Granlen-The Reliability 201605

A Reliable and Innovative Partner to Speed up Your Success

The Reliable Leading Nucleoside Pioneer!

Outline

Overview ∙ Experience ∙ Services ∙ Granlen

Corporate Locations

美国加州圣地亚哥–太平洋彼岸的“人间天堂”，最适于居住的城市San Diego, CA

- The Paradise on Earth；the

most livable city

中国郑州 - 重要交通枢纽，商贸中心，国家园林城市Zhengzhou, China

- The key transportation and

business central garden city

About Granlen

• Provides reliable chemistry related services for the biotech, pharmaceutical, diagnostic, cosmeceutical, and related industries with:

– A broad spectrum of chemistry

– A wide range of drug discovery services

– An integrated drug development process to IND

The Granlen Difference

Satisfy your needs Speed your success

Committed to Total Quality Excellence

Granlen’s Strengths

Synthetic Organic Chemistry

Medicinal Chemistry

Combinatorial Technologies

Drug discovery and development to IND

Immunogens and bioreagents

6

Synthetic Organic Chemistry

Heterocyclic and macrocyclic derivatives

Natural products and derivatives

Peptides, carbohydrates, glycopeptides

Process development and large scale synthesis – mg to multi-kg scale

Medicinal Chemistry

Hit-to-lead

Lead Optimization– Natural products

– SAR studies

– Liability removal

– Automation for expansion

Integrated preclinical discovery services

Medicinal Chemistry

Target Expertise

KinasesMicrotubulesPolymerases

ProteasomeReverse TranscriptaseRNA

GPCRsOther key enzymes

Therapeutic Experience

Oncology

Infectious AntiviralAntibacterialAnti-TB

Metabolic disordersObesityDyslipidemiaDiabetes

Our History of Success

OncologyMicrotubule polymerization inhibitor (Phase II)

Kinase inhibitor (Phase II)

Proteasome Inhibitor (Preclinical)

Medicinal Chemistry and Drug Development

AntiviralAn HBV drug (Phase III)

An HIV drug (Phase II)

An HCV drug (Phase II)

An HIV drug (Phase I)

An HCV candidate (IND)

