. 1H-NMR is (D 2 0): 51.14 (T, 2 H, J-7.0 Hz), 1.38-1.70 (m,. 7 H), 1.96 (D, 2H, J = 13.3 Hz), 2.99-3.14 (m, H. 4 ), 3.50 (d, 2 H, J = 11.0 Hz), 4.37 (s, 2H), 5.93 (s, 2H), 6.28 (s, 1 H), 6.75 (s, 1 H), 7.47 (dd, J = 7.8, 1.7 Hz), 8.58 (d, 1 H, J = 4.4 Hz), 7.55 (d, 1 H, J = 7.8 Hz), 7.91 (td, ; MS (ESI): m / z 406 [M-Cl] & lt; + & gt ; .

Example 48: 6- [2- [l- (2-Pyridylmethyl) -4-piperidinyl] ethyl] spiro [[1,3] dioxolo [4,5-f ] Isoindole-7, Γ-cyclopropan-5-one phosphate (Compound I-3S)

To the reaction flask was added 2 g (0.0049 mole) of compound 1-29 and 40 ml of ethanol, stirred at 60 ° C until all dissolved, 0.57 g (0.0049 mole) of 85% phosphoric acid was added, stirred and solidified,

Liter of ethyl acetate, cooled to room temperature, stirred for 1 hour, filtered, and a small amount of ethyl acetate was used to wash the filter cake and dried to give 2.1 g of compound 1-35 in a yield of 84.7%. 1H-NMR (D 2 0): δ 1.10 (t, 2 H, J = 7.2 Hz), 1.33-1.64 (m, 7 H), 1.92 (d, 2 H, J = 13.4 Hz), 2.95-3.09 (m, (S, 1 H), 6.69 (s, 1 H), 7.45 (s, 2 H), 4.34 (s, (d, 1 H, J-7.8 Hz), 7.88 (td, 1 H, J = 7.7, 1.2 Hz), 8.54 (d, 1 H, J = 4.6 Hz).

PATENT

CN 103524515

https://encrypted.google.com/patents/CN103524515B?cl=en

PATENT

CN 105859732

https://www.google.com/patents/CN105859732A?cl=en

Example 14: 6- [2- [l_ (2- pyridylmethyl) -4-piperidinyl] ethyl] spiro [[1,3] dioxolo [4,5 -f] isoindole-7, prepared Γ- cyclopropane] phosphate 5-one (compound I) is

Figure CN105859732AD00182

[0146] Compound was added 2g (4.9 mmol) of formula XI to the reaction flask 50mL, 40mL of ethanol, 60 ~ 70 ° C dissolved by heating, added with stirring square. 57g 85% (4.9mmol) phosphoric acid, and the precipitated solid was added dropwise 40mL of acetic acid ethyl cooled to room temperature, stirred for 1 hour, filtered, the filter cake washed with a small amount of ethyl acetate, dried to give 2.3g white solid (compound I, HPLC purity: 99.8%). Yield: 92.7%, H bandit R (D2O): δ1 · l〇 (t, 2H, J = 7.2Hz), 1.33-1.64 (m, 7H), 1.92 (d, 2H, J = 13.4Hz), 2.95 -3.09 (m, 4H), 3.46 (d, 2H, J = 10.7Hz), 4.34 (s, 2H), 5.89 (s, 2H), 6.20 (s, 1H), 6.69 (s, 1H), 7.45 ( , 7.53 (d, lH, J 7.8Hz dd, lH, J = 5.2,7.4Hz) =), 7.88 (td, lH, J =

PATENT

WO 2017177816

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017177816&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Process for preparing AD-35 and its intermediates – comprising the reaction of a cyano ester with a Grignard reagent, followed by condensation and further manipulative steps.

A novel intermediate of AD-35 is claimed. Also claimed is a processes for preparing 6,7-dihydro-[1,3]dioxolo[4,5-f]isoindol-5-one comprising the reaction of a cyano ester compound in an isopropyl ester (Ti(i-Pr)4)) with a Grignard reagent in the presence of an ethyl magnesium halide. Further claimed are processes for preparing synthon of intermediates. A process for preparing a benzodioxole derivative, particularly AD-35 from intermediates is also claimed.

WO2014005421 reports a class of benzodioxole compounds, which have the activity to inhibit acetylcholinesterase and can be used to treat Alzheimer’s disease. Of these compounds, it is particularly noteworthy that 6- [2- [1- (2-pyridylmethyl) -4-piperidinyl] ethyl] spiro [[1,3] dioxole And [4,5-f] isoindole-7,1′-cyclopropane] -5-one phosphate, codon AD-35, whose chemical structure is as follows:
AD-35 is a weaker acetylcholinesterase inhibitor that inhibits acetylcholinesterase activity in vitro is about one tenth of the activity of donepezil, but the compound exhibits comparable efficacy with donepezil in the Morris water maze test , That is, the effect of improving memory and learning ability is comparable to donepezil. This suggests that the AD-35 is likely to also have the effect of improving memory and learning through other mechanisms in the body. A further study of the rat model of Alzheimer’s disease induced by Aβ 25-35 found that AD-35 significantly inhibited the production and release of proinflammatory cytokines TNF-α and IL-1β, Small Aβ 25-35 on the nerve cell toxicity, effectively protect the nerve cells.
In addition, AD-35 also exhibits a certain ability to chelate transition metal ions such as Cu 2+ in vitro , while Cu 2+ accelerates the formation of Aβ fibers and enhances the toxicity of Aβ to neuronal cells, thereby promoting neuronal cell death , So excessive Cu 2+ in the brain is also considered to be one of the risk factors for Alzheimer’s disease (Sarell et al. J. Biol. Chem. 2010, 285 (53), 41533). From the chemical structure point of view, AD-35 molecules in the piperidine ring and pyridine ring on the two nitrogen atoms constitute a structural unit similar to ethylenediamine, which should be able to explain why this compound to a certain extent Chelating transition metal ions. In terms of the safety of the compounds, the acute toxicity of mice showed that the toxicity of AD-35 was much less than that of donepezil. A newly completed clinical single-dose incremental tolerance test (SAD) showed that the subjects taking 90 mg of AD-35 did not have any adverse effects at once, indicating that the compound was safe.
In summary, the AD-35 is promising to be a small side-effect drug for the treatment of Alzheimer’s disease, and its multiple mechanisms of action are likely to make this compound not only alleviate the symptoms of Alzheimer’s patients , And can delay the process of the disease.
Since the synthesis route of AD-35 and its analogs reported in WO2014005421 is too long, the operation is complicated and the yield is low, and some steps are not suitable for industrial production. Therefore, it is necessary to develop a new process route to overcome the above- Preparation method.
The preferred reaction conditions of the present invention are listed in the following schemes:
Step (1) :
Step (2) :
Step (3) :
Step (4) :
Step (5) :
Step (6) :
Step (7) :
Step (8) :

Specific implementation plan

The following examples are provided for the purpose of further illustrating the invention, but this is not intended to be limiting of the invention.
Reference Example 1: Preparation of the starting material of tert-butyl 4- [2- (p-toluenesulfonyloxy) ethyl] piperidine-1-carboxylate (Formula VIa)

[0103]

[0104]
To a 10 L reaction flask was added 800 g (3.49 mol) of tert-butyl 4- (2-hydroxyethyl) piperidine-1-carboxylate, 5 L of dichloromethane, 974 ml of (6.75 mol) of triethylamine and 16 g of 4-dimethyl (3L × 3), the organic phase was collected, dried over anhydrous sodium sulfate, and the reaction mixture was washed with anhydrous sodium sulfate , Filtered and the filtrate was concentrated under reduced pressure to give 1360.3 g of compound VIa (HPLC purity: 85%). 1 H NMR (DMSO-d 6 ): δ 0.85-0.93 (m, 2H), 1.38 (s, 9H), 1.42-1.52 (m, 5H), 2.43 (s, 3H), 2.59 (br s, 2H (D, 2H, J = 11.3 Hz), 4.05 (t, 2H, J = 6.1 Hz), 7.50 (d, 2H, J = 8.1 Hz), 7.79 (d, 2H, J = 8.3 Hz) MS (ESI): m / z 383 [M + Na] & lt; + & gt ; .
Reference Example 2: Preparation of the starting material 4- (2-iodoethyl) piperidine-1-carboxylate (Formula VIb)
To a 50 mL reaction flask was added 5 g (13.0 mmol) of tert-butyl 4- [2- (p-toluenesulfonyloxy) ethyl] piperidine-1-carboxylate (Formula VIa), 35 mL of acetone and 2.9 g (19.3 mmol The organic phase was washed with 50 mL of water. The organic phase was collected and the aqueous phase was extracted again with 50 mL of ethyl acetate. The organic phase was washed with 50 mL of water and extracted with 50 mL of water and 50 mL of water. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness to give 3.5 g of compound VIb in a yield of 79.5%. 1 H NMR (DMSO-d 6 ): δ 0.97-1.07 (m, 2H), 1.41 (s, 9H), 1.51-1.58 (m, 1H), 1.63-1.66 (m, 2H), 1.73-1.78 (m, 2H), 2.69 (br s, 2H), 3.31 (t, 2H, J = 7.3Hz), 3.96 (d, 2H, J = 10.3Hz); MS (ESI): m / + H] + .
Example 1: Preparation of 6-bromo-1,3-benzodioxole-5-carboxylic acid (Compound II)
To the 2L reaction flask, 100 g (0.60 mol) of piperine, 29 g (0.725 mol) of sodium hydroxide and 1 L of water were successively added, and 150 g (0.84 mol) of N-bromosuccinimide was added thereto, After the reaction was carried out for 45 min, the reaction was monitored by TLC. The reaction solution was concentrated dropwise with concentrated hydrochloric acid to adjust the pH of the reaction solution to 2 to 3, and the solid was precipitated. The ice was cooled, filtered and washed with water to obtain 117.4 g of compound II (HPLC purity: 82%), Yield 79.5%. 1 H NMR (DMSO-d 6 ): δ 6.15 (s, 2H), 7.30 (s, 1H), 7.32 (s, 1H), 13.17 (s, 1H).
Example 2: Preparation of 6-bromo-1,3-benzodioxole-5-carboxylic acid (Compound II)
To the 2L reaction flask, 100 g (0.60 mol) of piperine, 29 g (0.725 mol) of sodium hydroxide and 1 L of water were successively added, and 150 g (0.84 mol) of N-bromosuccinimide was added thereto, After the reaction was complete for 45 min, the reaction was monitored by TLC. After 1 L of ethyl acetate and 40 mL of concentrated hydrochloric acid were added, the mixture was stirred for 20 min. The organic phase was collected, concentrated to dryness, 200 mL of water and 600 mL of petroleum ether, stirred for 1 h, , And 116 g of compound II (HPLC purity: 92.0%) was dried to a yield of 78.9%. & Lt; 1 & gt ; H NMR data with Example 1.
Example 3: Preparation of ethyl 6-bromo-1,3-benzodioxole-5-carboxylate (Compound IIIa)
To a 2 L reaction flask was added 117.3 g (0.39 mol) of 6-bromo-1,3-benzodioxole-5-carboxylic acid (II), 585 mL of absolute ethanol, opened with a stirrer, (1.4mol) concentrated sulfuric acid, heating reflux reaction 6h, TLC monitoring reaction is completed. Water was added dropwise, and 1.2 L of water was added dropwise to remove the solid, filtered and washed with water, and dried at 35 to 45C to obtain 124.0 g of compound IIIa (HPLC purity: 85%) in a yield of 93.9%. . 1 H NMR (CDCl3 . 3 ): [delta] 1.39 (T, 3H, J = 7.1Hz), 4.34 (Q, 2H, J = 7.1Hz), 6.04 (S, 2H), 7.07 (S, IH), 7.31 ( s, 1H).
Example 4: Preparation of methyl 6-bromo-1,3-benzodioxole-5-carboxylate (Compound IIIb)
To a 1 L reaction flask was added 50 g (0.30 mol) of 6-bromo-1,3-benzodioxole-5-carboxylic acid (II), 500 mL of anhydrous methanol, opened with a stirrer, 33.3 mL (0.60 mol) of concentrated sulfuric acid was added dropwise and heated under reflux for 6 h. TLC test reaction is completed, ice water cooling, precipitation of solids, dropping 500mL of water, filtration, water washing filter cake, 45 ~ 55 ℃ drying 44.4 g compound IIIb, yield: 84.0%. 1 H NMR (DMSO-d 6 ): δ 3.83 (s, 3H), 6.19 (s, 2H), 7.35 (s, 1H), 7.36 (s, 1H).
Example 5: Preparation of 6-cyano-1,3-benzodioxole-5-carboxylate (Compound IVa)
To a 2 L reaction flask was charged 124 g (0.38 mol) of ethyl 6-bromo-1,3-benzodioxole-5-carboxylate (IIIa), 990 mL of N, N-dimethylformamide, After opening the stirrer, 33.1 g (0.09 mol) of potassium ferrocyanide and 103.3 g (0.54 mol) of cuprous iodide were added, heated to 120-140C for 5 h, and the TLC reaction was completed. Cooling, dropping water to precipitate a solid, filtering, and washing the filter cake. The filter cake was stirred in 1.9 L of dichloromethane for 30 min, filtered, the filtrate was added with 9 g of activated charcoal, decolorized for 30 min, filtered and the filtrate was concentrated to a small amount. The solid was precipitated, n-hexane was added dropwise, cooled with ice water, filtered and dried to give 82.8 g of compound IVa (HPLC purity: 99.5%), yield: 83.2%. . 1 H NMR (DMSO-D . 6 ): [delta] 1.34 (T, 3H, J = 7.1Hz), 4.33 (Q, 2H, J = 7.1Hz), 6.29 (S, 2H), 7.51 (S, IH), 7.57 (s, 1H).
Example 6: Preparation of 6-cyano-1,3-benzodioxole-5-carboxylate (Compound IVa)
To a 50 mL reaction flask was added 3.5 g (12.8 mmol) of ethyl 6-bromo-1,3-benzodioxole-5-carboxylate (IIIa), 35 mL of N, N-dimethylformamide , 2.3g (25.7mmol) cuprous cyanide, open stirring, 120 ~ 140 ℃ reaction 30 ~ 60min, TLC detection reaction is completed, cooling, dropping 30mL saturated ammonium chloride aqueous solution, precipitate solid, filter, water washing cake. The filter cake was dissolved in 200 mL of ethyl acetate and washed with saturated aqueous ammonium chloride (30 ml x 2 times). The organic phase was collected and the aqueous phase was extracted again with 100 ml of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and filtered , And concentrated to give 2.0 g of compound IVa in a yield of 62.5%. & Lt; 1 & gt ; H NMR data with Example 5.
Example 7: Preparation of 6-cyano-1,3-benzodioxole-5-carboxylate (Compound IVb)
To a 1 L reaction flask was added 40 g (0.15 mol) of methyl 6-bromo-1,3-benzodioxole-5-carboxylate (IIIb), 11.4 g (31.0 mmol) of potassium ferrocyanide , 35.2 g (0.18 mol) of cuprous iodide, 240 mL of N, N-dimethylacetamide, 120 to 140 ° C in an oil bath for 2 to 3 hours, and the TLC reaction was completed. After cooling, 480 mL of water was added dropwise, Ice water cooling, filtration, water washing filter cake. Filter cake was dissolved in 500mL ethyl acetate and 200mL tetrahydrofuran mixture, heated to 80 ℃, adding 2g activated carbon, filtered, the filtrate was concentrated to a small amount, precipitation of solid, dropping 200mL petroleum ether, ice water cooling, filtration, petroleum ether washing filter The cake was dried to give 27.7 g of compound IVb in a yield of 87.6%. 1 H NMR (DMSO-d 6 ): δ 3.87 (s, 3H), 6.28 (s, 2H), 7.49 (s, 1H), 7.55 (s, 1H).
Example 8: Preparation of Spiro [6H- [1,3] dioxolo [4,5-f] isoindole-7,1′-cyclopropane] -5-one (Compound V)