CombiChem and Automation for Medicinal Chemistry

Solution-phase chemistry - parallel or indexedSolid-phase methodologies

• Method development

• Focused libraries and parallel synthesis

• Supporting material modification

• Solid-phase extraction technology

• Library enumeration and tracking

Expertise in nucleoside libraries andfocused heterocyclic libraries

Carbohydrate Derivatives

S

OO

HO

S

OBzBzO

BzO

OAc

S

OHOH

HOO

OO

HO

OO

OOHO

O

O

OBnBnO

BnO

O

O

OAcF

p-TolOOAc O

OAcN3

p-TolOOAc

O

OHBzO

BzOOBz

O

OAc

BzO OAcO

OAcO

BzO OAcO

OAcBzO

BzO OAc

H3C

O

OAc

F

BzO OAc

H3C

O

OAcCH3

BzO OAc

O

OBzBzO

BzOOAc

CH3

O

OAcCl2BnO

Cl2BnOOAc

O

O

OBnO

BnO

IO

O

OBnO

BnO

HO

O

OAc

HO

BzO OAc

O

OAcp-TolO

OAc

Representative Pyrimidine Nucleosides

NO

OHH, F, N3, NH2, CH3,

MeO

HO

N

OH, NH2

O

R

O

H, F, N3, NH2, CH3

HO N

OH

O

OH

OF, N3, NH2,

HO

HO N

N

OH, NH2

O

O

H, F, N3, NH2, CH3

HO

OH

N

N

O

O

H, F, N3, NH2, CH3

HO

OH

N O

O2N

O

H, F, N3, NH2, CH3,

MeO,

HO

OH

N

N

O

NH2

R

H, OH

N

OH, NH2

ONO

OHHO

HO

N3, CH3, CN

R

NO

OHHO

HO

N

OH, NH2

O

R

CH3

NO

OH, N3, NH2, F, Cl, OMe

HO

HO

N

OH, NH2

O

R

O

HO

HO N

N

O

F

H, OH, NH2

R

O

F,HO

HO N

NH

O

S

OR

R

NS

OHHO

HO

N

OH, NH2

O

R

O

H, OH, OMe, F

OH

N

N

O

O

R

O

HO,F,N3

HO

H,OH,OR,F, N3

N

NH

S

O

R

NO

HO

N

OH, NH2

O

R

Representative Purine Nucleosides

N

N

N

H, OH, NH2, Cl, OMe, NHR, R

NO

OH, N3, NH2, OMe, OR, CH2CH2OMe, O-ethynyl

HO

HO

O

HO

HO

F, H

N

Y

N

N

H, NH2, Cl, OH, OMe

H, NH2, Cl, OH, OMe

NH

N

N

O

NO

OH, ORHO

HOH, NH2, I, SH, SR, CH3, NHR

R

N

NN

N+

O

HO

HO

NH2

NH, NHR

OH

R

N

OHO

R

N

NN

N

OH, NH2

H, NH2

H, NH2

H, OH

N

N

N

H, OH, NH2, Cl, OMe, NHR, R, Ar, Het

NO

OHH, F, N3, NH2, CH3, MeO

HO H, NH2

NH

NN

N

S

O

OH, HH, F, N3, CH3

HOH, NH2

O

H, F, N3, NH2, CH3, MeO,

HO

OH

N

N

NH

N

NH2

O

H, FOF, N3,

NH2, HO

HO

H, OH

N

N

N

H, OH, NH2, Cl

N H, NH2

3’-Fluoro-3’-deoxy Pyrimidine/Pyridinone Nucleosides

3’-Fluoro-3’-deoxy Purine Nucleosides

2’-Fluoro-2’-deoxy Pyrimidine Arabinonucleosides

2’-Fluoro-2’-deoxy Purine Arabinonucleosides

Azido-Nucleosides

Amino-Nucleosides

Isocytidines and Isoguanosines

Thio-Nucleosides

Xylofuranose-nucleosides

2’,3’-Dideoxy Substituted Nucleosides

2’,3’-Dideoxy / didehydro-Nucleosides

3’-Methyl-3’-deoxy and 3’-Deoxy Nucleosides

Pyrimidinone and Pyridinone Nucleosides

(3-Deaza-/4-deoxy Us)

6-Deamino and 6-Methylpurine Nucleosides

2-Subsituted Purine Nucleosides

5’-Modified Nucleosides

Nucleosides Having One Reactive Group on Sugar

Morpholino-Nucleosides

PNA Monomers

Drugs and Inhibitors

Nucleotides, Amidites and Phosphonates

O

O

NH2

O

O-

N

NN

NO

NH2

OO

O

P-O O

N

N

O

P O-O

NH

R

NVOCO

H

R'

ON

OHR

N

NH2

O

HOOH

ON

N

N

NH

O

O

OMeO

P O

P O-S

O

NH2

R = H, OMe

dinucleotides

N

OH, NH2

ONO

ROH

PHO O

OH

PO

N

NC

NH

O

ONO

RO

PRO O

OR RR

O

R

N

N

Z

NH

O

RPO

PO

P-O -O

OO

-O

O

O-

X

XR

phosphonamiditeH-phosphonate

N

NN

N

O

O

DMTrO

NHBz

OPO

N

NC

NH

NN

N

O

O

DMTrO

O

NHBui

OP

O

N

NC OCH3

N R

N

N

N

NH2

O

R OR

P O

RO

HO

XX

triphosphonatesphosphonates

phosphoramidites

phosphonate amidites

PO

O-

N

N

ONO

R

ODMTr

H3C

H

PO

N

NC

NH

O

ONO

R

ODMTr

H3CNCH3

+HNEt3

Representative Nucleoside Phosphoramidites

Nucleoside Phosphoramidites

NH

NN

N

O

O

O

O

NH

O

O

DMTr

PO

N

NC

NH

NN

N

O

O

O

O

NH

O

O

DMTr

PO

N

NC OCH3

Nucleoside Triphosphates (NTPs)