To a 2 L reaction flask was added 16 g (0.072 mol) of compound of formula IVa, 160 mL of dichloromethane, stirred and dissolved under nitrogen. 24 mL (0.080 mol) of isopropyl tetrafis (4) isopropyl ether was added and cooled to 0 to 20 ° C A solution of 73 mL (0.22 mol) of ethylmagnesium bromide in diethyl ether (3M) was added and the reaction was complete after TLC. Slowly drop the water / tetrahydrofuran solution (64 mL water / 240 mL tetrahydrofuran), heat to 50 ° C, decalcinate with 2 g of activated charcoal and stir for 20 min. Filtration, ethyl acetate washing filter residue, the filtrate 40 ~ 50 ° C concentrated under reduced pressure, add 96mL ethyl acetate and 96mL water, stirring solid precipitation, dropping 290mL n-hexane, ice water cooling, filtration, n-hexane washing cake, Dried to give 11.9 g of compound V (HPLC purity: 70%) in a yield of 80.2%. 1 H NMR (DMSO-d 6 ): δ 1.33-1.41 (m, 4H), 6.11 (s, 2H), 6.86 (s, 1H), 7.09 (s, 1H), 8.53 (s, 1H).
Example 9: Preparation of Spiro [6H- [1,3] dioxolo [4,5-f] isoindole-7,1′-cyclopropane] -5-one (Compound V)
To a 500 mL reaction flask was added 10 g (48.8 mmol) of 6-cyano-1,3-benzodioxole-5-carboxylate (IVb), 200 mL of methyl tert-butyl ether, (50.7 mmol) of (IV) isopropyl ester was cooled to 0 to 20 ° C, and 49 mL (0.15 mol) of ethyl magnesium bromide in diethyl ether (3M) was slowly added dropwise. After completion of the drop, the TLC reaction was completed. (10 mL x 2 times), the organic phase was collected and the aqueous phase was extracted again with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the activated charcoal was dried over 100 mL of ethyl acetate and extracted with 250 mL of ethyl acetate. Decolorization, filtration, the filtrate was concentrated to a small amount, dropping petroleum ether, ice water cooling, filtration, petroleum ether washing cake, drying 2.3g compound V, yield: 23.2%. & Lt; 1 & gt ; H NMR data with Example 8.
Example 10: 4- [2- (5-oxospiro [[1,3] dioxolo [4,5-f] isoindole-7,1′-cyclopropane] -6 Yl) ethyl] piperidine-1-carboxylate (Compound VIIa)
To a 250 mL reaction flask was added 11.9 g (0.041 mol) of compound of formula V, 84 mL of dimethylsulfoxide, 4 g (0.071 mol) of potassium hydroxide, 27.3 g (0.06 mol) of 4- [2- (p-toluenesulfonyloxy ) Ethyl] piperidine-1-carboxylate (Formula VIa), heated to 55-65 ° C for 3 to 4 hours, and the TLC reaction was completed. (150 mL x 2 times), the aqueous phase was extracted again with 200 mL of ethyl acetate, the organic phase was combined, and 3 g of activated charcoal was added to decolorize, stirred for 30 min, filtered, and the mixture was washed with 300 mL of ethyl acetate. The filtrate was concentrated to dryness under reduced pressure to give compound VIIa. 1 H NMR (CDCl 3 ): δ 1.08-1.19 (m, 2H), 1.28 (dd, 2H, J = 6.2, 7.4 Hz), 1.45 (s, 9H), 1.48-1.57 (m, 5H) (d, 2H, J = 12.7 Hz), 2.69 (t, 2H, J = 11.6 Hz), 3.20 (t, 2H, J = 7.6 Hz), 4.07 (d, 2H, J = 13.1 Hz) , 2H), 6.43 (S, IH), 7.23 (S, IH); the MS (ESI): m / Z 437 [m + of Na] + .
Example 11: 4- [2- (5-oxospiro [[1,3] dioxolo [4,5-f] isoindole-7,1′-cyclopropane] -6 Yl) ethyl] piperidine-1-carboxylate (Compound VIIa)
To a 250 mL reaction flask, 6.7 g (33.0 mmol) of compound of formula V, 100 mL of N, N-dimethylformamide, 2.6 g (65.0 mmol) of sodium hydroxide, 14 g (41.3 mmol) of 4- (2-iodoethyl ) Piperidine-1-carboxylic acid tert-butyl ester (VIb), 25-30 ° C for 1.5 h, TLC detection reaction was completed, 100 mL of water and 100 mL of ethyl acetate were added and the organic phase was washed with water (50 mL x 2 times) The organic phase was collected and the aqueous phase was extracted again with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness to give compound VIIa. & Lt; 1 & gt ; H NMR data with Example 10.
Example 12: 6- [2- (4-Piperidine) ethyl] spiro [[l, 3] dioxolo [4,5-f] isoindole- Propane] -5-one hydrochloride (Compound VIIIa)
To a 100 mL reaction flask was added the compound of formula VIIa obtained in Example 10, 30 mL of ethanol, 45 mL of ethyl acetate, 10.5 mL of concentrated hydrochloric acid. Open the stirrer, 50 ~ 60 ℃ reaction 3h, TLC detection reaction is completed, stop heating, ice water cooling, filtration, ethyl acetate detergent cake, drying, 8.5g off-white solid (compound VIIIa, HPLC purity: 97%) The Yield: 41.4% (calculated based on the amount of compound V in Example 10). 1 H NMR (D 2 O): δ 1.06 (t, 2H, J = 6.7Hz), 1.32-1.46 (m, 6H), 1.60 (m, 1H), 1.91 (d, 2H, J = 13.5Hz) (M, 4H), 3.39 (d, 2H, J = 12.8 Hz), 5.90 (s, 2H), 6.18 (s, 1H), 6.68 (s, 1H); MS (ESI): m / z 315 [M-Cl] + .
Example 13: 6- [2- [1- (2-Pyridylmethyl) -4-piperidinyl] ethyl] spiro [[1,3] dioxolo [4,5-f ] Isoindole-7,1′-cyclopropane] -5-one (Compound XI)
A solution of 128.6 g (0.35 mol) of the compound of formula VIIIa, 90 g (0.54 mol) of 2-chloromethylpyridine hydrochloride (formula IXa), 965 mL of water, 26 g of activated carbon and 60 to 65C for 30 minutes were charged into a 2 L reaction flask, , And the residue was washed with 643 ml of water and 215 mL of ethanol. The solution was slowly added with 161 g (1.16 mol) of potassium carbonate. The reaction was carried out at 55 to 65 ° C for 4 to 5 hours. After completion of the TLC reaction, the reaction was cooled, filtered and dried to obtain 137 g of crude The crude product was dissolved in 1.37L ethanol and dissolved at 60-65 ° C. After decontamination with activated charcoal (27.4 g / times x 2 times), 4.11 L of water was added dropwise with stirring, the solid was precipitated, the ice was cooled, filtered, And dried to give 118.9 g of compound XI in 80% yield. 1 H NMR (CDCl 3 ): δ 1.26 (dd, 2H, J = 6.1, 7.6 Hz), 1.35 (br s, 3H), 1.49-1.57 (m, 4H), 1.72 (d, 2H, J = 8.6 (T, 2H, J = 7.9 Hz), 3.64 (s, 2H), 6.03 (s, & lt; RTI ID = 0.0 & gt; 2H), 6.42 (s, 1H), 7.15 (dd, 1H, J = 5.2, 6.7 Hz), 7.24 (s, 1H), 7.41 (d, 1H, J = 7.7 Hz), 7.64 (td, 7.6, 1.8 Hz =), 8.55 (D, IH, J = 4.2Hz); the MS (ESI): m / Z 406 [m + H] + .
Example 14: 6- [2- [1- (2-Pyridylmethyl) -4-piperidinyl] ethyl] spiro [[1,3] dioxolo [4,5-f ] Isoindole-7,1′-cyclopropane] -5-one phosphate (Compound I)
To a 50 mL reaction flask was added 2 g (4.9 mmol) of the compound of formula XI, 40 mL of ethanol, dissolved at 60-70 ° C and 0.57 g of 85% (4.9 mmol) of phosphoric acid was added with stirring. The solid was precipitated, 40 mL of ethyl acetate was added dropwise, To room temperature, stirred for 1 hour, filtered, a small amount of ethyl acetate to wash the filter cake, and dried to obtain 2.3 g of a white solid (Compound I, HPLC purity: 99.8%). Yield: 92.7%. 1 H NMR (D 2 O): δ 1.10 (t, 2H, J = 7.2Hz), 1.33-1.64 (m, 7H), 1.92 (d, 2H, J = 13.4Hz), 2.95-3.09 (m, 4H), 3.46 (d, 2H, J = 10.7 Hz), 4.34 (s, 2H), 5.89 (s, 2H), 6.20 (s, 1H), 6.69 (s, 1H), 7.45 (dd, 1H, J = 7.5, 7.4 Hz), 7.53 (d, 1H, J = 7.8 Hz), 7.88 (td, 1H, J = 7.7, 1.2 Hz), 8.54 (d, 1H, J = 4.6 Hz)
Multifunctional compound AD-35 improves cognitive impairment and attenuates the production of TNF-alpha and IL-1beta in an alphabeta25-35-induced rat model of alzheimer’s disease
J Alzheimer’s Dis 2017, 56(4): 1403
CN101626688A * Dec 11, 2007 Jan 13, 2010 雷维瓦药品公司 Compositions, synthesis, and methods of using indanone based cholinesterase inhibitors
WO2014005421A1 * Jul 3, 2013 Jan 9, 2014 Zhejiang Hisun Pharmaceutical Co., Ltd. Benzodioxole derivative and preparation method and use thereof
////////////Alzheimers disease, Zhejiang Hisun Pharmaceutical, AD 35, PHASE1, IND-120499
O=C5N(CCC2CCN(Cc1ccccn1)CC2)C3(CC3)c4cc6OCOc6cc45

BMS 986205


ChemSpider 2D Image | BMS 986205 | C24H24ClFN2Oimg

BMS 986205

(2R)-N-(4-Chlorophenyl)-2-[cis-4-(6-fluoro-4-quinolinyl)cyclohexyl]propanamide
Cyclohexaneacetamide, N-(4-chlorophenyl)-4-(6-fluoro-4-quinolinyl)-α-methyl-, cis-
Cyclohexaneacetamide, N-(4-chlorophenyl)-4-(6-fluoro-4-quinolinyl)-α-methyl-, cis-(αR)-
(i?)-N-(4-chlorophenyl)-2- c 5-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide

CAS: 1923833-60-6

Phase 1 cancer

BMS-986205, ONO-7701,  F- 001287

  • Molecular Formula C24H24ClFN2O
  • Average mass 410.912 Da
  • Originator Bristol-Myers Squibb
  • Class Antineoplastics
  • 01 Feb 2016 Phase-I/II clinical trials in Cancer (Combination therapy, Late-stage disease, Second-line therapy or greater) in Canada (PO) (NCT02658890)
  • 31 Jan 2016 Preclinical trials in Cancer in USA (PO) before January 2016
  • 01 Jan 2016 Bristol-Myers Squibb plans a phase I/IIa trial for Cancer (Late-stage disease, Combination therapy, Second-line therapy or greater) in USA, Australia and Canada (PO) (NCT02658890)
Inventors Hilary Plake Beck, Juan Carlos Jaen, Maksim OSIPOV, Jay Patrick POWERS, Maureen Kay REILLY, Hunter Paul SHUNATONA, James Ross WALKER, Mikhail ZIBINSKY, James Aaron Balog, David K Williams, Jay A MARKWALDER, Emily Charlotte CHERNEY, Weifang Shan, Audris Huang
Applicant Flexus Biosciences, Inc.

Hilary Beck

Hilary Beck

FLX Bio, Inc.EX Principal Investigator, Company NameFLX Bio, Inc., 

CURRENTLY Director, Medicinal Chemistry at IDEAYA Biosciences, IDEAYA Biosciences, The University of Texas at Austin

Image result for Flexus Biosciences, Inc.

Brian Wong

Brian Wong

Chief Executive Officer at FLX Bio, Inc.

Bristol-Myers Squibb, following its acquisition of Flexus Biosciences, is developing BMS-986205 (previously F- 001287), the lead from an immunotherapy program of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors for the potential treatment of cancer. In February 2016, a phase I/IIa trial was initiated .

BMS-986205 (ONO-7701) is being evaluated at Bristol-Myers Squibb in phase I/II clinical trials for the oral treatment of adult patients with advanced cancers in combination with nivolumab. Early clinical development is also ongoing at Ono in Japan for the treatment of hematologic cancer and for the treatment of solid tumors.