LC (TIC)

LC (UV)

1) P(O)(OMe)3 proton sponge 2) POCl3 3) Pyrophosphate

1) ion exchange column2) reverse phase column

3) LyopholizationN

O

OCH3OH

OP

O

O

O-

P

O

O-

OP

O

O-

-O

NH

O

O

n Et3NH+

NO

OCH3OH

HO

NH

O

O

H3C H3C

39

Other Products with Different Applications

N

SN

N+N

Cl-

HO OH

Dipropofol/ drug standard

Catalyst

HON

OH

OH

OH

OH CH3

O

Mega 8 /Bio-reagent

N NCOOR

N

ROOC

COOR

COORROOC

H2N

MRI Contrasting Agents

DDAIP-HCl (Formulation)

O

NH+

O

Cl-

Phenothiazine

O

O

O

O

R

R

R

R

RuN+

N+

X

X

OH

O

O

O-

Complex /bio-reagent

SO3H

SO3H

N

N N

N

O

OHOH

ONH

NC

ClCl

NH2

HSP30 inhibitorFlavor Additive

O O

Purine Derivatives

Pyrimidines, Pyrazines and Pyradazines

Other Building Blocks

Natural Products and Derivatives

N N

H2N

CH3

O

OCH3

O

HN

O

HO

HN

HN

CH3

N

H2N

NH

NH2

OO

NH

HO

S

O

O

S

NNH

O

R2

O

OHO

HO

HO

OH R1

OH

OH

NH

N

H

H

H

HH

H

NH2

H

HCH3

R1 = OCONH2, OH; R2 = SMe, +SMe2

7 Bleomycins including: Bleomycin A2, Bleomycin

demethyl A2, and Decarbamoyl Bleomycin Demethyl A2

>48 steps each for the total synthesis

Bleomycin Antitumor Antibiotics

R3

H

O

X

OR

H

OR

H

O

OR

Oridonin

5'-Alkylresorcinols isolated from Hakea trifurcatea DNA cleaving agents

l m n

HO

OH

OH

OH

Our Specialties

Carbohydrates, nucleosides/tides, & libraries

Phosphoramidites, phosphates, triphosphates,

C-phosphonates

Natural product total synthesis

Heterocycles, macrocycles, super-chelating and MRI contrast agents

Immunogens/antigens and bio-reagents

Prodrug and conjugation technologies

Chemistry Services

Hit to lead & lead optimization

Screening & focused libraries

Custom Synthesis

Chemistry &Drug Discovery

PreclinicalDevelopment

ClinicalDevelopment

Hit and Lead Optimization

Hit re-synthesis for activity confirmation

Lead selection and optimization for SAR studies

Design & synthesis of analogs for lead improvement

Optimize potency, selectivity, specificity, and safety

Improve PK, PD, and druggability

Enhancement of IP coverage

Screening and Focused Libraries

Screening library enhancement

Drug-like or Lead-like (Ro5)

Toxicophore filtration

Focused libraries around specified targets

Structure/Ligand-based design

Optimization by virtual screening

10-50 mg per sample with >90% purity

Custom Synthesis

Products, intermediates, scaffolds, building

blocks, monomers, raw materials

Reference and competitor compounds

Drug standards, metabolites and impurities

Immunogens/antigens, bio-reagents

Radiolabeling method development

IND-Enabling Preclinical Services

Process development research & LSS

Analytical method development and stability studies

Regulatory and documentation

Chemistry &Drug Discovery

PreclinicalDevelopment

ClinicalDevelopment

Process Development & LSS

Route scouting to Route finalization

Reaction condition / process optimization

Efficient processes for multi-kilo scales

Scalable and transferable

processes

Kilo to ton scale manufacture

Analytical Services

Develop and validate analytical methods

Establish drug criteria for drug substances and pharmaceutical products

Drug stability studies:

– Freeze-thaw

– Forced degradation

– Accelerated and long-term stability

Intellectual Property ProtectionIntellectual Property Protection

Highest Priority

Isolated facility to ensure IP protection

Strict documentation procedures

Professional management team focused on IP protection

Intellectual property belongs to the client

Our ClientsGlobal clients in US, Canada, Singapore, Japan, India,

Europe, and China

Custom synthesis, drug discovery, analytical method,

process development, LS synthesis, pre-clinic CMC etc

Services include Focused libraries, hit design and synthesis, lead optimization for SAR

Synthesis of nucleosides, phosphoramidites, triphosphates, heterocyclic and macrocyclic derivatives, drug standards, metabolites, impurities, etc

Conjugation, asymmetric compounds, formulation products, organic materials, dyes, bio-reagents, etc

Pre-clinical development, methods and pharmaceutical

53

Example 1 - Drug Discovery Project

Participated in the project plan from very early stage

Designed potential hit/lead structures to be selected

Designed routes and worked out synthesis

Bi-weekly report and adjust direction as needed

Submitted high quality samples for biological tests

and write-up document

Secure confidentiality and client owns the IP

Luckily, a great lead was discovered

Example 2 – IND Enabling Drug Development

Require: pre-clinical CMC and pharmaceutical for IND

Explored possible routes and finalized the best one

Fine-tuned reaction conditions and processes (batches)

Allow cost reduction of 80% for production

3 kg high quality product met drug requirements and used for clinical studies

Developed anal method, established drug criteria, QC

Provided all documents to support IND application

Example 3 –New Phosphonate Amidite

Required: 20 g of new phosphonate phosphoramidite

Designed reasonable and doable route

Worked out the key steps and accomplished smoothly

Delivered high-quality product and write-up document

with all data in ~60% expected time frame

“Harry, That’s great and fast! I had a failed delivery

before on the same compound”, the client said after

the project was completed

Example 4 – Halo-Nucleoside

Required: 50 g scale synthesis (for big pharma; failed

by other vendors before)

Designed the un-reported new route, and it was

agreed by client

Explored and synthesized halo-sugar

Synthesized and delivered final product in high

quality and timely fashion

We are the only group who can make this type of

nucleosides in sizable scale (a Large CRO failed on the

same compound)

Here is what one of our clients said:

Haoyun,

Very impressive! No one can beat you on this area. Please send me the invoice for this PO.

Best Regards,John

Operation & Facilities

Headquartered in San Diego, CA (Sign CDA in US)

Operation in Zhengzhou, China

The transportation and business central garden city

Hydrogenator, high-pressure reactors, shakers, large

evaporator, and 100 L reactors for large scale synthesis

Anal/semi-preparative HPLCs, medium pressure LC,

lyophilizer, LC-MS, NMR, HRMS, FT-IR, UV-Vis, DSC/TG,

X-ray, polarimeter, stability test chambers, etc

60

The quality of our equipment is nothing

when compared to the quality of our people!

Corners of Granlen

One View in Zhengzhou

Summary

Highly experienced management

Unique specialties and highly skilled teams

Quality > Reliability > Costs

No challenge to great or small (Serve/Help)

Timely communication for high efficiency

Continuously improving infrastructure

We deliver regardless what it takes

We Work Harder!

han@granlen.com

Skype: haoyun.an

QQ: 1015260133

1-760-846-6460 (US)

011-86-158-38132863 (China)

011-86-371-86026726 (China)

The Reliable Leading Nucleoside Pioneer!