In April 2017, data from the trial were presented at the 108th AACR Annual Meeting in Washington DC. As of February 2017, the MTD had not been reached, but BMS-986205 plus nivolumab treatment was well tolerated, with only two patients discontinuing treatment due to DLTs. The most commonly reported treatment-related adverse events (TRAEs) were decreased appetite, fatigue, nausea, diarrhea, and vomiting. Grade 3 TRAEs were reported in three patients during the combination therapy; however, no grade 3 events were reported during BMS-986205 monotherapy lead-in. No grade 4 or 5 TRAEs were reported with BMS-986205 alone or in combination with nivolumab

Indoleamine 2,3-dioxygenase (IDO; also known as IDOl) is an IFN-γ target gene that plays a role in immunomodulation. IDO is an oxidoreductase and one of two enzymes that catalyze the first and rate-limiting step in the conversion of tryptophan to N-formyl-kynurenine. It exists as a 41kD monomer that is found in several cell populations, including immune cells, endothelial cells, and fibroblasts. IDO is relatively well-conserved between species, with mouse and human sharing 63% sequence identity at the amino acid level. Data derived from its crystal structure and site-directed mutagenesis show that both substrate binding and the relationship between the substrate and iron-bound dioxygenase are necessary for activity. A homolog to IDO (ID02) has been identified that shares 44% amino acid sequence homology with IDO, but its function is largely distinct from that of IDO. (See, e.g., Serafini P, et al, Semin. Cancer Biol, 16(l):53-65 (Feb. 2006) and Ball, H.J. et al, Gene, 396(1):203-213 (Jul. 2007)).

IDO plays a major role in immune regulation, and its immunosuppressive function manifests in several manners. Importantly, IDO regulates immunity at the T cell level, and a nexus exists between IDO and cytokine production. In addition, tumors frequently manipulate immune function by upregulation of IDO. Thus, modulation of IDO can have a therapeutic impact on a number of diseases, disorders and conditions.

A pathophysiological link exists between IDO and cancer. Disruption of immune homeostasis is intimately involved with tumor growth and progression, and the production of IDO in the tumor microenvironment appears to aid in tumor growth and metastasis. Moreover, increased levels of IDO activity are associated with a variety of different tumors (Brandacher, G. et al, Clin. Cancer Res., 12(4): 1144-1151 (Feb. 15, 2006)).

Treatment of cancer commonly entails surgical resection followed by chemotherapy and radiotherapy. The standard treatment regimens show highly variable degrees of long-term success because of the ability of tumor cells to essentially escape by regenerating primary tumor growth and, often more importantly, seeding distant metastasis. Recent advances in the treatment of cancer and cancer-related diseases, disorders and conditions comprise the use of combination therapy incorporating immunotherapy with more traditional chemotherapy and radiotherapy. Under most scenarios, immunotherapy is associated with less toxicity than traditional chemotherapy because it utilizes the patient’s own immune system to identify and eliminate tumor cells.

In addition to cancer, IDO has been implicated in, among other conditions, immunosuppression, chronic infections, and autoimmune diseases or disorders (e.g. , rheumatoid arthritis). Thus, suppression of tryptophan degradation by inhibition of IDO activity has tremendous therapeutic value. Moreover, inhibitors of IDO can be used to enhance T cell activation when the T cells are suppressed by pregnancy, malignancy, or a virus (e.g., HIV). Although their roles are not as well defined, IDO inhibitors may also find use in the treatment of patients with neurological or neuropsychiatric diseases or disorders (e.g., depression).

Small molecule inhibitors of IDO have been developed to treat or prevent IDO-related diseases. For example, the IDO inhibitors 1-methyl-DL-tryptophan; p-(3-benzofuranyl)-DL-alanine; p-[3-benzo(b)thienyl]-DL-alanine; and 6-nitro-L-tryptophan have been used to modulate T cell-mediated immunity by altering local extracellular concentrations of tryptophan and tryptophan metabolites (WO 99/29310). Compounds having IDO inhibitory activity are further reported in WO 2004/094409.

In view of the role played by indoleamine 2,3-dioxygenase in a diverse array of diseases, disorders and conditions, and the limitations (e.g., efficacy) of current IDO inhibitors, new IDO modulators, and compositions and methods associated therewith, are needed.

In April 2017, preclinical data were presented at the 108th AACR Annual Meeting in Washington DC. BMS-986205 inhibited kynurenine production with IC50 values of 1.7, 1.1 and > 2000 and 4.6, 6.3 and > 2000 nM in human (HeLa, HEK293 expressing human IDO-1 and tryptophan-2, 3-dioxygenase cell-based assays) and rat (M109, HEK293 expressing mouse ID0-1 and -2 cell-based assays) respectively. In human SKOV-3 xenografts (serum and tumor) AUC (0 to 24h; pharmacokinetic and pharmacodynamic [PK and PD])) was 0.8, 4.2 and 23 and 3.5, 11 and 40 microM h, respectively; area under the effect curve (PK and PD) was 39, 32 and 41 and 60, 63 and 76% kyn, at BMS-986205 (5, 25 and 125 mg/kg, qd×5), respectively

In April 2017, preclinical data were presented at the 253rd ACS National Meeting and Exhibition in San Francisco, CA. BMS-986205 showed potent and selective inhibition of IDO-1 enzyme (IC50 = 1.7nM) and potent growth inhibition in cellular assays (IC50 = 3.4 nM) in SKOV3 cells. A good pharmacokinetic profile was seen at oral and iv doses in rats, dogs and monkeys. The compound showed good oral exposure and efficacy in in vivo assays

Preclinical studies were performed to evaluate the activity of BMS-986205, a potent and selective optimized indoleamine 2, 3-dioxygenase (IDO)- 1inhibitor, for the treatment of cancer. BMS-986205 inhibited kynurenine production with IC50 values of 1.7, 1.1 and > 2000 and 4.6, 6.3 and > 2000 nM in human (HeLa, HEK293 expressing human IDO-1 and tryptophan-2, 3-dioxygenase cell-based assays) and rat (M109, HEK293 expressing mouse ID0-1 and -2 cell-based assays) respectively. BMS-986205 was also found to be potent when compared with IDO-1from other species (human < dog equivalent monkey equivalent mouse > rat). In cell-free systems, incubation of inhibitor lead to loss of heme absorbance of IDO-1 which was observed in the presence of BMS-986205 (10 microM), while did not observed with epacadostat (10 microM). The check inhibitory activity and check reversibility (24 h after compound removal) of BMS-986205 was found to be < 1 and 18% in M109 (mouse) and < 1 and 12% SKOV3 (human) cells, respectively. In human whole blood IDO-1, human DC mixed lymphocyte reaction and human T cells cocultured with SKOV3 cells- cell based assays, BMS-986205 showed potent cellular effects (inhibition of kynurenine and T-cell proliferation 3H-thymidine) with IC50 values of 2 to 42 (median 9.4 months), 1 to 7 and 15 nM, respectively. In human SKOV-3 xenografts (serum and tumor) AUC (0 to 24h; pharmacokinetic and pharmacodynamic [PK and PD])) was 0.8, 4.2 and 23 and 3.5, 11 and 40 microM h, respectively; area under the effect curve (PK and PD) was 39, 32 and 41 and 60, 63 and 76% kyn, at BMS-986205 (5, 25 and 125 mg/kg, qd×5), respectively. In vivo human-SKOV3 and hWB-xenografts, IC50 values of BMS-986205 were 3.4 and 9.4 NM, respectively. The ADME of BMS-986205 at parameters iv/po dose was 0.5/2, 0.5/1.5 and 0.5/1.2 mg/kg, respectively; iv/clearance was 27, 25 and 19 ml, min/kg, respectively; iv Vss was 3.8, 5.7 and 4.1 l/kg, respectively; t1/2 (iv) was 3.9, 4.7 and 6.6 h, respectively; fraction (po) was 64, 39 and 10%, respectively. At the time of presentation, BMS-986205 was being evaluated in combination with nivolumab.

The chemical structure and preclinical profile was presented for BMS-986205 ((2R)-N-(4-Chlorophenyl)-2-[cis-4-(6-fluoroquinolin-4-yl)cyclohexyl]propanamide), a potent IDO-1 inhibitor in phase I for the treatment of cancer. This compound showed potent and selective inhibition of IDO-1 enzyme (IC50 = 1.7nM) and potent growth inhibition in cellular assays (IC50 = 3.4 nM) in SKOV3 cells. The pharmacokinetic profile in rats dosed at 0.5 mg/kg iv and 2 mg/kg po, with clearance, Vss, half-life and bioavailability of 27 ml/min/kg, 3.8 l/kg, 3.9 h and 4%, respectively; in dogs at 0.5 iv and 1.5 po mg/kg dosing results were 25 ml/min/kg, 5.7 l/kg, 4.7 h and 39%; and, in cynomolgus monkeys with the same doses as dogs results were 19 ml/min/kg, 4.1 l/kg, 6.6 h and 10%, respectively. The compound showed good oral exposure and efficacy in in vivo assays.

BMS-986158: a BET inhibitor for cancerAshvinikumar Gavai of Bristol Myers Squibb (BMS) gave an overview of his company’s research into Bromodomian and extra-terminal domain (BET) as oncology target for transcriptional suppression of key oncogenes, such as MYC and BCL2. BET inhibition has been defined as strong rational strategy for the treatment of hematologic malignancies and solid tumors. From crystal-structure guided SAR studies, BMS-986158, 2-{3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol, was chosen as a potent BET inhibitor, showing IC50 values for BRD2, BRD3 and BRD4 activity of 1 nM; it also inhibited Myc oncogene (IC50 = 0.5 nM) and induced chlorogenic cancer cell death. In vitro the compound also displayed significant cytotoxicity against cancer cells.  When administered at 0.25, 0.5 and 1 mg/kg po, qd to mice bearing human lung H187 SCLC cancer xenograft, BMS-986158 was robust and showed efficacy as a anticancer agent at low doses. In metabolic studies, it showed t1/2 of 36, 40 and 24 min in human, rat and mice, respectively, and it gave an efflux ratio of 3 in Caco-2 permeability assay. In phase 1/II studies, BMS-986158 was well tolerated at efficacious doses and regimens, and drug tolerable toxicity at efficacy doses and regimens. Selective Itk inhibitors for inflammatory disordersThe development of highly selective Itk inhibitors for the treatment of diseases related to T-cell function, such as inflammatory disorders, was described by Shigeyuki Takai (Ono Pharmaceutical). Inhibitory properties of a hit compound, ONO-8810443, were modified via X-ray structure and Molecular Dynamics stimulation to get ONO-212049 with significant kinase selectivity (140-fold) against Lck, a tyrosine kinase operating upstream of Itk in the TCR cascade. Further modifications identified final lead compound ONO-7790500 (N-[6-[3-amino-6-[2-(3-methoxyazetidin-1-yl)pyridin-4-yl]pyrazin-2-yl]pyridin-3-yl]-1-(3-methoxyphenyl)-2,3-dimethyl-5-oxopyrazole-4-carboxamide), which selectively inhibited Itk (IC50 = < 0.004 microM) over Lck (IC50 = 9.1 microM; SI 2000-fold) and suppressed Jurkat T-cell proliferation (IC50 = 0.014 microM). This compound suppressed alphaCD3/CDP28 CD4+T-cell stimulation (IC50 = 0.074 microM) with selectivity over PMA/Ionomycin (IC50 = > 10 microM). ONO-7790500 also exhibited in vivo IL-2 inhibitory properties (62% inhibition at 30 mg/kg po) in mice. In pharmacokinetic studies in balb/c mice, the compound administered orally (10 mg/kg) showed a Cmax of 1420 ng/ml, AUClast of 11,700 ng*h/ml, t1/2 of 5.3 h and oral bioavailability of 68%. Administration iv at 0.3 mg/kg gave an AUC last of 610 ng*h/ml, t1/2 of 3.8 h, Vss of 1260 ml/kg and Cl of 5.1 ml/min/kg. ADMET data showed ONO-7790500 did not have relevant activity in cytochromes and hERG channels (IC50 > 10 microM) in toxicological studies, and gave a PAMPA value of 5.0 x 10(-6) cm/s. Fused imidazole and pyrazole derivatives as TGF-beta inhibitorsDual growth and differentiation factor-8 (GDF-8; also known as myostatin) and TGF-beta inhibitors were described. Both targets belong to TGF-beta superfamily consisting of a large group of structurally related cell regulatory proteins involved in fundamental biological and pathological processes, such as cell proliferation or immunomodulation. Myostatin (GDF8) is a negative regulator negative regulator of skeletal muscle growth and has also been related to bone metabolism. Investigators at Rigel Pharmaceuticals found that compounds designed to be GDF-8 inhibitors were able to inhibit TGF-beta as well, this could be an advantage for the treatment of diseases associated with muscle and adipose tissue disorders, as well as potentially immunosuppressive disorders. Jiaxin Yu from the company described  new fused imidazole derivatives, of which the best compound was 6-[2-(2,4,5-Trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl]quinoxaline. This compound was very potent at TGF-beta Receptor Type-1 (ALK5) inhibition with an IC50 value of 1nM. In an in vivo mouse assay this compound showed good activity at 59.7 mg/kg, po, and good plasma exposure; inhibition of GDF-8 and TGFbeta growth factors was 90 and 81.6 %, respectively.Rigel’s Ihab Darwish described a series of fused pyrazole derivatives, with the best compound being 6-[2-(2,4-Difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl][1,2,4]triazolo[1,5-a]pyridine. This compound showed an IC50 of 0.06 and 0.23 microM for GDF-8 and TGFbeta, respectively, in the pSMAD (MPC-11) signaling inhibition test. The compound had a good pharmacokinetic profile, with 40% of bioavailability in mice after a 5-mg/kg po dose. An iv dose of 1 mg/kg showed t1/2 of 0.7 h and Vss of 1.0 l/h/kgDiscovery of selective inhibitor of IDO BMS-986205 for cancerIndoleamine-2,3-dioxygenase (IDO)-1 enzyme initiates and regulates the first step of the kynurenine pathway (KP) of tryptophan metabolism, and evidence has shown that overexpression of IDO-1 in cancer tumors is a crucial mechanism facilitating tumor immune evasion and persistence. The chemical structure and preclinical profile of BMS-986205 was presented by Aaron Balog from BMS. BMS-986205 ((2R)-N-(4-Chlorophenyl)-2-[cis-4-(6-fluoroquinolin-4-yl)cyclohexyl]propanamide),  is a potent IDO-1 inhibitor in phase I for the treatment of cancer. This compound showed potent and selective inhibition of IDO-1 enzyme (IC50 = 1.7nM) and potent growth inhibition in cellular assays (IC50 = 3.4 nM) in SKOV3 cells. The pharmacokinetic profile in rats dosed at 0.5 mg/kg iv and 2 mg/kg po, with clearance, Vss, half-life and bioavailability of 27 ml/min/kg, 3.8 l/kg, 3.9 h and 4%, respectively; in dogs at 0.5 iv and 1.5 po mg/kg dosing results were 25 ml/min/kg, 5.7 l/kg, 4.7 h and 39%; and, in cynomolgus monkeys with the same doses as dogs results were 19 ml/min/kg, 4.1 l/kg, 6.6 h and 10%, respectively. The compound showed good oral exposure and efficacy in in vivo assays.Three further reports have been published from this meeting .The website for this meeting can be found at https://www.acs.org/content/acs/en/meetings/spring-2017.html.

SYNTHESIS

1 Wittig  NaH

2 REDUCTION H2, Pd, AcOEt, 4 h, rt, 50 psi

3 Hydrolysis HCl, H2O, Me2CO, 2 h, reflux

4  4-Me-2,6-(t-Bu)2-Py, CH2Cl2, overnight, rt

5 SUZUKI AcOK, 72287-26-4, Dioxane, 16 h, 80°C

6  Heck Reaction,  Suzuki Coupling, Hydrogenolysis of Carboxylic Esters, Reduction of Bonds, HYDROGEN

7 Et3N, THF, rt – -78°C , Pivaloyl chloride, 15 min, -78°C; 1 h, 0°C ,THF, 0°C – -78°C, BuLi, Me(CH2)4Me, 15 min, -78°C, R:(Me3Si)2NH •Na, THF, 10 min, -50°C , HYDROLYSIS,  (PrP(=O)O)3, C5H5N, AcOEt, 5 min, rt

Patent

WO2016073770

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=289DBE79BEFC6ADC558C89E7A74B19DB.wapp2nB?docId=WO2016073770&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example 19

(i?)-N-(4-chlorophenyl)-2- c 5-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide

Example 19 : (i?)-N-(4-chlorophenyl)-2-(cz5-4-(6-fluoroquinolin-4- yl)cyclohexyl)propanamide

[0277] Prepared using General Procedures K, B, E, L, M, N, and O. General Procedure L employed 2-(4-(6-fluoroquinolin-4-yl)-cyclohexyl)acetic acid (mixture of

diastereomers), and ( ?)-2-phenyl-oxazolidinone. General Procedure M employed the cis product and iodomethane. The auxiliary was removed following General Procedure N and the desired product formed employing General Procedure O with 4-chloroaniline.

Purified using silica gel chromatography (0% to 100% ethyl acetate in hexanes) to afford Example 19. 1H NMR of czs-isomer (400 MHz; CDC13): δ 9.14 (s, 1H), 8.70 (d, J= 4.6 Hz, 1H), 8.06 (dd, J= 9.2 Hz, J= 5.6 Hz, 1H), 7.58-7.64 (m, 3H), 7.45 (ddd, J= 9.3 Hz, J= 7.8 Hz, J= 2.7 Hz, 1H), 7.19-7.24 (m, 2H), 7.15 (d, J= 4.6Hz, 1H), 3.16-3.26 (m, 1H), 2.59-2.69 (m, 1H), 2.08-2.16 (m, 1H), 1.66-1.86 (m, 7H), 1.31-1.42 (m, 1H), 1.21 (d, J= 6.8Hz, 3H) ppm. m/z 411.2 (M+H)+.

REFERENCES

23-Feb-2015
Bristol-Myers Squibb To Expand Its Immuno-Oncology Pipeline with Agreement to Acquire Flexus Biosciences, Inc
Bristol-Myers Squibb Co; Flexus Biosciences Inc

17-Dec-2014
Flexus Biosciences, a Cancer Immunotherapy Company Focused on Agents for the Reversal of Tumor Immunosuppression (ARTIS), Announces $38M Financing
Flexus Biosciences Inc

2015106thApril 21Abs 4290
Potent and selective next generation inhibitors of indoleamine-2,3-dioxygenase (IDO1) for the treatment of cancer
American Association for Cancer Research Annual Meeting
Jay P. Powers, Matthew J. Walters, Rajkumar Noubade, Stephen W. Young, Lisa Marshall, Jan Melom, Adam Park, Nick Shah, Pia Bjork, Jordan S. Fridman, Hilary P. Beck, David Chian, Jenny V. McKinnell, Maksim Osipov, Maureen K. Reilly, Hunter P. Shunatona, James R. Walker, Mikhail Zibinsky, Juan C. Jaen

2017108thApril 04Abs 4964
Structure, in vitro biology and in vivo pharmacodynamic characterization of a novel clinical IDO1 inhibitor
American Association for Cancer Research Annual Meeting
John T Hunt, Aaron Balog, Christine Huang, Tai-An Lin, Tai-An Lin, Derrick Maley, Johnni Gullo-Brown, Jesse Swanson, Jennifer Brown

2017253rdApril 05Abs MEDI 368
Discovery of a selective inhibitor of indoleamine-2,3-dioxygenase for use in the therapy of cancer
American Chemical Society National Meeting and Exposition
Aaron Balog

April 2-62017
American Chemical Society – 253rd National Meeting and Exhibition (Part IV) – OVERNIGHT REPORT, San Francisco, CA, USA
Casellas J, Carceller V

Juan Jaen

Juan Jaen

Jordan Fridman

Jordan Fridman

Chief Scientific Officer at FLX Bio, Inc.

Rekha Hemrajani

Rekha Hemrajani

Chief Operating Officer at FLX Bio, Inc

Max Osipov

Max Osipov

////////////////PHASE 1, BMS 986205, 1923833-60-6, BMS-986205, ONO-7701,Bristol-Myers Squibb,  Antineoplastics,  F- 001287

 C[C@H]([C@H]1CC[C@@H](C2=CC=NC3=CC=C(F)C=C23)CC1)C(NC4=CC=C(Cl)C=C4)=O

Wrapping up ‘s 1st time disclosures is Aaron Balog of @bmsnews talking about an IOD-1 inhibitor to treat cancer

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BLU 285


BLU-285

CAS 1703793-34-3

  • Molecular FormulaC26H27FN10
  • Average mass498.558 Da
(1S)-1-(4-Fluorophenyl)-1-(2-{4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-1-piperazinyl}-5-pyrimidinyl)ethanamine
5-Pyrimidinemethanamine, α-(4-fluorophenyl)-α-methyl-2-[4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-1-piperazinyl]-, (αS)-
  • 5-Pyrimidinemethanamine, α-(4-fluorophenyl)-α-methyl-2-[4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-1-piperazinyl]-, (αS)-
  • Originator Blueprint Medicines
  • Class Antineoplastics; Skin disorder therapies; Small molecules
  • Mechanism of Action Platelet-derived growth factor alpha receptor modulators; Proto oncogene protein c-kit inhibitors
  • Orphan Drug Status Yes – Systemic mastocytosis; Gastrointestinal stromal tumours
  • Phase I Gastrointestinal stromal tumours; Solid tumours; Systemic mastocytosis
  • 04 Dec 2016 Proof-of-concept data from phase I trial in Systemic mastocytosis presented at the 58thAnnual Meeting and Exposition of the American Society of Hematology (ASH Hem-2016)
  • 03 Dec 2016 Pharmacodynamics data from preclinical studies in Systemic mastocytosis presented at the 58th Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem-2016)
  • 03 Dec 2016 Preliminary pharmacokinetic data from a phase I trial in Systemic mastocytosis presented at the 58th Annual Meeting and Exposition of the American Society of Hematology (ASH Hem-2016)

Image result for BLU 285

BLU 285

(S)- 1 – (4- fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (Compounds 44) WO2015057873

Inventors Yulian Zhang, Brian L. Hodous, Joseph L. Kim, Kevin J. Wilson, Douglas Wilson
Applicant Blueprint Medicines Corporation

Image result for BLU 285

Yulian Zhang,

Yulian Zhang,

Blueprint Medicines Corporation

ΚΓΓ and PDGFR.

The enzyme KIT (also called CD117) is a receptor tyrosine kinase expressed on a wide variety of cell types. The KIT molecule contains a long extracellular domain, a transmembrane segment, and an intracellular portion. The ligand for KIT is stem cell factor (SCF), whose binding to the extracellular domain of KIT induces receptor dimerization and activation of downstream signaling pathways. KIT mutations generally occur in the DNA encoding the juxtumembrane domain (exon 11). They also occur, with less frequency, in exons 7, 8, 9, 13, 14, 17, and 18. Mutations make KIT function independent of activation by SCF, leading to a high cell division rate and possibly genomic instability. Mutant KIT has been implicated in the pathogenesis of several disorders and conditions including systemic mastocytosis, GIST (gastrointestinal stromal tumors), AML (acute myeloid leukemia), melanoma, and seminoma. As such, there is a need for therapeutic agents that inhibit ΚΓΓ, and especially agents that inhibit mutant ΚΓΓ.Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer. A PDGFRA D842V mutation has been found in a distinct subset of GIST, typically from the stomach. The D842V mutation is known to be associated with tyrosine kinase inhibitor resistance. As such, there is a need for agents that target this mutation.

CONTD………..

PATENT

WO 2015057873

Example 7: Synthesis of (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, 1 -f\ [ 1 ,2,4] triazin-4-yl)piperazin- 1 -yl)pyrimidin-5-yl)ethanamine and (S)- 1 – (4- fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (Compounds 43 and 44)

Step 1 : Synthesis of (4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l-f] [ 1 ,2,4] triazin-4-yl)piperazin- 1 -yl)pyrimidin-5-yl)methanone:

4-Chloro-6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l-/] [l,2,4]triazine (180 mg, 0.770 mmol), (4-fluorophenyl)(2-(piperazin-l-yl)pyrimidin-5-yl)methanone, HC1 (265 mg, 0.821 mmol) and DIPEA (0.40 mL, 2.290 mmol) were stirred in 1,4-dioxane (4 mL) at room temperature for 18 hours. Saturated ammonium chloride was added and the products extracted into DCM (x2). The combined organic extracts were dried over Na2S04, filtered through Celite eluting with DCM, and the filtrate concentrated in vacuo. Purification of the residue by MPLC (25- 100% EtOAc-DCM) gave (4-fluorophenyl)(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2,l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methanone (160 mg, 0.331 mmol, 43 % yield) as an off-white solid. MS (ES+) C25H22FN90 requires: 483, found: 484 [M + H]+.

Step 2: Synthesis of (5,Z)-N-((4-fluorophenyl)(2-(4-(6-(l-methyl- lH-p razol-4-yl)p rrolo[2, l- ] [l,2,4]triazin-4- l)piperazin- l-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide:

(S)-2-Methylpropane-2-sulfinamide (110 mg, 0.908 mmol), (4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methanone (158 mg, 0.327 mmol) and ethyl orthotitanate (0.15 mL, 0.715 mmol) were stirred in THF (3.2 mL) at 70 °C for 18 hours. Room temperature was attained, water was added, and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0- 10% MeOH-EtOAc) gave (5,Z)-N-((4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)methylene)-2- methylpropane-2-sulfinamide (192 mg, 0.327 mmol, 100 % yield) as an orange solid. MS (ES+) C29H3iFN10OS requires: 586, found: 587 [M + H]+.

Step 3: Synthesis of (lS’)-N-(l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4- l)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-

(lS’,Z)-N-((4-Fluorophenyl)(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2,l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide (190 mg, 0.324 mmol) was taken up in THF (3 mL) and cooled to 0 °C. Methylmagnesium bromide (3 M solution in diethyl ether, 0.50 mL, 1.500 mmol) was added and the resulting mixture stirred at 0 °C for 45 minutes. Additional methylmagnesium bromide (3 M solution in diethyl ether, 0.10 mL, 0.300 mmol) was added and stirring at 0 °C continued for 20 minutes. Saturated ammonium chloride was added and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0-10% MeOH-EtOAc) gave (lS’)-N-(l-(4-fluorophenyl)-l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.199 mmol, 61.5 % yield) as a yellow solid (mixture of diastereoisomers). MS (ES+) C3oH35FN10OS requires: 602, found: 603 [M + H]+.

Step 4: Synthesis of l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l-f\ [ 1 ,2,4] triazin-4- l)piperazin- 1 -yl)pyrimidin-5-yl)ethanamine:

(S)-N- ( 1 – (4-Fluorophenyl)- 1 -(2- (4- (6-( 1 -methyl- 1 H-pyrazol-4-yl)pyrrolo [2,1-/] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.199 mmol) was stirred in 4 M HCl in 1,4-dioxane (1.5 mL)/MeOH (1.5 mL) at room temperature for 1 hour. The solvent was removed in vacuo and the residue triturated in EtOAc to give l-(4-fluorophenyl)- l-(2-(4-(6-(l -methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine, HCl (110 mg, 0.206 mmol, 103 % yield) as a pale yellow solid. MS (ES+) C26H27FN10 requires: 498, found: 482 [M- 17 + H]+, 499 [M + H]+.

Step 5: Chiral separation of (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine and (5)-1-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-1 -yl)pyrimidin- -yl)ethanamine:

The enantiomers of racemic l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (94 mg, 0.189 mmol) were separated by chiral SFC to give (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-

pyrazol-4-yl)pyrrolo[2, l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine (34.4 mg, 0.069 mmol, 73.2 % yield) and (lS,)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (32.1 mg, 0.064 mmol, 68.3 % yield). The absolute stereochemistry was assigned randomly. MS (ES+)

C26H27FN10 requires: 498, found: 499 [M + H]+.

str1

/////////BLU-285,  1703793-34-3, PHASE 1,  Brian Hodous, BlueprintMeds,  KIT & PDGFRalpha inhibitors, Orphan Drug Status

Fc1ccc(cc1)[C@](C)(N)c2cnc(nc2)N3CCN(CC3)c4ncnn5cc(cc45)c6cn(C)nc6

Next in 1st time disclosures Brian Hodous of @BlueprintMeds will talk about KIT & PDGFRalpha inhibitors

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